Diseases Skin Andrews’
OF THE
Clinical Dermatology
Commissioning Editor: Russell Gabbedy Development Editor: Sven Pinczewski Editorial Assistant: Kirsten Lowson / Rachael Harrison Project Manager: Elouise Ball Design: Stewart Larking Illustration Manager: Gillian Richards Illustrator: Richard Tibbits, Richard Prime Marketing Manager: Helena Mutak
Diseases Skin Andrews’
OF THE
Clinical Dermatology Eleventh Edition
William D James,
MD
Paul R Gross Professor of Dermatology Department of Dermatology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania USA
Dirk M Elston,
MD
Director Department of Dermatology Geisinger Medical Center Danville, Pennsylvania USA
For additional online content visit
www.expertconsult.com
Timothy G Berger,
MD
Professor of Clinical Dermatology Executive Vice Chair and Residency Program Director Chair in Dermatology Medical Student Education University of California, San Francisco San Francisco, California USA
is an imprint of Elsevier Inc. © 2011, Elsevier Inc. All rights reserved. 10th edition © 2006, Saunders Elsevier No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail:
[email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/ permissions. ISBN: 978-1-4377-0314-6 International ISBN: 978-0-8089-2417-3 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Notice Medical knowledge is constantly changing. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the author assume any liability for any injury and/or damage to persons or property arising from this publication. The Publisher
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James, William D. (William Daniel), 1950– Andrews’ Diseases of the skin : clinical dermatology. — 11th ed. 1. Skin—Diseases. 2. Dermatology. I. Title II. Diseases of the skin III. Elston, Dirk M. IV. Berger, Timothy G. V. Andrews, George Clinton, 1891-1978. Diseases of the skin. 616.5—dc22
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PREFACE AND ACKNOWLEDGEMENTS Andrews’ remains as it was from the beginning: an authored text whose one volume is filled with clinical signs, symptoms, diagnostic tests, and therapeutic pearls. The authors have remained general clinical dermatologists in an era of subspecialists in academia. They are committed to keeping Andrews’ as an excellent tool for anyone who needs help in diagnosing a patient with a clinical conundrum or treating a patient with a therapeutically challenging disease. Andrews’ is primarily intended for the practicing dermatologist. It is meant to be used on the desktop at his or her clinic, giving consistent, concise advice on the whole gamut of clinical situations faced in the course of a busy workday. While we have been true to our commitment to a single-volume work, we provide our text in a convenient online format as well. Because of its relative brevity but complete coverage of our field, many find the text ideal for learning dermatology the first time. It has been a mainstay of the resident yearly curriculum for many programs. We are hopeful that trainees will learn clinical dermatology by studying the clinical descriptions, disease classifications, and treatment insights that define Andrews’. We believe that students, interns, internists or other medical specialists, family practitioners, and other health professionals who desire a comprehensive dermatology textbook will find that ours meets their needs. Long-time dermatologists will hopefully discover Andrews’ to be the needed update that satisfies their lifelong learning desires. On our collective trips around the world, we have been gratified to see our international colleagues studying Andrews’. Several thousand books have been purchased by Chinese and Brazilian dermatologists alone. Many major changes have been made to this edition. Bill James, Tim Berger and Dirk Elston, three great friends of nearly three decades, have worked closely to continue to improve the quality of our text. The surgical chapters have been updated and expanded by Isaac Neuhaus. We thank him for his efforts to enhance the procedural portion of our textbook and acknowledge the contributions of Roy Grekin in prior editions. We have tried to ensure that each entity is only discussed once, in a complete yet concise manner. In order to do this we have had to make decisions regarding the placement of disease processes in only one site. Clearly, neutrophilic eccrine hidradenitis, for example, could be presented under drug eruptions, neutrophilic reactive conditions, infection or cancer-associated disease, or with eccrine disorders. The final decisions were a team effort and made in the interest of eliminating redundancy. This allows us to present our unified philosophy in treating patients in one dense volume. Medical science continues to progress with break-neck speed. Our understanding of the etiology of certain conditions has now led us to recategorize well-recognized disease states and dictated the addition over 70 newly described entities.
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Molecular investigative techniques, technologic breakthroughs, and designer therapeutics lead the way in providing advances in our specialty. We cover the new understanding following from such innovations by discussing the mechanisms at work in genetic diseases, covering the latest in dermatopathologic staining and analysis, adding a second chapter on cosmetic surgery, and enlarging the therapeutic recommendations to include our expanded therapeutic options, such as biologic response modifiers, and biologically engineered targeted medications. We have attempted to define therapeutics in a fashion that emphasizes those interventions with the highest level of evidence, but also present less critically investigated therapeutic options. To care for our patients we need a large array of options. Not all are fully supported by formal evidence, yet are helpful to individual patients. Extensive revisions were necessary to add this wealth of new information. We selectively discarded older concepts. By eliminating older, not currently useful information we maintain the brief but complete one-volume presentation that we and all previous authors have emphasized. Additionally, older references have been updated. The classic early works are not cited; instead we have chosen to include only new citations and let the bibliographies of the current work provide the older references as you need them. A major effort in this edition was to reillustrate the text with 567 new color images. Many have been added to the printed text; you will also find a large number only in the online version. Enjoy! We have looked to our own collections to accomplish this. These are the result of many hours of personal effort, the generosity of our patients, and a large number of residents and faculty of the programs in which we currently work or have worked in the past. Additionally, friends and colleagues from all parts of the globe have allowed us to utilize their photographs. They have given their permission for use of these wonderful educational photos to enhance your understanding of dermatology and how these diseases affect our patients. We cannot thank them enough. All of the authors recognize the importance of our mentors, teachers, colleagues, residents, and patients in forming our collective expertise in dermatology. Dirk, Tim and Bill were all trained in military programs, and our indebtedness to this fellowship of clinicians is unbounded. The many institutions we have called home, from the East Coast of Walter Reed, to the West Coast of the University of California at San Francisco, and many in between, such as Brooke in San Antonio and the Cleveland Clinic, nurtured us and expanded our horizons. Our friendship goes well beyond the limits of our profession; it is wonderful to work with people you not only respect as colleagues, but also enjoy as closely as family. Finally we are proud to be a part of the Elsevier team and have such professionals as Claire Bonnett, Sven Pinczewski, Elouise Ball, and Russell Gabbedy supporting us every step of the way.
DEDICATION For my family, whose love and support sustain me and make me happy. Bill D James My wife Jessica and my children, Olivia and Mateo, who give me the joy and strength to undertake such a task. Tim G Berger To my wife and best friend, Kathy, and our wonderful children, Carly and Nate. Dirk M Elston
The authors: William D James, Timothy G Berger, Dirk M Elston.
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CONTRIBUTOR Isaac M Neuhaus, MD Assistant Professor Dermatologic Surgery and Laser Center University of California, San Francisco San Francisco, California USA
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Bonus images for this chapter can be found online at http://www.expertconsult.com
Skin: Basic Structure and Function
Skin is composed of three layers: the epidermis, dermis, and subcutaneous fat (panniculus) (Fig. 1-1). The outermost layer, the epidermis, is composed of viable keratinocytes covered by a layer of keratin, the stratum corneum. The principal component of the dermis is the fibrillar structural protein collagen. The dermis lies on the panniculus, which is composed of lobules of lipocytes separated by collagenous septae that contain the neurovascular bundles. There is considerable regional variation in the relative thickness of these layers. The epidermis is thickest on the palms and soles, measuring approximately 1.5 mm. It is very thin on the eyelid, where it measures less than 0.1 mm. The dermis is thickest on the back, where it is 30–40 times as thick as the overlying epidermis. The amount of subcutaneous fat is generous on the abdomen and buttocks compared with the nose and sternum, where it is meager.
Epidermis and adnexa During the first weeks of life, the fetus is covered by a layer of nonkeratinizing cuboidal cells called the periderm (Fig. 1-2). Later, the periderm is replaced by a multilayered epidermis. Adnexal structures, particularly follicles and eccrine sweat units, originate during the third month of fetal life as downgrowths from the developing epidermis. Later, apocrine sweat units develop from the upper portion of the follicular epithelium and sebaceous glands from the midregion of the follicle. Adnexal structures appear first in the cephalic portion of the fetus and later in the caudal portions. The adult epidermis is composed of three basic cell types: keratinocytes, melanocytes, and Langerhans cells. An additional cell, the Merkel cell, can be found in the basal layer of the palms and soles, oral and genital mucosa, nail bed, and follicular infundibula. Merkel cells, located directly above the basement membrane zone, contain intracytoplasmic densecore neurosecretory-like granules, and, through their association with neurites, act as slow-adapting touch receptors. They have direct connections with adjacent keratinocytes by desmosomes and contain a paranuclear whorl of intermediate keratin filaments. Both polyclonal keratin immunostains and monoclonal immunostaining for keratin 20 stain this whorl of keratin filaments in a characteristic paranuclear dot pattern. Merkel cells also label for neuroendocrine markers such as chromogranin and synaptophysin.
Keratinocytes Keratinocytes, or squamous cells, are the principal cells of the epidermis. They are of ectodermal origin and have the specialized function of producing keratin, a complex filamentous protein that not only forms the surface coat (stratum corneum) of the epidermis but also is the structural protein of hair and nails. Multiple distinct keratin genes have been identified and
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consist of two subfamilies, acidic and basic. The product of one basic and one acidic keratin gene combines to form the multiple keratins that occur in many tissues. The presence of various keratin types is used as a marker for the type and degree of differentiation of a population of keratinocytes. Keratins are critical for normal functioning of the epidermis and keratin mutations are recognized causes of skin disease. Mutations in the genes for keratins 5 and 14 are associated with epidermo lysis bullosa simplex. Keratin 1 and 10 mutations are associated with epidermolytic hyperkeratosis. Mild forms of this disorder may represent localized or widespread expressions of mosaicism for these gene mutations. The epidermis may be divided into the following zones, beginning with the innermost layer: basal layer (stratum germinativum), Malpighian or prickle layer (stratum spinosum), granular layer (stratum granulosum), and horny layer (stratum corneum). On the palms and soles a pale clear to pink layer, the stratum lucidum, is noted just above the granular layer. When the skin in other sites is scratched or rubbed, the Malpighian and granular layers thicken, a stratum lucidum forms, and the stratum corneum becomes thick and compact. Histones appear to regulate epidermal differentiation and histone deacetylation suppresses expression of profilaggrin. Slow-cycling stem cells provide a reservoir for regeneration of the epidermis. Sites rich in stem cells include the deepest portions of the rete, especially on palmoplantar skin, as well as the hair bulge. Stem cells divide infrequently in normal skin, but in cell culture they form active growing colonies. They can be identified by their high expression of β1-integrins and lack of terminal differentiation markers. Stem cells can also be identified by their low levels of desmosomal proteins, such as desmoglein 3. The basal cells divide and, as their progeny move upward, they flatten and their nucleus disappears. Abnormal keratinization can manifest as parakeratosis (retained nuclei), as corps ronds (round, clear to pink, abnormally keratinized cells), or as grains (elongated, basophilic, abnormally keratinized cells). During keratinization, the keratinocyte first passes through a synthetic and then a degradative phase on its way to becoming a horn cell. In the synthetic phase, the keratinocyte accumulates within its cytoplasm intermediate filaments composed of a fibrous protein, keratin, arranged in an alpha-helical coiled coil pattern. These tonofilaments are fashioned into bundles, which converge on and terminate at the plasma membrane, where they end in specialized attachment plates called desmosomes. The degradative phase of keratinization is characterized by the disappearance of cell organelles and the consolidation of all contents into a mixture of filaments and amorphous cell envelopes. This programmed process of maturation resulting in death of the cell is termed terminal differentiation. Terminal differentiation is also seen in the involuting stage of keratoacanthomas, where the initial phase of proliferation gives way to terminal keratinization and involution.
1 Skin: Basic Structure and Function
Apocrine unit Straight duct Meissner nerve ending
Epidermis
Coiled gland
papillary Eccrine sweat unit
Dermis
Spiraled duct reticular
Straight duct
Sebaceous gland Arrector pili muscle Hair shaft Pacini nerve ending
Coiled duct Eccrine gland Dermal vasculature
Subcutaneous tissue
Superficial plexus Deep plexus
Fig. 1-1 Diagrammatic cross-section of the skin and panniculus.
Fig. 1-2 Fetal periderm covering fetal mesenchyme.
Premature programmed cell death, or apoptosis, appears in hematoxylin and eosin (H&E)-stained sections as the presence of scattered bright red cells, some of which may contain small black pyknotic nuclei. These cells are present at various levels of the epidermis, as this form of cell death does not represent part of the normal process of maturation. Widespread apoptosis is noted in the verrucous phase of incontinentia pigmenti. It is also a prominent finding in catagen hairs, where apoptosis results in the involution of the inferior segment of the hair follicle. In normal skin, the plasma membranes of adjacent cells are separated by an intercellular space. Electron microscopic histochemical studies have shown that this interspace contains glycoproteins and lipids. Lamellar granules (Odland bodies or membrane-coating granules) appear in this space, primarily at the interface between the granular and cornified cell layers. Lamellar granules contribute to skin cohesion and impermeability. Conditions such as lamellar ichthyosis and Flegel’s hyperkeratosis demonstrate abnormal lamellar granules. 2
Glycolipids such as ceramides contribute a water barrier function to skin and are commonly found in topical products meant to restore the epidermal barrier. Lamellar bodies form abnormally in the absence of critical ceramides such as glucosylceramide or there is disproportion of critical lipids. Desmosomal adhesion depends upon cadherins, including the calcium-dependent desmogleins and desmocollins. Antibodies to these molecules result in immunobullous diseases. Keratinocytes of the granular zone contain, in addition to the keratin filament system, keratohyaline granules, composed of amorphous particulate material of high sulfur–protein content. This material, called profilaggrin, is a precursor to filaggrin, so named because it is thought to be responsible for keratin filament aggregation. Conversion to filaggrin takes place in the granular layer, and this forms the electron-dense interfilamentous protein matrix of mature epidermal keratin. Keratohyaline is hygroscopic, and repeated cycles of hydration and dehydration contribute to normal desquamation of the stratum corneum. Ichthyosis vulgaris is characterized by a diminished or absent granular layer, contributing to the retention hyperkeratosis noted in this disorder. Keratohyalin results in the formation of soft, flexible keratin. Keratin that forms in the absence of keratohyaline granules is typically hard and rigid. Hair fibers and nails are composed of hard keratin. Keratinocytes play an active role in the immune function of the skin. In conditions such as allergic contact dermatitis they participate in the induction of the immune response, rather than acting as passive victims. Keratinocytes secrete a wide array of cytokines and inflammatory mediators, including tumor necrosis factor (TNF)-α. They also can express molecules on their surface, such as intercellular adhesion molecule-1 (ICAM-1) and major histocompatibility complex (MHC) class II molecules, suggesting that keratinocytes actively respond to immune effector signals.
Melanocytes Melanocytes are the pigment-producing cells of the epidermis. They are derived from the neural crest and by the eighth week
pigment by a near-normal number of melanocytes. Black “sunburn” or “ink spot” lentigines demonstrate basilar hyperpigmentation and prominent melanin within the stratum corneum. Nevi are benign proliferations of melanocytes. Melanomas are their malignant counterpart. Melanocytes and keratinocytes express neurotrophins (ectodermal nerve growth factors). Melanocytes release neurotrophin 4, but the release is downregulated by UVB irradiation, suggesting neurotrophins as possible targets for therapy of disorders of pigmentation. Melanocytes express toll-like receptors (TLRs) and stimulation by bacterial lipopolysaccharides increases pigmentation.
Epidermis and adnexa
of development can be found within the fetal epidermis. In normal, sun-protected, trunk epidermis, melanocytes reside in the basal layer at a frequency of approximately 1 in every 10 basal keratinocytes. Areas such as the face, shins, and genitalia have a greater density of melanocytes, and in heavily sundamaged facial skin, Mart-1 immunostaining can demonstrate ratios of melanocytes to basal keratinocytes that approach 1:1. Recognition of the variation in melanocyte to keratinocyte ratio is critical in the interpretation of biopsies of suspected lentigo maligna (malignant melanoma in situ) on sun-damaged skin. Racial differences in skin color are not caused by differences in the number of melanocytes. It is the number, size, and distribution of the melanosomes or pigment granules within keratinocytes that determine differences in skin color. Pale skin has fewer melanosomes and these are smaller and packaged within membrane-bound complexes. Dark skin has more melanosomes, and these tend to be larger and singly dispersed. Chronic sun exposure can stimulate melanocytes to produce larger melanosomes, thereby making the distribution of melanosomes within keratinocytes resemble the pattern seen in dark-skinned individuals. In histologic sections of skin routinely stained by H&E, the melanocyte appears as a cell with ample amphophilic cytoplasm, or as a clear cell in the basal layer of the epidermis. The apparent halo is an artifact formed during fixation of the specimen. This occurs because the melanocyte, lacking tonofilaments, cannot form desmosomal attachments with keratinocytes. Keratinocytes also frequently demonstrate clear spaces, but can be differentiated from melanocytes because they demonstrate cell–cell junctions and a layer of cytoplasm peripheral to the clear space. The melanocyte is a dendritic cell. Its dendrites extend for long distances within the epidermis and any one melanocyte is therefore in contact with a great number of keratinocytes; together they form the so-called epidermal melanin unit. Keratinocytes actively ingest the tips of the melanocytic dendrites, thus imbibing the melanosomes. Melanosomes are synthesized in the Golgi zone of the cell and pass through a series of stages in which the enzyme tyrosinase acts on melanin precursors to produce the densely pigmented granules. Melanocytes in red-heads tend to be rounder and produce more phaeomelanin. The melanocortin 1 receptor (MC1R) is important in the regulation of melanin production. Loss-of-function mutations in the MC1R gene bring about a change from eumelanin to phaeomelanin production, whereas activating gene mutations can enhance eumelanin synthesis. Most red-heads are compound heterozygotes or homozygotes for a variety of loss-of-function mutations in this gene. Eumelanin production is optimal at pH 6.8 and changes in cellular pH also result in alterations of melanin production and the eumelanin to phaeomelanin ratio. Within keratino cytes, melanin typically forms a cap over the nucleus, where it presumably functions principally in a photoprotective role. Evidence of keratinocyte photodamage in the form of thymidine dimer formation can be assessed using gas chromatography–mass spectrometry or enzyme-linked immunosorbent assays. Pigment within melanocytes also serves to protect the melanocytes themselves against photodamage, such as ultraviolet (UV) A-induced membrane damage. Areas of leukoderma or whitening of skin can be caused by very different phenomena. In vitiligo, the affected skin becomes white because of destruction of melanocytes. In albinism, the number of melanocytes is normal, but they are unable to synthesize fully pigmented melanosomes because of defects in the enzymatic formation of melanin. Local areas of increased pigmentation can result from a variety of causes. The typical freckle results from a localized increase in production of
Langerhans cells Langerhans cells are normally found scattered among keratino cytes of the stratum spinosum. They constitute 3–5% of the cells in this layer. Like melanocytes, they are not connected to adjacent keratinocytes by the desmosomes. The highest density of Langerhans cells in the oral mucosa occurs in the vestibular region, and the lowest density in the sublingual region, suggesting the latter is a relatively immunologically “privileged” site. At the light microscopic level, Langerhans cells are difficult to detect in routinely stained sections; however, they appear as dendritic cells in sections impregnated with gold chloride, a stain specific for Langerhans cells. They can also be stained with CD1α or S-100 immunostains. Ultrastructurally, they are characterized by a folded nucleus and distinct intracytoplasmic organelles called Birbeck granules. In their fully developed form, the organelles are rod-shaped with a vacuole at one end and they resemble a tennis racquet. The vacuole is an artifact of processing. Functionally, Langerhans cells are of the monocyte– macrophage lineage and originate in bone marrow. They function primarily in the afferent limb of the immune response by providing for the recognition, uptake, processing, and presentation of antigens to sensitized T lymphocytes, and are important in the induction of delayed-type sensitivity. Once an antigen is presented, Langerhans cells migrate to the lymph nodes. Hyaluronan (hyaluronic acid) plays a critical role in Langerhans cell maturation and migration. Langerhans cells express langerin, membrane ATPase (CD39), and CCR6, while CD1α+ dermal dendritic cells express macrophage mannose receptor, CD36, factor XIIIa, and chemokine receptor 5, suggesting different functions for these two CD1α+ populations. If skin is depleted of Langerhans cells by exposure to UV radiation, it loses the ability to be sensitized until its population of Langerhans cell is replenished. Macrophages that present antigen in Langerhans cell-depleted skin can induce immune tolerance. In contrast to Langerhans cells, which make interleukin (IL)-12, the macrophages found in the epidermis 72 h after UVB irradiation produce IL-10, resulting in downregulation of the immune response. At least in mice, viral immunity appears to require priming by CD8α+ dendritic cells, rather than Langerhans cells, suggesting a complex pattern of antigen presentation in cutaneous immunity. Ahn JH, et al: Human melanocytes express functional toll-like receptor 4. Exp Dermatol 2008 May; 17(5):412–417. Allam JP, et al: Distribution of Langerhans cells and mast cells within the human oral mucosa: new application sites of allergens in sublingual immunotherapy? Allergy 2008 Jun; 63(6):720–727. Baxter LL, et al: Networks and pathways in pigmentation, health, and disease. Wiley Interdiscip Rev Syst Biol Med 2009 Nov 1; 1(3):359–371. Boulais N, et al: The epidermis: a sensory tissue. Eur J Dermatol 2008 Mar–Apr; 18(2):119–127. Dusek RL, et al: Discriminating roles of desmosomal cadherins: beyond desmosomal adhesion. J Dermatol Sci 2007 Jan; 45(1):7–21.
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Ernfors P: Cellular origin and developmental mechanisms during the formation of skin melanocytes. Exp Cell Res 2010 May 1; 316(8):1397–1407. Imai Y, et al: Freshly isolated Langerhans cells negatively regulate naïve T cell activation in response to peptide antigen through cell-to-cell contact. J Dermatol Sci 2008 Jul; 51(1):19–29. Jennemann R, et al: Integrity and barrier function of the epidermis critically depend on glucosylceramide synthesis. J Biol Chem 2007 Feb 2; 282(5):3083–3094. Le Douarin NM, et al: The stem cells of the neural crest. Cell Cycle 2008 Jan; 24:7(8). Markova NG, et al: Inhibition of histone deacetylation promotes abnormal epidermal differentiation and specifically suppresses the expression of the late differentiation marker profilaggrin. J Invest Dermatol 2007 May; 127(5):1126–1139. Ortonne JP, et al: Latest insights into skin hyperpigmentation. J Investig Dermatol Symp Proc 2008 Apr; 13(1):10–14. Santegoets SJ, et al: Transcriptional profiling of human skin-resident Langerhans cells and CD1α+ dermal dendritic cells: differential activation states suggest distinct functions. J Leukoc Biol 2008 Apr; 24. Schwarz T: Regulatory T cells induced by ultraviolet radiation. Int Arch Allergy Immunol 2005; 137:187.
Skin: Basic Structure and Function
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Dermoepidermal junction The junction of the epidermis and dermis is formed by the basement membrane zone (BMZ). Ultrastructurally, this zone is composed of four components: the plasma membranes of the basal cells with the specialized attachment plates (hemidesmosomes); an electron-lucent zone called the lamina lucida; the lamina densa (basal lamina); and the fibrous components associated with the basal lamina, including anchoring fibrils, dermal microfibrils, and collagen fibers. At the light microscopic level, the periodic acid–Schiff (PAS)-positive basement membrane is composed of the fibrous components. The basal lamina is synthesized by the basal cells of the epidermis. Type IV collagen is the major component of the basal lamina. Type VII collagen is the major component of anchoring fibrils. The two major hemidesmosomal proteins are the BP230 (bullous pemphigoid antigen 1) and BP180 (bullous pemphigoid antigen 2, type XVII collagen). In the upper permanent portion of the anagen follicle, plectin, BP230, BP180, α6β4-integrin, laminin 5, and type VII collagen show essentially the same expression as that found in the interfollicular epidermis. Staining in the lower, transient portion of the hair follicle, however, is different. All BMZ components diminish and may become discontinuous in the inferior segment of the follicle. Hemidesmosomes are also not apparent in the BMZ of the hair bulb. The lack of hemidesmosomes in the deep portions of the follicle may relate to the transient nature of the inferior segment, while abundant hemidesmosomes stabilize the upper portion of the follicle. The BMZ is considered to be a porous semipermeable filter, which permits exchange of cells and fluid between the epidermis and dermis. It further serves as a structural support for the epidermis and holds the epidermis and dermis together, but also helps to regulate growth, adhesion, and movement of keratinocytes and fibroblasts, as well as apoptosis. Much of this regulation takes place through activation of integrins and syndecans. Extracellular matrix protein 1 demonstrates lossof-function mutations in lipoid proteinosis, resulting in reduplication of the basement membrane. Masunaga T: Epidermal basement membrane: its molecular organization and blistering disorders. Connect Tissue Res 2006; 47(2):55–66. McMillan JR, et al: Epidermal basement membrane zone components: ultrastructural distribution and molecular interactions. J Dermatol Sci 2003; 31:169. Schéele S, et al: Laminin isoforms in development and disease. J Mol Med 2007 Aug; 85(8):825–836.
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Sercu S, et al: Interaction of extracellular matrix protein 1 with extracellular matrix components: ECM1 is a basement membrane protein of the skin. J Invest Dermatol 2008 Jun; 128(6):1397–1408. Sugawara K, et al: Laminin-332 and 511 in skin. Exp Dermatol 2008 Jun; 17(6):473–480. Verdolini R, et al: Autoimmune subepidermal bullous skin diseases: the impact of recent findings for the dermatopathologist. Virchows Arch 2003; 443:184.
Epidermal appendages: adnexa Eccrine and apocrine glands, ducts, and pilosebaceous units constitute the skin adnexa. Embryologically, they originate as downgrowths from the epidermis and are therefore ectodermal in origin. Hedgehog signaling by the signal transducer known as smoothened appears critical for hair development. Abnormalities in this pathway contribute to the formation of pilar tumors and basal cell carcinoma. In the absence of hedghog signaling, embryonic hair germs may develop instead into modified sweat gland or mammary epithelium. While the various adnexal structures serve specific functions, they all can function as reserve epidermis in that re epithelialization after injury to the surface epidermis occurs, principally by virtue of the migration of keratinocytes from the adnexal epithelium to the skin surface. It is not surprising, therefore, that skin sites such as the face or scalp, which contain pilosebaceous units in abundance, reepithelialize more rapidly than do skin sites such as the back, where adnexae of all types are comparatively scarce. Once a wound has reepithelialized, granulation tissue is no longer produced. Deep saucerized biopsies in an area with few adnexae will slowly fill with granulation tissue until they are flush with the surrounding skin. In contrast, areas rich in adnexae will quickly be covered with epithelium. No more granulation tissue will form and the contour defect created by the saucerization will persist. The pseudoepitheliomatous hyperplasia noted in infections and inflammatory conditions consists almost exclusively of adnexal epithelium. Areas of thin intervening epidermis are generally evident between areas of massively hypertrophic adnexal epithelium.
Eccrine sweat units The eccrine sweat unit is composed of three sections that are modified from the basic tubular structure that formed during embryogenesis as a downgrowth of surface epidermis. The intraepidermal spiral duct, which opens directly on to the skin surface, is called the acrosyringium. It is derived from dermal duct cells through mitosis and upward migration. The acrosyringium is composed of small polygonal cells with a central round nucleus surrounded by ample pink cytoplasm. Cornification takes place within the duct and the horn cells become part of the stratum corneum of the epidermis. In the stratum corneum overlying an actinic keratosis, the lamellar spiral acrosyringeal keratin often stands out prominently against the compact red parakeratotic keratin produced by the actinic keratosis. The straight dermal portion of the duct is composed of a double layer of cuboidal epithelial cells and is lined by an eosinophilic cuticle on its luminal side. The coiled secretory acinar portion of the eccrine sweat gland may be found within the superficial panniculus. In areas of skin, such as the back, that possess a thick dermis, the eccrine coil is found in the deep dermis, surrounded by an extension of fat from the underlying panniculus. An inner layer of epithelial cells, the secretory portion of the gland, is surrounded by a layer of flattened myoepithelial cells. The secretory cells are of two types: glycogen-rich, large pale cells; and smaller, darker-staining
Apocrine units Apocrine units develop as outgrowths, not of the surface epidermis, but of the infundibular or upper portion of the hair follicle. Although immature apocrine units are found covering the entire skin surface of the human fetus, these regress and are absent by the time the fetus reaches term. The straight excretory portion of the duct, which opens into the infundibular portion of the hair follicle, is composed of a double layer of cuboidal epithelial cells. Hidrocystomas may show focal secretory cells, but are generally composed of cuboidal cells resembling the straight portion of the apocrine duct. Various benign cutaneous tumors demonstrate differentiation resembling apocrine duct cells, including hidroacanthoma simplex, poroma, dermal duct tumor, and nodular hidradenoma. Although some of these tumors were formerly classified as “eccrine” in differentiation, each may demonstrate focal apocrine decapitation secretion, suggesting apocrine differentiation. The coiled secretory gland is located at the junction of the dermis and subcutaneous fat. It is lined by a single layer of cells, which vary in appearance from columnar to cuboidal. This layer of cells is surrounded by a layer of myoepithelial cells. Apocrine coils appear more widely dilated than eccrine
coils, and apocrine sweat stains more deeply red in H&E sections, contrasting with the pale pink of eccrine sweat. The apices of the columnar cells project into the lumen of the gland and in histologic cross-section appear as if they are being extruded (decapitation secretion). Controversy exists about the mode of secretion in apocrine secretory cells, whether merocrine, apocrine, holocrine, or all three. The composition of the product of secretion is only partially understood. Protein, carbohydrate, ammonia, lipid, and iron are all found in apocrine secretion. It appears milky white, although lipofuscin pigment may rarely produce dark shades of brown and gray-blue (apocrine chromhidrosis). Apocrine sweat is odorless until it reaches the skin surface, where it is altered by bacteria, which makes it odoriferous. Apocrine secretion is mediated by adrenergic innervation and by circulating catecholamines of adrenomedullary origin. Vasoactive intestinal polypeptide may also play a role in stimulating apocrine secretion. Apocrine excretion is episodic, although the actual secretion of the gland is continuous. Apocrine gland secretion in humans serves no known function. In other species it has a protective as well as a sexual function, and in some species it is important in thermoregulation as well. Although occasionally found in an ectopic location, apocrine units of the human body are generally confined to the following sites: axillae, areolae, anogenital region, external auditory canal (ceruminous glands), and eyelids (glands of Moll). They are also generally prominent in the stroma of nevus sebaceous of Jadassohn. Apocrine glands do not begin to function until puberty.
Epidermal appendages: adnexa
cells. The pale glycogen-rich cells are thought to initiate the formation of sweat. The darker cells may function in a manner similar to that of cells of the dermal duct, which actively re absorb sodium, thereby modifying sweat from a basically isotonic solution to a hypotonic one by the time it reaches the skin surface. Sweat is similar in composition to plasma, containing the same electrolytes, though in a more dilute concentration. Physical conditioning in a hot environment results in production of larger amounts of extremely hypotonic sweat in response to a thermal stimulus. This adaptive response allows greater cooling with conservation of sodium. In humans, eccrine sweat units are found at virtually all skin sites. Other mammals have both apocrine and eccrine glands, but the apocrine gland is the major sweat gland, and eccrine glands are generally restricted to areas such as the footpad. Ringtailed lemurs have an antebrachial organ rich in sweat glands with hybrid characteristics of eccrine and apocrine glands. In humans, eccrine glands are abundant and serve a thermo regulatory function. They are most abundant on the palms, soles, forehead, and axillae. Some eccrine glands in the axillae, especially in patients with hyperhidrosis, may have widely dilated secretory coils that contain apocrine-appearing cells. These findings suggest the presence of hybrid glands in humans. On friction surfaces, such as the palms and soles, eccrine secretion is thought to assist tactile sensibility and improve adhesion. Physiologic secretion of sweat occurs as a result of many factors and is mediated by cholinergic innervation. Heat is a prime stimulus to increased sweating, but other physiologic stimuli, including emotional stress, are important as well. During early development, there is a switch between adrenergic and cholinergic innervation of sweat glands. Some responsiveness to both cholinergic and adrenergic stimuli persists. Cholinergic sweating involves a biphasic response, with initial hyperpolarization and secondary depolarization mediated by the activation of calcium and chloride ion conductance. Adrenergic secretion involves monophasic depolarization and is dependent on cystic fibrosis transmembrane conductance regulator-GCl. Cells from patients with cystic fibrosis demonstrate no adrenergic secretion. Vasoactive intestinal polypeptide may also play a role in stimulating eccrine secretion.
Hair follicles During embryogenesis, mesenchymal cells in the fetal dermis collect immediately below the basal layer of the epidermis. Epidermal buds grow down into the dermis at these sites. The developing follicle forms at an angle to the skin surface and continues its downward growth. At this base, the column of cells widens, forming the bulb, and surrounds small collections of mesenchymal cells. These papillary mesenchymal bodies contain mesenchymal stem cells with broad functionality. At least in mice, they demonstrate extramedullary hemato poietic stem cell activity, and represent a potential therapeutic source of hematopoietic stem cells and a possible source of extramedullary hematopoiesis in vivo. Along one side of the fetal follicle, two buds are formed: an upper, which develops into the sebaceous gland, and a lower, which becomes the attachment for the arrector pili muscle. A third epithelial bud develops from the opposite side of the follicle above the level of the sebaceous gland anlage, and gives rise to the apocrine gland. The uppermost portion of the follicle, which extends from its surface opening to the entrance of the sebaceous duct, is called the infundibular segment. It resembles the surface epidermis and its keratinocytes may be of epidermal origin. The portion of the follicle between the sebaceous duct and the insertion of the arrector pili muscle is the isthmus. The inner root sheath fully keratinizes and sheds within this isthmic portion. The inferior portion includes the lowermost part of the follicle and the hair bulb. Throughout life, the inferior portion undergoes cycles of involution and regeneration. Hair follicles develop sequentially in rows of three. Primary follicles are surrounded by the appearance of two secondary follicles; other secondary follicles subsequently develop around the principal units. The density of pilosebaceous units decreases throughout life, possibly because of dropout of the secondary follicles. In mouse models, signaling by molecules designated as ectodysplasin A and noggin is essential for the 5
Fig. 1-3 Anatomy of the hair follicle.
Skin: Basic Structure and Function
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Outer root sheath Inner root sheath Hair shaft
Crosssection
Hair cuticle Cortex Medulla Bulb with matrix cells Dermal papilla
development of primary hair follicles and induction of secondary follicles. Arrector pili muscles contained within the follicular unit interconnect at the level of the isthmus. The actual hair shaft, as well as an inner and an outer root sheath, is produced by the matrix portion of the hair bulb (Fig. 1-3). The sheaths and contained hair form concentric cylindrical layers. The hair shaft and inner root sheath move together as the hair grows upwards until the fully keratinized inner root sheath sheds at the level of the isthmus. The epidermis of the upper part of the follicular canal is contiguous with the outer root sheath. The upper two portions of the follicle (infundibulum and isthmus) are permanent; the inferior segment is completely replaced with each new cycle of hair growth. On the scalp, anagen, the active growth phase, lasts about 3–5 years. Normally, approximately 85–90% of all scalp hairs are in the anagen phase, a figure that decreases with age and decreases faster in individuals with male-pattern baldness (as the length of anagen decreases dramatically). Scalp anagen hairs grow at a rate of about 0.37 mm/day. Catagen, or involution, lasts about 2 weeks. Telogen, the resting phase, lasts about 3–5 months. Most sites on the body have a much shorter anagen phase and much longer telogen, resulting in short hairs that stay in place for long periods of time without growing longer. Prolongation of the anagen phase results in long eyelashes in patients with acquired immunodeficiency syndrome (AIDS). Human hair growth is cyclical, but each follicle functions as an independent unit (Fig. 1-4). Therefore, humans do not shed hair synchronously, as most animals do. Each hair follicle undergoes intermittent stages of activity and quiescence. 6
Synchronous termination of anagen or telogen results in telogen effluvium. Most commonly, telogen effluvium is the result of early release from anagen, such as that induced by a febrile illness, surgery, or weight loss. Various exogenous and endogenous physiologic factors can modulate the hair cycle. The hair papilla and the connective tissue sheath form a communicating network through gap junctions. This network may play a role in controlling hair cycling. Pregnancy is typically accompanied by retention of an increased number of scalp hairs in the anagen phase, as well as a prolongation of telogen. Soon after delivery, telogen loss can be detected as abnormally prolonged telogen hairs are released. At the same time, abnormally prolonged anagen hairs are converted synchronously to telogen. Between 3 and 5 months later, a more profound effluvium is noted. Patients on chemotherapy often have hair loss because the drugs interfere with the mitotic activity of the hair matrix, leading to the formation of a tapered fracture. Only anagen hairs are affected, leaving a sparse coat of telogen hairs on the scalp. As the matrix recovers, anagen hairs resume growth without having to cycle through catagen and telogen. The growing anagen hair is characterized by a pigmented bulb (Fig. 1-5) and an inner root sheath (Fig. 1-6). Histologically, catagen hairs are best identified by the presence of many apoptotic cells in the outer root sheath (Fig. 1-7). Telogen club hairs have a nonpigmented bulb with a shaggy lower border. The presence of bright red trichilemmal keratin bordering the club hair results in a flame thrower-like appearance in vertical H&E sections (Fig. 1-8). As the new anagen hair grows, the old telogen hair is shed.
Epidermal appendages: adnexa
Growing hair Sebaceous gland
Club hair
Growing hair
Dermal papilla
Anagen
Catagen
Telogen
Anagen
Fig. 1-4 Phases of the growth cycle of a hair.
Fig. 1-6 Cross-section of isthmus of anagen follicle demonstrating glycogenated outer root sheath and keratinized inner root sheath.
Fig. 1-5 Cross-section of anagen bulb demonstrating pigment within matrix.
The scalp hair of white people is round; pubic hair, beard hair, and eyelashes are oval. The scalp hair of black people is also oval, and it is this, plus a curvature of the follicle just above the bulb, that causes black hair to be curly. Uncombable hair is triangular with a central canal. Hair color depends on the degree of melanization and distribution of melanosomes within the hair shaft. Melanocytes of the hair bulb synthesize melanosomes and transfer them to the keratinocytes of the bulb matrix. Larger melanosomes are found in the hair of black persons; smaller melanosomes, which are aggregated within membrane-bound complexes, are found in the hair of white persons. Red hair is character-
ized by spherical melanosomes. Graying of hair is a result of a decreased number of melanocytes, which produce fewer melanosomes. Repetitive oxidative stress causes apoptosis of hair follicle melanocytes, resulting in normal hair graying. Premature graying is related to exhaustion of the melanocyte stem cell pool.
Sebaceous glands Sebaceous glands are formed embryologically as an outgrowth from the upper portion of the hair follicle. They are composed of lobules of pale-staining cells with abundant lipid droplets in their cytoplasm. At the periphery of the lobules basaloid germinative cells are noted. These germinative cells give rise to the lipid-filled pale cells, which are continuously being extruded through the short sebaceous duct into the infundibular portion of the hair follicle. The sebaceous duct is lined by a red cuticle that undulates sharply in a pattern resembling 7
Although sebaceous glands are independent miniorgans in their own right, they are anatomically and functionally related to the hair follicle. Cutaneous disorders attributed to sebaceous glands, such as acne vulgaris, are really disorders of the entire pilosebaceous unit. The clinical manifestations of acne, namely the comedo, papule, pustule, and cyst, would not form, regardless of increased sebaceous gland activity, as long as the sebaceous duct and infundibular portion of the hair follicle remained patent, and lipid and cell debris (sebum) were able to reach the skin surface. Most lipids produced by the sebaceous gland are also produced elsewhere in the body. Wax esters and squalene are unique secretory products of sebaceous glands. Sebocytes express histamine receptors and antihistamines can reduce squalene levels, suggesting that antihistamines could play a role in modulating sebum production. Skin lipids contribute to the barrier function and some have antimicrobial properties. Antimicrobial lipids include free sphingoid bases derived from epidermal ceramides and fatty acids like sapienic acid derived from sebaceous triglycerides.
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Fig. 1-7 Catagen hair with many apoptotic keratinocytes within the outer root sheath.
Drake DR, et al: Thematic review series: skin lipids. Antimicrobial lipids at the skin surface. J Lipid Res 2008 Jan; 49(1):4–11. Gritli-Linde A, et al: Abnormal hair development and apparent follicular transformation to mammary gland in the absence of hedgehog signaling. Dev Cell 2007 Jan; 12(1):99–112. Kizawa K, et al: Specific citrullination causes assembly of a globular S100A3 homotetramer: a putative Ca2+ modulator matures human hair cuticle. J Biol Chem 2008 Feb 22; 283(8):5004–5013. Novotný J, et al: Synthesis and structure-activity relationships of skin ceramides. Curr Med Chem 2010; 17(21):2301–2324. Pelle E, et al: Identification of histamine receptors and reduction of squalene levels by an antihistamine in sebocytes. J Invest Dermatol 2008 May; 128(5):1280–1285. Saga K: Structure and function of human sweat glands studied with histochemistry and cytochemistry. Prog Histochem Cytochem 2002; 37:323. Smith KR, et al: Thematic review series: skin lipids. Sebaceous gland lipids: friend or foe? J Lipid Res 2008 Feb; 49(2):271–281. Spatz KR, et al: Increased melanocyte apoptosis under stress-mediator substance P-elucidating pathways involved in stress-induced premature graying. Exp Dermatol 2008 Jul; 17(7):632. Xu X, et al: Co-factors of LIM domains (Clims/Ldb/Nli) regulate corneal homeostasis and maintenance of hair follicle stem cells. Dev Biol 2007 Dec 15; 312(2):484–500.
Nails
Fig. 1-8 Vertical section of telogen hair demonstrating “flame thrower” appearance of club hair.
shark’s teeth. This same undulating cuticle is seen in steatocystoma and some dermoid cysts. Sebaceous glands are found in greatest abundance on the face and scalp, though they are distributed throughout all skin sites except the palms and soles. They are always associated with hair follicles except at the following sites: tarsal plate of the eyelids (meibomian glands), buccal mucosa and vermilion border of the lip (Fordyce spots), prepuce and mucosa lateral to the penile frenulum (Tyson glands), labia minora, and female areola (Montgomery tubercles). 8
Nails act to assist in grasping small objects and in protecting the fingertip from trauma. Matrix keratinization leads to the formation of the nail plate. Fingernails grow an average of 0.1 mm/day, requiring about 4–6 months to replace a complete nail plate. The growth rate is much slower for toenails, with 12–18 months required to replace the great toenail. Abnormalities of the nail may serve as important clues to cutaneous and systemic disease, and may provide the astute clinician with information about disease or toxic exposures that occurred several months in the past. The keratin types found in the nail are a mixture of epidermal and hair types, with the hair types predominating. Nail isthmus keratinization differs from that of the nail bed in that K10 is only present in nail isthmus. Brittle nails demonstrate widening of the intercellular space between nail keratinocytes on electron microscopy. Whereas most of the skin is characterized by rete pegs that resemble an egg crate, the nail bed has true parallel rete ridges. These ridges result in the formation of splinter hemorrhages when small quantities of extravasated red cells mark their path. The nail cuticle is formed by keratinocytes of the proximal nailfold, whereas the nail plate is formed by matrix
Kitamori K, et al: Weakness in intercellular association of keratinocytes in severely brittle nails. Arch Histol Cytol 2006 Dec; 69(5):323–328. McCarthy DJ: Anatomic considerations of the human nail. Clin Podiatr Med Surg 2004; 21:477. Perrin C: Expression of follicular sheath keratins in the normal nail with special reference to the morphological analysis of the distal nail unit. Am J Dermatopathol 2007 Dec; 29(6):543–550.
Dermis The constituents of the dermis are mesodermal in origin except for nerves, which, like melanocytes, derive from the neural crest. Until the sixth week of fetal life, the dermis is merely a pool of acid mucopolysaccharide-containing, scattered dendritic-shaped cells, which are the precursors of fibroblasts. By the 12th week, fibroblasts are actively synthesizing reticulum fibers, elastic fibers, and collagen. A vascular network develops, and by the 24th week, fat cells have appeared beneath the dermis. During fetal development, Wnt/beta-catenin signaling is critical for differentiation of ventral versus dorsal dermis, and the dermis then serves as a scaffold for the adnexal structures identified with ventral or dorsal sites. Infant dermis is composed of small collagen bundles that stain deeply red. Many fibroblasts are present. In adult dermis, few fibroblasts persist; collagen bundles are thick and stain pale red. Two populations of dermal dendritic cells are noted in the adult dermis. Factor XIIIa-positive dermal dendrocytes appear to give rise to dermatofibromas, angiofibromas, acquired digital fibrokeratomas, pleomorphic fibromas, and fibrous papules. CD34+ dermal dendroctyes are accentuated around hair follicles, but exist throughout the dermis. They disappear from the dermis early in the course of morphea. Their loss can be diagnostic in subtle cases. CD34+ dermal dendrocytes re appear in the dermis when morphea responds to UVA1 light treatment. The principal component of the dermis is collagen, a family of fibrous proteins comprising at least 15 genetically distinct types in human skin. Collagen serves as the major structural protein for the entire body; it is found in tendons, ligaments, and the lining of bones, as well as in the dermis. It represents 70% of the dry weight of skin. The fibroblast synthesizes the procollagen molecule, a helical arrangement of specific polypeptide chains that are subsequently secreted by the cell and assembled into collagen fibrils. Collagen is rich in the amino acids hydroxyproline, hydroxylysine, and glycine. The fibrillar collagens are the major group found in the skin. Type I collagen is the major component of the dermis. The structure of type I collagen is uniform in width and each fiber displays characteristic cross-striations with a periodicity of 68 nm. Collagen fibers are loosely arranged in the papillary and adventitial (periadnexal) dermis. Large collagen bundles are noted in the reticular dermis (the dermis below the level of the postcapillary venule). Collagen I mRNA and collagen III mRNA are both expressed in the reticular and papillary dermis, and are downregulated by UV light, as is the collagen regulatory proteoglycan decorin. This downregulation may play a role in photoaging.
Type IV collagen is found in the BMZ. Type VII collagen is the major structural component of anchoring fibrils and is produced predominately by keratinocytes. Abnormalities in type VII collagen are seen in dystrophic epidermolysis bullosa, and autoantibodies to this collagen type characterize acquired epidermolysis bullosa. Collagen fibers are continuously being degraded by proteolytic enzymes called spare collagenases, and replaced by newly synthesized fibers. Additional information on collagen types and diseases can be found in Chapter 25. The fibroblast also synthesizes elastic fibers and the ground substance of the dermis, which is composed of glycosaminoglycans or acid mucopolysaccharides. Elastic fibers differ both structurally and chemically from collagen. They consist of aggregates of two components: protein filaments and elastin, an amorphous protein. The amino acids desmosine and isodesmosine are unique to elastic fibers. Elastic fibers in the papillary dermis are fine, whereas those in the reticular dermis are coarse. The extracellular matrix or ground substance of the dermis is composed of sulfated acid mucopolysaccharide, principally chondroitin sulfate and dermatan sulfate, neutral mucopolysaccharides, and electrolytes. Sulfated acid mucopolysaccharides stain with colloidal iron and with alcian blue at both pH 2.5 and 0.5. They stain metachromatically with toluidine blue at both pH 3.0 and 1.5. Hyaluronan (hyaluronic acid) is a minor component of normal dermis, but is the major mucopolysaccharide that accumulates in pathologic states. It stains with colloidal iron, and with both alcian blue and toluidine blue (metachromatically), but only at the higher pH for each stain. Collagen is the major stress-resistant material of the skin. Elastic fibers contribute very little to resisting deformation and tearing of skin, but have a role in maintaining elasticity. Connective tissue disease is a term generally used to refer to a clinically heterogeneous group of autoimmune diseases, including lupus erythematosus, scleroderma, and dermatomyositis. Scleroderma involves the most visible collagen abnormalities, as collagen bundles become hyalinized and the space between collagen bundles diminishes. Both lupus and dermatomyositis produce increased dermal mucin, mostly hyaluronic acid. Bullous lupus has autoantibodies directed against type VII collagen. Defects in collagen synthesis have been described in a number of inheritable diseases, including Ehlers–Danlos syndrome, X-linked cutis laxa, and osteogenesis imperfecta. Defects in elastic tissue are seen in Marfan syndrome and pseudoxanthoma elasticum.
Dermis
keratinocytes. Endogenous pigments tend to follow the contour of the lunula (the distal portion of the matrix), whereas exogenous pigments tend to follow the contour of the cuticle. The dorsal nail plate is formed by the proximal matrix, and the ventral nail plate is formed by the distal matrix with some contribution from the nail bed. The location of a melanocytic lesion within the matrix can be assessed by the presence of pigment within the dorsal or ventral nail plate.
Vasculature The dermal vasculature consists principally of two intercommunicating plexuses. The subpapillary plexus, or upper horizontal network, contains the postcapillary venules and courses at the junction of the papillary and reticular dermis. This plexus furnishes a rich supply of capillaries, end arterioles, and venules to the dermal papillae. The deeper, lower horizontal plexus is found at the dermal–subcutaneous interface and is composed of larger blood vessels than those of the superficial plexus. Nodular lymphoid infiltrates surrounding this lower plexus are typical of early inflammatory morphea. The vasculature of the dermis is particularly well developed at sites of adnexal structures. Associated with the vascular plexus are dermal lymphatics and nerves.
Muscles Smooth muscle occurs in the skin as arrectores pilorum (erectors of the hairs), as the tunica dartos (or dartos) of the scrotum, 9
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and in the areolas around the nipples. The arrectores pilorum are attached to the hair follicles below the sebaceous glands and, in contracting, pull the hair follicle upward, producing gooseflesh. The presence of scattered smooth muscle throughout the dermis is typical of anogenital skin. Smooth muscle also comprises the muscularis of dermal and subcutaneous blood vessels. The muscularis of veins is composed of small bundles of smooth muscle that criss-cross at right angles. Arterial smooth muscle forms a concentric wreath-like ring. Specialized aggregates of smooth muscle cells (glomus bodies) are found between arterioles and venules, and are especially prominent on the digits and at the lateral margins of the palms and soles. Glomus bodies serve to shunt blood and regulate temperature. Most smooth muscle expresses desmin intermediate filaments, but vascular smooth muscle expresses vimentin instead. Smooth muscle actin is consistently expressed by all types of smooth muscle. Striated (voluntary) muscle occurs in the skin of the neck as the platysma muscle and in the skin of the face as the muscles of expression. This complex network of striated muscle, fascia, and aponeuroses is known as the superficial muscular aponeurotic system (SMAS).
Nerves In the dermis, nerve bundles are found together with arterioles and venules as part of the neurovascular bundle. In the deep dermis, nerves travel parallel to the surface, and the presence of long sausage-like granulomas following this path is an important clue to the diagnosis of Hansen’s disease. Touch and pressure are mediated by Meissner corpuscles found in the dermal papillae, particularly on the digits, palms, and soles, and by Vater–Pacini corpuscles located in the deeper portion of the dermis of weight-bearing surfaces and genitalia. Mucocutaneous end organs are found in the papillary dermis of modified hairless skin at the mucocutaneous junctions: namely, the glans, prepuce, clitoris, labia minora, perianal region, and vermilion border of the lips. Temperature, pain, and itch sensation are transmitted by unmyelinated nerve fibers which terminate in the papillary dermis and around hair follicles. Impulses pass to the central nervous system by way of the dorsal root ganglia. Histamine-evoked itch is transmitted by slow-conducting unmyelinated C-polymodal neurons. Signal transduction differs for sensations of heat and cold, and in peripheral nerve axons. Postganglionic adrenergic fibers of the autonomic nervous system regulate vasoconstriction, apocrine gland secretions, and contraction of arrector pili muscles of hair follicles. Cholinergic fibers mediate eccrine sweat secretion.
Mast cells Mast cells play an important role in the normal immune response, as well as immediate-type sensitivity, contact allergy, and fibrosis. Measuring 6–12 microns in diameter, with ample amphophilic cytoplasm and a small round central nucleus, normal mast cells resemble fried eggs in histologic sections. In telangiectasia macularis eruptiva perstans (TMEP mastocytosis), they are spindle-shaped and hyperchromatic, resembling large, dark fibroblasts. Mast cells are distinguished by containing up to 1000 granules, each measuring 0.6–0.7 microns in diameter. Coarse particulate granules, crystalline granules, and granules containing scrolls may be seen. On the cell’s surface are 100 000–500 000 glycoprotein receptor sites for immunoglobulin E (IgE). There is heterogeneity to mast cells with type I or connective tissue mast cells found in the dermis and submucosa, and type II or mucosal mast cells found in the bowel and respiratory tract mucosa. 10
Mast cell granules stain metachromatically with toluidine blue and methylene blue (in the Giemsa stain) because of their high content of heparin. They also contain histamine, neutrophil chemotactic factor, eosinophil chemotactic factor of anaphylaxis, tryptase, kininogenase, and β-glucosaminidase. Slow-reacting substance of anaphylaxis (leukotrienes C4 and D4), leukotriene B4, platelet activating factor, and prostaglandin D2 are formed only after IgE-mediated release of granules. Mast cells stain reliably with the Leder ASD-chloracetase esterase stain. Because this stain does not rely on the presence of mast cell granules, it is particularly useful in situations when mast cells have degranulated. In forensic medicine, fluorescent labeling of mast cells with antibodies to the mast cell enzymes chymase and tryptase is useful in determining the timing of skin lesions in regard to death. Lesions sustained while living show an initial increase, then decline in mast cells. Lesions sustained postmortem demonstrate few mast cells. Cutaneous mast cells respond to environmental changes. Dry environments result in an increase in mast cell number and cutaneous histamine content. In mastocytosis, mast cells accumulate in skin because of abnormal proliferation, migration, and failure of apoptosis. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) method is commonly used to assess apoptosis, and demonstrates decreased staining in mastocytomas. Proliferation is usually only moderately enhanced. Abraham SN, et al: Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol 2010 Jun; 10(6):440–452. Charkoudian N: Skin blood flow in adult human thermoregulation: how it works, when it does not, and why. Mayo Clin Proc 2003; 78:603. Galli SJ, et al: Mast cells: versatile regulators of inflammation, tissue remodeling, host defense and homeostasis. J Dermatol Sci 2008 Jan; 49(1):7–19. Hendrix S, et al: Skin and hair follicle innervation in experimental models: a guide for the exact and reproducible evaluation of neuronal plasticity. Exp Dermatol 2008 Mar; 17(3):214–227. Hoffmann T, et al: Sensory transduction in peripheral nerve axons elicits ectopic action potentials. J Neurosci 2008 Jun 11; 28(24):6281–6284. Metz M, et al: Mast cell functions in the innate skin immune system. Immunobiology 2008; 213(3–4):251–260. Norman MU, et al: Mast cells regulate the magnitude and the cytokine microenvironment of the contact hypersensitivity response. Am J Pathol 2008 Jun; 172(6):1638–1649. Ohtola J, et al: β-Catenin has sequential roles in the survival and specification of ventral dermis. Development 2008 Jul; 135(13):2321–2329.
Subcutaneous tissue (fat) Beneath the dermis lies the panniculus, lobules of fat cells or lipocytes separated by fibrous septa composed of collagen and large blood vessels. The collagen in the septa is continuous with the collagen in the dermis. Just as the epidermis and dermis vary in thickness according to skin site, so does the subcutaneous tissue. The panniculus provides buoyancy, and functions as a repository of energy and an endocrine organ. It is an important site of hormone conversions, such as that of androstenedione into estrone by aromatase. Leptin, a hormone produced in lipocytes, regulates body weight via the hypothalamus and influences how we react to flavors in food. Various substances can affect lipid accumulation within lipocytes. Obestatin is a polypeptide that reduces feed intake and weight gain in rodents. (–)-ternatin, a highly N-methylated cyclic heptapeptide that inhibits fat accumulation, produced by the mushroom Coriolus versicolor, has similar effects in mice. Study of these molecules provides insight into the molecular basis of weight gain and obesity. Abnormal fat distribution and insulin resistance are seen in Cushing syndrome and as a result of antiretroviral therapy. In obese children and adolescents
Nagaraj S, et al: Fragments of obestatin as modulators of feed intake, circulating lipids, and stored fat. Biochem Biophys Res Commun 2008 Feb 15; 366(3):731–737. Shimokawa K, et al: Biological activity, structural features, and synthetic studies of (-)-ternatin, a potent fat-accumulation inhibitor of 3T3-L1 adipocytes. Chem Asian J 2008 Feb 1; 3(2):438–446. Weiss R, et al: Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet 2003; 362:951.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 1-1 Electron micrograph illustrating the three basic cell types in the epidermis and their relationships. Fig. 1-2 Ultrastructural appearance of the desmosome specialized attachment plate between adjacent keratinocytes. Fig. 1-3 Upper portion of the epidermis. Fig. 1-4 Portion of a melanocyte from dark skin. Fig. 1-5 Relationship between melanocytes (M) and basal keratinocytes (K) in light skin. Fig. 1-6 Ultrastructural appearance of the Langerhans cell. Fig. 1-7 Ultrastructural appearance of the basement membrane zone at the junction of the epidermis and dermis.
Subcutaneous tissue (fat)
developing diabetes, severe peripheral insulin resistance is associated with intramyocellular and intra-abdominal lipocyte lipid accumulation. Certain inflammatory dermatoses, known as the panniculitides, principally affect this level of the skin, producing subcutaneous nodules. The pattern of the inflammation, specifically whether it primarily affects the septa or the fat lobules, serves to distinguish various conditions which may resemble one another clinically.
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Bonus images for this chapter can be found online at http://www.expertconsult.com
2
Cutaneous Signs and Diagnosis
In some cases, the appearance of skin lesions may be so distinctive that the diagnosis is clear at a glance. In other cases, subjective symptoms and clinical signs in themselves are inadequate, and a complete history and laboratory examinations, including a biopsy, are essential to arrive at a diagnosis. The same disease may show variations under different conditions and in different individuals. The appearance of the lesions may have been modified by previous treatment or obscured by extraneous influences, such as scratching or secondary infection. Subjective symptoms may be the only evidence of a disease, as in pruritus, and the skin appearance may be generally unremarkable. Although history is important, the diagnosis in dermatology is most frequently made based on the objective physical characteristics and location or distribution of one or more lesions that can be seen or felt. Therefore, careful physical examination of the skin is paramount in dermatologic diagnosis.
Cutaneous signs Typically, most skin diseases produce or present with lesions that have more or less distinct characteristics. They may be uniform or diverse in size, shape, and color, and may be in different stages of evolution or involution. The original lesions are known as the primary lesions, and identification of such lesions is the most important aspect of the dermatologic physical examination. They may continue to full development or be modified by regression, trauma, or other extraneous factors, producing secondary lesions.
Primary lesions Primary lesions are of the following forms: macules (or patches), papules (or plaques), nodules, tumors, wheals, vesicles, bullae, and pustules.
Macules (maculae, spots) Macules are variously sized, circumscribed changes in skin color, without elevation or depression (nonpalpable) (Fig. 2-1). They may be circular, oval, or irregular, and may be distinct in outline or fade into the surrounding skin. Macules may constitute the whole or part of the eruption, or may be merely an early phase. If the lesions become slightly raised, they are then designated papules or, sometimes, morbilliform eruptions.
acuminate, rounded, conical, flat-topped, or umbilicated, and may appear white (as in milium), red (as in eczema), yellowish (as in xanthoma), or black (as in melanoma). Papules are generally centered in the dermis and may be concentrated at the orifices of the sweat ducts or at the hair follicles. They may be of soft or firm consistency. The surface may be smooth or rough. If capped by scales, they are known as squamous papules, and the eruption is called papulosquamous. Some papules are discrete and irregularly distributed, as in papular urticaria, whereas others are grouped, as in lichen nitidus. Some persist as papules, whereas those of the inflammatory type may progress to vesicles and even to pustules, or may erode or ulcerate before regression takes place. The term maculopapular should not be used. There is no such thing as a maculopapule, but there may be both macules and papules in an eruption. Most typically such eruptions are morbilliform.
Plaques A plaque is a broad papule (or confluence of papules), 1 cm or more in diameter (Fig. 2-2). It is generally flat, but may be centrally depressed. The center of a plaque may be normal skin.
Nodules Nodules are morphologically similar to papules, but they are larger than 1 cm in diameter. They most frequently are centered in the dermis or subcutaneous fat.
Tumors Tumors are soft or firm and freely movable or fixed masses of various sizes and shapes (but in general greater than 2 cm in diameter). General usage dictates that the word “tumor” means a neoplasm. They may be elevated or deep-seated, and in some instances are pedunculated (fibromas). Tumors have a tendency to be rounded. Their consistency depends on the constituents of the lesion. Some tumors remain stationary indefinitely, whereas others increase in size or break down.
Wheals (hives)
A patch is a large macule, 1 cm or greater in diameter, as may be seen in nevus flammeus or vitiligo.
Wheals are evanescent, edematous, plateau-like elevations of various sizes (Fig. 2-3). They are usually oval or of arcuate contours, pink to red, and surrounded by a “flare” of macular erythema. They may be discrete or may coalesce. These lesions often develop quickly. Because the wheal is the prototypic lesion of urticaria, diseases in which wheals are prominent are frequently described as “urticarial” (e.g. urticarial vasculitis). Dermatographism, or pressure-induced whealing, may be evident.
Papules
Vesicles (blisters)
Papules are circumscribed, solid elevations with no visible fluid, varying in size from a pinhead to 1 cm. They may be
Vesicles are circumscribed, fluid-containing, epidermal elevations, 1–10 mm in size. They may be pale or yellow from
Patches
Cutaneous signs Fig. 2-3 Multiple wheals and dermatographism, urticarial vasculitis.
Fig. 2-1 Macular depigmentation, vitiligo.
Fig. 2-4 Vesicles, bullae, and erosions, bullous pemphigoid.
Bullae
Fig. 2-2 Multiple hyperpigmented patches and plaques, cutaneous T-cell lymphoma.
serous exudate, or red from serum mixed with blood. The apex may be rounded, acuminate, or umbilicated as in eczema herpeticum. Vesicles may be discrete, irregularly scattered, grouped as in herpes zoster, or linear as in allergic contact dermatitis from urushiol (poison ivy/oak). Vesicles may arise directly or from a macule or papule, and generally lose their identity in a short time, breaking spontaneously or developing into bullae through coalescence or enlargement, or developing into pustules (Fig. 2-4). When the contents are of a seropurulent character, the lesions are known as vesicopustules. Vesicles consist of either a single cavity (unilocular) or several compartments (multilocular) containing fluid.
Bullae are rounded or irregularly shaped blisters containing serous or seropurulent fluid. They differ from vesicles only in size, being larger than 1 cm. They are usually unilocular but may be multilocular. Bullae may be located superficially in the epidermis, so that their walls are flaccid and thin, and subject to rupture spontaneously or from slight injury. After rupture, remnants of the thin walls may persist and, together with the exudate, may dry to form a thin crust; or the broken bleb may leave a raw and moist base, which may be covered with seropurulent or purulent exudate. More rarely, irregular vegetations may appear on the base (as in pemphigus vegetans). When the bullae are subepidermal, they are tense, and ulceration and scarring may result. Nikolsky’s sign refers to the diagnostic maneuver of putting lateral pressure on unblistered skin in a bullous eruption and having the epithelium shear off. Asboe–Hansen’s sign refers to the extension of a blister to adjacent unblistered skin when pressure is put on the top of the blister. Both of these signs demonstrate the principle that in some diseases the extent of microscopic vesiculation is more than is evident by simple inspection. These findings are useful in evaluating the severity of pemphigus vulgaris and severe bullous drug reactions. Hemorrhagic bullae are common in pemphigus, herpes zoster, severe bullous drug reactions, and lichen sclerosus. The cellular contents of bullae may be useful in cytologically confirming the diagnosis of pemphigus, herpes zoster, and herpes simplex. 13
Cutaneous Signs and Diagnosis
2
Pustules
Excoriations and abrasions (scratch marks)
Pustules are small elevations of the skin containing purulent material (usually necrotic inflammatory cells) (Fig. 2-5). They are similar to vesicles in shape and usually have an inflammatory areola. They are usually white or yellow centrally, but may be red if they also contain blood. They may originate as pustules or may develop from papules or vesicles, passing through transitory early stages, during which they are known as papulopustules or vesicopustules.
An excoriation is a punctate or linear abrasion produced by mechanical means, usually involving only the epidermis but not uncommonly reaching the papillary layer of the dermis. Excoriations are caused by scratching with the fingernails in an effort to relieve itching in a variety of diseases. If the skin damage is the result of mechanical trauma or constant friction, the term abrasion may be used. Frequently there is an inflammatory areola around the excoriation or a covering of yellowish dried serum or red dried blood. Excoriations may provide access for pyogenic microorganisms and the formation of crusts, pustules, or cellulitis, occasionally associated with enlargement of the neighboring lymphatic glands. In general, the longer and deeper excoriations are, the more severe was the pruritus that provoked them. Lichen planus is an exception, however, in which pruritus is severe, but excoriations are rare.
Secondary lesions Secondary lesions are of many kinds; the most important are scales, crusts, erosions, ulcers, fissures, and scars.
Scales (exfoliation) Scales are dry or greasy laminated masses of keratin. The body ordinarily is constantly shedding imperceptible tiny, thin fragments of stratum corneum. When the formation of epidermal cells is rapid or the process of normal keratinization is interfered with, pathologic exfoliation results, producing scales. These vary in size, some being fine, delicate, and branny, as in tinea versicolor, others being coarser, as in eczema and ichthyosis, while still others are stratified, as in psoriasis. Large sheets of desquamated epidermis are seen in toxic epidermal necrolysis, staphylococcal scalded skin syndrome, and infection-associated (toxin-mediated) desquamations, such as scarlet fever. Scales vary in color from white–gray to yellow or brown from the admixture of dirt or melanin. Occasionally, they have a silvery sheen from trapping of air between their layers; these are micaceous scales, characteristic of psoriasis. When scaling occurs, it usually implies that there is some pathologic process in the epidermis, and parakeratosis is often present histologically.
Fissures (cracks, clefts)
Crusts (scabs)
Erosions
Crusts are dried serum, pus, or blood, usually mixed with epithelial and sometimes bacterial debris. They vary greatly in size, thickness, shape, and color, according to their origin, composition, and volume. They may be dry, golden yellow, soft, friable, and superficial, as in impetigo; yellowish, as in favus; thick, hard, and tough, as in third-degree burns; or lamellated, elevated, brown, black, or green masses, as in late syphilis. The latter have been described as oyster-shell (ostraceous) crusts and are known as rupia. When crusts become detached, the base may be dry or red and moist.
Loss of all or portions of the epidermis alone, as in impetigo or herpes zoster or simplex after vesicles rupture, produces an erosion. It may or may not become crusted, but it heals without a scar.
Fig. 2-5 Erythematous plaques studded with sheets of pustules, pustular psoriasis.
14
A fissure is a linear cleft through the epidermis or into the dermis. These lesions may be single or multiple, and vary from microscopic to several centimeters in length with sharply defined margins. They may be dry or moist, red, straight, curved, irregular, or branching. They occur most commonly when the skin is thickened and inelastic from inflammation and dryness, especially in regions subjected to frequent movement. Such areas are the tips and flexural creases of the thumbs, fingers, and palms; the edges of the heels; the clefts between the fingers and toes; at the angles of the mouth; the lips; and about the nares, auricles, and anus. When the skin is dry, exposure to cold, wind, water, and cleaning products (soap, detergents) may produce a stinging, burning sensation, indicating microscopic fissuring is present. This may be referred to as chapping, as in “chapped lips.” When fissuring is present, pain is often produced by movement of the parts, which opens or deepens the fissures or forms new ones.
Ulcers Ulcers are rounded or irregularly shaped excavations that result from complete loss of the epidermis plus some portion of the dermis. They vary in diameter from a few millimeters to several centimeters (Fig. 2-6). They may be shallow, involving
Fig. 2-6 Ulcer of lip, chancre of primary syphilis.
Scars Scars are composed of new connective tissue that replaced lost substance in the dermis or deeper parts as a result of injury or disease, as part of the normal reparative process. Their size and shape are determined by the form of the previous destruction. Scarring is characteristic of certain inflammatory processes and is therefore of diagnostic value. The pattern of scarring may be characteristic of a particular disease. Lichen planus and discoid lupus erythematosus, for example, have inflammation that is in relatively the same area anatomically, yet discoid lupus characteristically causes scarring as it resolves, whereas lichen planus rarely results in scarring of the skin. Both processes, however, cause scarring of the hair follicles when they occur on the scalp. Scars may be thin and atrophic, or the fibrous elements may develop into neoplastic overgrowths, as in keloids. Some individuals and some areas of the body, such as the anterior chest, are especially prone to scarring. Scars may be smooth or rough, pliable or firm, and tend at first to be pink or violaceous, later becoming white, glistening, and rarely, hyperpigmented. Scars are persistent but tend to become less noticeable in the course of time. At times, and especially in certain anatomic locations (central chest), they grow thick, tough, and corded, forming a hypertrophic scar or keloid.
General diagnosis Interpretation of the clinical picture may be difficult, because identical manifestations may result from widely different causes. Moreover, the same etiologic factors may give rise to a great diversity of eruptions. There is one great advantage in dermatology: namely, that of dealing with an organ that can be seen and felt. Smears and cultures may be readily made for bacteria and fungi. Biopsy and histologic examination of skin lesions are usually very minor procedures, making histo pathology an important component of the evaluation in many clinical situations. Given the ease of histologic confirmation of diagnoses in skin diseases, the threshold for biopsy should be low. This is especially true of inflammatory dermatoses, potentially infectious conditions, and skin disorders in immunosuppressed and hospitalized patients where clinical morphology may be atypical. Once therapy is begun empirically, histologic features may be altered by the treatment, making pathologic diagnosis more difficult.
History Knowledge of the patient’s age, health, occupation, hobbies, and living conditions, and of the onset, duration, and course of the disease, and its response to previous treatment are important. The family history of similar disorders and other related diseases may be useful. A complete drug history is one of the most important aspects of a thorough history. This includes prescription and over-thecounter medications, supplements, and herbal products. Drug reactions are frequently seen and may simulate many different diseases. Anti-inflammatory agents (steroidal or nonsteroidal), antibiotics, antihypertensives, antiarrhythmics, cholesterollowering agents, antiepileptics, and antidepressants may all produce cutaneous disorders. All may simulate entities not usually attributed to drugs. It is equally important to inquire about topical agents that have been applied to the skin and
mucous membranes for medicinal or cosmetic purposes, for these agents may cause cutaneous or systemic reactions. Other illnesses, travel abroad, the patient’s environment at home and at work, seasonal occurrences and recurrences of the disease, and the temperature, humidity, and weather exposure of the patient are all important items in a dermatologic history. Habitation in certain parts of the world predisposes to distinctive diseases for that particular geographic locale. San Joaquin Valley fever (coccidioidomycosis), Hansen’s disease, leishmaniasis, and histoplasmosis are examples. Sexual orientation and practices may be relevant, as in genital ulcer diseases, human immunodeficiency virus (HIV) infection, and infestations (e.g. scabies, pubic lice).
General diagnosis
little beyond the epidermis, as in dystrophic epidermolysis bullosa, the base being formed by the papillary layer, or they may extend deep into the dermis, subcutaneous tissues, or deeper, as with leg ulcers. They heal with scarring.
Examination Examination should be conducted in a well-lit room. Natural sunlight is the ideal illumination. Fluorescent bulbs that produce wavelengths of light closer to natural sunlight than standard fluorescent bulbs are commercially available. Abnormalities of melanin pigmentation, e.g. vitiligo and melasma, are more clearly visible under ultraviolet (UV) light. A Wood’s light (365 nm) is most commonly used and is also valuable for the diagnosis of some types of tinea capitis, tinea versicolor, and erythrasma. A magnifying lens is of inestimable value in examining small lesions. It may be necessary to palpate the lesion for firmness and fluctuation; rubbing will elucidate the nature of scales; scraping will reveal the nature of the lesion’s base. Pigmented lesions, especially in infants, should be rubbed in an attempt to elicit Darier’s sign (whealing), as seen in urticaria pigmentosa. Dermoscopy is an essential part of the examination of pigmented lesions. The entire eruption must be seen to evaluate distribution and configuration. This is optimally done by having the patient completely undress and viewing him/her from a distance to take in the whole eruption at once. “Peek-a-boo” examination, by having the patient expose one anatomic area after another while remaining clothed, is not optimal because the examination of the skin will be incomplete and the overall distribution is hard to determine. After the patient is viewed at a distance, individual lesions are examined to identify primary lesions and to determine the evolution of the eruption and the presence of secondary lesions.
Diagnostic details of lesions Distribution Lesions may be few or numerous, and in arrangement they may be discrete or may coalesce to form patches of peculiar configuration. They may appear over the entire body, or follow the lines of cleavage (pityriasis rosea), dermatomes (herpes zoster), or lines of Blaschko (epidermal nevi). Lesions may form groups, rings, crescents, or unusual linear patterns. A remarkable degree of bilateral symmetry is characteristic of certain diseases such as dermatitis herpetiformis, vitiligo, and psoriasis.
Evolution Some lesions appear fully evolved. Others develop from smaller lesions, then may remain the same during their entire existence (e.g. warts). When lesions succeed one another in a series of crops, as they do in varicella and dermatitis herpetiformis, a polymorphous eruption results with lesions in various stages of development or involution all present at the same time. 15
Cutaneous Signs and Diagnosis
2
Fig. 2-8 Acral small blue papule, blue nevus.
Fig. 2-7 Annular, arcuate, and polycyclic configurations on granuloma annulare.
Involution Certain lesions disappear completely, whereas others leave characteristic residual pigmentation or scarring. Residual dyspigmentation, although a significant cosmetic issue, is not considered a scar. The pattern in which lesions involute may be useful in diagnosis, e.g. the typical keratotic papule of pity riasis lichenoides varioliformis acuta.
Grouping Grouping is a characteristic of dermatitis herpetiformis, herpes simplex, and herpes zoster. Small lesions arranged around a large one are said to be in a corymbose arrangement. Concentric annular lesions are typical of borderline Hansen’s disease and erythema multiforme. These are sometimes said to be in a cockade pattern, like the tricolor cockade hats worn by French revolutionists. Flea and other arthropod bites are usually grouped and linear (breakfast-lunch-and-dinner sign). Grouped lesions of various sizes may be termed agminated.
Configuration Certain terms are used to describe the configuration that an eruption assumes either primarily or by enlargement or coalescence. Lesions in a line are called linear, and they may be confluent or discrete. Lesions may form a complete circle (annular) or a portion of a circle (arcuate or gyrate), or may be composed of several intersecting portions of circles (poly cyclic) (Fig. 2-7). If the eruption is not straight but does not form parts of circles, it may be serpiginous . Round lesions may be small, like drops, called guttate; or larger, like a coin, called nummular. Unusual configurations that do not correspond to these patterns or to normal anatomic or embryonic patterns should raise the possibility of an exogenous dermatosis or factitia.
Color The color of the skin is determined by melanin, oxyhemoglobin, reduced hemoglobin, and carotene. Not only do the proportions of these components affect the color, but their depth within the skin, the thickness of the epidermis, and 16
hydration also play a role. The Tyndall effect modifies the color of skin and of lesions by the selective scattering of light waves of different wavelengths. The blue nevus and Mongolian spots are examples of this light dispersion effect, in which brown melanin in the dermis appears blue–gray (Fig. 2-8). The color of lesions may be very valuable as a diagnostic factor. Dermatologists should be aware that there are many shades of pink, red, and purple, each of which tends to suggest a diagnosis or disease group. Interface reactions such as lichen planus or lupus erythematosus are described as violaceous. Lipid-containing lesions are yellow, as in xanthomas or steato cystoma multiplex. The orange–red (salmon) color of pityriasis rubra pilaris is characteristic. The constitutive color of the skin determines the quality of the color one observes with a specific disorder. In dark-skinned persons, erythema is hard to perceive. Pruritic lesions in African-Americans may evolve to be small, shiny, flat-topped papules with a violaceous hue (due to the combination of erythema and pigmentary incontinence). These lichenified lesions would be suspected of being lichenoid by the untrained eye, but are in fact eczematous. Patches lighter in color than the normal skin may be completely depigmented or have lost only part of their pigment (hypopigmented). This is an important distinction, since certain conditions are or may be hypopigmented, such as tinea versicolor, nevus anemicus, Hansen’s disease, hypomelanotic macules of tuberous sclerosis, hypomelanosis of Ito, seborrheic dermatitis, and idiopathic guttate hypomelanosis. True depigmentation should be distinguished from this; it suggests vitiligo, nevus depigmentosus, halo nevus, scleroderma, morphea, or lichen sclerosus. Hyperpigmentation may result from epidermal or dermal causes. It may be related to either increased melanin or deposition of other substances. Epidermal hyperpigmentation occurs in nevi, melanoma, café-au-lait spots, melasma, and lentigines. These lesions are accentuated when examined with a Wood’s light. Dermal pigmentation occurs subsequent to many inflammatory conditions (postinflammatory hyperpigmentation) or from deposition of metals, medications, medication–melanin complexes, or degenerated dermal material (ochronosis). These conditions are not enhanced when examined by a Wood’s light. The hyperpigmentation following inflammation is most commonly the result of dermal melanin deposition, but in some conditions, such as lichen aureus, is caused by iron. Dermal iron deposition appears more yellow–brown or golden than dermal melanin.
Consistency Palpation is an essential part of the physical examination of lesions. Does the lesion blanch on pressure? If not, it may be
Fig. 2-9 Scalp plaque with scarring alopecia hyperpigmentation and depigmentation, discoid lupus erythematosus.
purpuric. Is it fluctuant? If so, it may have free fluid in it. Is it cold or hot? If there is a nodule or tumor, does it sink through a ring into the panniculus, like a neurofibroma? Is it hard enough for calcification to be suspected, merely very firm, like a keloid or dermatofibroma, or branny, like scleredema?
Hyperesthesia/anesthesia Certain conditions may be associated with increased or decreased sensation. For example, the skin lesions of borderline and tuberculoid Hansen’s disease typically are anesthetic in their centers. In neuropathic conditions (such as notalgia paresthetica), the patient may perceive both pruritus and hyperesthesia. Neurally mediated itch may be accompanied by other neural sensations such as heat or burning. The combination of pruritus with other neural symptoms suggests the involvement of nerves in the pathological process.
Involvement of hair-bearing areas by certain skin disorders causes characteristic lesions. Discoid lupus, for example, causes scarring alopecia with characteristic dyspigmentation (Fig. 2-9). On the skin the lesions may be much less characteristic. Diffuse hair loss may be seen in certain conditions such as acrodermatitis enteropathica, and may be a clue to the diagnosis. In addition, loss of hair within a skin lesion may be suggestive of the correct diagnosis, e.g. the alopecia seen in the tumid plaques of follicular mucinosis. Some skin disorders cause characteristic changes of the nails, even when the periungual tissue is not involved. The pitting seen in psoriasis and alopecia areata may be useful in confirming these diagnoses when other findings are not characteristic. In addition, the nails and adjacent structures may be the sole site of pathology, as in candidal paronychia. The complete skin examination includes examination of the oral mucosa. Oral lesions are characteristically found in viral syndromes (exanthems), lichen planus, HIV-associated Kaposi sarcoma, and autoimmune bullous diseases (pemphigus vulgaris).
General diagnosis
Hair, nails, and oral mucosa
http://www.dermatologylexicon.org/ http://missinglink.ucsf.edu/lm/DermatologyGlossary/index.html
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 2-1 Serpiginous lesions, cutaneous larva migrans. Fig. 2-2 Erythematous plaques studded with sheets of pustules, pustular psoriasis. Fig. 2-3 Penile ulcer with a purulent base, chancroid. Fig. 2-4 Erythematous papules in an annular configuration, granuloma annulare. Fig. 2-5 Scalp plaque with scarring alopecia hyperpigmentation and depigmentation, discoid lupus erythematosus.
17
Bonus images for this chapter can be found online at http://www.expertconsult.com
3
Dermatoses Resulting from Physical Factors
The body requires a certain amount of heat, but beyond definite limits, insufficient or excessive amounts are injurious. The local action of excessive heat causes burns or scalds; on the other hand, undue cold causes chilblains, frostbite, and congelation. Thresholds of tolerance exist in all body structures sensitive to electromagnetic wave radiation of varying frequencies, such as x-rays and ultraviolet (UV) rays. The skin, which is exposed to so many external physical forces, is more subject to injuries caused by them than is any other organ.
Heat injuries Thermal burns Injury of varying intensity may be caused by the action of excessive heat on the skin. If this heat is extreme, the skin and underlying tissue may be destroyed. The changes in the skin resulting from dry heat or scalding are classified in four degrees. • First-degree burns of the skin result merely in an active congestion of the superficial blood vessels, causing erythema that may be followed by epidermal desquamation (peeling). Ordinary sunburn is the most common example of a first-degree burn. The pain and increased surface heat may be severe, and it is not rare to have some constitutional reaction if the involved area is large. • Second-degree burns are subdivided into superficial and deep forms. – In the superficial type there is a transudation of serum from the capillaries, which causes edema of the superficial tissues. Vesicles and blebs are formed by the serum gathering beneath the outer layers of the epidermis (Fig. 3-1). Complete recovery without scarring is usual in burns of this kind. – The deep second-degree burn is pale and anesthetic. Injury to the reticular dermis compromises blood flow and destroys appendages, so that healing takes over 1 month to occur and results in scarring. • Third-degree burns involve loss of tissue of the full thickness of the skin, and often some of the subcutaneous tissues. Since the skin appendages are destroyed, there is no epithelium available for regeneration of the skin. An ulcerating wound is produced, which in healing leaves a scar. • Fourth-degree burns involve the destruction of the entire skin and subcutaneous fat with any underlying tendons. Both third- and fourth-degree burns require grafting for closure. All third- and fourth-degree burns are followed by constitutional symptoms of varied gravity, their severity depending on the size of the involved surface, the depth of the burn, and particularly the location of the burned surface. The
more vascular the involved area, the more severe the symptoms. The prognosis is poor for any patient in whom a large area of skin surface is involved, particularly if more than two-thirds of the body surface has been burned. Women, infants, and toddlers all have an increased risk of death from burns when compared to men. Excessive scarring, with either keloid-like scars or flat scars with contractures, may produce deformities and dysfunctions of the joints, as well as chronic ulcerations due to impairment of local circulation. Delayed post-burn blistering may occur in partial-thickness wounds and skin-graft donor sites. It is most common on the lower extremities, and is self-limited. Burn scars may be the site of development of carcinoma or sarcoma. With modern reconstructive surgery these unfortunate end results can be minimized.
Treatment Immediate first aid for minor thermal burns consists of prompt cold applications (ice water, or cold tap water if no ice is at hand), continued until pain does not return on stopping them. The vesicles or blebs of second-degree burns should not be opened but should be protected from injury, since they form a natural barrier against contamination by microorganisms. If they become tense and unduly painful, the fluid may be evacuated under strictly aseptic conditions by puncturing the wall with a sterile needle, allowing the blister to collapse on to the underlying wound. Excision of full-thickness and deep dermal wounds that will not reepithelialize within 3 weeks reduces wound infections, shortens hospital stays, and improves survival. Additionally, contractures and functional impairment may be mitigated by such early intervention and grafting. The most superficial wounds may be dressed with greasy gauze, while silver-containing dressings are used for their antiobitic properties in intermediate wounds. Fluid resuscitation, treatment of inhalation injury and hypercatabolism, monitoring and early intervention of sepsis, and intensive care management in a burn center are all recommended in large partialthickness wounds and full-thickness burns.
Electrical burns Electrical burns may occur from contact or as a flash exposure. A contact burn is small but deep, causing some necrosis of the underlying tissues. Low-voltage injuries usually occur in the home, are treated conservatively, and generally heal well. Oral commissure burns may require reconstructive procedures. High-voltage burns are often occupational; internal damage may be masked by little surface skin change, and be complicated by subtle and slowly developing sequelae. Early surgical intervention to improve circulation and repair vital tissues is helpful in limiting loss of the extremity. Flash burns usually cover a large area and, being similar to any surface burn, are treated as such. Lightning may cause burns after a direct strike (Fig. 3-2), where an entrance and an
Heat injuries Fig. 3-1 Hot coffee burn.
Fig. 3-3 Miliaria crystallina.
Dega S, et al: Electrical burn injuries. Burns 2007; 33:653. Demling R, et al: Management of hot tar burns. J Trauma 1980; 20:24. Heffernan EJ, et al: Thunderstorms and iPods. N Engl J Med 2007; 357:198. Kerby JD, et al: Sex differences in mortality after burn injury. Burn Care Res 2006; 27:452. Mellemkjaer I, et al: Risks for skin and other cancers up to 25 years after burn injuries. Epidemiology 2006; 17:668. Pham TN, Gibran NS: Thermal and electrical injuries. Surg Clin N Am 2007; 87:185. Tennenhaus M, et al: Burn surgery. Clin Plast Surg 2007; 34:697. Volinsky JB, et al: Picture of the month—lightning injury. Arch Pediatr Adolesc Med 1994; 148:529. Wasaik J, et al: Minor thermal burns. Clin Evid 2005; 14:2388.
Miliaria
Fig. 3-2 Lightning strike.
exit wound are visible. This is the most lethal type of strike, and cardiac arrest or other internal injuries may occur. Other types of strike are indirect and result in burns that are either: • linear in areas on which sweat was present • in a feathery or arborescent pattern, which is believed to be pathognomonic • punctate with multiple, deep, circular lesions • thermal burns from ignited clothing or heated metal. These may occur if the patient was speaking on a cellphone or listening to an iPod when struck.
Hot tar burns Polyoxyethylene sorbitan in neosporin ointment or sunflower oil is an excellent dispersing agent that facilitates the removal of hot tar from burns. Barrow RE, et al: Mortality related to gender, age, sepsis, and ethnicity in severely burned children. Shock 2005; 23:485. Chetty BV, et al: Blisters in patients with burns. Arch Dermatol 1992; 128:181. Church D, et al: Burn wound infections. Clin Microbiol Rev 2006; 19:403. Compton CC: The delayed postburn blister. Arch Dermatol 1992; 128:24.
Miliaria, the retention of sweat as a result of occlusion of eccrine sweat ducts, produces an eruption that is common in hot, humid climates, such as in the tropics and during the hot summer months in temperate climates. Staphylococcus epidermidis, which produces an extracellular polysaccharide substance, induces miliaria in an experimental setting. This polysaccharide substance may obstruct the delivery of sweat to the skin surface. The occlusion prevents normal secretion from the sweat glands, and eventually pressure causes rupture of the sweat gland or duct at different levels. The escape of sweat into the adjacent tissue produces miliaria. Depending on the level of the injury to the sweat gland or duct, several different forms are recognized.
Miliaria crystallina (sudamina) Miliaria crystallina (Fig. 3-3) is characterized by small, clear, superficial vesicles with no inflammatory reaction. It appears in bedridden patients in whom fever produces increased perspiration or in situations in which clothing prevents dissipation of heat and moisture, as in bundled children. The lesions are generally asymptomatic and their duration is short-lived because they tend to rupture at the slightest trauma. One patient with post-exercise itching was found to have miliaria crystallina; it resolved spontaneously. Drugs such as isotretinoin, bethanechol and doxorubicin may induce it. The lesions are self-limited; no treatment is required.
Miliaria rubra (prickly heat) The lesions of miliaria rubra (Fig. 3-4) appear as discrete, extremely pruritic, erythematous papulovesicles accompanied by a sensation of prickling, burning, or tingling. They later may become confluent on a bed of erythema. The sites most 19
may be a sign of type I pseudohypoaldosteronism, as saltlosing crises may precipitate miliaria pustulosa or rubra, with resolution after stabilization.
Dermatoses Resulting from Physical Factors
3
Miliaria profunda Non-pruritic, flesh-colored, deep-seated, whitish papules characterize this form of miliaria. It is asymptomatic, usually lasts only 1 h after overheating has ended, and is concentrated on the trunk and extremities. Except for the face, axillae, hands, and feet, where there may be compensatory hyperhidrosis, all the sweat glands are nonfunctional. The occlusion is in the upper dermis. This form is observed only in the tropics and usually follows a severe bout of miliaria rubra.
Postmiliarial hypohidrosis
Fig. 3-4 Miliaria rubra.
Postmiliarial hypohidrosis results from occlusion of sweat ducts and pores, and may be severe enough to impair an individual’s ability to perform sustained work in a hot environment. Affected persons may show decreasing efficiency, irritability, anorexia, drowsiness, vertigo, and headache; they may wander in a daze. It has been shown that hypohidrosis invariably follows miliaria, and that the duration and severity of the hypohidrosis are related to the severity of the miliaria. Sweating may be depressed to half the normal amount for as long as 3 weeks.
Tropical anhidrotic asthenia This is a rare form of miliaria with long-lasting poral occlusion, which produces anhidrosis and heat retention.
Treatment The most effective treatment for miliaria is to place the patient in a cool environment. Even a single night in an air-conditioned room helps to alleviate the discomfort. Next best is the use of circulating air fans to cool the skin. Anhydrous lanolin resolves the occlusion of pores and may help to restore normal sweat secretions. Hydrophilic ointment also helps to dissolve keratinous plugs and facilitates the normal flow of sweat. Soothing, cooling baths containing colloidal oatmeal or cornstarch are beneficial if used in moderation. Mild cases may respond to dusting powders, such as cornstarch or baby talcum powder.
Fig. 3-5 Miliaria pustulosa. (Courtesy of Curt Samlaska, MD)
frequently affected are the antecubital and popliteal fossae, trunk, inframammary areas (especially under pendulous breasts), abdomen (especially at the waistline), and inguinal regions; these sites frequently become macerated because evaporation of moisture has been impeded. Exercise-induced itching may also be caused by miliaria rubra. The site of injury and sweat escape is in the prickle cell layer, where spongiosis is produced.
Miliaria pustulosa Miliaria pustulosa (Fig. 3-5) is preceded by another dermatitis that has produced injury, destruction, or blocking of the sweat duct. The pustules are distinct, superficial, and independent of the hair follicle. The pruritic pustules occur most frequently on the intertriginous areas, flexure surfaces of the extremities, scrotum, and back of bedridden patients. Contact dermatitis, lichen simplex chronicus, and intertrigo are some of the associated diseases, although pustular miliaria may occur several weeks after these diseases have subsided. Recurrent episodes 20
Akeakus M, et al: Newborn with pseudohypaldosteronism and miliaria rubra. Int J Dermatol 2006; 45:1432. Dimon NS, et al: Goosefleshlike lesions and hypohidrosis. Arch Dermatol 2007; 143:1323. Godkar D, et al: Rare skin disorder complicating doxorubicin therapy: miliaria crystallina. Am J Ther 2005; 12:275. Haas N, et al: Congenital miliaria crystallina. J Am Acad Dermatol 2002; 47:S270. Kirk JF, et al: Miliaria profunda. J Am Acad Dermatol 1996; 35:854. La Shell MS, et al: Pruritus, papules, and perspiration. Ann Allergy Immunol 2007; 98:299. Mowad CM, et al: The role of extracellular polysaccharide substance produced by Staphylococcus epidermidis in miliaria. J Am Acad Dermatol 1995; 20:713. Wenzel FG, et al: Nonneoplastic disorders of the eccrine glands. J Am Acad Dermatol 1998; 38:1.
Erythema ab igne Erythema ab igne is a persistent erythema—or the coarsely reticulated residual pigmentation resulting from it—that is usually produced by long exposure to excessive heat without the production of a burn (Fig. 3-6). It begins as a mottling caused by local hemostasis and becomes a reticulated erythema, leaving pigmentation. Multiple colors are simultaneously present in an active patch, varying from pale pink to old rose or dark purplish-brown. After the cause is removed, the
Cold injuries Fig. 3-6 Erythema ab igne.
Fig. 3-7 Acrocyanosis.
affection tends to disappear gradually, but sometimes the pigmentation is permanent. Histologically, an increased amount of elastic tissue in the dermis is noted. The changes in erythema ab igne are similar to those of actinic elastosis. Interface dermatitis and epithelial atypia may be noted. Erythema ab igne occurs on the legs as a result of habitually warming them in front of open fireplaces, space heaters, or car heaters. Similar changes may be produced at sites of an electric heating pad application such as the low back, or the upper thighs with laptop computers. The condition occurs also in cooks, silversmiths, and others exposed over long periods to direct moderate heat. Epithelial atypia, which may lead to Bowen’s disease and squamous cell carcinoma, has rarely been reported to occur overlying erythema ab igne. Treatment with 5-fluorouracil (5-FU) or imiquimod cream may be effective in reversing this epidermal alteration. The use of emollients containing α-hydroxy acids or a cream containing fluocinolone acetonide 0.01%, hydroquinone 4%, and tretinoin 0.05% may help reduce the unsightly pigmentation.
Acrocyanosis
Chan CC, et al: Erythema ab igne. N Engl J Med 2007; 356:e8. Chatterjee S: Erythema ab igne from prolonged use of a heating pad. Mayo Clin Proc 2005; 80:1500. Levinbook WS, et al: Laptop computer-associated erythema ab igne. Cutis 2007; 80:319.
Cold injuries Exposure to cold damages the skin by at least three mechanisms. • Reduced temperature directly damages the tissue, as in frostbite and cold immersion foot. • Vasospasm of vessels perfusing the skin prevents adequate perfusion of the tissue and causes vascular injury and consequent tissue injury (pernio, acrocyanosis, and frostbite). • In unusual circumstances, adipose tissue is predisposed to damage by cold temperatures due to fat composition or location (cold panniculitis, see Chapter 23). Outdoor workers and recreationalists, the armed forces, alcoholics, and the homeless are particularly likely to suffer cold injuries. Jurkovich GJ: Environmental cold-induced injury. Surg Clin N Am 2007: 87:247.
Acrocyanosis is a persistent blue discoloration of the entire hand or foot worsened by cold exposure. The hands and feet may be hyperhidrotic (Fig. 3-7). It occurs chiefly in young women. Cyanosis increases as the temperature decreases and changes to erythema with elevation of the dependent part. The cause is unknown. Smoking should be avoided. Acrocyanosis is distinguished from Raynaud syndrome by its persistent nature (as opposed to the episodic nature of Raynaud) and lack of tissue damage (ulceration, distal fingertip resorption). Acrocyanosis with swelling of the nose, ears, and dorsal hands may occur after inhalation of butyl nitrite. Interferon-α 2a may induce it. Repeated injection of the dorsal hand with narcotic drugs may produce lymphedema and an appearance similar to the edematous phase of scleroderma. This so-called puffy hand syndrome may include erythema or a bluish discoloration of the digits. Patients with anorexia nervosa frequently manifest acrocyanosis as well as perniosis, livedo reticularis and acral coldness. It may improve with weight gain. Acral vascular syndromes may also be a sign of malignancy. In 47% of the 66 reported cases the diagnosis of cancer coincided with the onset of the acral disease. These are most likely to be vasospastic or occlusive; however, acrocyanosis has also been reported. Brown PJ, et al: The purple digit. Am J Clin Derm 2010; 11:103. Del Giudice P, et al: Hand edema and acrocyanosis: puffy hand syndrome. Arch Dermatol 2006; 142:1084. Nousari HC, et al: Chronic idiopathic acrocyanosis. J Am Acad Dermatol 2001; 45:S207. Solak Y, et al: Acrocyanosis as a presenting symptom of Hodgkin lymphoma. Am J Hematol 2006; 81:149. Strumia R: Dermatologic signs in patients with eating disorders. Am J Clin Dermatol 2005; 6:165.
Chilblains (pernio) Chilblains constitute a localized erythema and swelling caused by exposure to cold. Blistering and ulcerations may develop in severe cases. In people predisposed by poor peripheral circulation, even moderate exposure to cold may produce chilblains. Cryoglobulins, cryofibrinogens or cold agglutinins may be present and pathogenic. Chilblain-like lesions may occur in discoid and systemic lupus erythematosus (chilblain lupus) or as a presenting sign of leukemia cutis. The chronic use of crack 21
Dermatoses Resulting from Physical Factors
3
Fig. 3-8 Pernio.
cocaine and its attendant peripheral vasoconstriction will lead to perniosis with cold, numb hands and atrophy of the digital fat pads, especially of the thumbs and index fingers, as well as nail curvature. Chilblains occur chiefly on the hands, feet, ears, and face, especially in children; onset is enhanced by dampness (Fig. 3-8). A variant occurs on the lateral thighs in women equestrians who ride on cold damp days (equestrian perniosis). Tightfitting jeans with a low waistband may produce this type of cold injury on the hips. Wading across cold streams may produce similar lesions. Erythrocyanosis crurum has been used to describe similar cases. Lesions of cold injury of the lateral thighs can be nodular. Patients with chilblains are often unaware of the cold injury when it is occurring, but later burning, itching, and redness call it to their attention. The affected areas are bluish-red, the color partially or totally disappearing on pressure, and are decidedly cool to the touch. Sometimes the extremities are clammy because of excessive sweating. As long as the damp/ cold exposure continues, new lesions will continue to appear and lesions may resolve slowly. Investigation into an under lying cause should be undertaken in cases that are recurrent, chronic, extending into warm seasons or poorly responsive to treatment. Perniosis histologically demonstrates a lymphocytic vasculitis. There is dermal edema, and a superficial and deep perivascular, tightly cuffed, lymphocytic infiltrate. The infiltrate involves the vessel walls and is accompanied by characteristic “fluffy” edema of the vessel walls.
Treatment The affected parts should be protected against further exposure to cold or dampness. If the feet are affected, woolen socks should be worn at all times during the cold months. Because patients are often not conscious of the cold exposure that triggers the lesions, appropriate dress must be stressed, even if patients say they do not sense being cold. Since central cooling triggers peripheral vasoconstriction, keeping the whole body (not just the affected extremity) warm is critical. Heating pads may be used judiciously to warm the parts. Smoking is strongly discouraged. Nifedipine, 20 mg three times a day, has been effective. Vasodilators such as nicotinamide, 500 mg three times a day, or dipyridamole, 25 mg three times a day, or the phosphodiesterase inhibitor sildenafil, 50 mg twice daily, may be used to improve circulation. Pentoxifylline may be effective. Spontaneous resolution occurs without treatment in 1–3 weeks. Systemic corticoid therapy is useful in chilblain lupus erythematosus. 22
Fig. 3-9 Frostbite in a homeless person. Affleck AG, et al: Chilblain-like leukemia cutis. Pediatr Dermatol 2007; 24:38. Bouaziz JD, et al: Cutaneous lesions of the digits in SLE: 50 cases. Lupus 2007; 16:163. Cribier B, et al: A histologic and immunohistochemical study of chilblains. J Am Acad Dermatol 2001; 45:924. Long WB 3rd, et al: Cold injuries. J Long Term Eff Med Implants 2005; 15:67. McClesky PE, et al: Tender papules on the hands. Arch Dermatol 2006; 142:1501. Payne-James JJ, et al: Pseudosclerodermatous triad of perniosis, pulp atrophy and parrot-beaked clawing of the nails—newly recognized syndrome of chronic crack cocaine use. J Forensic Leg Med 2007; 14:65. Price RD, Murdoch DR: Perniosis (chilblains) of the thigh: report of five cases, including four following river crossings. High Alt Med Biol 2001; 2:535. Simon TD, et al: Pernio in pediatrics. Pediatrics 2005; 116:e472. Viguier M, et al: Clinical and histopathologic features and immunologic variables in patients with severe chilblains. A study of the relationship to lupus erythematosus. Medicine (Baltimore) 2001; 80:180. Weismann K, et al: Pernio of the hips in young girls wearing tight-fitting jeans with a low waistband. Acta Derm Venereol 2006; 86:558. Yang X, et al: Adult perniosis and cryoglobulinemia. J Am Acad Dermatol 2010; 62:e21.
Frostbite When soft tissue is frozen and locally deprived of blood supply, the damage is called frostbite. The ears, nose, cheeks, fingers, and toes are most often affected. The frozen part painlessly becomes pale and waxy. Various degrees of tissue destruction similar to those caused by burns are encountered. These are erythema and edema, vesicles and bullae, superficial gangrene, deep gangrene, and injury to muscles, tendons, periosteum, and nerves (Fig. 3-9). The degree of injury is directly related to the temperature and duration of freezing. African Americans are at increased risk of frostbite.
Treatment Early treatment of frostbite before swelling develops should consist of covering the part with clothing or with a warm hand or other body surface to maintain a slightly warm temperature so that adequate blood circulation can be maintained. Rapid rewarming in a water bath between 37 and 43°C (100–110°F) is the treatment of choice for all forms of frostbite. Rewarming should be delayed until the patient has been removed to an area where there is no risk of refreezing. Slow thawing results in more extensive tissue damage. Analgesics, unless contraindicated, should be administered because of the
Actinic injury
considerable pain experienced with rapid thawing. When the skin flushes and is pliable, thawing is complete. The use of tissue plasminogen activator to lyse thrombi decreases the need for amputation if given within 24 h of injury. Supportive measures such as bed rest, a high-protein/high-calorie diet, wound care, and avoidance of trauma are imperative. Any rubbing of the affected part should be avoided, but gentle massage of proximal portions of the extremity that are not numb may be helpful. After swelling and hyperemia have developed, the patient should be kept in bed with the affected limb slightly flexed, elevated, and at rest. Exposing the affected limb to air at room temperature relieves pain and helps prevent tissue damage. Protection by a heat cradle may be desirable. The use of anticoagulants to prevent thrombosis and gangrene during the recovery period has been advocated. Pentoxifylline, ibuprofen, and aspirin may be useful adjuncts. Antibiotics should be given as a prophylactic measure against infection and tetanus immunization should be updated. Recovery may take many months. Injuries that affect the proximal phalanx or the carpal or tarsal area, especially when accompanied by a lack of radiotracer uptake on bone scan, have a high likelihood of requiring amputation. Whereas prior cold injury is a major risk factor for recurrent disease, sympathectomy may be preventative against repeated episodes. Arthritis may be a late complication.
Fig. 3-10 Warm water immersion foot. (Courtesy of James WD (ed): Textbook of Military Medicine, Office of the Surgeon General, United States Army, 1994)
Bruen KJ, et al: Reduction in the incidence of amputation in frostbite injury with thrombolytic therapy. Arch Surg 2007; 142:546. Cauchy E, et al: Retrospective study of 70 cases of severe frostbite lesions. Wilderness Environ Med 2001; 12:248. Kahn JE, et al: Frostbite arthritis. Ann Rheum Dis 2005; 64:966.
Immersion foot syndromes Trench foot Trench foot results from prolonged exposure to cold, wet conditions without immersion or actual freezing. The term is derived from trench warfare in World War I, when soldiers stood, sometimes for hours, in trenches with a few inches of cold water in them. Fishermen, sailors, and shipwreck survivors are sometimes seen with this condition. The lack of circulation produces edema, paresthesias, and damage to the blood vessels. Gangrene may occur in severe cases. Treatment consists of removal from the causal environment, bed rest, and restoration of the circulation. Other measures, such as those used in the treatment of frostbite, should be employed.
Warm water immersion foot Exposure of the feet to warm, wet conditions for 48 h or more may produce a syndrome characterized by maceration, blanching, and wrinkling of the soles and sides of the feet (Fig. 3-10). Itching and burning with swelling may persist for a few days after removal of the cause, but disability is temporary. It was commonly seen in military service members in Vietnam but has also been seen in persons wearing insulated boots. This condition should be differentiated from tropical immersion foot, seen after continuous immersion of the feet in water or mud at temperatures above 22°C (71.6°F) for 2–10 days. This was known as “paddy foot” in Vietnam. It involves erythema, edema, and pain of the dorsal feet, as well as fever and adenopathy (Fig. 3-11). Resolution occurs 3–7 days after the feet have been dried. Warm water immersion foot can be prevented by allowing the feet to dry for a few hours in every 24 or by greasing the soles with a silicone grease once a day. Recovery is usually rapid if the feet are thoroughly dry for a few hours.
Fig. 3-11 Tropical immersion foot. (Courtesy of James WD (ed): Textbook of Military Medicine, Office of the Surgeon General, United States Army, 1994) Adnot J, et al: Immersion foot syndromes. In: James WD (ed): Military Dermatology. Washington, DC: Office of the Surgeon General, 1994. Wrenn K: Immersion foot. Arch Intern Med 1991; 151:785.
Actinic injury Sunburn and solar erythema The solar spectrum has been divided into different regions by wavelength. The parts of the solar spectrum important in photomedicine include UV radiation (below 400 nm), visible light (400–760 nm), and infrared radiation (beyond 760 nm). Visible light has limited biologic activity, except for stimulating the retina. Infrared radiation is experienced as radiant heat. Below 400 nm is the UV spectrum, divided into three 23
3 Dermatoses Resulting from Physical Factors
Table 3-1 Skin types (phototypes)
Fig. 3-12 Acute sunburn. (Courtesy of Dr L Lieblich)
bands: UVA, 320–400 nm; UVB, 280–320 nm; and UVC, 200– 280 nm. UVA is divided into two subcategories: UVA I (340– 400 nm) and UVA II (320–340 nm). Virtually no UVC reaches the earth’s surface because it is absorbed by the ozone layer above the earth. The minimal amount of a particular wavelength of light capable of inducing erythema on an individual’s skin is called the minimal erythema dose (MED). Although the amount of UVA radiation is 100 times greater than UVB radiation during midday hours, UVB is up to 1000 times more erythemogenic than UVA, and so essentially all solar erythema is caused by UVB. The most biologically effective wavelength of radiation from the sun for sunburn is 308 nm. UVA does not play a significant role in solar erythema and sunburn; however, in the case of drug-induced photosensitivity, UVA is of major importance. The amount of UV exposure increases at higher altitudes, is substantially larger in temperate climates in the summer months, and is greater in tropical regions. UVA may be reflected somewhat more than UVB from sand, snow, and ice. While sand and snow reflect as much as 85% of the UVB, water allows 80% of the UV to penetrate up to 3 feet. Cloud cover, although blocking substantial amounts of visible light, is a poor UV absorber. During the middle 4–6 h of the day, the intensity of UVB is 2–4 times greater than in the early morning and late afternoon.
Clinical signs and symptoms Sunburn is the normal cutaneous reaction to sunlight in excess of an erythema dose. UVB erythema becomes evident at around 6 h after exposure and peaks at 12–24 h, but the onset is sooner and the severity greater with increased exposure. The erythema is followed by tenderness, and in severe cases, blistering, which may become confluent (Fig. 3-12). Discomfort may be severe; edema commonly occurs in the extremities and face; chills, fever, nausea, tachycardia, and hypotension may be present. In severe cases such symptoms may last for as long as a week. Desquamation is common about a week after sunburn, even in areas that have not blistered. After UV exposure, skin pigment undergoes two changes: immediate pigment darkening (IPD, Meirowsky phenomenon) and delayed melanogenesis. IPD is maximal within hours after sun exposure and results from metabolic changes and redistribution of the melanin already in the skin. It occurs after exposure to long-wave UVB, UVA, and visible light. With large doses of UVA, the initial darkening is prolonged and may blend into the delayed melanogenesis. IPD is not photoprotective. Delayed tanning is induced by the same wave24
Skin type
Baseline skin color
Sunburn and tanning history
I
White
Always burns, never tans
II
White
Always burns, tans minimally
III
White
Burns moderately, tans gradually
IV
Olive
Minimal burning, tans well
V
Brown
Rarely burns, tans darkly
VI
Dark brown
Never burns, tans darkly black
lengths of UVB that induce erythema, begins 2–3 days after exposure, and lasts 10–14 days. Delayed melanogenesis by UVB is mediated through the production of DNA damage and the formation of cyclobutane pyrimidine dimers (CPD). Therefore, although UVB-induced delayed tanning does provide some protection from further solar injury, it is at the expense of damage to the epidermis and dermis. Hence, tanning is not recommended for sun protection. Commercial sunbed-induced tanning, while increasing skin pigment, does not increase UVB MED, and is therefore not protective for UVB damage. An individual’s inherent baseline pigmentation, ability to tan, and the ease with which he/she burns are described as his/her “skin type.” Skin type (Table 3-1) is used to determine starting doses of phototherapy and sunscreen recommendations, and reflects the risk of development of skin cancer and photoaging. Exposure to UVB and UVA causes an increase in the thickness of the epidermis, especially the stratum corneum. This increased epidermal thickness leads to increased tolerance to further solar radiation. Patients with vitiligo may increase their UV exposure without burning by this mechanism.
Treatment Once redness and other symptoms are present, treatment of sunburn has limited efficacy. The damage is done and the inflammatory cascades are triggered. Prostaglandins, especially of the E series, are important mediators. Aspirin (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs), including indomethacin, have been studied, as well as topical and systemic steroids. Medium potency (class II) topical steroids applied 6 h after the exposure (when erythema first appears) give a small reduction in signs and symptoms. Since oral NSAIDs and systemic steroids have been tested primarily prior to or immediately after sun exposure, there is insufficient evidence to recommend their routine use, except immediately after solar over-exposure. Therefore treatment of sunburn should be supportive, with pain management (using acetaminophen, ASA, or NSAIDs), plus soothing topical emollients or corticosteroid lotions. In general, a sunburn victim experiences at least 1 or 2 days of discomfort and even pain before much relief occurs.
Prophylaxis Sunburn is best prevented. Use of the UV index, published daily by the National Weather Service for many US cities and found in newspapers, facilitates taking adequate precautions to prevent solar injury. Numerous educational programs have been developed to make the public aware of the hazards of sun exposure. Despite this, sunburn and excessive sun exposure continue to occur in the US and Western Europe,
• • • •
Avoid midday sun. Seek shade. Wear protective clothing. Apply a sunscreen.
The period of highest UVB intensity, between 9 am and 3–4 pm, accounts for the vast majority of potentially hazardous UV exposure. This is the time when the angle of the sun is less than 45° or when a person’s shadow is shorter than his/her height. In temperate latitudes it is almost impossible to burn if these hours of sun exposure are avoided. Trees and artificial shade provide substantial protection from UVB. Foliage in trees provides the equivalent of sun protection factor (SPF) 4–50, depending on the density of the greenery. Clothing can be rated by its ability to block UVB radiation. The scale of measure is the UV protection factor (UPF) (analogous to SPF in sunscreens). Although it is an in vitro measurement, as with SPF, it correlates well with the actual protection the product provides in vivo. In general, denser weaves, older, washed clothing, and loose-fitting clothing screen UVB more effectively. Wetting a fabric may substantially reduce its UPF. Laundering a fabric in a Tinosorb-containing material (SunGuard) will add substantially to the UPF of the fabric. Hats with at least a 4-inch brim all around are recommended. A sunscreen’s efficacy in blocking the UVB (sunburninducing) radiation is expressed as an SPF. This is the ratio of the number of MEDs of radiation required to induce erythema through a film of sunscreen (2 mg/cm2), compared with unprotected skin. Most persons apply sunscreens in too thin a film, so the actual “applied SPF” is about half that on the label. Sunscreening agents include UV-absorbing chemicals (chemical sunscreens) and UV-scattering or blocking agents (physical sunscreens). Available sunscreens, especially those of high SPFs (>30), usually contain both chemical sunscreens (such as p-aminobenzoic acid [PABA], PABA esters, cinnamates, salicylates, anthranilates, benzophenones, benzylidene camphors such as ecamsule [Mexoryl], dibenzoylmethanes [Parsol 1789, in some products present as a multicompound technology Helioplex], and Tinosorb [S/M]) and physical agents (zinc oxide or titanium dioxide). They are available in numerous formulations, including sprays, gels, emollient creams, and wax sticks. Sunscreens may be water-resistant (maintaining their SPF after 40 min of water immersion) or waterproof (maintaining their SPF after 80 min of water immersion). For skin types I–III (see Table 3-1), daily application of a sunscreen with an SPF of 30 in a facial moisturizer, foundation, or aftershave is recommended. For outdoor exposure, a sunscreen of SPF 30 or higher is recommended for regular use. In persons with severe photosensitivity and at times of high sun exposure, high-intensity sunscreens of SPF 30+ with inorganic blocking agents may be required. Application of the sunscreen at least 20 min before and 30 min after sun exposure has begun is recommended. This dual application approach will reduce the amount of skin exposure by two- to three-fold over a single application. Sunscreen should be reapplied after swimming or vigorous activity or toweling. Sunscreen failure occurs mostly in men, due to failure to apply it to all the sun-exposed skin, or failure to reapply sunscreen after swimming. Sunscreens may be applied to babies (under 6 months) on limited areas. Vitamin D supplementation may be recommended with the most stringent sun-protection practices. Photoaging and cutaneous immunosuppression are mediated by UVA as well as UVB. For this reason, sunscreens with
improved UVA coverage have been developed (Parsol 1789, Mexoryl, Tinosorb). The UVA protection does not parallel the SPF on the label. If UVA protection is sought, a combination sunscreen with inorganic agents and UVA organic sunscreens (identified by name in the list of ingredients) is recommended. Baron ED, Stevens SR: Sunscreens and immune protection. Br J Dermatol 2002; 146:933. Diffey BL, Diffey JL: Sun protection with trees. Br J Dermatol 2002; 147:385. D’Souza G, et al: Mexoryl. Plast Reconstr Surg 2007; 120:1071. Duteil L, et al: A randomized, controlled study of the safety and efficacy of topical corticosteroid treatments of sunburn in healthy volunteers. Clin Exp Dermatol 2002; 27:314. Faurschaou A, et al: Topical corticosterids in the treatment of acute sunburn. Arch Dermatol 2008; 144:620. Hatch KL, et al: Garments as solar ultraviolet radiation screening materials. Dermatol Clin 2006; 24:85. Iuternschlager S, et al: Photoprotection. Lancet 2007; 370:528. Lim HW, et al: Sunlight, tanning booths and vitamin D. J Am Acad Dermatol 2005; 52:868. Lowe NJ: An overview of ultraviolet protection, sunscreens, and photo-induced dermatoses. Dermatol Clin 2006; 24:9. Medeiras VL, et al: Sunscreens in the management of photodermatoses. Skin Therapy Lett 2010; 15:1. Moehrle M, et al: UV exposure in cars. Photodermatol Photoimmunol Photomed 2003; 19:175. Palm MD, et al: Update on photoprotection. Dermatol Ther 2007; 20:360. Thieden E, et al: Sunburn related to UV radiation exposure, age, sex, occupation and sun bed use based on time-stamped personal dosimetry and sun behaviour diaries. Arch Dermatol 2005; 141:482.
Actinic injury
especially in white persons under the age of 30, among whom more than 50% report at least one sunburn per year. Sun protection programs have four messages:
Ephelis (freckle) and lentigo Freckles are small (95%) but a positive predictive value of only 30–65%. For example, more than 8% of the US population has a positive prick test to peanut, but only 0.4% are actually clinically allergic. Possible food allergy detected by testing should be confirmed by clinical history. For instance, a positive radioallergosorbent test (RAST) or skin prick test for a food that the child rarely or never ingests is probably not causally relevant to their AD. Higher serum IgE levels and larger wheal sizes (>8–10 mm) are associated with greater likelihood of reacting to these foods when challenged. Around 90% of food allergy is due to a limited number of foods: • infants: cow’s milk, egg, soybean, wheat • children (2–10 years): cow’s milk, egg, peanut, tree nuts, fish, crustacean shellfish, sesame, and kiwi fruit older children: peanut, tree nuts, fish, shellfish, sesame, • pollen-associated foods. Breast-feeding mothers must avoid the incriminated foods if their infant has been diagnosed with a food allergy.
Clinical manifestations AD can be divided into three stages: infantile AD, occurring from 2 months to 2 years of age; childhood AD, from 2 to 10 years; and adolescent/adult AD. In all stages, pruritus is the hallmark. Itching often precedes the appearance of lesions; hence the concept that AD is “the itch that rashes.” Useful diagnostic criteria include those of Hannifin and Rajka, the UK Working Party, and the American Academy of Dermatology’s Consensus Conference on Pediatric Atopic Dermatitis (Boxes 5-1 and 5-2). These criteria have specificity at or above 90%, but have much lower sensitivities (40–100%). Therefore, they are useful for enrolling patients in studies and insuring that they have AD, but are not so useful in diagnosing a specific patient with AD.
Infantile atopic dermatitis Fifty percent or more of cases of AD present in the first year of life, but usually not until after 2 months of age. Eczema in
Box 5-1 Criteria for atopic dermatitis Major criteria Must have three of the following: 1. Pruritus 2. Typical morphology and distribution • Flexural lichenification in adults • Facial and extensor involvement in infancy 3. Chronic or chronically relapsing dermatitis 4. Personal or family history of atopic disease (asthma, allergic rhinitis, atopic dermatitis)
Atopic dermatitis
review found no clear evidence of protective effect for AD. Soy formulas do not appear to reduce the risk of developing AD. Early introduction of solids does, in a dose-dependent fashion, increase the risk of AD. Prolonged breast feeding (>4–6 months) appears to reduce the risk of AD. In two independent cohorts, cat ownership at birth substantially increases the risk of developing AD within the first year of life in children with FLG loss-of-function mutations, but not in those without. Dog and dust mite exposure was NOT associated with the development of AD. Filaggrin-deficient individuals should avoid cat exposure early in life.
Minor criteria Must also have three of the following: 1. Xerosis 2. Ichthyosis/hyperlinear palms/keratosis pilaris 3. IgE reactivity (immediate skin test reactivity, RAST test positive) 4. Elevated serum IgE 5. Early age of onset 6. Tendency for cutaneous infections (especially Staphylococcus aureus and herpes simplex virus) 7. Tendency to nonspecific hand/foot dermatitis 8. Nipple eczema 9. Cheilitis 10. Recurrent conjunctivitis 11. Dennie–Morgan infraorbital fold 12. Keratoconus 13. Anterior subcapsular cataracts 14. Orbital darkening 15. Facial pallor/facial erythema 16. Pityriasis alba 17. Itch when sweating 18. Intolerance to wool and lipid solvents 19. Perifollicular accentuation 20. Food hypersensitivity 21. Course influenced by environmental and/or emotional factors 22. White dermatographism or delayed blanch to cholinergic agents
Box 5-2 Modified criteria for children with atopic dermatitis Essential features 1. Pruritus 2. Eczema • Typical morphology and age-specific pattern • Chronic or relapsing history
Important features 1. 2. 3. 4. 5.
Early age at onset Atopy Personal and/or family history IgE reactivity Xerosis
Associated features 1. Atypical vascular responses (e.g. facial pallor, white dermatographism) 2. Keratosis pilaris/ichthyosis/hyperlinear palms 3. Orbital/periorbital changes 4. Other regional findings (e.g. perioral changes/periauricular lesions) 5. Perifollicular accentuation/lichenification/prurigo lesions
63
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
5
Fig. 5-1 Involvement of the cheeks in infantile atopic dermatitis.
Fig. 5-2 Flexural involvement in childhood atopic dermatitis.
infancy usually begins as erythema and scaling of the cheeks (Fig. 5-1). The eruption may extend to the scalp, neck, forehead, wrists, and extensor extremities. The areas involved correlate with the capacity of the child to scratch or rub the site, and the activities of the infant, such as crawling. There may be a significant amount of exudate, and there are many secondary effects from scratching, rubbing, and infection: crusts, infiltration, and pustules, respectively. The infiltrated plaques eventually take on a characteristic lichenified appearance. The infantile pattern of AD usually disappears by the end of the second year of life. Worsening of AD is often observed in infants after immunizations and viral infections. Partial remission may occur during the summer, with relapse in winter. This may relate to the therapeutic effects of ultraviolet (UV) B and humidity in many atopic patients, and the aggravation by wool and dry air in the winter.
diets and steroid usage may exacerbate growth retardation. Aggressive management of such children with phototherapy or systemic immunosuppressives may allow for rebound growth. Children with severe AD may also have substantial psychological disturbances. Parents should be questioned with regard to school performance and socialization.
Childhood atopic dermatitis During childhood, lesions are apt to be less exudative. The classic locations are the antecubital and popliteal fossae (Fig. 5-2), flexor wrists, eyelids, face, and around the neck. Lesions are often lichenified, indurated plaques, and in AfricanAmerican patients may have a lichenoid appearance and favor the extensor surfaces. These are intermingled with isolated, excoriated 2–4 mm papules that are scattered more widely over the uncovered parts. Pruritus is a constant feature and most of the cutaneous changes are secondary to it. Itching is paroxysmal. Scratching induces lichenification and may lead to secondary infection. A vicious cycle may be established (the itch–scratch cycle), as pruritus leads to scratching, and scratching causes secondary changes that in themselves cause itching. Instead of scratching causing pain, in the atopic patient the “pain” induced by scratching is perceived as itch and induces more scratching. The scratching impulse is beyond the control of the patient. Severe bouts of scratching occur during sleep, leading to poor rest and chronic tiredness in atopic children. This can affect their school performance. Severe AD involving a large percentage of the body surface area can be associated with growth retardation. Restriction 64
Atopic dermatitis in adolescents and adults Most adolescents and adults with AD will give a history of childhood disease. In only 6–14% of patients diagnosed with AD will it begin after age 18. One exception is the patient who moves from a humid, tropical region to a more temperate one of higher latitude. This climatic change is often associated with the appearance of AD. In older patients, AD may occur as localized erythematous, scaly, papular, exudative, or lichenified (Fig. 5-3) plaques. In adolescents, the eruption often involves the classic antecubital and popliteal fossae, front and sides of the neck, forehead, and area around the eyes. In older adults the distribution is generally less characteristic, and localized dermatitis may be the predominant feature, especially hand, nipple, or eyelid eczema). At times the eruption may generalize, with accentuation in the flexures. The skin, in general, is dry and somewhat erythematous. Lichenification and prurigo-like papules are common (Fig. 5-4). Papular lesions tend to be dry, slightly elevated, and flat-topped. They are nearly always excoriated and often coalesce to form plaques. Staphylococcal colonization is nearly universal. In darker-skinned patients, the lesions are often dramatically hyperpigmented, frequently with focal hypopigmented areas related to healed excoriations. Itching usually occurs in crises or paroxysms, often during the evening when the patient is trying to relax, or during the night. Adults frequently complain that flares of AD are triggered by acute emotional upsets. Stress, anxiety, and depression reduce the threshold at which itch is perceived and result in damage to the epidermal permeability barrier, further exacerbating AD. Atopic persons may sweat poorly, and may complain of severe pruritus related to heat or exercise. Physical conditioning and liberal use of emollients improve this component, and atopic patients can participate in competitive sports.
Atopic dermatitis Fig. 5-5 Nasal crease.
Fig. 5-3 Flexural lichenification in adult atopic dermatitis.
as a trigger, and new-onset AD in an at-risk adult should lead to counseling and testing for HIV if warranted. The hands, including the wrists, are frequently involved in adults, and hand dermatitis is a common problem for adults with a history of AD. It is extremely common for atopic hand dermatitis to appear in young women after the birth of a child, when increased exposure to soaps and water triggers their disease. Wet work is a major factor in hand eczema in general, including those patients with AD. Atopic hand dermatitis can affect both the dorsal and palmar surfaces. Keratosis punctata of the creases, a disorder seen almost exclusively in black persons, is also more common in atopics. Patients with AD have frequent exposure to preservatives and other potential allergens in the creams and lotions that are continually applied to their skin. Contact allergy may manifest as chronic hand eczema. Patch testing with clinical correlation is the only certain way to exclude contact allergy in an atopic patient with chronic hand dermatitis. Eyelids are commonly involved. In general, the involvement is bilateral and the condition flares with cold weather. As in hand dermatitis, irritants and allergic contact allergens must be excluded by a careful history and patch testing.
Associated features and complications Cutaneous stigmata Fig. 5-4 Prurigo-like papules in adult atopic dermatitis.
Even in patients with AD in adolescence or early adulthood, improvement usually occurs over time, and dermatitis is uncommon after middle life. In general, these patients retain mild stigmata of the disease, such as dry skin, easy skin irritation, and itching in response to heat and perspiration. They remain susceptible to a flare of their disease when exposed to the specific allergen or environmental situation. Some will flare in response to aeroallergens, and a few patients will develop flexural dermatitis in response to niacin-induced flushing. Photosensitivity develops in approximately 3% of AD patients, and may manifest as either a polymorphous light eruption-type reaction or simply exacerbation of the AD by UV exposure. Most patients (65%) are sensitive to UVA and UVB, but about 17% are sensitive to only UVA or UVB. The average age for photosensitive AD is the mid- to late thirties. Human immunodeficiency virus (HIV) infection can also serve
A linear transverse fold just below the edge of the lower eyelids, known as the Dennie–Morgan fold, is widely believed to be indicative of the atopic diathesis, but may be seen with any chronic dermatitis of the lower lids. In atopic patients with eyelid dermatitis, increased folds and darkening under the eyes is common. When taken together with other clinical findings, they remain helpful clinical signs. A prominent nasal crease may also be noted (Fig. 5-5). The less involved skin of atopic patients is frequently dry and slightly erythematous, and may be scaly. Histologically, the apparently normal skin of atopics is frequently inflamed subclinically. The dry, scaling skin of AD may represent lowgrade dermatitis. Filaggrin is processed by caspase 14 during terminal keratinocyte differentiation into highly hydroscopic pyrrolidone carboxylic acid and urocanic acid, collectively known as the “natural moisturizing factor” or NMF. Null mutations in FLG lead to reduction in NMF, which probably contributes to the xerosis that is almost universal in AD. Transepidermal water loss (TEWL) is increased. This may be due to subclinical dermatitis, but is also caused by abnormal 65
Ophthalmologic abnormalities
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Up to 10% of patients with AD develop cataracts, either anterior or posterior subcapsular ones. Posterior subcapsular cataracts in atopic individuals are indistinguishable from corticosteroid-induced cataracts. Development of cataracts is more common in patients with severe dermatitis. Keratoconus is an uncommon finding, occurring in approximately 1% of atopic patients. Contact lenses, keratoplasty, and intraocular lenses may be required to treat this condition.
Susceptibility to infection
Fig. 5-6 Pityriasis alba.
delivery of lamellar body epidermal lipids (especially ceramide) to the interstices between the terminally differentiated keratinocytes. The defective lipid bilayers that result retain water poorly, leading to increased TEWL and clinical xerosis. Pityriasis alba is a form of subclinical dermatitis, frequently atopic in origin. It presents as poorly marginated, hypopigmented, slightly scaly patches on the cheeks (Fig. 5-6), upper arms, and trunk, typically in children and young adults. It usually responds to emollients and mild topical steroids, preferably in an ointment base. Keratosis pilaris (KP), horny follicular lesions of the outer aspects of the upper arms, legs, cheeks, and buttocks, is commonly associated with AD. The keratotic papules on the face may be on a red background, a variant of KP called keratosis pilaris rubra facei. KP is often refractory to treatment. Moisturizers alone are only partially beneficial. Some patients will respond to topical lactic acid, urea, or retinoids. Retinoids can easily irritate the skin of atopics, and treatment should begin with applications only once or twice a week. KP must be distinguished from follicular eczema, as AD and other eczemas are commonly folliculocentric, especially in black patients. Thinning of the lateral eyebrows, Hertoghe’s sign, is sometimes present. This apparently occurs from chronic rubbing due to pruritus and subclinical dermatitis. Hyperkeratosis and hyperpigmentation, which produce a “dirty neck” appearance, are also frequent in AD.
Vascular stigmata Atopic individuals often exhibit perioral, perinasal, and periorbital pallor (“headlight sign”). White dermatographism is blanching of the skin at the site of stroking with a blunt instrument. This reaction differs from the triple response of Lewis, in that it typically lacks a wheal, and the third response (flaring) is replaced by blanching to produce a white line. When 0.1 mL of a 1 : 100 000 solution of histamine is injected intradermally, the flare phase of the triple response is absent or diminished. Atopics are at increased risk of developing various forms of urticaria, including contact urticaria. Episodes of contact urticaria may be followed by typical eczematous lesions at the affected site. 66
More than 90% of chronic eczematous lesions contain S. aureus, often in large numbers. In addition, the apparently normal nonlesional skin of atopic patients is also commonly colonized by S. aureus. The finding of increasing numbers of pathogenic staphylococci on the skin of a patient with AD is frequently associated with weeping and crusting of skin lesions, retroand infra-auricular and perinasal fissures, folliculitis, and adenopathy. In any flaring atopic the possibility of secondary infection must be considered. IgE antibodies directed against Staphylococcus and its toxins have been documented in some atopic individuals. Staphylococcal production of superantigens is another possible mechanism for staphylococcal flares of disease. Treatment of lesions of AD with topical steroids is associated with reduced numbers of pathogenic bacteria on the surface, even if antibiotics are not used. Despite the frequent observation that the presence of staphylococcal infection of lesions of AD is associated with worsening of disease, it has been impossible to prove that oral antibiotic therapy makes a long-term difference in the course of the AD. None the less, treatment of the “infected” AD patient with oral antibiotics is a community standard of dermatologists worldwide. With the widespread presence of antibiotic-resistant S. aureus, dermatologists have shifted from the chronic use of oral antibiotics in managing patients with frequent flares of AD associated with staphylococcal infection. Rather, bleach baths and reduction of nasal carriage have become the basis for controlling infection-triggered AD. In an occasional patient with AD and frequent infections, chronic suppressive oral antibiotic therapy may stabilize the disease. Options include cephalosporins, trimethoprim–sulfamethoxazole, clindamycin, and (in older patients) doxycycline. Identifying and treating S. aureus carriers in the family may also be of benefit. An unusual complication of S. aureus infection in patients with AD is subungual infection, with osteomyelitis of the distal phalanx. In atopic patients with fever who appear very toxic, the possibility of streptococcal infection must be considered. These children may require hospital admission and intravenous antibiotics. AD patients have increased susceptibility to generalized herpes simplex infection (eczema herpeticum), as well as widespread vaccinia infection (eczema vaccinatum) and complicated varicella. Eczema herpeticum is seen most frequently in young children and is usually associated with herpes simplex virus (HSV)-1 transmitted from a parent or sibling. Once infected, the atopic may have recurrences of HSV and repeated episodes of eczema herpeticum. Eczema herpeticum presents as the sudden appearance of vesicular, pustular, crusted, or eroded lesions concentrated in the areas of dermatitis. The lesions may continue to spread and most of the skin surface may become involved. Secondary staphylococcal infection is frequent, and local edema and regional adeno pathy commonly occur. If lesions of eczema herpeticum occur on or around the eyelids, ophthalmologic evaluation is recommended. The severity of eczema herpeticum is quite variable, but most cases requires systemic antiviral therapy and an antistaphylococcal antibiotic.
Pathogenesis Immunologic events noted early in the development of atopic lesions include activation of the Th2 immune response, with synthesis of cytokines IL-4, IL-5, IL-10, and IL-13. These immunological propensities are already evident in newborns. Neonatal cord blood mononuclear cells stimulated with phyto hemagglutinin show significantly higher IL-13 levels in children who subsequently develop AD. IL-4 and IL-5 produce elevated IgE levels and eosinophilia in tissue and peripheral blood. IL-10 inhibits delayed-type hypersensitivity. IL-4 downregulates interferon (IFN)-γ production. Early lesions of AD are often urticarial in character, a manifestation of Th2 hyperreactivity. These immunologic alterations result in the reduced production of antimicrobial peptides (AMP), specifically LL-37 (cathelicidin) and β-defensins 2 and 3. This loss of AMP production may predispose atopics to widespread skin infections due to viruses (herpes, molluscum, and vaccinia) and bacteria, especially Staphylococcus. AD patients who develop eczema herpeticum are more likely to be Th2polarized, supporting the causal relationship between reduced AMP production and cutaneous viral infection. Epicutaneous exposure to staphylococcal superantigens, to which AD patients develop IgE antibodies, further skews the immune response toward Th2 cytokine production, explaining the association of staphylococcal infection with exacerbations of AD. Staphylococcal superantigens, such as SEB, SEE, and TSST-1, cause profound reduction in steroid responsiveness of T cells. This is another possible mechanism for flares of AD associated with staphylococcal skin infection or colonization. While AD begins as a Th2-mediated disorder, in its chronic phase, cutaneous inflammation is characterized by Th1 cytokines. This explains why chronic AD histologically resembles other chronic dermatoses. Monocytes in the peripheral blood of patients with AD produce elevated levels of prostaglandin E2 (PGE2). PGE2 reduces IFN-γ production but not IL-4 from helper T cells, enhancing the Th2 dominance. PGE2 also directly enhances IgE production from B cells. Abnormalities of cutaneous nerves and the products they secrete (neuropeptides) have been identified in atopic patients. These may explain the abnormal vascular responses, reduced itch threshold, and perhaps some of the immunologic imbalances seen in atopic skin. Decreased activation of peripheral pruriceptors has been demonstrated in patients with atopy, suggesting that itch in lesional skin might have a central component (central sensitization) based on altered spinal impulses rather than in primary afferent neurons. The acetylcholine content of atopic skin is markedly elevated, and acetylcholine may play a role in atopic signs and symptoms. In subjects with AD, acetylcholine injected intradermally will produce marked pruritus, while it produces pain in control patients. Epidermal nerve fibers are “stretched” in the acanthotic, lichenified lesions of AD, reducing their threshold for stimulation. Fissures in the skin in AD expose these epidermal nerve fibers, perhaps triggering pruritus, and explaining the rapid reduc-
tion of pruritus by simple emollients in some lesions. In addition, in chronic AD, mu opiate receptors are absent from the surface of keratinocytes. This may allow endogenous opiates in the epidermis to bind directly to epidermal nerves, triggering itch. In fact, topical opiate antagonists can reduce itch in AD. In atopic patients, the epidermal barrier is abnormal, even in apparently normal skin. An increase in TEWL correlates with the severity of the disease. AD usually worsens in the winter due to decreased ambient humidity. Stress also results in poor formation of epidermal lipid bilayers, worsening TEWL. This is mediated by endogenous corticoid production, and systemic corticosteroid therapy of AD results in similar abnormalities in epidermal lipid bilayer synthesis. This could explain the flares of AD seen with stress and following systemic steroid therapy. Correction of barrier dysfunction is critical to improving AD; hence the value of skin hydration, ointments, and occlusion. Optimizing this component of AD treatment appears to have the greatest benefit in reducing the severity of AD.
Atopic dermatitis
Vaccination against smallpox is contraindicated in persons with AD, even when the dermatitis is in remission. Widespread and even fatal vaccinia can occur in patients with an atopic diathesis. Atopic individuals may also develop extensive flat warts or molluscum contagiosum. Because the skin is very easily irritated, chemical treatments such as salicylic acid and cantharidin are poorly tolerated. Destruction with curettage (for molluscum), cryosurgery, or electrosurgery may be required to clear the lesions.
Differential diagnosis Typical AD in infancy and childhood is not difficult to diagnose because of its characteristic morphology, predilection for symmetric involvement of the face, neck, and antecubital and popliteal fossae, and association with food allergy, asthma, and allergic rhinoconjunctivitis. Dermatoses that may resemble AD include seborrheic dermatitis (especially in infants), irritant or allergic contact dermatitis, nummular dermatitis, photodermatitis, scabies, and cases of psoriasis with an eczematous morphology. Certain immunodeficiency syndromes (see below) may exhibit a dermatitis remarkably similar or identical to AD.
Histopathology The histology of AD varies with the stage of the lesion, with many of the changes induced by scratching. Hyperkeratosis, acanthosis, and excoriation are common. Staphylococcal colonization may be noted histologically. Although eosinophils may not be seen in the dermal infiltrate, staining for eosinophil major basic protein (MBP) reveals deposition in many cases. Heavy MBP deposition is often seen in specimens from patients with AD and a personal or family history of respiratory atopy.
General management Education and support Parental and patient education is of critical importance in the management of AD. In the busy clinic setting dermatologists frequently have insufficient time to educate patients adequately regarding the multiple factors that are important in managing AD. Educational formats that have proved effective have been immediate nursing education on the correct use of medications, weekly evening educational sessions, and multidisciplinary day treatment venues. In all cases, “written action plans” outlining a “stepwise approach” have been important for parent/patient education. In addition, patients with chronic disease often become disenchanted with medical therapies or simply “burn out” from having to spend significant amounts of time managing their skin disease. The psychological support that can be piggy-backed into educational sessions can help motivate parents/patients and keep them engaged in the treatment plan. Having a child with AD is extremely stressful and generates significant stress within the family. Sleep is lost by both the patient and the parents. Supportive 67
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educational techniques can help the family cope with this burden. Finally, the dermatologist must consider the complexity and time commitment of any prescribed regimen and make sure the parents/patient both understand and are committed to undertaking the treatments proposed.
Barrier repair In virtually all cases of AD, there is xerosis and an impaired epidermal barrier. The cornerstone of treatment and prevention of AD lies in addressing this problem. Patients should moisturize daily, especially after bathing. This may be with petrolatum or a petrolatum-based product, an oil-based product, vegetable shortening, or a “barrier repair” moisturizer that contains the essential lipids of the epidermal barrier. These special barrier repair moisturizers have similar benefits in AD to low-potency topical steroids. They are easier to apply and, if they are available to the patient, may enhance compliance. Petrolatum and petrolatum-based moisturizers are most commonly recommended and are the cheapest and most effective for most patients. However, men with significant body hair, AD patients triggered by heat, and the rare patient with true allergic contact dermatitis to petrolatum may not be able to tolerate petrolatum-based agents. Patients should be instructed on the barrier-damaging properties of soaps, hot water, and scrubbing. Synthetic detergents that have a more acidic pH are preferred to harsh soaps. Detergent use should be restricted to the axilla, groin, face, soles, and scalp. Oilbased cleansers can be used to “wash” the skin without water. For flares of AD, the soak and smear technique (soak in a tub then seal in the water with a heavy moisturizer or medicated ointments) or wet dressings (wet wraps) with topical steroids can be very effective. In dry climates, AD patients may note some benefit with humidifiers. Alpha-hydroxy acid-containing products (lactic acid, glycolic acid) can be irritating and can exacerbate inflamed AD. These products should only be used for the xerosis of AD when there is absolutely no inflammation or pruritus.
Antimicrobial therapy When there is evidence of infection, treatment with topical or systemic antibiotics may be appropriate. Rather than treating once an infection occurs, it appears that the key in AD is to reduce nasal staphylococcal carriage pre-emptively and to keep the skin decolonized from Staphylococcus. Bleach bathes have rapidly become a mainstay in AD patients. Twice-weekly bathing in a tepid bath with 1 2 cup of standard household bleach (6%) diluted into 40 gallons of water dramatically improves AD on the trunk and extremities, but less so on the face. This treatment combines decolonization of the skin with hydration, addressing two of the major factors in worsening of AD. Adequate moisturization following bathing is critical. Intranasal application of mupirocin is beneficial in reducing nasal carriage and improving the AD. In 80% of families, at least one parent is carrying the same staphylococcal strain as a colonized AD child. If recurrent infections afflict a patient with AD, look for other carriers in the family and treat them aggressively. Recurrent infections, especially furunculosis, are a cardinal feature of children and adults with AD who have systemic immunological abnormalities, especially hyper-IgE syndrome.
Environmental factors Stress, heat, sweating, and external irritants may precipitate an attack of itching and flare AD. Wool garments should be avoided. Addressing these triggers may improve the AD. Exercise may need to be limited in patients with significant flares to swimming or walking during cool times of the day to 68
avoid triggering sweating. Itch nerves are more active at higher temperatures, so overheating should be avoided. Irritants and allergens in the numerous products that AD patients may use can lead to flares of AD. Patients should avoid products that contain common allergens, and should be evaluated for allergic contact dermatitis if a topical agent is associated with worsening of their AD.
Antipruritics Sedating antihistamines are optimally used nightly (not as needed) for their antipruritic and sedative effects. Diphenhydramine, hydroxyzine, and Sinequan can all be efficacious. Cetirizine and fexofenadine have both demonstrated efficacy in managing the pruritus of AD in children and adults, respectively. These can be added without significant sedation if standard first-generation antihistamines are not adequate in controlling pruritus. Applying ice during intense bouts of itch may help to “break” an itch paroxysm. Moisturizing lotions containing menthol, phenol, or pramocaine can be used between steroid applications to moisturize and reduce local areas of severe itch. More widespread use of topical Sinequan is limited by systemic absorption and sedation.
Specific treatment modalities Topical corticosteroid therapy Topical corticosteroids are the most commonly used class of medications, along with moisturizers, for the treatment of AD. They are effective and economical. In infants, low-potency steroid ointments, such as hydrocortisone 1% or 2.5%, are preferred. Emphasis must be placed on regular application of emollients. Once corticosteroid receptors are saturated, additional applications of a steroid preparation contribute nothing more than an emollient effect. In most body sites, once-a-day application of a corticosteroid is almost as effective as more frequent applications, at lower cost and with less systemic absorption. In some areas, twice-a-day applications may be beneficial, but more frequent applications are almost never of benefit. Steroid phobia is common in parents and patients with AD. Less frequent applications of lower-concentration agents, with emphasis on moisturizing, address these concerns. Application of topical corticosteroids under wet wraps or vinyl suit occlusion (soak and smear) can increase efficiency. For refractory areas, a stronger corticosteroid, such as desonide, aclomethasone, or triamcinolone, may be used. A more potent molecule is more appropriate than escalating concentrations of a weaker molecule because the effect of the latter plateaus rapidly as receptors become saturated. Do not undertreat! This leads to loss of faith on the part of the patient/ parents and prolongs the suffering of the patient. For severe disease, use more potent topical steroids in short bursts of a few days to a week to gain control of the disease. In refractory and relapsing AD, twice-weekly steroid application may reduce flares. In older children and adults, medium-potency steroids such as triamcinolone are commonly used, except on the face, where milder steroids or calcineurin inhibitors are preferred. For thick plaques and lichen simplex chronicus-like lesions, very potent steroids may be necessary. These are generally applied on weekends, with a milder steroid used during the week. Ointments are more effective, due to their moisturizing properties, and require no preservatives, reducing the likelihood of allergic contact dermatitis. If an atopic patient worsens or fails to improve after the use of topical steroids and moisturizers, the possibility of allergic contact dermatitis to a preservative or the corticosteroids must be considered. Contact allergy to the corticosteroid itself is not uncommon.
Topical calcineurin inhibitors (TCIs) Topical calcineurin inhibitors, such as tacrolimus or pimecrolimus, offer an alternative to topical steroids. Systemic absorption is generally not significant with either of these agents. Although a 0.03% tacrolimus ointment is marketed for use in children, it is unclear whether it really offers any safety advantage over the 0.1% formulation. Tolerability is improved if the ointment is applied to bone-dry skin. Patients experience less burning if eczematous patches are treated initially with a corticosteroid, with transition to a calcineurin inhibitor after partial clearing. Improvement tends to be steady, with progressively smaller areas requiring treatment. These agents are particularly useful on the eyelids and face, in areas prone to steroid atrophy, when steroid allergy is a consideration, or when systemic steroid absorption is a concern. Tacrolimus is more effective than pimecrolimus, with tacrolimus 0.1% ointment equivalent to triamcinolone acetonide 0.1%, and pimecrolimus equivalent to a class V or VI topical corticosteroid.
Tar Crude coal tar 1–5% in white petrolatum or hydrophilic ointment USP, or liquor carbonis detergens (LCD) 5–20% in hydrophilic ointment USP, is sometimes helpful for an area of refractory AD. Tar preparations are especially beneficial when used for intensive treatment for adults in an inpatient or daycare setting, especially in combination with UV phototherapy.
Phototherapy If topical modalities fail to control AD, phototherapy is the next option on the therapeutic ladder. Narrow-band UVB (NBUVB) is highly effective and has replaced broadband UV for treating AD. When acutely inflamed, AD patients may tolerate UV poorly. Initial treatment with a systemic immunosuppressive can cool off the skin enough to institute UV treatments. Patients with significant erythema must be introduced to UV at very low doses to avoid nonspecific irritancy and flaring of the AD. Often the initial dose is much lower and the dose escalation much slower than in patients with psoriasis. In acute flares of AD, UVA-1 can be used. In patients in whom NB-UVB fails, photochemotherapy (PUVA) can be effective. It requires less frequent treatments, and can be given either topically (soak/bath PUVA) or systemically (oral PUVA). Goeckerman therapy with tar and UVB in a day treatment setting will lead to improvement in more than 90% of patients with refractory AD, and a prolonged remission can be induced.
Systemic therapy Systemic corticosteroids In general, systemic steroids should be used only to control acute exacerbations. In patients requiring systemic steroid therapy, short courses (3 weeks or less) are preferred. If repeated or prolonged courses of systemic corticosteroids are required to control the AD, phototherapy or a steroid-sparing
agent should be considered. Chronic corticosteroid therapy for AD frequently results in significant corticosteroid-induced side effects. Osteoporosis in women requires special consideration and should be addressed with a bisphosphonate early in the course of therapy when bone loss is greatest. Preventive strategies, such as calcium supplements, vitamin D supplementation, bisphosphonates, regular exercise, and stopping smoking, should be strongly encouraged. Dual energy x-ray absorptiometry (DEXA) scans are recommended.
Cyclosporine
Atopic dermatitis
Corticosteroid allergy seldom manifests as acute worsening of the eczema. Instead, it manifests as a flare of eczema whenever the corticosteroid is discontinued, even for a day. This may be difficult to differentiate from stubborn AD. Although the potential for local and even systemic toxicity from corticosteroids is real, the steroid must be strong enough to control the pruritus and remove the inflammation. Even in small children, strong topical steroids may be necessary in weekly pulses to control severe flares. Weekend pulses are always preferable to daily application of a potent steroid. Monitoring of growth parameters should be carried out in infants and young children.
Cyclosporine is highly effective in the treatment of severe AD, but the response is rarely sustained after the drug is discontinued. It is very useful to gain rapid control of severe AD. It has been shown to be safe and effective in both children and adults, although probably tolerated better in children. Potential long-term side effects, especially renal disease, require careful monitoring, with attempts to transition the patient to a potentially less toxic agent if possible. The dose range is 3–5 mg/kg, with a better and more rapid response at the higher end of the dose range.
Other immunosuppressive agents Several immunosuppressive agents have demonstrated efficacy in patients with AD. There are no comparative trials, so the relative efficacy of these agents is unknown. They do not appear to be as effective or quick to work as cyclosporine. However, over the long term, they may have a better safety profile, so patients requiring long-term immunosuppression may benefit from one of these agents. They include azathioprine (Immuran), mycophenolate mofetil (Cellcept), and methotrexate (Rheumatrex). The dosing of azathioprine is guided by the serum thiopurine methyltransferase level. Mycophenolate mofetil is generally well tolerated and, like azathioprine, takes about 6 weeks to begin to reduce the AD. Low-dose weekly methotrexate is very well tolerated in the elderly and may have special benefit in that population. Intravenous immunoglobulin (IVIG) has had some limited success in managing AD, but its high cost precludes it use, except when other reasonable therapeutic options have been exhausted. IFN-γ given by daily injection has demonstrated efficacy in both children and adults with severe AD. The onset of response can be delayed. It is well tolerated but can cause flu-like symptoms. Omalizumab can be considered in refractory cases, but only 20% of patients achieve a 50% or greater reduction of their AD. Infliximab has not been beneficial in AD. Traditional Chinese herb mixtures have shown efficacy in children and in animal models for AD. The active herbs appear to be ophiopogon tuber and schisandra fruit. Chinese herbs are usually delivered as a brewed tea to be drunk daily. Their bitter taste makes them unpalatable to most Western patients. However, this option should be considered in patients who might accept this treatment approach.
Management of an acute flare Initially, the precipitating cause of the flare should be sought. Recent stressful events may be associated with flares. Secondary infection with S. aureus should be assumed in most cases. Less commonly, herpes simplex or coxsackie virus may be involved. Pityriasis rosea may also cause AD to flare. The development of contact sensitivity to an applied medication or photosensitivity must be considered. In the setting of an acute flare, treating triggers (see above) may lead to improvement. A short course of systemic steroids may be of benefit, but patients should be counseled that 69
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prolonged systemic corticosteroid therapy must be avoided. “Home hospitalization” may be useful. The patient goes home to bed, isolated from work and other stressors; large doses of an antihistamine are given at bedtime; the patient soaks in the tub twice daily, then applies a topical steroid ointment under wet pajamas and a sauna suit (soak and smear). Often, 3–4 days of such intensive home therapy will break a severe flare. Akhavan A, et al: Atopic dermatitis: systemic immunosuppressive therapy. Semin Cutan Med Surg 2008; 27:151. Allen HB, et al: Lichenoid and other clinical presentations of atopic dermatitis in an inner city practice. J Am Acad Dermatol 2008; 58:503. Annesi-Maesano I, et al: Time trends in prevalence and severity of childhood asthma and allergies from 1995 to 2002 in France. Allergy 2009; 64:798. Ashcroft DM, et al: Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials. BMJ 2005; 330:516. Barker JN, et al: Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J Invest Dermatol 2007; 127:564. Beck LA, et al: Phenotype of atopic dermatitis subjects with a history of eczema herpeticum. J Allergy Clin Immunol 2009; 124:260. Bigliardi PL, et al: Treatment of pruritus with topically applied opiate receptor antagonist. J Am Acad Dermatol 2007; 56:979. Bisgaard H, et al: Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PLoS Med 2008; 5:e131. Boguniewicz M, et al: A multidisciplinary approach to evaluation and treatment of atopic dermatitis. Semin Cutan Med Surg 2008; 27:115. Bonness S, et al: Pulsed-field gel electrophoresis of Staphylococcus aureus isolates from atopic patients revealing presence of similar strains in isolates from children and their parents. J Clin Microbiol 2008; 46:456. Bremmer MS, et al: Are biologics safe in the treatment of atopic dermatitis? A review with a focus on immediate hypersensitivity reactions. J Am Acad Dermatol 2009. Brenninkmeijer EE, et al: Diagnostic criteria for atopic dermatitis: a systematic review. Br J Dermatol 2008; 158:754. Brown SJ, et al: Atopic eczema and the filaggrin story. Semin Cutan Med Surg 2008; 27:128. Chisolm SS, et al: Written action plans: potential for improving outcomes in children with atopic dermatitis. J Am Acad Dermatol 2008; 59:677. Clausen M, et al: High prevalence of allergic diseases and sensitization in a low allergen country. Acta Paediatr 2008; 97:1216. Clayton TH, et al: The treatment of severe atopic dermatitis in childhood with narrowband ultraviolet B phototherapy. Clin Exp Dermatol 2007; 32:28. Diepgen TL: Long-term treatment with cetirizine of infants with atopic dermatitis: a multi-country, double-blind, randomized, placebocontrolled trial (the ETAC trial) over 18 months. Pediatr Allergy Immunol 2002; 13:278. Eichenfield LF, et al: Consensus conference on pediatric atopic dermatitis. J Am Acad Dermatol 2003; 49:1088. Hata TR, et al: Antimicrobial peptides, skin infections, and atopic dermatitis. Semin Cutan Med Surg 2008; 27:144. Howell MD, et al: Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007; 120:150. Huang JT, et al: Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics 2009; 123:e808. Jolles S, et al: Use of IGIV in the treatment of atopic dermatitis, urticaria, scleromyxedema, pyoderma gangrenosum, psoriasis, and pretibial myxedema. Int Immunopharmacol 2006; 6:579. Kawashima M, et al: Addition of fexofenadine to a topical corticosteroid reduces the pruritus associated with atopic dermatitis in a 1-week randomized, multicentre, double-blind, placebo-controlled, parallelgroup study. Br J Dermatol 2003; 148:1212. Leung D: Superantigens, steroid insensitivity and innate immunity in atopic eczema. Acta Derm Venereol Suppl (Stockh) 2005:11. Makino T, et al: Effect of bakumijiogan, an herbal formula in traditional Chinese medicine, on atopic dermatitis-like skin lesions induced by mite antigen in NC/Jic mice. Biol Pharm Bull 2008; 31:2108.
Meduri NB, et al: Phototherapy in the management of atopic dermatitis: a systematic review. Photodermatol Photoimmunol Photomed 2007; 23:106. Moore E, et al: Nurse-led clinics reduce severity of childhood atopic eczema: a review of the literature. Br J Dermatol 2006; 155:1242. Morales Suarez-Varela M, et al: Parents’ smoking habit and prevalence of atopic eczema in 6–7 and 13–14 year-old schoolchildren in Spain. ISAAC phase III. Allergol Immunopathol (Madr) 2008; 36:336. Morar N, et al: Filaggrin mutations in children with severe atopic dermatitis. J Invest Dermatol 2007; 127:1667. Murray ML, et al: Mycophenolate mofetil therapy for moderate to severe atopic dermatitis. Clin Exp Dermatol 2007; 32:23. Naldi L, et al: Prevalence of atopic dermatitis in Italian schoolchildren: factors affecting its variation. Acta Derm Venereol 2009; 89:122. O’Regan GM, et al: Filaggrin in atopic dermatitis. J Allergy Clin Immunol 2008; 122:689. Ozkaya E: Adult-onset atopic dermatitis. J Am Acad Dermatol 2005; 52:579. Paller AS, et al: Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from 3 randomized, comparative studies. J Am Acad Dermatol 2005; 52:810. Rance F, et al: New visions for atopic eczema: an iPAC summary and future trends. Pediatr Allergy Immunol 2008; 19(Suppl 19):17. Ricci G, et al: Three years of Italian experience of an educational program for parents of young children affected by atopic dermatitis: improving knowledge produces lower anxiety levels in parents of children with atopic dermatitis. Pediatr Dermatol 2009; 26:1. Schmitt J, et al: Cyclosporin in the treatment of patients with atopic eczema—a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2007; 21:606. Selnes A, et al: Diverging prevalence trends of atopic disorders in Norwegian children. Results from three cross-sectional studies. Allergy 2005; 60:894. Sugarman JL: The epidermal barrier in atopic dermatitis. Semin Cutan Med Surg 2008; 27:108. ten Berge O, et al: Throwing a light on photosensitivity in atopic dermatitis: a retrospective study. Am J Clin Dermatol 2009; 10:119. van Os-Medendorp H, et al: Costs and cost-effectiveness of the nursing program ‘Coping with itch’ for patients with chronic pruritic skin disease. Br J Dermatol 2008; 158:1013. Verhoeven EW, et al: Biopsychosocial mechanisms of chronic itch in patients with skin diseases: a review. Acta Derm Venereol 2008; 88:211. Weiland SK, et al: Climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children. Occup Environ Med 2004; 61:609. Williams HC: Clinical practice. Atopic dermatitis. N Engl J Med 2005; 352:231. Zoller L, et al: Low dose methotrexate therapy is effective in late-onset atopic dermatitis and idiopathic eczema. Isr Med Assoc J 2008; 10:413.
Eczema The word eczema seems to have originated in AD 543 and is derived from the Greek work ekzein, meaning to “to boil forth” or “to effervesce.” In its modern use, the term refers to a broad range of conditions that begin as spongiotic dermatitis and may progress to a lichenified stage. The term encompasses such disorders as dyshidrotic eczema and nummular eczema. The acute stage generally presents as a red edematous plaque that may have grossly visible, small, grouped vesicles. Subacute lesions present as erythematous plaques with scale or crusting. Later, lesions may be covered by a dryer scale or become lichenified. In most eczematous reactions, severe pruritus is a prominent symptom. The degree of irritation at which itching begins (the itch threshold) is lowered by stress. Itching is often prominent at bedtime and commonly results in insomnia. Heat and sweating may also provoke episodes of itching.
Regional eczemas Ear eczema Eczema of the ears or otitis externa may involve the helix, postauricular fold, and external auditory canal. By far the most frequently affected site is the external canal, where it is often a manifestation of seborrheic dermatitis or allergic contact dermatitis (Fig. 5-7). Secretions of the ear canal derive from the
Fig. 5-7 Ear eczema secondary to allergic contact dermatitis.
specialized apocrine and sebaceous glands, which form cerumen. Rubbing, wiping, scratching, and picking exacerbate the condition. Secondary bacterial colonization or infection is common. Infection is usually caused by staphylococci, streptococci, or Pseudomonas. Contact dermatitis from neomycin, benzocaine, and preservatives may be caused by topical remedies. Pseudomonas aeruginosa can result in malignant external otitis with ulceration and sepsis. Earlobe dermatitis is virtually pathognomonic of metal contact dermatitis (especially nickel) and occurs most frequently in women who have pierced ears. Treatment should be directed at removal of causative agents, such as topically applied allergens. Scales and cerumen should be removed by gentle lavage with an ear syringe. Antibiotic– corticoid preparations, such as Cortisporin otic suspension, have frequently been prescribed, and ingredients such as neomycin are therefore frequently found as relevant contact allergens. A combination of ciprofloxacin plus a topical steroid (Ciprodex) is preferred to neomycin-containing products. Corticosteroids alone can be effective for noninfected dermatitis. For very weepy lesions, Domeboro optic solution may be drying and beneficial.
Eczema
Histologically, the hallmark of all eczematous eruptions is a serous exudate between cells of the epidermis (spongiosis), with an underlying dermal perivascular lymphoid infiltrate and exocytosis (lymphocytes noted within spongiotic foci in the dermis). Spongiosis is generally out of proportion to the lymphoid cells in the epidermis. This is in contrast to mycosis fungoides, which demonstrates minimal spongiosis confined to the area immediately surrounding the lymphocytes. In most eczematous processes, spongiosis is very prominent in the acute stage, where it is accompanied by little acanthosis or hyperkeratosis. Subacute spongiotic dermatitis demonstrates epidermal spongiosis with acanthosis and hyperkeratosis. Chronic lesions may have little accompanying spongiosis, but it is not uncommon for acute and chronic stages to overlap, as episodes of eczematous dermatitis follow one another. Scale corresponds to foci of parakeratosis produced by the inflamed epidermis. A crust is composed of serous exudate, acute inflammatory cells, and keratin. Eczema, regardless of cause, will manifest similar histologic changes if allowed to persist chronically. These features are related to chronic rubbing or scratching, and correspond clinically to lichen simplex chronicus or prurigo nodularis. Histologic features at this stage include compact hyperkeratosis, irregular acanthosis, and thickening of the collagen bundles in the papillary portion of the dermis. The dermal infiltrate at all stages is predominantly lymphoid, but an admixture of eosinophils may be noted. Neutrophils generally appear in secondarily infected lesions. Spongiosis with many intraepidermal eosinophils may be seen in the early spongiotic phase of pemphigoid, pemphigus, and incontinentia pigmenti, as well as some cases of allergic contact dermatitis.
Eyelid dermatitis Eyelid dermatitis is most commonly related to atopic dermatitis or allergic contact dermatitis, or both (see Chapter 6). Allergic conjunctivitis in an atopic patient may lead to rubbing and scratching of the eyelid and result in secondary eyelid dermatitis. Seborrheic dermatitis, psoriasis, and airborne dermatitis are other possible causes. Ninety percent of patients with eyelid dermatitis are female. When an ocular medication contains an allergen, the allergen passes through the nasolacrimal duct, and dermatitis may also be noted below the nares in addition to the eyelids. Some cases of eyelid contact dermatitis are caused by substances transferred by the hands to the eyelids. If eyelid dermatitis occurs without associated atopic dermatitis, an allergen is detected in more than 50% of cases. More than 25% of patients with atopic dermatitis and eyelid dermatitis will also have allergic contact dermatitis contributing to the condition. Fragrances and balsam of Peru, metals (nickel and gold), paraphenylene diamine, thiomersal, quaternium 15, oleamidopropyl di methlyamine, thiuram (in rubber pads used to apply eyelid cosmetics), and tosylamide formaldehyde (in nail polish) are common environmental allergens causing eyelid dermatitis. In medications, preservatives such as cocamidopropyl betaine and active agents such as phenylephrine hydrochloride, sodium cromoglycate, papaine, and idoxuridine have all been implicated. Eyelid dermatitis requires careful management, often in collaboration with an ophthalmologist. The most important aspect is to identify and eliminate any possible triggering allergens as noted above. Patch testing for standard allergens, as well as the patient’s ocular medications, is required. Preservative-free eye medications should be used. The ophthalmologist should monitor the patient for conjunctival complications, measure the intraocular pressure, and monitor for the development of cataracts, especially in patients with atopic dermatitis who have an increased risk for cataracts, Initially, topical corticosteroids and petrolatum-based emollients are recommended. If the dermatitis is persistent, the patient may be transitioned to TCIs to reduce the long-term risk of ocular steroid complications. The TCIs are often not initially tolerated on inflamed eyelids due to the burning. If there is an associated allergic conjunctivitis, or in patients who fail treatment with topical medications applied to the eyelid, ocular instillation of cyclosporine ophthalmic emulsion (Restasis) can be beneficial. Cromolyn sodium ophthalmic drops may be used 71
to stabilize mast cells in the eyelid and reduce pruritus. In balsam of Peru-allergic patients, a balsam of Peru elimination diet may benefit.
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Breast eczema (nipple eczema) Eczema of the breasts usually affects the areolae, and may extend on to the surrounding skin (Fig. 5-8). The area around the base of the nipple is usually spared, and the nipple itself is less frequently affected. The condition is rarely seen in men. Usually, eczema of the nipples is of the moist type with oozing and crusting. Painful fissuring is frequently seen, especially in nursing mothers. Atopic dermatitis is a frequent cause, and nipple eczema may be the sole manifestation of atopic dermatitis in adult women. It frequently presents during breastfeeding. The role of secondary infection with bacteria and Candida should be considered in breastfeeding women. Other causes of nipple eczema are allergic contact dermatitis and irritant dermatitis. Irritant dermatitis occurs from friction (jogger’s nipples), or from ill-fitting brassieres with seams in women with asymmetrical and large breasts. In patients in whom eczema of the nipple or areola has persisted for more than 3 months, especially if it is unilateral, a biopsy is mandatory to rule out the possibility of Paget’s disease of the breast. Topical corticosteroids or TCIs are often effective in the treatment of non-Paget eczema of the breast. Nevoid hyperkeratosis of the nipples is a chronic condition that may mimic nipple eczema, but is not steroid-responsive. Nipple eczema in the breastfeeding woman is a therapeutic challenge. The dermatitis may appear in an atopic woman when her child begins to ingest solid foods. This may signal contact dermatitis to a food. Allergic contact dermatitis may develop to topically applied protective creams (containing vitamin A and E, aloe, chamomile, or preservatives). Staphylococcal superinfection may develop, and can be identified by culture. Oral antibiotics are the preferred treatment for bacterial secondary infection. Candidal infection of the areola may present as normal skin, erythema, or an acute or chronic eczema. The area of the areola immediately adjacent to the nipple tends to be involved, sometimes with fine hairline cracks. Patients frequently complain of severe pain, especially with nursing. Analgesia may be required, and breastfeeding
Fig. 5-8 Nummular eczema of the breast.
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may need to be suspended for a period. Pumping and the use of a silicone nipple shield may be helpful. Associated conditions include oral thrush in the infant, antibiotic use, and a personal history of vaginal candidiasis. Cultures may or may not be positive from the affected areola/nipple. The child’s mouth should also be cultured, even if the examination is completely normal, as candidal colonization of the breastfeeding infant’s mouth may be asymptomatic with no findings on clinical examination. A positive culture from the infant in the setting of nipple eczema in the mother would warrant therapy of the mother and infant. Therapy with topical or systemic antifungal agents may be required to determine whether Candida is pathogenic. Oral fluconazole can be dramatically effective in these patients. Topical gentian violet 0.5%, applied once daily to the nipple, or all-purpose nipple ointment [(mupirocin 2% (10 g), nystatin 100 000 units/mL ointment (10 g), clotrimazole 10% (vaginal cream) (10 g), and betamethasone 0.1% ointment (10 g)] is an effective topical agent. The child’s thrush should also be treated. A lactation consultant or nurse may be helpful in managing these patients, since poor positioning during breastfeeding is a common cofactor in the development of nipple eczema.
Hand eczema Hand eczema is a common and important skin condition. Every year, about 10% of the population has at least one episode of hand dermatitis, and at any time about 5% of the population is affected. The genetic risk factors for the development of hand dermatitis are unknown. Even among patients with atopic dermatitis, it is unclear whether patients with null mutations for FLG are at increased risk. Hand eczema is the most common occupational skin condition, accounting for more than 80% of all occupational dermatitis. Tobacco smoking and alcohol consumption do not appear to be risk factors for the development of hand eczema. Women are at increased risk for the development of hand eczema. Most of this increased risk is accounted for by a “spike” in the rate of hand eczema in the 20–29-year age group, when increased environmental exposures increase women’s risk (childcare, housecleaning, etc). Chronic hand eczema, especially if severe, significantly reduces the patient’s quality of life and is associated with symptoms of depression. A significant portion of patients with hand eczema will still be affected 15 years later. The risk for persistence of the hand eczema is doubled if there is associated eczema at other sites at presentation, if there is a childhood history of atopic dermatitis, and if the onset of the hand eczema was before age 20. Preventive interventions have been successful on two fronts: 1. Persons at high risk for hand eczema can be identified and counseled to avoid high-risk occupations. 2. Once occupational hand eczema develops, there are some occupation-specific strategies that can lead to improvement and prevent recurrence. The evaluation and management of hand eczema have been hampered by the lack of a uniform classification system and a dearth of controlled therapeutic trials. The diagnostic dilemma in hand dermatitis is in part related to two factors. The clinical appearance of the skin eruption on the palms and soles may be very similar, independent of the etiology. In addition, virtually all chronic hand dermatitis demonstrates a chronic dermatitis histologically, again independent of pathogenic cause. Psoriasis, specifically, on the palms and soles, may show spongiosis and closely resemble a dermatitis (Fig. 5-9). As a consequence, the proposed classification schemes rely on a combination of morphological features, history of coexistent illnesses, occupational exposure, and results of patch testing. The different types of hand eczema are:
Eczema Fig. 5-10 Acute vesiculobullous hand eczema.
Fig. 5-9 Hand eczema.
1. allergic contact dermatitis (with or without an additional irritant component) 2. irritant hand dermatitis 3. atopic hand eczema (with or without an additional irritant component) 4. vesicular (or vesiculobullous) endogenous hand eczema 5. hyperkeratotic endogenous hand eczema. A complete history, careful examination of the rest of the body surface, and, at times, patch testing are essential in establishing a diagnosis. The importance of patch testing cannot be overemphasized. Allergens in the environment (especially shower gels and shampoos), in the workplace, and in topical medications may be important in any given patient. Patch testing must include broad screens of common allergens or cases of allergic contact dermatitis will be missed. The role of ingested nickel in the development of hand eczema in nickel-allergic patients is controversial. Some practitioners treat such patients with low-nickel diets and even disulfiram chelation with reported benefit. However, the risk of development of hand eczema in adulthood is independent of nickel allergy. Similarly, the role of low-balsam diets in the management of balsam of Peru-allergic patients with hand eczema is unclear. Wet work (skin in liquids or gloves for more than 2 hours per day, or handwashing more than 20 times per day) is a strong risk factor for hand eczema. High-risk occupations include those that entail wet work, and those with exposure to potential allergens. These nine “high-risk” occupations include bakers, hairdressers, dental surgery assistants, kitchen workers/cooks, butchers, healthcare workers, cleaners, doctors/dentists/veterinarians, and laboratory technicians. In about 5% of patients with hand eczema, especially if this is severe, it is associated with prolonged missed work, job change, and job loss. In healthcare workers, the impaired barrier poses a risk for infection by blood-borne pathogens. Almost one-third of baker’s apprentices develop hand dermatitis within 12 months of entering the profession. Among hairdressers, the incidence approaches 50% after several years. Both irritant dermatitis and allergic contact dermatitis are important factors, with glyceryl monothioglycolate and ammonium persulfate being the most common allergens among hairdressers. Among those with preservative allergy, the hands are preferentially involved in patients allergic to isothiazolinones and formaldehyde, while the hands and face are equally involved with paraben allergy. Cement workers have a high rate of hand dermatitis related to contact allergy,
alkalinity, and hygroscopic effects of cement. Dorsal hand dermatitis in a cement worker suggests contact allergy to chromate or cobalt. The addition of ferrous sulfate to cement has no effect on irritant dermatitis, but reduces the incidence of allergic chromate dermatitis by two-thirds. Among patients with occupational hand dermatitis, atopic patients are disproportionately represented. Hand dermatitis is frequently the initial or only adult manifestation of an atopic diathesis. The likelihood of developing hand eczema is greatest in patients with atopic dermatitis, more common if the atopic dermatitis was severe, but still increased in incidence in patients with only respiratory atopy. Atopic patients should receive career counseling in adolescence to avoid occupations that are likely to induce hand dermatitis. Contact urticaria syndrome may present as immediate burning, itching, or swelling of the hands, but a chronic eczematous phase may also occur. Latex is an important cause of the syndrome, but raw meat, lettuce, garlic, onion, carrot, tomato, spinach, grapefruit, orange, radish, fig, parsnip, cheese, or any number of other foods may be implicated.
Vesiculobullous hand eczema (pompholyx, dyshidrosis) Idiopathic acute vesicular hand dermatitis is not related to blockage of sweat ducts, although palmoplantar hyperhidrosis is common in these patients and control of hyperhidrosis improves the eczema. Acute pompholyx, also known as cheiropompholyx if it affects the hands, presents with severe, sudden outbreaks of intensely pruritic vesicles. Primary lesions are macroscopic, deep-seated multilocular vesicles resembling tapioca on the sides of the fingers (Fig. 5-10), palms, and soles. The eruption is symmetrical and pruritic, with pruritus often preceding the eruption. Coalescence of smaller lesions may lead to bulla formation severe enough to prevent ambulation. Individual outbreaks resolve spontaneously over several weeks. Bullous tinea or an id reaction from a dermatophyte should be excluded, and patch testing should be considered to rule out allergic contact dermatitis.
Chronic vesiculobullous hand eczema In chronic cases the lesions may be hyperkeratotic, scaling, and fissured, and the “dyshidrosiform” pattern may be recognized only during exacerbations. There is a tendency for the pruritic 1–2 mm vesicles to be most pronounced at the sides of the fingers. In long-standing cases the nails may become dystrophic. The distribution of the lesions is, as a rule, bilateral and roughly symmetrical.
Hyperkeratotic hand dermatitis Males outnumber females by 2 : 1, and the patients are usually older adults. The eruption presents as hyperkeratotic, fissureprone, erythematous areas of the middle or proximal palm. The volar surfaces of the fingers may also be involved (Fig. 5-11). Plantar lesions occur in about 10% of patients. 73
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Fig. 5-11 Hyperkeratotic hand dermatitis.
Histologically, the lesions show chronic spongiotic dermatitis. The most important differential diagnosis is psoriasis, and some of the patients with chronic hyperkeratotic hand dermatitis will ultimately prove to be psoriatic. The presence of sharply demarcated plaques, nail pitting, or occasional crops of pustules is an important clue to psoriatic hand involvement.
Treatment The hands are essential for work both in and out of the home. Treatment regimens must be practical and allow patients to function as normally as possible. There are few controlled treatment trials for hand dermatitis, and only recently has the type of hand eczema been identified in the trial. As one might suspect, the efficacy of some of the treatments depends on the morphology of the eruption and the diagnostic classification (see above). Protection Vinyl gloves may be worn during wet work, especially when detergents are used. Although vinyl gloves protect against chemicals, they do not prevent exposure to heat through the glove or the macerating effect of sweat, which accumulates under the gloves. They are also far less durable than rubber gloves. Rubber gloves may be used at home if patients do not exhibit allergy to rubber chemicals or latex. Wearing white cotton gloves under the vinyl gloves is beneficial. For rough work, such as gardening, wearing protective cloth or leather gloves is essential. Cotton can adsorb allergens in the environment, and cotton gloves worn throughout the day offer little protection from many allergens. Barrier repair Moisturizing is a critical component of the management of hand dermatitis. Application of a protective moisturizing cream or ointment after each handwashing or water exposure is recommended. Creams require a preservative and have a higher risk of contact sensitivity. Ointments tend to have few ingredients and do not generally require a preservative. At night, even during periods of remission, a heavy moisturizing ointment should be applied to the hands after soaking in water. If palmar dryness is present, occlusion of the moisturizer with a plastic bag or vinyl gloves is recommended. White petrolatum is cheap and nonsensitizing, and remains a valuable agent in the treatment of hand dermatitis. Topical agents Superpotent and potent topical steroid agents are first-line pharmacologic therapy. Their efficacy is enhanced by presoaking and occlusion (soak and smear technique or wet dressings). A single application with occlusion at night is often more effective than multiple daytime applications. As in the treatment of atopic dermatitis, once steroid receptors are saturated, additional applications of a corticos-
teroid contribute only an emollient effect. Triamcinolone 0.1% ointment is available in a nonsensitizing white petrolatum base. It is fairly potent and inexpensive, does not irritate, and has a low incidence of sensitization. In refractory cases, superpotent steroids may be used for a period of 2–3 weeks, then on weekends, with a milder corticosteroid applied during the week. The addition of 2.5% zinc sulfate to clobetasol seemed to enhance efficacy of the topical steroid. Chronic use of potent fluorinated corticosteroids may be associated with skin atrophy. TCIs may be of benefit in some mildly affected patients. Soaks with a tar bath oil or applications of 20% liquor carbonis detergens or 2% crude coal tar in an ointment base may be of benefit, especially in those patients with the hyperkeratotic type of hand eczema. Bexarotene gel can be beneficial in up to 50% of patients with refractory hand eczema. Phototherapy Phototherapy in the form of high-dose UVA-1, soak or cream PUVA, and oral PUVA can be effective. Given the thickness of the palms, UVA irradiation should be delivered 30 min after soaking, as opposed to bath PUVA, which can be done immediately after bathing. Relatively few phototoxic reactions are seen with regimens that use a 15– 20 min soak in a 3 mg/L solution of 8-methoxypsoralen, starting with 0.25–0.5 J/cm2 and increasing by 0.25–0.5 J/cm2 three times a week. Superficial Grenz ray radiotherapy remains a viable modality, but well-maintained machines are few in number. The depth of penetration is limited, so it is best used after acute crusting and vesiculation have been cleared with other treatment. Doses of 200 cG are delivered at weekly intervals for a total of 800–1000 cG. Therapy may be repeated after 6 months. The total lifetime dose should not exceed 5000 cG. Botulinum toxin In patients with palmoplantar hyperhidrosis and associated hand eczema, treatment of the hyperhidrosis with intradermal injections of botulinum toxin leads to both dramatic resolution of the sweating and clearing of the hand eczema. The hand eczema returns when the sweating returns. Iontophoresis, which also reduces sweating, can similarly improve hand dermatitis. This illustrates the importance of wetness in the exacerbation of hand eczema. Systemic agents The systemic agents used to treat severe chronic hand dermatitis are identical to those used for atopic dermatitis. The use of systemic corticosteroids usually results in dramatic improvement. Unfortunately, relapse frequently occurs almost as rapidly, so systemic steroids are recommended only to control acute exacerbations. For instance, patients with infrequent, but severe, outbreaks of pompholyx may benefit from a few weeks of systemic steroids, starting at about 1 mg/kg/day. Patients with persistent severe hand dermatitis should be considered for alternative, steroid-sparing therapy. Methotrexate, in psoriatic doses, azathioprine, and mycophenolate mofetil (in doses of 1–1.5 g twice a day for an adult) can all be considered. Cyclosporine can be effective, but given the chronicity of hand eczema, its use is best reserved for severe outbreaks. Oral retinoids may have a place in the management of hand dermatitis. Alitretinoin, at a dose of 30 mg per day, will lead to complete or near-complete clearance of chronic refractory hand eczema in about 50% of cases. The onset of response is delayed, with some patients achieving optimal benefit only after more than 6 months of treatment. Workplace modifications The incidence of hand dermatitis in the workplace can be reduced by identifying major irritants and allergens, preventing exposure through engineering controls, substituting less irritating chemicals when possible, enforcing personal protection and glove use, and instituting organized worker education. Hand eczema classes have been
Diaper (napkin) dermatitis Diaper dermatitis has dramatically decreased due to highly absorbable disposable diapers. None the less, dermatitis of the diaper area in infants remains a common cutaneous disorder. The highest prevalence occurs between 6 and 12 months of age. Diaper dermatitis is also seen in adults with urinary or fecal incontinence who wear diapers. Irritant diaper dermatitis is an erythematous dermatitis limited to exposed surfaces. The folds remain unaffected, in contrast to intertrigo, inverse psoriasis, and candidiasis, where the folds are frequently involved. In severe cases of irritant dermatitis there may be superficial erosion or even ulceration. The tip of the penis may become irritated and crusted, with the result that the baby urinates frequently and spots of blood appear on the diaper. Complications of diaper dermatitis include punched-out ulcers or erosions with elevated borders (Jacquet erosive diaper dermatitis); pseudoverrucous papules and nodules; and violaceous plaques and nodules (granuloma gluteale infantum). The importance of ammonia in common diaper dermatitis has been overstated, but constant maceration of the skin is critical. The absence of diaper dermatitis in societies in which children do not wear diapers clearly implicates the diaper environment as the cause of the eruption. Moist skin is more easily abraded by friction of the diaper as the child moves. Wet skin is more permeable to irritants. Skin wetness also allows the growth of bacteria and yeast. Bacteria raise the local pH, increasing the activity of fecal lipases and proteases. Candida albicans is frequently a secondary invader and, when present, produces typical satellite erythematous lesions or pustules at the periphery as the dermatitis spreads. Napkin psoriasis (Fig. 5-12), seborrheic dermatitis, atopic dermatitis, Langerhans cell histiocytosis, tinea cruris, allergic contact dermatitis, acrodermatitis enteropathica, amino acidurias, biotin deficiency, and congenital syphilis should be included in the differential diagnosis. Given the skill of most pediatricians in the management of diaper dermatitis, dermatologists should think about these conditions in infants who have failed the standard interventions used by pediatricians. Refractory diaper dermatitis may require a biopsy to exclude some of the above conditions. Prevention is the best treatment. Diapers that contain superabsorbent gel have been proved effective in preventing diaper dermatitis in both neonates and infants. They work by absorbing the wetness away from the skin and by buffering the pH. Cloth diapers and regular disposable diapers are equal to each other in their propensity to cause diaper dermatitis and are inferior to the superabsorbent gel diapers. The frequent changing of diapers is also critical.
Eczema
documented to reduce the burden of occupational dermatitis. It is important to note that prevention of exposure to a weak but frequent irritant can have more profound effects than removal of a strong but infrequently contacted irritant. Proper gloves are essential in industrial settings. Nitrile gloves are generally less permeable than latex gloves. Gloves of ethylene vinyl alcohol copolymer sandwiched with polyethylene are effective against epoxy resin, methyl methacrylate, and many other organic compounds. Latex and vinyl gloves offer little protection against acrylates. The 4H (4 h) glove and nitrile are best in this setting. As hospitals transition to nonlatex gloves, it is important to note that even low-protein, powder-free latex gloves reduce self-reported skin problems among health workers. Barrier products can improve hand dermatitis if used in the appropriate setting. Foams containing dimethicone and glycerin can reduce hand dermatitis related to wet work.
Fig. 5-12 Napkin psoriasis.
Protecting the skin of the diaper area is of great benefit in all forms of diaper dermatitis. Zinc oxide paste is excellent. Zinc oxide paste with 0.25% miconazole may be considered if Candida may be present. If simple improved hygiene and barrier therapy are not effective, the application of a mixture of equal parts nystatin ointment and 1% hydrocortisone ointment at each diaper change offers both anticandidal activity and an occlusive protective barrier from urine and stool, and can be very effective.
Circumostomy eczema Eczematization of the surrounding skin frequently occurs after an ileostomy or colostomy. It is estimated that some 75% of ileostomy patients have some postoperative sensitivity as a result of the leakage of intestinal fluid on to unprotected skin. As the consistency of the intestinal secretion becomes viscous, the sensitization subsides. Proprietary medications containing karaya powder have been found to be helpful. Twenty percent cholestyramine (an ion-exchange resin) in Aquaphor, and topical sucralfate as a powder or emollient at 4 g% concentration, are both effective treatments. Psoriasis may also appear at ostomy sites. Topical treatment may be difficult, as the appliance adheres poorly after the topical agents are applied. A topical steroid spray may be used, and will not interfere with appliance adherence. Contact dermatitis to the ostomy bag adhesive can be problematic, as even supposed hypo allergenic ostomy bags may still trigger dermatitis in these patients.
Autosensitization and conditioned irritability The presence of a localized, chronic, and usually severe focus of dermatitis may affect distant skin in two ways. Patients with a chronic localized dermatitis may develop dermatitis at distant sites from scratching or irritating the skin. This is called “conditioned irritability.” The most common scenario is distant dermatitis in a patient with a chronic eczematous leg ulcer. Autoeczematization refers to the spontaneous development of widespread dermatitis or dermatitis distant from a local inflammatory focus. The agent causing the local inflammatory focus is not the direct cause of the dermatitis at the distant sites. Autoeczematization most commonly presents as a generalized acute vesicular eruption with a prominent dyshidrosiform component on the hands. The most common associated condition is a chronic eczema of the legs, with or without ulceration. The “angry back” or “excited skin” syndrome observed with strongly positive patch tests, and the local dermatitis seen around infectious foci (infectious eczematoid dermatitis), may represent a limited form of this reaction. 75
Id reactions
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Patients with a variety of infectious disorders may present with eczematous dermatitis. The classic example is the vesicular id reactions of the hands in response to an inflammatory tinea of the feet. Similarly, inflammatory tinea capitis is often associated with a focal or diffuse dermatitis, primarily of the upper half of the body. Nummular eczematous lesions or pity riasis rosea-like lesions may occur in patients with head or pubic louse infestation. Id reactions clear when the focus of infection or infestation is treated.
Juvenile plantar dermatosis Juvenile plantar dermatosis is an eczematous disorder of children, first described by Enta and Moller in 1972, and named by Mackie in 1976. It is probably the same disease as symmetrical lividity of the soles described by Pernet in 1925. It usually begins as a patchy, symmetrical, smooth, red, glazed macule on the base or medial surface of the great toes, sometimes with fissuring and desquamation, in children aged 3 to puberty. Lesions evolve into red scaling patches involving the weightbearing and frictional areas of the feet, usually symmetrically (Fig. 5-13). The forefoot is usually much more involved than the heel. Toe webs and arches are spared. The eruption is disproportionately more common in atopic children. In some patients, a similar eruption occurs on the fingers. The disease is caused by the repeated maceration of the feet by occlusive shoes, especially athletic shoes, or by the abrasive effects of pool surfaces or diving boards. The affected soles remain wet in the rubber bottoms of the shoes or are macerated by pool water. Thin, nonabsorbent, synthetic socks contribute to the problem. Histologically, there is psoriasiform acanthosis and a sparse, largely lymphocytic infiltrate in the upper dermis, most dense around sweat ducts at their point of entry into the epidermis. Spongiosis is commonly present and the stratum corneum is thin but compact. The diagnosis is apparent on inspection, especially if there is a family or personal history of atopy and the toe webs are spared. Allergic contact dermatitis to shoes and dermatophytosis should be considered in the differential diagnosis.
Fig. 5-13 Glazed appearance of the weight-bearing surfaces in juvenile plantar dermatosis.
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Allergic shoe dermatitis usually involves the dorsal foot, but some patients with rubber allergy have predominant involvement of the soles. Treatment involves avoidance of maceration. Foot powders, thick absorbent socks, absorbent insoles, and having alternate pairs of shoes to wear to allow the shoes to dry out are all beneficial. Topical steroid medications are of limited value and often are no more effective than occlusive barrier protection. Petrolatum or urea preparations can sometimes be of benefit. Most cases clear within 4 years of diagnosis.
Xerotic eczema Xerotic eczema is also known as winter itch, eczema craquelé, and asteatotic eczema. These vividly descriptive terms are all applied to dehydrated skin showing redness, dry scaling, and fine crackling that may resemble crackled porcelain or the fissures in the bed of a dried lake or pond. The primary lesion is an erythematous patch covered with an adherent scale. As the lesion enlarges, fine cracks in the epidermis occur (Fig. 5-14). Nummular lesions may occur. Xerotic “nummular” eczema is less weepy than classic nummular dermatitis. Favored sites are the anterior shins, extensor arms, and flank. Elderly persons are particularly predisposed, and xerosis appears to be the most common cause of pruritus in older individuals. Xerotic eczema is seen most frequently during the winter, when there is low relative humidity. Bathing with hot water and harsh soaps contributes. The epidermal water barrier is impaired and TEWL is increased. Epidermal barrier repair begins to decrease after age 55. It is correlated with an increase in epidermal pH. This is why older patients complain that they have not changed their bathing routine or soaps, yet have developed xerotic dermatitis. The loss of barrier repair ability is improved by acidifying the epidermis; hence the benefit of mild acids in treating xerosis. Short tepid baths, limitation of the use of soap to soiled and apocrine-bearing areas, avoiding harsh soaps and using acid pH synthetic detergents, and prompt application of an emollient after bathing are usually effective. White petrolatum and emollients containing 10% urea or 5% lactic acid are effective.
Fig. 5-14 Fine network of epidermal fissures in eczema craquelé.
Fig. 5-15 Nummular eczema.
Topical steroids in ointment vehicles are useful for inflamed areas.
Nummular eczema (discoid eczema) Nummular eczema usually begins on the lower legs, dorsa of the hands, or extensor surfaces of the arms. A single lesion often precedes the eruption and may be present for some time before other lesions appear. The primary lesions are discrete, coin-shaped, erythematous, edematous, vesicular, and crusted patches (Fig. 5-15). Most lesions are 2–40 cm in diameter. Lesions may form after trauma (conditioned hyperirritability). As new lesions appear, the old lesions expand as tiny papulo vesicular satellite lesions appear at the periphery and fuse with the main plaque. In severe cases the condition may spread into palm-sized or larger patches. Pruritus is usually severe and of the same paroxysmal, compulsive quality and nocturnal timing seen in atopic dermatitis and prurigo nodularis. Atopic dermatitis frequently has nummular morphology in adolescents, but in atopy the lesions tend to be more chronic and lichenified. Histologically, nummular eczema is characterized by acute or subacute spongiotic dermatitis. Initial treatment consists of simple soaking and greasing with an occlusive ointment, and once or twice a day application of a potent or superpotent topical steroid cream or ointment. Ointments are more effective and occlusion may be necessary. If secondary staphylococcal infection is present, an antibiotic with appropriate coverage is recommended. Sedating antihistamines at bedtime are useful to help with sleep and reduce night-time scratching. In some cases refractory to topical agents, intralesional or systemic corticosteroid therapy may be required. In cases failing topical steroids, phototherapy with NB-UVB, or soak or oral PUVA can be effective. For refractory plaques, the addition of topical tar as 2% crude coal tar or 20% LCD may be beneficial.
Pruritic dermatitis in the elderly Pruritic skin conditions are common in elderly patients. They begin to appear around age 60 and increase in severity with
Hormone-induced dermatoses
age. Males are more commonly affected. The dermatoses seen in this age group are typically either eczematous or papular. The eczematous plaques may resemble nummular dermatitis, a feature recognized by Marion Sulzberger when he coined the phrase “exudative discoid and lichenoid chronic dermatitis” or “oid-oid disease.” The pathogenic basis of this component of dermatitis in the elderly may be related to barrier failure due to loss of acidification of the epidermis. In addition, patients often have urticarial papules on the trunk and proximal extremities that resemble insect bites. These lesions are termed “subacute prurigo.” Histologically, they demonstrate features of an arthropod assault, with superficial and deep perivascular lymphohistiocytic infiltrates, dermal edema, and at times interstitial eosinophils. Lesions may also show features of transient acantholytic dermatitis or eosinophilic folliculitis. This component of the eruption may be related to the tendency of the elderly to have immune systems that skew toward Th2, due to loss of Th1 function. At times patients will have both types of eruption, either simultaneously or sequentially. The combination of barrier failure and an immune system skewed toward Th2 is parallel to what occurs in the setting of atopic dermatitis. For this reason, some practitioners consider this “adult atopic dermatitis.” However, it is unknown whether these conditions have a genetic basis, or more likely, given the time of onset, are due to acquired barrier and immune system abnormalities. In these patients, allergic contact dermatitis and photodermatitis may be present or develop. Patch testing may identify important allergens, avoidance of which leads to improvement. Calcium channel blockers may be associated with this condition, but stopping them will clear only about one-quarter of patients on that class of medication. Treatment for these patients is similar to treatment of atopic dermatitis, with antihistamines, emollients, and topical steroids (soak and smear) as the first line. In refractory cases, phototherapy (UVB or PUVA), Goeckerman therapy (UVB plus crude coal tar) in a day-treatment setting, and immunosuppressive agents can be effective. Inadvertent use of phototherapy in the patient with coexistent photosensitivity will lead to an exacerbation of the disorder.
Hormone-induced dermatoses Autoimmune progesterone dermatitis may appear as urticarial papules, deep gyrate lesions, papulovesicular lesions, an eczematous eruption, or targetoid lesions. Urticarial and erythema multiforme-like lesions are most characteristic. Lesions typically appear 5–7 days before menses, and improve or resolve a few days following menses. Biopsies show dense superficial and deep dermal lymphocytic infiltration, with involvement of the follicles, and an admixture of eosinophils. There may be an accompanying mild interface component, as seen in drug eruptions. Pruritus is common. Onset is typically in the third and fourth decades. Familial cases have been reported. When urticaria is the predominant skin lesion, there is a generalized distribution, and it may be accompanied by laryngospasm. Anaphylactoid reactions may occur. Oral erosions may be present. The eruption typically appears during the luteal phase of the menstrual period, and spontaneously clears following menstruation, only to return in the next menstrual period. Many of the reported patients had received artificial progestational agents before the onset of the eruption. In some it appeared during a normal pregnancy. The eruption may worsen or clear during pregnancy. Rarely, it can occur in males and adolescent females. Progesterone luteal phase support during in vitro fertilization has exacerbated the disease. 77
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In most cases, diagnosis has been confirmed by intradermal testing with 0.01 mL of aqueous progesterone suspension (50 mg/mL). A positive test may be immediate (30 min) or delayed (24–96 h). Flares may be induced by intramuscular or oral progesterone. The most commonly used treatment is an oral contraceptive to suppress ovulation, thereby reducing progesterone levels. Topical steroids, antihistamines (cetirizine plus hydroxyzine), conjugated estrogen, leuprolide acetate, danazol, and tamoxifen may be effective in some cases. Autoimmune estrogen dermatitis also presents as a cyclic skin disorder that may appear eczematous, papular, bullous, or urticarial. Pruritus is typically present. Skin eruptions may be chronic but are exacerbated premenstrually or occur only immediately before the menses. Characteristically, the dermatosis clears during pregnancy and at menopause. Intracutaneous skin testing with estrone produces a papule lasting longer than 24 h or an immediate urticarial wheal (in cases with urticaria). Injections of progesterone yield negative results, ruling out autoimmune progesterone dermatitis. Tamoxifen is effective in some cases. Agner T, et al: Hand eczema severity and quality of life: a crosssectional, multicentre study of hand eczema patients. Contact Dermatitis 2008; 59:43. Amato L, et al: Atopic dermatitis exclusively localized on nipples and areolas. Pediatr Dermatol 2005; 22:64. Amin KA, et al: The aetiology of eyelid dermatitis: a 10-year retrospective analysis. Contact Dermatitis 2006; 55:280. Aydin O, et al: Non-pustular palmoplantar psoriasis: is histologic differentiation from eczematous dermatitis possible? J Cutan Pathol 2008; 35:169. Barankin B, et al: Nipple and areolar eczema in the breastfeeding woman. J Cutan Med Surg 2004; 8:126. Behrens S, et al: PUVA-bath photochemotherapy (PUVA-soak therapy) of recalcitrant dermatoses of the palms and soles. Photodermatol Photoimmunol Photomed 1999; 15:47. Chawla SV, et al: Autoimmune progesterone dermatitis. Arch Dermatol 2009; 145:341. Cvetkovski RS, et al: Prognosis of occupational hand eczema: a follow-up study. Arch Dermatol 2006; 142:305. Diepgen TL, et al: Hand eczema classification: a cross-sectional, multicentre study of the aetiology and morphology of hand eczema. Br J Dermatol 2009; 160:353. Elston DM, et al: Hand dermatitis. J Am Acad Dermatol 2002; 47:291. Faghihi G, et al: The efficacy of ‘0.05% clobetasol + 2.5% zinc sulphate’ cream vs. ‘0.05% clobetasol alone’ cream in the treatment of the chronic hand eczema: a double-blind study. J Eur Acad Dermatol Venereol 2008; 22:531. Feser A, et al: Periorbital dermatitis—a recalcitrant disease: causes and differential diagnoses. Br J Dermatol 2008; 159:858. Guillet MH, et al: A 3-year causative study of pompholyx in 120 patients. Arch Dermatol 2007; 143:1504. Halevy S, et al: Autoimmune progesterone dermatitis manifested as erythema annulare centrifugum: confirmation of progesterone sensitivity by in vitro interferon-gamma release. J Am Acad Dermatol 2002; 47:311. Hanifin JM, et al: Novel treatment of chronic severe hand dermatitis with bexarotene gel. Br J Dermatol 2004; 150:545. Jacob SE: Ciclosporin ophthalmic emulsion—a novel therapy for benzyl alcohol-associated eyelid dermatitis. Contact Dermatitis 2008; 58:169. Jarvikallio A, et al: Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch Dermatol Res 2003; 295:2. Jenkins J, et al: Autoimmune progesterone dermatitis associated with infertility treatment. J Am Acad Dermatol 2008; 58:353. Kontochristopoulos G, et al: Letter: regression of relapsing dyshidrotic eczema after treatment of concomitant hyperhidrosis with botulinum toxin-A. Dermatol Surg 2007; 33:1289. Kucharekova M, et al: A randomized comparison of an emollient containing skin-related lipids with a petrolatum-based emollient as adjunct in the treatment of chronic hand dermatitis. Contact Dermatitis 2003; 48:293.
Lerbaek A, et al: Incidence of hand eczema in a population-based twin cohort: genetic and environmental risk factors. Br J Dermatol 2007; 157:552. Meding B, et al: Fifteen-year follow-up of hand eczema: persistence and consequences. Br J Dermatol 2005; 152:975. Meding B, et al: Fifteen-year follow-up of hand eczema: predictive factors. J Invest Dermatol 2005; 124:893. Modak S, et al: A topical cream containing a zinc gel (allergy guard) as a prophylactic against latex glove-related contact dermatitis. Dermatitis 2005; 16:22. Mutasim DF, et al: Bullous autoimmune estrogen dermatitis. J Am Acad Dermatol 2003; 49:130. Nivenius E, et al: Tacrolimus ointment vs steroid ointment for eyelid dermatitis in patients with atopic keratoconjunctivitis. Eye 2007; 21:968. Oskay T, et al: Autoimmune progesterone dermatitis. Eur J Dermatol 2002; 12:589. Petering H, et al: Comparison of localized high-dose UVA1 irradiation versus topical cream psoralen-UVA for treatment of chronic vesicular dyshidrotic eczema. J Am Acad Dermatol 2004; 50:68. Pozo-Roman T, et al: Psoralen cream plus ultraviolet A photochemotherapy (PUVA cream): our experience. J Eur Acad Dermatol Venereol 2006; 20:136. Rasi A, et al: Autoimmune progesterone dermatitis. Int J Dermatol 2004; 43:588. Robertson L: New and existing therapeutic options for hand eczema. Skin Therapy Lettercom, 2009. Ruzicka T, et al: Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebocontrolled, multicentre trial. Br J Dermatol 2008; 158:808. Salam TN, et al: Balsam-related systemic contact dermatitis. J Am Acad Dermatol 2001; 45:377. Shackelford KE, et al: The etiology of allergic-appearing foot dermatitis: a 5-year retrospective study. J Am Acad Dermatol 2002; 47:715. Snyder JL, et al: Autoimmune progesterone dermatitis and its manifestation as anaphylaxis: a case report and literature review. Ann Allergy Asthma Immunol 2003; 90:469. Swartling C, et al: Treatment of dyshidrotic hand dermatitis with intradermal botulinum toxin. J Am Acad Dermatol 2002; 47:667. Temesvari E, et al: Periocular dermatitis: a report of 401 patients. J Eur Acad Dermatol Venereol 2009; 23:124. Veien NK, et al: Hand eczema: causes, course, and prognosis I. Contact Dermatitis 2008; 58:330. Veien NK, et al: Hand eczema: causes, course, and prognosis II. Contact Dermatitis 2008; 58:335. Walling HW, et al: Autoimmune progesterone dermatitis. Case report with histologic overlap of erythema multiforme and urticaria. Int J Dermatol 2008; 47:380.
Immunodeficiency syndromes Primary immunodeficiency diseases (PIDs), although rare, are important to the dermatologist. They may present with skin manifestations, and the dermatologist may be instrumental in referring appropriate patients for immunodeficiency evaluations. These conditions have also given us tremendous insight into the genetic makeup and functioning of the immune system. The PIDs are still classified as those with predominantly antibody deficiency, impaired cell-mediated immunity (cellular immunodeficiencies, T cells, natural killer (NK) cells), combined B- and T-cell deficiencies, defects of phagocytic function, complement deficiencies, and wellcharacterized syndromes with immunodeficiency. More than 120 PIDs were identified, as of the 2005 classification. While many PIDs will present within the first year of life, adult presentations can occur. The dermatologist should suspect a PID in certain situations. Skin infections, especially chronic and recurrent bacterial skin infections, are often the initial manifestation of a PID. Fungal (especially Candida) and viral infections (warts, molluscum) less commonly are the dermatological presentation of a PID.
Abrams M, et al: Genetic immunodeficiency diseases. Adv Dermatol 2007; 23:197. Notarangelo L, et al: Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J Allergy Clin Immunol 2006; 117:883. Ozcan E, et al: Primary immune deficiencies with aberrant IgE production. J Allergy Clin Immunol 2008; 122:1054. Sillevis Smitt JH, et al: The skin in primary immunodeficiency disorders. Eur J Dermatol 2005; 15:425.
Disorders of antibody deficiency X-linked agammaglobulinemia (XLA) Also known as Bruton syndrome, this rare hereditary immunologic disorder usually only becomes apparent between 4 and 12 months of life, since the neonate obtains adequate immunoglobulin from the mother to protect it from infection in young infancy. The affected boys present with infections of the upper and lower respiratory tracts, gastrointestinal tract, skin, joints, and central nervous system (CNS). The infections are usually due to Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas. Recurrent skin staphylococcal infection may be a prominent component of this condition. Atopic-like dermatitis and pyoderma gangrenosum have been described. Hepatitis B, enterovirus, and rotavirus infections are common in XLA patients and onethird develop a rheumatoid-like arthritis. Enterovirus infection may result in a dermatomyositis–meningoencephalitis syndrome. An absence of palpable lymph nodes is characteristic. IgA, IgM, IgD, and IgE are virtually absent from the serum, although IgG may be present in small amounts. The spleen and lymph nodes lack germinal centers, and plasma cells are absent from the lymph nodes, spleen, bone marrow, and connective tissues. In XLA B cells usually only make up 0.1% of circulating peripheral blood lymphocytes (normal 5–20%). More than 500 different mutations have been identified in the Btk gene in XLA patients. Some of these mutations only partially compromise the gene, so some patients may have milder phenotype and up to 7% circulating B cells, making differentiation from common variable immunodeficiency difficult. The Bruton tyrosine kinase (Btk) is essential for the development of B lymphocytes. Treatment with relatively high-dose gamma globulin has enabled many patients to live into adulthood. Chronic sinusitis and pulmonary infection remain problematic due to the lack of IgA. Chronic pulmonary disease affects 76% of XLA patients over the age of 20 years. Hunter HL, et al: Eczema and X-linked agammaglobulinaemia. Clin Exp Dermatol 2008; 33:148. Lin MT, et al: De novo mutation in the BTK gene of atypical X-linked agammaglobulinemia in a patient with recurrent pyoderma. Ann Allergy Asthma Immunol 2006; 96:744.
Isolated IgA deficiency An absence or marked reduction of serum IgA occurs in approximately 1 in 600, making it the most common immunodeficiency state. Autosomal-dominant, autosomal-recessive, and sporadic cases have been reported. Certain medications appear to induce selective IgA deficiency, including phenytoin, sulfasalazine, cyclosporine, nonsteroidal antiinflammatory drugs (NSAIDs), and hydroxychloroquine. The genetic cause in most cases is unknown, but a few cases have a mutation in the tumor necrosis factor (TNF) receptor family member TACI. Common variable immunodeficiency (CVID) may develop in patients with IgA deficiency, or other members of IgA-deficient patients’ families may have CVID. Ten to fifteen percent of all symptomatic immunodeficiency patients have IgA deficiency. Most IgA-deficient patients are entirely well, however. Of those with symptoms, half have repeated infections of the gastrointestinal and respiratory tracts, and one-quarter have autoimmune disease. Allergies such as anaphylactic reactions to transfusion or IVIG, asthma, and atopic dermatitis are common in the symptomatic group. There is an increased association of celiac disease, dermatitis herpetiformis, and inflammatory bowel disease. Vitiligo, alopecia areata, and other autoimmune diseases such as systemic lupus erythematosus, dermatomyositis, scleroderma, thyroiditis, rheumatoid arthritis, polyarteritis-like vasculitis and Sjögren syndrome have all been reported to occur in these patients. Malignancy is increased in adults with IgA deficiency.
Immunodeficiency syndromes
Eczematous dermatitis and erythroderma, at times closely resembling severe atopic dermatitis or seborrheic dermatitis, may affect the skin of PID patients. They may be refractory to standard therapies. Granuloma formation, autoimmune disorders, and vasculitis are other cutaneous manifestations seen in some forms of primary immunodeficiency. The PIDs in which a specific infection or finding is the more common presentation are discussed in other chapters (for example, chronic mucocutaneous candidiasis in Chapter 15; Hermansky– Pudlak, Chédiak–Higashi, and Griscelli syndromes with pigmentary anomalies (Chapter 36), and cartilage–hair hypoplasia syndrome with disorders of hair (Chapter 33). The conditions described below are the most important PID conditions with which dermatologists should be familiar.
Mellemkjaer L, et al: Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study. Clin Exp Immunol 2002; 130:495. Paradela S, et al: Necrotizing vasculitis with a polyarteritis nodosa-like pattern and selective immunoglobulin A deficiency: case report and review of the literature. J Cutan Pathol 2008; 35:871. Samolitis NJ, et al: Dermatitis herpetiformis and partial IgA deficiency. J Am Acad Dermatol 2006; 54:S206. Uram R, et al: Isolated IgA deficiency after chemotherapy for acute myelogenous leukemia in an infant. Pediatr Hematol Oncol 2003; 20:487.
Common variable immunodeficiency Common variable immunodeficiency (CVID), also known as acquired hypogammaglobulinemia, is a heterogeneous disorder and is the most common immunodeficiency syndrome after IgA deficiency. Patients have low levels of IgG and IgA, and 50% also have low levels of IgM. The genetic defect is unknown. These patients do not form antibodies to bacterial antigens, and have recurrent sinopulmonary infections. They have a predisposition to autoimmune disorders, such as vitiligo and alopecia areata, gastrointestinal abnormalities, lymphoreticular malignancy, and gastric carcinoma. Cutaneous, as well as visceral, granulomas have been reported in as many as 22% of patients. These can involve both the skin and the viscera, creating a sarcoidosis-like clinical syndrome. Replacement of the reduced immunoglobulins with IVIG may help reduce infections. Topical, systemic, and intralesional corticosteroids may be used for the granulomas, depending on their extent. Infliximab and etanercept have been effective in steroid-refractory cases. Artac H, et al: Sarcoid-like granulomas in common variable immunodeficiency. Rheumatol Int 2009 (Epub ahead of print). Fernandez-Ruiz M, et al: Fever of unknown origin in a patient with common variable immunodeficiency associated with multisystemic granulomatous disease. Intern Med 2007; 46:1197. Lin JH, et al: Etanercept treatment of cutaneous granulomas in common variable immunodeficiency. J Allergy Clin Immunol 2006; 117:878.
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Lun KR, et al: Granulomas in common variable immunodeficiency: a diagnostic dilemma. Australas J Dermatol 2004; 45:51. Mazzatenta C, et al: Granulomatous dermatitis in common variable immunodeficiency with functional T-cell defect. Arch Dermatol 2006; 142:783. Mitra A, et al: Cutaneous granulomas associated with primary immunodeficiency disorders. Br J Dermatol 2005; 153:194.
Class-switch recombination defects (formerly immunodeficiency with hyper-IgM) This group of diseases includes disorders which are combined T- and B-cell abnormalities, such as CD40 deficiency and CD40 ligand deficiency, and disorders of primary B cells, such as cytidine deaminase and uracil-DNA glycosylase deficiencies. They are rare, and the different genetic diseases included in this group appear to have different clinical manifestations. These patients experience recurrent sinopulmonary infections, diarrhea, and oral ulcers. Neutropenia may be associated with the ulcers. Recalcitrant human papillomavirus infections may occur. Chang MW, et al: Mucocutaneous manifestations of the hyper-IgM immunodeficiency syndrome. J Am Acad Dermatol 1998; 38:191. Gilmour KC, et al: Immunological and genetic analysis of 65 patients with a clinical suspicion of X-linked hyper-IgM. Mol Pathol 2003; 56:256. Kasahara Y, et al: Hyper-IgM syndrome with putative dominant negative mutation in activation-induced cytidine deaminase. J Allergy Clin Immunol 2003; 112:755. Kutukculer N, et al: Disseminated Cryptosporidium infection in an infant with hyper-IgM syndrome caused by CD40 deficiency. J Pediatr 2003; 142:194.
Thymoma with immunodeficiency Thymoma with immunodeficiency, also known as Good syndrome, occurs in adults in whom profound hypogammaglobulinemia and benign thymoma appear almost simultaneously. It is now classified predominantly as an antibody deficiency disorder. There is a striking deficiency of B and pre-B cells. One patient developed vulvovaginal gingival lichen planus. Myelodysplasia and pure red cell aplasia may occur. Patients are at risk for fatal opportunistic pulmonary infections with fungi and Pneumocystis. Thymectomy does not prevent the development of the infectious or lymphoreticular complications. Supportive therapy with IVIG, GM-CSF, and transfusions may be required. Di Renzo M, et al: Myelodysplasia and Good syndrome. A case report. Clin Exp Med 2008; 8:171. Jian L, et al: Fatal Pneumocystis pneumonia with Good syndrome and pure red cell aplasia. Clin Infect Dis 2004; 39:1740. Moutasim KA, et al: A case of vulvovaginal gingival lichen planus in association with Good’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105:e57. Ohuchi M, et al: Good syndrome coexisting with leukopenia. Ann Thorac Surg 2007; 84:2095.
Disorders with T-cell deficiency T-cell deficiency states can occur due to lack of thymic tissue, enzyme defects toxic to T lymphocytes (purine nucleoside phosphorylase deficiency), failure to express surface molecules required for immune interactions (CD3, major histocompatibility complex (MHC) class I and II), or defects in signaling molecules (ZAP-70).
DiGeorge syndrome DiGeorge syndrome is also called congenital thymic hypoplasia, the velocardiofacial syndrome, and III and IV pharyngeal 80
pouch syndrome. It is an autosomal-dominant disorder, which, in 50% of cases, is due to hemizygous deletion of 22q11pter and rarely due to deletions in 10p. Many cases are sporadic. Most DiGeorge syndrome patients have the congenital anomalies and only minor thymic anomalies. They present with hypocalcemia or congenital heart disease. The syndrome includes congenital absence of the parathyroids and an abnormal aorta. Aortic and cardiac defects are the most common cause of death. DiGeorge syndrome is characterized by a distinctive facies: notched, low-set ears, micrognathia, shortened philtrum, and hypertelorism. Patients with these DiGeorge congenital malformations and complete lack of thymus are deemed to have “complete DiGeorge syndrome.” Cellmediated immunity is absent or depressed, and few T cells with the phenotype of recent thymus emigrants are found in the peripheral blood or tissues. Opportunistic infections commonly occur despite normal immunoglobulin levels. Maternally derived graft-versus-host disease (GVHD) may occur in these patients. A small subset of patients with complete DiGeorge syndrome develop an eczematous dermatitis, lymphadenopathy, and an oligoclonal T-cell proliferation. The condition may present as an atopic-like dermatitis, severe and extensive seborrheic dermatitis, or an erythroderma. This is called “atypical complete DiGeorge syndrome.” Biopsies show features of a spongiotic dermatitis with eosinophils, necrotic keratinocytes with satellite necrosis, and characteristically peri- and intraeccrine inflammation. This resembles the histology of grade 1–2 GVHD, lichen striatus, and some cases of mycosis fungoides. One African American patient with DiGeorge syndrome developed a granulomatous dermatitis. The treatment for complete DiGeorge syndrome is thymic transplantation. Jyonouchi H, et al: SAPHO osteomyelitis and sarcoid dermatitis in a patient with DiGeorge syndrome. Eur J Pediatr 2006; 165:370. Patel JY, et al: Thymus transplantation advances in DiGeorge syndrome. Curr Allergy Asthma Rep 2005; 5:348. Selim MA, et al: The cutaneous manifestations of atypical complete DiGeorge syndrome: a histopathologic and immunohistochemical study. J Cutan Pathol 2008; 35:380.
Purine nucleoside phosphorylase deficiency This very rare autosomal-recessive enzyme defect leads to greatly reduced T-cell counts and depressed cell-mediated immunity. B-cell numbers are normal, but immunoglobulins may be normal or decreased. Mutation in the gene for the enzyme located on chromosome 14q13 is responsible. Accumulation of purines in cells of the lymphoid system and CNS leads to the clinical findings of T-cell deficiency and neurological impairment. Patients usually present at between 3 and 18 months of age with recurrent infections involving the upper and lower respiratory tracts, spasticity, ataxia, developmental delay, and autoimmune hemolytic anemia. They usually die from overwhelming viral infections. Bone marrow transplant may be life-saving. Aytekin C, et al: An unconditioned bone marrow transplantation in a child with purine nucleoside phosphorylase deficiency and its unique complication. Pediatr Transplant 2008; 12:479. Delicou S, et al: Successful HLA-identical hematopoietic stem cell transplantation in a patient with purine nucleoside phosphorylase deficiency. Pediatr Transplant 2007; 11:799. Gregoriou S, et al: Cutaneous granulomas with predominantly CD8(+) lymphocytic infiltrate in a child with severe combined immunodeficiency. J Cutan Med Surg 2008; 12:246. Liao P, et al: Lentivirus gene therapy for purine nucleoside phosphorylase deficiency. J Gene Med 2008; 10:1282. Ozkinay F, et al: Purine nucleoside phosphorylase deficiency in a patient with spastic paraplegia and recurrent infections. J Child Neurol 2007; 22:741.
TAP 1 and TAP 2 gene deficiencies are very, very rare autosomal-recessive disorders that result in severe reduction of MHC class I expression on the surface of cells. CD8 cells are decreased but CD4 cells are normal, as are B-cell numbers and serum immunoglobulins. Three forms of disease occur. One phenotype develops severe bacterial, fungal, and parasitic infection, and dies by age 3. The second phenotype is completely asymptomatic. The third group is the most common. Group 3 patients present in childhood with recurrent and chronic bacterial respiratory infections. These lead to bronchiectasis and eventually fatal respiratory failure in adulthood. The skin abnormalities appear in late childhood or more commonly in young adulthood (after age 15). Necrotizing granulomatous lesions appear as plaques or ulcerations on the lower legs and on the midface around the nose. The perinasal lesions are quite destructive and resemble “lethal midline granuloma” or Wegener’s granulomatosis. Nasal polyps with necrotizing granulomatous histology also occur. One patient also developed leukocytoclastic vasculitis. MHC class II deficiency is due to mutations in transcription factors for MHC class II proteins (C2TA, RFX5, RFXAP, RFSANK genes). It is inherited in an autosomal-recessive manner and results in decreased CD4 cells. ZAP-70 deficiency is an autosomal-recessive disorder of considerable heterogeneity. This enzyme is required for T-cell receptor intracellular signaling. Patients present before age 2 with recurrent bacterial, viral, and opportunistic infections, diarrhea, and failure to thrive. They have a lymphocytosis with normal CD4 cells and decreased CD8 cells. Some patients develop an exfoliative erythroderma, eosinophilia, and elevated IgE levels. Omenn syndrome is a rare autosomal-recessive disorder that presents at birth or in the neonatal period. Clinical features are exfoliative erythroderma, eosinophilia, diarrhea, hepatosplenomegaly, lymphadenopathy, hypogammaglobulinemia with elevated IgE, recurrent infections, and early death (usually by 6 months of age). Both antibody production and cell-mediated immune function are impaired. T-cell receptor rearrangements are severely restricted in patients with Omenn syndrome. Mutations in RAG1, RAG2, Artemis, and IL-7Ralpha genes may result in Omenn syndrome. Anhidrotic ectodermal dysplasia with immunodeficiency is an X-linked recessive disorder with lymphocytosis and elevated CD3 and CD4 cells, and low levels of NK cells. It is due to a mutation in the gene that codes for nuclear factor κ B essential modulator (NEMO). The mother may have mild stigmata of incontinentia pigmentii. The mutations are hypomorphic (some NEMO function is preserved). These male infants present within the first few months of life with hypohidrosis, delayed tooth eruption, and immunodeficiency. Hair may be absent. Frequent infections of the skin and respiratory tract are common. The eruption has been characterized as an “atopic dermatitis-like eruption,” although some cases may have prominent intertriginous lesions resembling seborrheic dermatitis. Treatment is bone marrow transplantation. A similar autosomal-dominant syndrome is caused by a mutation in the gene IKBA (inhibitory κ B kinase γ). IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) is a rare disorder with neonatal autoimmune enteropathy, diabetes, thyroiditis, food allergies, and skin eruptions. IPEX is caused by mutations in FOXP3, the master control gene for regulatory T-cell (Treg) development. Patients present with diffuse and severe erythematous exudative plaques resembling atopic dermatitis. The skin eruption may be follicularly based or lead to prurigo
nodularis. The scalp develops hyperkeratotic psoriasiform plaques. Cheilitis and onychodystrophy can occur. Staphylococcal sepsis may develop.
Severe combined immunodeficiency disease This heterogeneous group of genetic disorders is characterized by severely impaired humoral and cellular immunity. Moniliasis of the oropharynx and skin, intractable diarrhea, and pneumonia are the triad of findings that commonly lead to the diagnosis of severe combined immunodeficiency disease (SCID). In addition, severe recurrent infections may occur, caused by Pseudomonas, Staphylococcus, Enterobacteriaceae, or Candida. Overwhelming viral infections are the usual cause of death. Engraftment of maternally transmitted or transfusionderived lymphocytes can lead to GVHD. The initial seborrheic dermatitis-like eruption may represent maternal engraftment GVHD. This cutaneous eruption may be asymptomatic but tends to generalize. More severe eczematous dermatitis and erythroderma may develop with alopecia. Cutaneous granulomas have been reported in a Jak-3-deficient SCID patient. SCID is characterized by deficiency or total absence of circulating T lymphocytes. Immunoglobulin levels are consistently very low, but B-cell numbers may be reduced, normal, or increased. The thymus is very small; its malformed architecture at autopsy is pathognomonic. The inheritance may be autosomal-recessive or X-linked; the most common type of SCID is X-linked. A deficiency of a common γ-chain that is an essential component of the IL-2 receptor is responsible for the profound lymphoid dysfunction in X-linked SCID. This abnormality also causes defects in IL-4, 7, 9, 15, and 21. The mutation has been mapped to Xq13.1. About half the autosomal-recessive cases have a deficiency of adenosine deaminase, the gene for which is located on chromosome 20q13. Mutations in Jak-3, IL-7Ralpha, CD45, CD3delta/CD3epsilon, RAG1 or RAG2, and Artemis (DCLREC1C) can all also cause the SCID phenotype. Reticular dysgenesis causes SCID, granulocytopenia, and thrombocytopenia. Prenatal diagnosis and carrier detection are possible for many forms of SCID. The definitive treatment is hematopoietic stem cell transplantation (HSCT, bone marrow transplantation). This should ideally be carried out before 3 months of age for optimal outcome. The success rate is less than 90%. In utero hematopoietic stem cell transplantation has been successful in X-linked SCID. SCID patients rarely live longer than 2 years without transplantation. On average, 8 years after successful HSCT, SCID patients may develop severe human papillomavirus (HPV) infection with common warts, flat warts, or even epidermodysplasia verruciformis. The development of HPV infections in SCID patients following HSCT is only seen in patients with either JAK-3 or γ-chain (gamma c) deficiency, but in those patients more than 50% may develop this complication.
Immunodeficiency syndromes
Miscellaneous T-cell deficiencies
Gadola SD, et al: TAP deficiency syndrome. Clin Exp Immunol 2000; 121:173. Gaspar HB, et al: Severe cutaneous papillomavirus disease after haematopoietic stem-cell transplantation in patients with severe combined immunodeficiency. Br J Haematol 2004; 127:232. Halabi-Tawil M, et al: Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br J Dermatol 2009; 160:645. Katugampola RP, et al: Omenn’s syndrome: lessons from a red baby. Clin Exp Dermatol 2008; 33:425. Laffort C, et al: Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gamma c cytokine receptor subunit or JAK-3 deficiency. Lancet 2004; 363:2051.
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Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
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Mancini AJ, et al: X-linked ectodermal dysplasia with immunodeficiency caused by NEMO mutation: early recognition and diagnosis. Arch Dermatol 2008; 144:342. Moins-Teisserenc HT, et al: Association of a syndrome resembling Wegener’s granulomatosis with low surface expression of HLA class-I molecules. Lancet 1999; 354:1598. O’Shea JJ, et al: Jak3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol 2004; 41:727. Plebani A, et al: Defective expression of HLA class I and CD1a molecules in boy with Marfan-like phenotype and deep skin ulcers. J Am Acad Dermatol 1996; 35:814. Turul T, et al: Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency. Eur J Pediatr 2009; 168:87. Zimmer J, et al: Clinical and immunological aspects of HLA class I deficiency. QJM 2005; 98:719.
WHIM syndrome WHIM (warts, hypogammaglobulinemia, infections, myelo kathexis) syndrome is an autosomal-dominant syndrome with hypogammaglobulinemia, reduced B cell numbers, and neutropenia. The most common genetic cause is a truncation mutation of CXCR4, which leads to gain of function in that gene. Additional mutations that are not in the CXCR4 gene can also cause WHIM, but all of them lead to functional hyper activity of CXCR4. CXCR4 causes retention of neutrophils in the bone marrow and is the basis of the neutropenia and myelokathexis (increased apoptotic neutrophils in the bone marrow). There is profound loss of circulating CD27+ memory B cells, resulting in hypogammaglobulinemia, and the observation that WHIM patients have normal antibody response to certain antigens, but fail to maintain this antibody production. However, normal immunoglobulin levels do not exclude the diagnosis of WHIM. Almost 80% of WHIM patients have warts at the time of their diagnosis. These include common and genital wart types. A significant number of female WHIM patients have cervical and vulval dysplasia, which can progress to carcinoma. WHIM patients have disproportionately more HPV infections than SCID patients, yet WHIM patients have little problem resolving other viral infections. They may develop Epstein–Barr virus (EBV)-induced lymphomas, however. The vast majority of patients in early childhood suffer recurrent sinopulmonary infections, skin infections, osteomyelitis, and urinary tract infections. Recurrent pneumonias lead to bronchiectasis. Treatment is G-CSF, IVIG, prophylactic antibiotics, and aggressive treatment of infections. The HPV infections can progress to fatal carcinomas and therefore male patients must be regularly examined by dermatologists and female ones by gynecologists; a low threshold for biopsy of genital lesions is required. Hagan JB, et al: WHIM syndrome. Mayo Clin Proc 2007; 82:1031. Kawai T, et al: WHIM syndrome: congenital immune deficiency disease. Curr Opin Hematol 2009; 16:20.
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Fig. 5-16 Eczematous eruption with purpura in Wiskott–Aldrich syndrome.
hematopoietic cells in response to external stimuli. The hematopoietic cells of affected patients cannot polarize or migrate in response to physiologic stimuli, accounting for the protean clinical features of the syndrome. Wiskott–Aldrich syndrome occurs when mutations in WASP lead to absence or truncation of the WASP protein (WASP− mutations). Mutations that result in normal length but some loss of function in the WASP protein (WASP+ mutations) result in three different syndromes: X-linked thrombocytopenia (XLT), intermittent X-linked thrombocytopenia, and X-linked neutropenia. Patients with XLT may also have an atopic-like dermatitis, but this is usually milder than the severe and difficult to control eczema affecting patients with the full Wiskott–Aldrich syndrome. WASP/XLT patients may also develop autoimmune disease, especially autoimmune hemolytic anemia, vasculitis, Henoch–Schönlein-like purpura, and inflammatory bowel disease. High IgM is associated with the development of autoimmune disease. Treatment is with platelet transfusions, antibiotics, and IVIG, if required. Often splenectomy is performed to help control bleeding, but this leads to increased risk of sepsis and is not routinely recommended. Immunosuppressive therapy or rituximab may be used to control autoimmune complications. Bone marrow transplantation from a human leukocyte antigen (HLA)-identical sibling as early as possible in the disease course provides complete reversal of the platelet and immune dysfunction, as well as improvement or clearing of the eczematous dermatitis. Survival at 7 years with a matched sibling donor transplant approaches 90%. Ochs HD, et al: Wiskott–Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment. Biol Blood Marrow Transplant 2008; 15:84.
Wiskott–Aldrich syndrome
Ataxia telangiectasia
Wiskott–Aldrich syndrome, an X-linked recessive syndrome, consists of a triad of chronic eczematous dermatitis resembling atopic dermatitis (Fig. 5-16); increased susceptibility to bacterial infections, such as pyoderma or otitis media; and thrombocytopenic purpura with small platelets. There are normal levels of IgM and IgG, but elevated levels of IgA and IgE. T cells progressively decline in number and activity. Untreated survival is about 15 years, with death from infection, bleeding, or lymphoma. The genetic cause of Wiskott–Aldrich syndrome is a mutation in the WASP gene. This gene codes for a protein called WASP, which is universally expressed in hematopoietic cells and is critical in the reorganization of the actin cytoskeleton in
Ataxia telangiectasia is an autosomal-recessive condition that is due to mutations in a single gene on chromosome 11 (ATM), which encodes a protein called ATM. This protein is critical in cell cycle control. When ATM is absent, the cell cycle does not stop to repair DNA breaks or for B(D)J recombination of immunoglobulin and T-cell receptor genes. This results in immunodeficiency and an increased risk for malignancy. The clinical features of the patients are progressive ocular and cutaneous telangiectasias, premature aging, and progressive neuro degeneration. Skin changes that are characteristic are cutaneous non-infectious granulomas (which can be ulcerative and painful), loss of subcutaneous fat, premature gray hair, large irregular café-au-lait spots, vitiligo, seborrheic dermatitis,
Nowak-Wegrzyn A, et al: Immunodeficiency and infections in ataxiatelangiectasia. J Pediatr 2004; 144:505.
Defects of phagocyte number, function, or both Chronic granulomatous disease Chronic granulomatous disease (CGD) is a rare disorder caused by mutations in one of the genes that encode the sub units of the superoxide-generating phagocyte NADPH oxidase system responsible for the respiratory burst involved in organism killing. CGD is characterized by repeated and recurrent bacterial and fungal infections of the lungs, skin, lymph nodes, and bones. Gingivostomatitis (aphthous-like ulcerations) and a seborrheic dermatitis of the periauricular, perinasal, and perianal area are characteristic. The dermatitis is frequently infected with S. aureus, and regional adenopathy and abscesses may complicate the infections. The term “suppurative dermatitis” is used in the immunology literature to describe this seborrheic-like dermatitis with secondary infection (very ana logous to the “infective dermatitis” seen in human T-cell lymphotropic virus (HTLV)-1 infection). In addition to S. aureus, Serratia species are commonly isolated from skin abscesses, liver abscesses, and osteomyelitis. Aspergillus is the most common agent causing pneumonia in CGD patients. In tuberculosis-endemic areas, CGD patients frequently develop active tuberculosis or prolonged scarring, abscesses, or disseminated infection following BCG immunization. There are four types of CGD, one X-linked and three autosomal-recessive. The X-linked form is the most common (65–75% of CGD patients) and is due to a mutation in the CYBB gene, which leads to absence of the high molecular weight subunit of cytochrome b 558 (gp 91-phox) and a total absence of NADPH oxidase activity. In autosomal-recessive forms, mutations in the genes encoding for the remaining three oxidase components have been described: p22-phox (CYBA), p47-phox (NCF-1), and p67-phox (NCF-2). The X-linked variant has the most severe phenotype. Compared to the autosomalrecessive CGD patients, the X-linked patients present at an
earlier age (14 months vs 30 months), and are diagnosed at an earlier age (3 years vs 6 years). The lack of superoxide generation apparently causes disease, not because the bacteria are not being killed by the superoxide, but because the superoxide is required to activate proteases in phagocytic vacuoles that are needed to kill infectious organisms. Granuloma formation is characteristic of CGD and can occur in the skin, gastrointestinal tract, liver, bladder, bone, and lymph node. Up to 40% of biopsies from these organs will demonstrate granulomas, at times with identifiable fungal or mycobacterial organisms. Since these patients are often on prophylactic antibiotics, organisms are frequently not found, however. Subcorneal pustular eruptions can also be seen in CGD patients. In the intestinal tract an inflammatory bowel disease-like process occurs, with granulomas in the colon. This can cause significant gastrointestinal symptoms. The diagnosis of CGD is made by demonstrating low reduction of yellow nitro-blue tetrazolium (NBT) to blue formazan in the “NBT test.” Dihydrorhodamine 123 flow cytometry, chemiluminescence production, and the ferricytochrome C reduction assay are also confirmatory and may be more accurate. Female carriers of the X-linked form of CGD have a mixed population of normal and abnormal phagocytes, and therefore show intermediate NBT reduction. The majority of carriers have skin complaints. Raynaud phenomenon can occur. More than half will report a photosensitive dermatitis, 40% have oral ulcerations, and a third have joint complaints. Skin lesions in carriers have been described as DLElike (Discoid lupus erythematosus), but histologically there is often an absence of the interface component and they resemble tumid lupus. DIF examination is usually negative, as is common in tumid lupus erythematosus (LE). Less commonly, CGD patients themselves have been described as having similar LE-like lesions, or “arcuate dermal erythema.” Despite these findings, the vast majority of patients with LE-like skin lesions, both carriers and CGD patients, are antinuclear antibody (ANA)-negative. Treatment of infections should be early and aggressive. There should be a low threshold to biopsy skin lesions, as they may reveal important and potentially life-threatening infections. Patients usually receive chronic trimethoprim– sulfamethoxazole prophylaxis, chronic oral itraconazole or another anti-Aspergillus agent, and IFN-γ injections. Bone marrow or stem cell transplantation has been successful in restoring enzyme function, reducing infections, and improving the associated bowel disease. However, survival is NOT increased with bone marrow transplantation, so it is not routinely undertaken.
Immunodeficiency syndromes
atopic dermatitis, recurrent impetigo, and acanthosis nigricans. Late tightening of the skin can occur and resembles acral sclerosis. Sinopulmonary infections are common, especially otitis media, sinusitis, bronchitis, and pneumonia. Varicella, at times severe, herpes simplex, molluscum contagiosum, and herpes zoster can occur. Refractory warts occur in more than 5% of patients. Aside from candidal esophagitis, unusual opportunistic infections are rare. Childhood immunizations, including liver viral vaccines, are well tolerated. Lymphopenia is common, with reduction of both B and T cells occurring in the majority of patients. Helper T-cell counts can be below 200. IgA, IgG4, IgG2, and IgE deficiencies can all be present. Paradoxically, IgM, IgA, and IgG can be elevated in some patients, including the presence of monoclonal gammopathy in more than 10% of cases. The immunological abnormalities are not progressive. Lymphoma risk is increased more than 200-fold (especially B-cell lymphoma), and leukemia (especially T-cell chronic lymphocytic leukemia) is increased 70-fold. Treatment includes high vigilance for infection and malignancy. In patients with low CD4 counts, prophylaxis to prevent Pneumocystis pneumonia can be considered. When IgG deficiency is present and infections are frequent, IVIG may be beneficial. IVIG and intralesional corticosteroids may be used for the cutaneous granulomas. Carriers of ataxia telangiectasia have an increased risk for hematologic and breast malignancies. Due to the accumulation of chromosomal breaks following radiation exposure, both the ataxia telangiectasia patients and the carriers should minimize radiation exposure.
Cale CM, et al: Cutaneous and other lupus-like symptoms in carriers of X-linked chronic granulomatous disease: incidence and autoimmune serology. Clin Exp Immunol 2007; 148:79. Gallin JI, et al: Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med 2003; 348:2416. Holland SM: Chronic granulomatous disease. Clin Rev Allergy Immunol 2010; 38:3. Lee PP, et al: Susceptibility to mycobacterial infections in children with X-linked chronic granulomatous disease: a review of 17 patients living in a region endemic for tuberculosis. Pediatr Infect Dis J 2008; 27:224. Levine S, et al: Histopathological features of chronic granulomatous disease (CGD) in childhood. Histopathology 2005; 47:508. Luis-Montoya P, et al: Chronic granulomatous disease: two members of a single family with different dermatologic manifestations. Skinmed 2005; 4:320. Martire B, et al: Clinical features, long-term follow-up and outcome of a large cohort of patients with chronic granulomatous disease: an Italian multicenter study. Clin Immunol 2008; 126:155. Vieira AP, et al: Lymphadenopathy after BCG vaccination in a child with chronic granulomatous disease. Pediatr Dermatol 2004; 21:646.
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Leukocyte adhesion molecule deficiency
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
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This rare autosomal-recessive disorder has three types. Leukocyte adhesion molecule deficiency (LAD) type I is due to a mutation in the common chain (CD18) of the β2 integrin family. It is characterized by recurrent bacterial infections of the skin and mucosal surfaces, especially gingivitis and periodontitis. Skin ulcerations from infection may continue to expand. Cellulitis and necrotic abscesses, especially in the peri rectal area, can occur. Minor injuries may lead to pyoderma gangrenosum-like ulcerations that heal slowly. Infections begin at birth, and omphalitis with delayed separation of the cord is characteristic. Neutrophilia is marked, usually 5–20 times normal, and the count may reach up to 100 000 during infections. Despite this, there is an absence of neutrophils at the sites of infection, demonstrating the defective migration of neutrophils in these patients. LAD type I patients are either severely ( liver > kidney > heart. In liver and small intestine transplants the risk is 1–2%, but when it occurs the mortality is 85%. Close matching increases the risk of GVHD in organ transplantation, since the immunocompetent recipient cells are less likely to recognize the donor lymphocytes as “non-self” and destroy them. The onset is usually 1–8 weeks following transplantation, but can be delayed for years. Fever, rash, and pancytopenia are the cardinal features. The skin is the first site of involvement and only cutaneous disease occurs in 15% of cases. Both acute and chronic GVHD skin findings can occur. Skin biopsies tend to show more inflammation than in HSCT-associated GVHD. In GVHD accompanying liver transplantation, the liver is unaffected, since it is syngeneic with the donor lymphocytes. In these patients pancytopenia can occur and is a frequent cause of mortality. The diagnosis of GVHD in the setting of organ transplantation can be aided by documenting macrochimerism in the peripheral blood and skin after the first month of transplantation. Alkhatib AA, et al: Colitis secondary to engraftment syndrome in a patient with autologous peripheral blood stem cell transplant. Dig Dis Sci 2009.
Calzavara Pinton P, et al: Prospects for ultraviolet A1 phototherapy as a treatment for chronic cutaneous graft-versus-host disease. Haematologica 2003; 88:1169. Carcagni MR, et al: Extracorporeal photopheresis in graft-versus-host disease. J Dtsch Dermatol Ges 2008; 6:451. Carpenter PA: Late effects of chronic graft-versus-host disease. Best Pract Res Clin Haematol 2008; 21:309. Dai E, et al: Bilateral marginal keratitis associated with engraftment syndrome after hematopoietic stem cell transplantation. Cornea 2007; 26:756. Ferrara JL: Novel strategies for the treatment and diagnosis of graft-versus-host disease. Best Pract Res Clin Haematol 2007; 20:91. Ferrara JL, et al: Graft-versus-host disease. Lancet 2009; 373:1550. Flowers ME, et al: A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versushost disease. Blood 2008; 112:2667. Foncillas MA, et al: Engraftment syndrome emerges as the main cause of transplant-related mortality in pediatric patients receiving autologous peripheral blood progenitor cell transplantation. J Pediatr Hematol Oncol 2004; 26:492. Ghoreschi K, et al: PUVA-bath photochemotherapy and isotretinoin in sclerodermatous graft-versus-host disease. Eur J Dermatol 2008; 18:667. Goiriz R, et al: Cutaneous lichenoid graft-versus-host disease mimicking lupus erythematosus. Lupus 2008; 17:591. Gorak E, et al: Engraftment syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation: incidence and effects on survival. Biol Blood Marrow Transplant 2005; 11:542. Hausermann P, et al: Cutaneous graft-versus-host disease: a guide for the dermatologist. Dermatology 2008; 216:287. Horger M, et al: Musculocutaneous chronic graft-versus-host disease: MRI follow-up of patients undergoing immunosuppressive therapy. AJR Am J Roentgenol 2009; 192:1401. Katzel JA, et al: Engraftment syndrome after hematopoietic stem cell transplantation in multiple myeloma. Clin Lymphoma Myeloma 2006; 7:151. Kuykendall TD, et al: Lack of specificity in skin biopsy specimens to assess for acute graft-versus-host disease in initial 3 weeks after bone-marrow transplantation. J Am Acad Dermatol 2003; 49:1081. Magro L, et al: Efficacy of imatinib mesylate in the treatment of refractory sclerodermatous chronic GVHD. Bone Marrow Transplant 2008; 42:757. Miano M, et al: Early complications following haematopoietic SCT in children. Bone Marrow Transplant 2008; 41(Suppl 2):S39. Moreno-Romero JA, et al: Imatinib as a potential treatment for sclerodermatous chronic graft-vs-host disease. Arch Dermatol 2008; 144:1106. Nellen RG, et al: Eruption of lymphocyte recovery or autologous graft-versus-host disease? Int J Dermatol 2008; 47(Suppl 1):32. Norian JM, et al: Labial fusion: a rare complication of chronic graftversus-host disease. Obstet Gynecol 2008; 112:437. Patel AR, et al: Rippled skin, fasciitis, and joint contractures. J Am Acad Dermatol 2008; 59:1070. Perfetti P, et al: Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant 2008; 42:609. Rapoport AP, et al: Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of costimulated autologous T cells. Clin Cancer Res 2009; 15:4499. Scarisbrick JJ, et al: U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease. Br J Dermatol 2008; 158:659. Schaffer JV: The changing face of graft-versus-host disease. Semin Cutan Med Surg 2006; 25:190.
Immunodeficiency syndromes
with PUVA. The extent of involvement of the deep tissues, such as muscle and fascia, cannot be easily defined by clinical examination, and may be aided by magnetic resonance imaging (MRI). Rarely, the myositis of chronic GVHD may be accompanied by a skin eruption very similar to dermatomyositis. The “distinctive” features include depigmentation resembling vitiligo; scarring or non-scarring alopecia; nail dystrophy (longitudinal ridging, brittle thin nails, pterygium, and nail loss); and xerostomia and other Sjögren-like mucosal symptoms. Histologically, acute GVHD demonstrates vacuolar interface dermatitis. Individual keratinocyte necrosis with adjacent lymphocytes (satellite necrosis) is typically present, suggesting cell-mediated cytotoxicity. The extent of necrosis, bulla formation, and slough is used in grading schemes. In early acute GVHD, the findings may be focal and restricted to hair follicles and sweat ducts. The histologic findings in very early disease may be nonspecific, and many treatment protocols do not depend on histologic features to initiate therapy. A background of epidermal disorder and atypia resembling bowen oid actinic keratosis is almost universally present in later lesions of acute GVHD, and is a helpful diagnostic feature. Similar epidermal changes may be seen with cancer chemotherapy, especially in acral erythema or after busulfan. Chronic GVHD demonstrates lichenoid dermatitis or dermal sclerosis with hyalinization of collagen bundles and narrowing of the space between the collagen bundles. Prevention of post-transfusion GVHD is most safely achieved by irradiating the blood before transfusion in highrisk individuals. Acute GVHD is managed on the skin with topical steroids, TCIs, and UV phototherapy. When systemic symptoms appear, a glucocorticoid, cyclosporine, or tacrolimus is instituted. Blocking the cytokine storm with monoclonal antibodies such as etanercept, infliximab, and others can be beneficial in some patients. Extracorporeal photopheresis can be considered in acute and chronic GVHD that fails to respond to these first-line therapies. Bath PUVA, with or without isotretinoin, can improve sclerodermatous chronic GVHD. Imatinib can be beneficial in refractory sclerodermatous chronic GVHD.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 5-1 Dennie–Morgan folds. Fig. 5-2 Perioral pallor. Fig. 5-3 Napkin psoriasis. Fig. 5-4 Eczematous eruption with purpura in Wiskott–Aldrich syndrome. Fig. 5-5 Early punctate eruption of graft-versus-host disease. Fig. 5-6 Involvement of the diaper area in graft-versus-host disease.
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Contact Dermatitis and Drug Eruptions
Contact dermatitis There are two types of dermatitis caused by substances coming in contact with the skin: irritant dermatitis and allergic contact dermatitis. Irritant dermatitis is an inflammatory reaction in the skin resulting from exposure to a substance that causes an eruption in most people who come in contact with it. Allergic contact dermatitis is an acquired sensitivity to various substances that produce inflammatory reactions in those, and only those, who have been previously sensitized to the allergen.
Irritant contact dermatitis Many substances act as irritants that produce a nonspecific inflammatory reaction of the skin. This type of dermatitis may be induced in any person if a sufficiently high concentration is used. No previous exposure is necessary and the effect is evident within minutes, or a few hours at most. The concentration and type of the toxic agent, the duration of exposure, and the condition of the skin at the time of exposure produces the variation in the severity of the dermatitis from person to person, or from time to time in the same person. The skin may be more vulnerable by reason of maceration from excessive humidity, or exposure to water, heat, cold, pressure, or friction. Dry skin is less likely to react to contactants. Thick skin is less reactive than thin. Repeated exposure to some of the milder irritants may, in time, produce a hardening effect. This process makes the skin more resistant to the irritant effects of a given substance. Symptomatically, pain and burning are more common in irritant dermatitis, contrasting with the usual itch of allergic reactions.
Alkalis Irritant dermatitis is often produced by alkalis such as soaps, detergents, bleaches, ammonia preparations, lye, drain pipe cleaners, and toilet bowl and oven cleansers. Alkalis penetrate and destroy deeply because they dissolve keratin. Strong solutions are corrosive and immediate application of a weak acid such as vinegar, lemon juice, or 0.5% hydrochloric acid solution will lessen their effects. The principal compounds are sodium, potassium, ammonium, and calcium hydroxides. Occupational exposure is frequent among workers in soap manufacturing. Alkalis in the form of soaps, bleaching agents, detergents, and most household cleansing agents figure prominently in the causes of hand eczema. Sodium silicate (water glass) is a caustic used in soap manufacture and paper sizing, and for the preservation of eggs. Alkaline sulfides are used as depilatories (Fig. 6-1). Calcium oxide (quicklime) forms slaked lime when water is added. Severe burns may be caused in plasterers.
Acids (Fig. 6-2) The powerful acids are corrosive, whereas the weaker ones are astringent. Hydrochloric acid produces burns that are less
deep and more liable to form blisters than injuries from sulfuric and nitric acids. Hydrochloric acid burns are encountered in those who handle or transport the product, and in plumbers and those who work in galvanizing or tin-plate factories. Sulfuric acid produces a brownish charring of the skin, beneath which is an ulceration that heals slowly. Sulfuric acid is used more widely than any other acid in industry; it is handled principally by brass and iron workers and by those who work with copper or bronze. Nitric acid is a powerful oxidizing substance that causes deep burns; the tissue is stained yellow. Such injuries are observed in those who manufacture or handle the acid or use it in the making of explosives in laboratories. Hydrofluoric acid is used widely in rust remover, in the semiconductor industry, and in germicides, dyes, plastics, and glass etching. It may act insidiously at first, starting with erythema and ending with vesiculation, ulceration, and, finally, necrosis of the tissue. It is one of the strongest inorganic acids, capable of dissolving glass. Oxalic acid may produce paresthesia of the fingertips, with cyanosis and gangrene. The nails become discolored yellow. Oxalic acid is best neutralized with limewater or milk of magnesia to produce precipitation. Phenol (carbolic acid) is a protoplasmic poison that produces a white eschar on the surface of the skin. It can penetrate deep into the tissue. If a large surface of the skin is treated with phenol for cosmetic peeling effects, the absorbed phenol may produce glomerulonephritis and arrhythmias. Locally, temporary anesthesia may also occur. Phenol is readily neutralized with 65% ethyl or isopropyl alcohol. Titanium hydrochloride is used in the manufacture of pigments. Application of water to the exposed part will produce severe burns. Therefore, treatment consists only of wiping away the noxious substance. Other strong acids that are irritants include acetic, trichlor acetic, arsenious, chlorosulfonic, chromic, fluoroboric, hydriodic, hydrobromic, iodic, perchloric, phosphoric, salicylic, silicofluoric, sulfonic, sulfurous, tannic, and tungstic acids. Treatment of acid burns consists of immediate rinsing with copious amounts of water and alkalization with sodium bicarbonate, calcium hydroxide (limewater), or soap solutions. Some chemicals require unusual treatment measures. Fluorine is best neutralized with magnesium oxide. Periungual burns should be treated intralesionally with 10% calcium gluconate solution, which deactivates the fluoride ion and averts more tissue damage. Hypocalcemia, hypomagnesemia, hyper kalemia, and cardiac dysrhythmias may complicate hydrofluoric acid burns. Phosphorus burns should be rinsed off with water followed by application of copper sulfate to produce a precipitate.
Airbag dermatitis Airbags are deployed as a safety feature on cars when rapid deceleration occurs. Activation of a sodium azide and cupric oxide propellant cartridge releases nitrogen gas, which expands the bag at speeds exceeding 160 km/h. Talcum
Contact dermatitis Fig. 6-2 Acid burn. Fig. 6-1 Alkali burn from depilatory.
powder, sodium hydroxide, and sodium carbonate are released into the bag. Abrasions, thermal, friction, and chemical burns, and an irritant contact dermatitis may result. Superficial erythema may respond well to topical steroids, but full-thickness burns may occur and require debridement and grafting.
Other irritants Some metal salts that act as irritants are the cyanides of calcium, copper, mercury, nickel, silver, and zinc, and the chlorides of calcium and zinc. Bromine, chlorine, fluorine, and iodine are also irritants. Occupational exposure to methyl bromide may produce erythema and vesicles in the axillary and inguinal areas. Insecticides, including 2,2-dichlorovinyl dimethyl phosphate used in roach powder and fly repellents and killers, can act as irritants.
Fiberglass dermatitis Fiberglass dermatitis is seen after occupational or inadvertent exposure. The small spicules of glass penetrate the skin and cause severe irritation with tiny erythematous papules, scratch marks, and intense pruritus. Usually, there is no delayed hypersensitivity reaction. Wearing clothes that have been washed together with fiberglass curtains, handling air conditioner filters, or working in the manufacture of fiberglass ma terial may produce severe folliculitis, pruritus, and eruptions that may simulate scabies or insect or mite bites. Fiberglass is also used in thermal and acoustic installations, padding, vibration isolation, curtains, draperies, insulation for automobile bodies, furniture, gasoline tanks, and spacecraft. Talcum powder dusted on the flexure surfaces of the arms prior to exposure makes the fibers slide off the skin. A thorough washing of the skin after handling fiberglass is helpful. Patch testing to epoxy resins should be done when evaluating workers in fiberglass/reinforced plastics operations, as an allergic contact dermatitis may be difficult to discern from fiberglass dermatitis.
Dusts Some dusts and gases may irritate the skin in the presence of heat and moisture, such as perspiration. The dusts of lime, zinc, and arsenic may produce folliculitis. Dusts from various woods, such as teak, may incite itching and dermatitis. Dusts from cinchona bark, quinine, and pyrethrum produce widespread dermatitis. Tobacco dust in cigar factories, powdered orris root, lycopodium, and dusts of various nutshells may cause swelling of the eyelids and dermatitis of the face, neck, and upper extremities, the distribution of an airborne contact dermatitis. Dusts formed during the manufacture of high explosives may cause erythematous, vesicular, and eczema-
Fig. 6-3 Mustard gas burn. (Courtesy of James WD [ed]: Textbook of Military Medicine. Office of the Surgeon General, United States Army, 1994.)
tous dermatitis that may lead to generalized exfoliative dermatitis.
Capsaicin Hand irritation produced by capsaicin in hot peppers used in Korean and North Chinese cuisine (Hunan hand) may be severe and prolonged. Pepper spray, used by police in high concentrations, and by civilians in less concentrated formulas, contains capsaicin and may produce severe burns. Cold water is not much help; capsaicin is insoluble in water. Acetic acid 5% (white vinegar) or antacids (Maalox) may completely relieve the burning even if applied an hour or more after the contact. Application should be continued until the area can be dried without return of the discomfort.
Tear gas dermatitis Lacrimators such as chloroacetophenone in concentrated form may cause dermatitis, with a delayed appearance some 24– 72 h after exposure. Irritation or sensitization, with erythema and severe vesiculation, may result. Treatment consists of lavage of the affected skin with sodium bicarbonate solution and instillation of boric acid solution into the eyes. Contaminated clothing should be removed. Sulfur mustard gas, also known as yperite, has been used in chemical warfare such as in the Iraq–Iran war. Erythema, vesicles, and bullae, followed by healing with hyperpigmentation over a 1-week period, result from mild to moderate exposure (Fig. 6-3). Toxic epidermal necrolysis (TEN)-like appearance may follow more concentrated contact. The earliest and most frequently affected sites are areas covered by clothing and humidified by sweat, such as the groin, axilla, and genitalia. 89
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Fig. 6-4 Mace reaction.
Mace is a mixture of tear gas (chloroacetophenone) in trichloroethane and various hydrocarbons resembling kerosene. It is available in a variety of self-defense sprays. It is a potent irritant (Fig. 6-4) and may cause allergic sensitization. Treatment consists of changing clothes, then washing with oil or milk, followed by washing with copious amounts of water.
Chloracne Workers in the manufacture of chlorinated compounds may develop chloracne, with small straw-colored follicular plugs and papules, chiefly on the malar crescent, retroauricular areas, earlobes, neck, shoulders, and scrotum. The synthetic waxes chloronaphthalene and chlorodiphenyl, used in the manufacture of electric insulators and in paints, varnishes, and lacquers, similarly predispose workers engaged in the manufacture of these synthetic waxes to chloracne. Exposure to 2,6-dichlorobenzonitrile during the manufacture of a herbicide, and to 3,4,3′,4′-tetrachloroazooxybenzene, which is an unwanted intermediate byproduct in the manufacture of a pesticide, may also produce chloracne. A contaminant in the synthesis of herbicides and hexachlorophene, 2,3,7,8-tetracholorodibenzo-p-dioxin, produces a chemical burn in the acute stage, but chloracne, hyperpigmentation, hirsutism, and skin fragility (with or without criteria for porphyria cutanea tarda) are manifestations of chronic toxicity. Gastrointestinal tract cancer and malignancies of the lymphatic and hematopoietic systems are suspected to result but the studies are still inconclusive. While contact is the usual method of exposure, inhalation, ingestion, or contact with contaminated clothing may also result in chloracne. Chloracne may persist for long periods because dioxin is stored in the liver and released slowly into the circulation. Treatment is with medications used in acne vulgaris, including isotretinoin.
Hydrocarbons Many hydrocarbons produce skin eruptions. Crude petroleum causes generalized itching, folliculitis, or acneiform eruptions. The irritant properties of petroleum derivatives are directly proportional to their fat-solvent properties and inversely proportional to their viscosity. Oils of the naphthalene series are more irritating than those of the paraffin series. Refined fractions from petroleum are less irritating than the unrefined products, although benzene, naphtha, and carbon disulfide may cause a mild dermatitis. 90
Lubricating and cutting oils are causes of similar cutaneous lesions. They represent a frequent cause of occupational dermatoses in machine tool operators, machinists, layout men, instrument makers, and set-up men. Insoluble (neat) cutting oils are responsible for a follicular acneiform eruption on the dorsa of the hands, the forearms, face, thighs, and back of the neck. Hyperpigmentation, keratoses, and scrotal cancer have been found in those exposed to insoluble cutting oils. Soluble oils and synthetic fluids used in metalworking do not result in acne, but rather an eczematous dermatitis, usually of the dorsal forearms and hands. Approximately 50% of the time it is irritant and in the remainder it is allergic. Allergic contact dermatitis arises from various additives, such as biocides, coloring agents, and deodorizers. Coal briquette makers develop dermatitis as a result of a tarry residue from petroleum used in their trade. Paraffin exposure leads to pustules, keratoses, and ulcerations. Shale oil workers develop an erythematous, follicular eruption that eventually leads to keratoses, which may become the sites of carcinoma. It is estimated that 50% of shale oil workers have skin problems. Impure and low-grade paraffins and mineral oils cause similar skin eruptions. Initially, the skin changes are similar to those in chloracne. In due time, a diffuse erythema with dappled pigmentation develops. Gradually, keratoses appear, and after many years some of these are the sites of carcinoma. Melanoderma may occur from exposure to mineral oils and lower-grade petroleum, from creosote, asphalt, and other tar products. Photosensitization may play a role. Creosote is a contact irritant, sensitizer, and photosensitizer. Allergy is demonstrated by patch testing with 10% creosote in oil. Petrolatum dermatitis may appear as a verrucous thickening of the skin caused by prolonged contact with impure petroleum jelly or, occasionally, lubricating oil. A follicular centered process may occur in which erythematous horny nodules are present, usually on the anterior and inner aspects of the thighs. There are no comedones and the lesions are separated by apparently normal skin. Acne corne consists of follicular keratosis and pigmentation resulting from crude petroleum, tar oils, and paraffin. The dorsal aspects of the fingers and hands, the arms, legs, face, and thorax are the areas usually involved. The lesions are follicular, horny papules, often black, and are associated at first with a follicular erythema and later with a dirty brownish or purplish spotty pigmentation, which in severe cases becomes widespread and is especially marked around the genitals. This syndrome may simulate pityriasis rubra pilaris or lichen spinulosus. Coal tar and pitch and many of their derivatives produce photosensitization and an acneiform folliculitis of the forearms, legs, face, and scrotum. Follicular keratoses (pitch warts) may develop and later turn into carcinoma. Soot, lamp black, and the ash from peat fires produce dermatitis of a dry, scaly character, which in the course of time forms warty outgrowths and cancer. Chimney sweep’s cancer occurs under a soot wart and is usually located on the scrotum, where soot, sebum, and dirt collect in the folds of the skin. This form of cancer has virtually disappeared. Acquired perforating disease may occur in oil field workers who use drilling fluid containing calcium chloride. Patients develop tender, umbilicated papules of the forearms that microscopically show transepidermal elimination of calcium.
Solvents These cause approximately 10% of occupational dermatitis. When they are applied to the hands to cleanse them, the surface oil is dissolved and a chronic fissured dermatitis results. Additionally, peripheral neuropathy and chemical
Amshel CE, et al: Anhydrous ammonia burns. Burns 2000; 26:493. Bordel-Gomez MT, et al: Fiberglass dermatitis. Contact Dermatitis 2008; 59:120. Bourke J, et al: Guidelines for the management of contact dermatitis. Br J Dermatol 2009; 160:946. Bullman T, et al: A 50 year mortality follow-up study of veterans exposed to low level chemical warfare agent, mustard gas. Ann Epidemiol 2000; 10:333. Edlich RF, et al: Modern concepts of treatment and prevention of chemical injuries. J Long Term Eff Med Implants 2005; 15:303. Finkelstein E, et al: Oil acne. J Am Acad Dermatol 1994; 30:491. Flammiger A, et al: Sulfuric acid burns. Cutan Ocul Toxicol 2006: 25:55. Fyhrquist-Vanni N, et al: Contact dermatitis. Dermatol Clin 2007; 25:615. Goon AT, et al: A case of trichloroethylene hypersensitivity syndrome. Arch Dermatol 2001; 137:274. Herzemans-Boer M, et al: Skin lesions due to methyl bromide. Arch Dermatol 1988; 124:917. Jia X, et al: Adverse effects of gasoline on the skin of gasoline workers. Contact Dermatitis 2002; 46:44. Minamoto K, et al: Occupational dermatoses among fibreglassreinforced plastics factory workers. Contact Dermatitis 2002; 46:339. Momeni AZ, et al: Skin manifestations of mustard gas. Arch Dermatol 1992; 128:775. Panteleyev AA, et al: Dioxin-induced chloracne. Exp Dermatol 2006: 15:705. Salzman M, et al: Updates on the evaluation and management of caustic exposures. Emerg Med Clin N Am 2007; 25:459. Sanz-Gallen P, et al: Hypocalcaemia and hypomagnesaemia due to hydrofluoric acid. Occup Med 2001; 51:294. Stuke LE, et al: Hydrofluoric acid burns. J Burn Care Res 2008; 29:893. Suchard JR: Treatment of capsaicin dermatitis. Am J Emerg Med 1999; 17:210. Treudler R, et al: Occupational contact dermatitis due to 2-chloracetophenone tear gas. Br J Dermatol 1999; 140:531. Ueno S, et al: Metalworking fluid hand dermatitis. Ind Health 2002; 40:291. Varma S, et al: Severe cutaneous reaction to CS gas. Clin Exp Dermatol 2001; 26:248. Williams SR, et al: Contact dermatitis associated with capsaicin: Hunan hand syndrome. Ann Emerg Med 1995; 25:713. Wu JJ, et al: A case of air bag dermatitis. Arch Dermatol 2002; 138:1383.
Allergic contact dermatitis Allergic contact dermatitis results when an allergen comes into contact with previously sensitized skin. It is due to a specific acquired hypersensitivity of the delayed type, also known as cell-mediated hypersensitivity or immunity. Occasionally, dermatitis may be induced when the allergen is taken internally by a patient first sensitized by topical application; this occurs, for example, with substances such as cinnamon oil or various medications. The anamnestic response is termed systemic contact dermatitis. It may appear first at the site of the prior sensitization or past positive patch test, but may spread to a generalized morbilliform or eczematous eruption.
Additional morphologic patterns include vesicular hand eczema, urticaria, erythema multiforme, vasculitis, or the baboon syndrome. The latter is a deep red–violet eruption on the buttocks, genital area, inner thighs, and sometimes axilla. The most common causes of contact dermatitis in the US are: toxicodendrons (poison ivy, oak, or sumac), nickel, balsam of Peru (Myroxylon pereirae), neomycin, fragrance, thimerosal, gold, formaldehyde and the formaldehyde-releasing preservatives, bacitracin, and rubber compounds. Frequent positive reactions to thimerosal do not often correlate with clinical exposure histories. These reactions are probably related to its use as a preservative in commonly administered vaccines and skin-testing material. It also serves as a marker for piroxicam photosensitivity. These sensitizers do not cause demonstrable skin changes on initial contact. Persons may be exposed to allergens for years before finally developing hypersensitivity. Once sensitized, however, subsequent outbreaks may result from extremely slight exposure. When allergens are applied to the skin, Langerhans cells in the epidermis process them and display them in a complex with human leukocyte antigen (HLA)-DR on their surface. This is presented to a CD4+ T cell, interaction with the T-cell receptor–CD3 complex occurs, and the allergen is recognized. This leads to proliferation and recruitment of lymphocytes with release of vasoactive substances and direct inflammatory mediators. Genetic variability in these processes and other factors, such as concentration of the allergen applied, its vehicle, timing and site of the exposure, presence of occlusion, age, sex, and race of the patient, and presence of other skin or systemic disorders, likely determine whether any given exposure will result in sensitization. Eczematous delayed-type hypersensitivity reaction, as exemplified by allergic contact dermatitis and the patch test, must be distinguished from immediate-type hypersensitivity reactions. The latter presents within minutes of exposure with urticaria and is proven with a scratch test. It should be kept in mind, however, that persons who develop contact urticaria to a substance may concomitantly have a type IV delayed-type sensitization and eczema from the same allergen. In some instances, impetigo, pustular folliculitis, and irritations or allergic reactions from applied medications are superimposed on the original dermatitis. A particularly vexing situation is when allergy to topical steroids complicates an eczema, in which case the preexisting dermatitis usually does not flare, but simply does not heal as expected. The cutaneous reaction may also provoke a hypersusceptibility to various other previously innocuous substances, which continues the eczematous inflammatory response indefinitely. These eruptions resolve when the cause is identified and avoided. For acute generalized allergic contact dermatitis treatment with systemic steroidal agents is effective, beginning with 40–60 mg/day prednisone in a single oral dose, and tapering slowly to topical steroids. When the eruption is limited in extent and severity, local application of topical corticosteroid creams, lotions, or aerosol sprays is preferred.
Contact dermatitis
lymphangitis may occur after the solvents are absorbed through the fissured skin. Solvent sniffers may develop an eczematous eruption about the mouth and nose. There is erythema and edema. It is a direct irritant dermatitis caused by the inhalation of the solvent placed on a handkerchief. Trichloroethylene is a chlorinated hydrocarbon solvent and degreasing agent, and is also used in the dry-cleaning and refrigerant industry. Inhalation may produce exfoliative erythroderma, mucous membrane erosions, eosinophilia, and hepatitis. Allergic contact dermatitis caused by alcohol is rarely encountered with lower aliphatic alcohols. A severe case of bullous and hemorrhagic dermatitis on the fingertips and deltoid region was caused by isopropyl alcohol. Though rare, ethyl alcohol dermatitis may also be encountered. Cetyl and stearyl alcohols may provoke contact urticaria.
Testing for sensitivity Patch test The patch test is used to detect hypersensitivity to a substance that is in contact with the skin so that the allergen may be determined and corrective measures taken. So many allergens can cause allergic contact dermatitis that it is impossible to test a person for all of them. In addition, a good history and observation of the pattern of the dermatitis, its localization on the body, and its state of activity are all helpful in determining the cause. The patch test is confirmatory and diagnostic, but only within the framework of the history and physical findings; it 91
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is rarely helpful if it must stand alone. Interpretation of the relevance of positive tests and the subsequent education of patients are challenging in some cases. The Contact Allergen Avoidance Database (CARD) provides names of alternative products that may be used by patients when an allergen is identified. This is available through the American Contact Dermatitis Society. The patch test consists of application of substances suspected to be the cause of the dermatitis to intact uninflamed skin. Patch testing may be administered by the thin-layer rapid-use epicutaneous (TRUE) test or by individually prepared aluminum (Finn) chambers mounted on Scanpor tape. The TRUE test has resulted in more screening for allergic contact dermatitis than in the past; however, if this test does not reveal the allergen for a highly suspect dermatitis, testing with an expanded series by the Finn chamber technique may yield relevant allergens in more than half of these patients. Test substances are applied usually to the upper back, although if only one or two are applied, the upper outer arm may be used. Each patch should be numbered to avoid confusion. The patches are removed after 48 h (or sooner if severe itching or burning occurs at the site) and read. The patch sites need to be evaluated again at day 4 or 5 because positive reactions may not appear earlier. Some allergens may take up to day 7 to show a reaction and the patient should be advised to return if such a delayed reaction occurs. Erythematous papules and vesicles with edema are indicative of allergy (Fig. 6-5). Occasionally, patch tests for potassium iodide, nickel, or mercury will produce pustules at the site of the test application. Usually no erythema is produced; therefore, the reaction has no clinical significance. Strong patch-test reactions may induce a state of hyperirritability (“excited skin syndrome”) in which negative tests appear as weakly positive. Weakly positive tests in the presence of strong ones do not prove sensitivity. There is wide variation in the ability of the skin and mucous membranes to react to antigens. The oral mucosa is more resistant to primary irritants and is less liable to be involved in allergic reactions. This may be because the keratin layer of the skin more readily combines with haptens to form allergens. Also, the oral mucosa
is bathed in saliva, which cleanses and buffers the area and dilutes irritants. However, patch testing for various types of oral signs and symptoms, such as swelling, tingling and burning, perioral dermatitis, and the appearance of oral lichen planus, is useful in determining a cause in many cases. The ability of the skin to react to allergens also depends on the presence of functional antigen-presenting cells, the Langerhans cells. Potent topical steroids, ultraviolet (UV) light, various immunosuppressants such as oral prednisone and the acquired immunodeficiency syndrome (AIDS) have been reported to interfere with the number and function of these key cells. False-negative reactions may result; the value of testing in such circumstances is that if a positive reaction occurs, a diagnosis may be made. Vitiliginous skin is less reactive than normally pigmented adjacent skin.
Provocative use test The provocative use test will confirm a positive closed patchtest reaction to ingredients of a substance, such as a cosmetic; it is used to test products that are made to stay on the skin once applied. The material is rubbed on to normal skin of the inner aspect of the forearm several times a day for 5 days.
Photopatch test The photopatch test is used to evaluate for contact photo allergy to such substances as sulfonamides, phenothiazines, p-aminobenzoic acid, oxybenzone, 6-methyl coumarin, musk ambrette, or tetrachlorsalicylanilide. A standard patch test is applied for 48 h; this is then exposed to 5–15 J/m2 of UVA and read after another 48 h. To test for 6-methyl coumarin sensitivity, the patch is applied in the same manner but for only 30 min before light exposure, rather than for 48 h. A duplicate set of nonirradiated patches is used in testing for the presence of routine delayed hypersensitivity reactions. Also, a site of normal skin is given an identical dose of UVA to test for increased sensitivity to light without prior exposure to chemicals. There is a steady increase in incidence of photoallergy to sunscreening agents and a falling incidence of such reactions to fragrance.
Regional predilection Familiarity with certain contactants and the typical dermatitis they elicit on specific parts of the body will assist in diagnosis of the etiologic agent.
Head and neck
Fig. 6-5 Positive patch-test reaction.
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The scalp is relatively resistant to the development of contact allergies; however, involvement may be caused by hair dye, hair spray, shampoo, or permanent wave solutions. The surrounding glabrous skin, including the ear rims and backs of the ears, may be much more inflamed and suggestive of the cause. Persistent otitis of the ear canal may be caused by sensitivity to the neomycin that is an ingredient of most aural medications. The eyelids are the most frequent site for nail polish dermatitis. Volatile gases, false-eyelash adhesive, fragrances, preservatives, mascara, rubber in sponges used to apply cosmetics, and eyeshadow are also frequently implicated (Fig. 6-6). Perioral dermatitis and cheilitis may be caused by flavoring agents in dentifrices and gum, as well as fragrances, shellac, medicaments, and sunscreens in lipstick and lip balms. Perfume dermatitis may cause redness just under the ears or on the neck. Earlobe dermatitis is indicative of nickel sensitivity. Photocontact dermatitis may involve the entire face and may be sharply cut off at the collar line or extend down on to the sternum in a V shape. There is a typical clear area under the chin where there is little or no exposure to sunlight. In men, in whom shaving lotion fragrances may
Fig. 6-6 Eyelid dermatitis.
be responsible, the left cheek and left side of the neck (from sun exposure while driving) may be the first areas involved.
Trunk The trunk is an infrequent site; however, the dye or finish of clothing may cause dermatitis. The axilla may be the site of deodorant and clothing-dye dermatitis. Involvement of the axillary vault suggests the former; of the axillary folds, the latter. In women, brassieres cause dermatitis from either the material itself, the elastic, or the metal snaps or underwires.
Arms The wrists may be involved because of jewelry or the backs of watches and clasps, all of which may contain nickel. Wristbands made of leather are a source of chrome dermatitis.
Hands Innumerable substances may cause allergic contact dermatitis of the hands, which typically occurs on the backs of the hands and spares the palms. Florists will often develop fingertip or palmar lesions. A hand dermatitis that changes from web spaces to fingertips or from palms to dorsal hands should trigger patch testing. Poison ivy and other plant dermatitides frequently occur on the hands and arms. Rubber glove sensitivity must be kept constantly in mind. Usually irritancy is superimposed on allergic contact dermatitis of the hands, altering both the morphologic and histologic clues to the diagnosis.
Abdomen The abdomen, especially the waistline, may be the site of rubber dermatitis from the elastic in pants and undergarments. The metallic rivets in blue jeans may lead to periumbilical dermatitis in nickel-sensitive patients, as may piercings of the umbilicus.
Groin The groin is usually spared, but the buttocks and upper thighs may be sites of dermatitis caused by dyes. The penis is frequently involved in poison ivy dermatitis. Condom dermatitis may also occur. The perianal region may be involved from the “caine” medications in suppositories, as well as preservatives and fragrances in cleansing materials. Nearly half of women with pruritus vulvae have one or more relevant allergens; often these are medicaments, fragrances, or preservatives.
Lower extremities The shins may be the site of rubber dermatitis from elastic stockings. Feet are sites for shoe dermatitis, most often attrib-
Bryden AM, et al: Photopatch testing of 1155 patients. Br J Dermatol 2006; 155:737. Diepgen TL, et al: Management of chronic hand eczema. Contact Dermatitis 2007; 57:203. Duarte I, et al: Excited skin syndrome: study of 39 patients. Am J Contact Dermat 2002; 13:59. Feser A, et al: Periorbital dermatitis. Br J Dermatol 2008; 159:858. Guin JD: Eyelid dermatitis. J Am Acad Dermatol 2002; 47:755. Kockentiet B, et al: Contact dermatitis in athletes. J Am Acad Dermatol 2007; 56:1048. Lazzarini R, et al: Contact dermatitis of the feet. Dermatitis 2004; 15:125. Marks JG Jr, et al: Contact and Occupational Dermatology, 3rd edn. St Louis: Mosby, 2002. Mowad CM: Patch testing. Curr Opin Allergy Clin Immunol 2006; 6:340. Nardelli A, et al: Contact allergic reactions of the vulva. Dermatitis 2004; 15:131. Prakash AV, et al: Contact dermatitis in older adults. Am J Clin Dermatol 2010; epub. Rietschel RL, Fowler JF Jr: Fisher’s Contact Dermatitis, 6th edn. Hamilton, BC: Decker, 2008. Saary J, et al: A systematic review of contact dermatitis treatment and prevention. J Am Acad Dermatol 2005; 53:845. Schena D, et al: Contact allergy in chronic eczematous lip dermatitis. Eur J Dermatol 2008: 18:688. Sheman A, et al: Contact allergy alternatives. Dis Mon 2008: 54:7. Thyssen JP, et al: The epidemiology of contact allergy in the general population. Contact Dermatitis 2007; 57:287. Torgerson RR, et al: Contact allergy in oral disease. J Am Acad Dermatol 2007; 57:315. Uter W, et al: Patch test results with patients’ own perfumes, deodorants and shaving lotions. J Eur Acad Dermatol Venereol 2007; 21:374. Warshaw EM, et al: Shoe allergens. Dermatitis 2007: 18:191. Zug KA, et al: Contact allergy in children referred for patch testing. Arch Dermatol 2008; 144:1329. Zug KA, et al: Patch-test results of the North American Contact Dermatitis Group 2005–2006. Dermatitis 2009; 20:149.
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utable to rubber sensitivity, chrome-tanned leather, dyes, or adhesives. Application of topical antibiotics to stasis ulcers commonly leads to sensitivity and allergic contact dermatitis.
Dermatitis resulting from plants A large number of plants, including trees, grasses, flowers, vegetables, fruits, and weeds, are potential causes of dermatitis. Eruptions from them vary considerably in appearance but are usually vesicular and accompanied by marked edema. After previous exposure and sensitization to the active substance in the plant, the typical dermatitis results from re-exposure. The onset is usually a few hours or days after contact. The characteristic linearly grouped lesions are probably produced by brushing the skin with a leaf edge or a broken twig, or by carriage of the allergen under the nails. Contrary to general belief, the contents of vesicles are not capable of producing new lesions.
Toxicodendron (poison ivy) Toxicodendron dermatitis includes dermatitis from members of the Anacardiaceae family of plants: poison ivy (Fig. 6-7), poison oak, poison sumac, Japanese lacquer tree, cashew nut tree (the allergen is in the nutshell), mango (the allergen is in the rind, leaves, or sap), Rengas tree, and Indian marking nut tree. The ginkgo (the allergen is in the fruit pulp), spider flower or silver oak, Gluta species of trees and shrubs in Southeast Asia, Brazilian pepper tree, also known as Florida holly, and poisonwood tree contain nearly identical antigens. Toxicodendron dermatitis appears within 48 h of exposure of a person previously sensitized to the plant. It usually begins on the backs of the fingers, interdigital spaces, wrists, and eyelids, although it may begin on the ankles or other parts that have been exposed. Marked pruritus is the first symptom; then 93
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Fig. 6-7 Toxicodendron radicans subsp radicans. Poison ivy species found commonly in the eastern US. (Courtesy of James WD [ed]: Textbook of Military Medicine. Office of the Surgeon General, United States Army, 1994)
Fig. 6-9 Acute poison ivy reaction.
Fig. 6-10 Black dot sign in poison ivy reaction.
Fig. 6-8 Acute poison ivy reaction.
inflammation, vesicles, and bullae may appear. The vesicles are usually grouped and often linear (Fig. 6-8). Large bullae may be present, especially on the forearms and hands. The eyelids are puffy; they will be worst in the morning and improve as the day progresses (Fig. 6-9). Pruritus ani and involvement of the genital areas occur frequently. A black lacquer deposit may occur in which the sap of the plant has been oxidized after being bound to the stratum corneum (Fig. 6-10). Untreated toxicodendron dermatitis usually lasts 2–3 weeks. The fingers transfer the allergen to other parts, especially the forearms and the male prepuce, which become greatly swollen. However, once the causative oil has been washed off, there is no spreading of the allergen and no further spread of the dermatitis. Some persons are so susceptible that direct contact is 94
not necessary, the allergen apparently being carried by the fur of their pets or by the wind. It can also be acquired from golf clubs or fishing rods, or even from furniture that a dog or cat might have occupied after exposure to the catechol. Occasionally, eating the allergen, as occurred in a patient who ingested raw cashew nuts in an imported pesto sauce, may result in the baboon syndrome (a deep red–violet eruption on the buttocks, genital area, inner thighs, and sometimes axilla), or a systematized allergic contact dermatitis with the morphology of a generalized erythematous papular eruption. The cause is an oleoresin known as urushiol, of which the active agent is a mixture of catechols. This and related resorcinol allergens are present in many plants and also in philodendron species, wood from Persoonia elliptica, wheat bran, and marine brown algae. The most striking diagnostic feature is the linearity of the lesions. It is rare to see vesicles arranged in a linear fashion except in plant-induced dermatitis. A history of exposure in the country or park to plants that have shiny leaves in groups of three, followed by the appearance of vesicular lesions within 2 days, usually establishes the diagnosis. Persons with known susceptibility not only should avoid touching plants having
Other toxicodendron-related dermatitis Lacquer dermatitis is caused by a furniture lacquer made from the Japanese lacquer tree, used on furniture, jewelry, or brica-brac. Antique lacquer is harmless, but lacquer less than 1 or 2 years old is highly antigenic. Cashew nutshell oil is extracted from the nutshells of the cashew tree (Anacardium occidentale). This vesicant oil contains cardol, a phenol similar to urushiol in poison ivy. The liquid has many commercial applications, such as the manufacture of brake linings, varnish, synthetic glue, paint, and sealer for concrete. Mango dermatitis is uncommon in natives of mangogrowing countries (the Philippines, Guam, Hawaii, Cuba) who have never been exposed to contact with toxicodendron species. Many persons who have been so exposed, however, whether they had dermatitis from it or not, are sensitized by one or a few episodes of contact with the peel of the mango fruit. The palms carry the allergen, so the eyelids and the male prepuce are often early sites of involvement. Sponging all contaminated or itchy areas meticulously and systematically with equal parts of ether and acetone at the outset will often remove the oleoresin and ameliorate any worsening of the dermatitis, which can be treated with topical or oral steroids as needed. Ginkgo tree dermatitis simulates toxicodendron dermatitis with its severe vesiculation, erythematous papules, and edema. The causative substances are ginkgolic acids from the fruit pulp of the ginkgo tree. Ingestion of the ginkgo fruit may result in perianal dermatitis. Ginkgo biloba given orally for cerebral disturbances is made from a leaf extract so it does not elicit a systemic contact allergy when ingested.
Flowers and houseplants Among the more common houseplants, the velvety-leafed philodendron, Philodendron crystallinum (and its several variants), known in India as the money plant, is a frequent cause of contact dermatitis. The eruption is often seen on the face, especially the eyelids, carried there by hands that have watered or cared for the plant. English ivy follows philodendron in frequency of cases of occult contact dermatitis. Primrose derma-
Contact dermatitis
the grouped “leaves-of-three,” but should also exercise care in handling articles of clothing, tools, toys, and pets that have come in contact with such plants. Eradication of these plants growing in frequented places is one easy preventive measure, as is recognition of the plants to avoid. An excellent resource is a pamphlet available from the American Academy of Dermatology. If the individual is exposed, washing with soap and water within 5 min may prevent an eruption. Protective barrier creams are available that are somewhat beneficial. Quaternium-18 bentonite has been shown to prevent or diminish experimentally produced poison ivy dermatitis. Innumerable attempts have been made to immunize against poison ivy dermatitis by oral administration of the allergen, or subcutaneous injections of oily extracts. To date, no accepted method of immunization is available. Repeated attacks do not confer immunity, although a single severe attack may achieve this by what has been called massive-dose desensitization. When the diagnosis is clear and the eruption severe or extensive, systemic steroidal agents are effective, beginning with 40–60 mg of prednisone in a single oral dose daily, tapered off over a 3-week period. When the eruption is limited in extent and severity, local application of topical corticosteroid creams, lotions, or aerosol sprays is preferred. Time-honored calamine lotion without phenol is helpful and does no harm. Antihistaminic ointments should be avoided because of their sensitization potential. This also applies to the local application of the “caine” topical anesthetics.
Fig. 6-11 Chronic fissured fingertip dermatitis in a florist.
titis affects the fingers, eyelids, and neck with a punctate or diffuse erythema and edema. It was formerly most frequently encountered in Europe; however, the primrose is now a common houseplant in the US. Primin, a quinone, is the causative oleoresin abounding in the glandular hairs of the plant Primula obconica. The popular cut flower, the Peruvian lily, is the most common cause of allergic contact dermatitis in florists. When handling flowers of the genus Alstroemeria the florist utilizes the thumb, and second and third digits of the dominant hand. Since it is chronic, fissured hyperkeratotic dermatitis results and is identical to the so-called tulip fingers seen among sensitized tulip workers (Fig. 6-11). Testing is done with the allergen tuliposide A. It does not penetrate nitrile gloves. Chrysanthemums frequently cause dermatitis, with the hands and eyelids of florists most commonly affected. The α-methylene portion of the sesquiterpene lactone molecule is the antigenic site, as it is in the other genera of the Compositae family. A severe inflammatory reaction with bulla formation may be caused by the prairie crocus (Anemone patens L), the floral emblem of the province of Manitoba. Several species of ornamental “bottle brush” from Queensland, Grevillea banksii, G. Robyn Gordon, and G. robusta, may cause allergic contact dermatitis. It is exported to the US and other Western countries. The allergen is a long-chain alkyl resorcinol. A cross-sensitivity to toxicodendron has been demonstrated. Contact dermatitis may be caused by handling many other flowers, such as the geranium, scorpion flower (Phacelia crenulata or campanularia), hydrangea, creosote bush (Larvia tridentata), Heracula, daffodil, foxglove, lilac, lady slipper, magnolia, and tulip and narcissus bulbs. The poinsettia and oleander almost never cause dermatitis, despite their reputation for it, although they are toxic if ingested. Treatment of all these plant dermatitides is the same as that recommended for toxicodendron dermatitis. Parthenium hysterophorus, a photosensitizing weed, was accidentally introduced into India in 1956 and has spread over most of the country; it is also spreading in Australia, China, and Argentina. The well-deserved reputation for harmfulness of dieffenbachia, a common, glossy-leafed house plant, rests on the high content of calcium oxalate crystals in its sap, which burn the mouth and throat severely if any part of the plant is chewed or swallowed. Severe edema of the oral tissues may result in complete loss of voice; hence its common nickname, “dumb cane.” It does not appear to sensitize. The castor bean, the seed of Ricinus communis, contains ricin, a poisonous substance (phytotoxin). Its sap contains an antigen that may cause anaphylactic hypersensitivity and also dermatitis. 95
Fruit and vegetables
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Many vegetables may cause contact dermatitis, including asparagus, carrot, celery, cow-parsnip, cucumber, garlic, Indian bean, mushroom, onion, parsley, tomato, and turnip. Onion and celery, among other vegetables, have been incriminated in the production of contact urticaria and even anaphylaxis. Several plants, including celery, fig, lime, and parsley, can cause a phototoxic dermatitis because of the presence of psoralens.
Trees Trees whose timber and sawdust may produce contact dermatitis include ash, birch, cedar, cocobolo, elm, Kentucky coffee tree, koa, mahogany, mango, maple, mesquite, milo, myrtle, pine, and teak. The latex of fig and rubber trees may also cause dermatitis, usually of the phototoxic type. Melaleuca oil (tea tree oil), which may be applied to the skin to treat a variety of maladies, can cause allergic contact dermatitis, primarily through the allergen D-limonene. The exotic woods, especially cocobolo and rosewood, and tea tree oil are prominent among allergens that may produce erythema multiforme after cutaneous exposure. Toxicodendron, various medicaments, and a variety of other allergens may induce this reaction.
Tree-associated plants Foresters and lumber workers can be exposed to allergenic plants other than trees. Lichens are a group of plants composed of symbiotic algae and fungi. Foresters and wood choppers exposed to these lichens growing on trees may develop severe allergic contact dermatitis. Exposure to the lichens may also occur from firewood, funeral wreaths, and also fragrances added to aftershave lotions (oak moss and tree moss). Sensitization is produced by D-usnic acid and other lichen acids contained in lichens. The leafy liverwort (Frullania nisquallansis), a forest epiphyte growing on tree trunks, has produced allergic dermatitis in forest workers. The eruption is commonly called cedar poisoning. It resembles toxicodendron dermatitis; its attacks are more severe during wet weather. The allergen is sesquiterpene lactone.
eruption produced by contact with a marine blue–green alga, which has been identified as Lyngbya majuscula Gomont. The onset is within a few minutes of leaving the ocean, with severe itching and burning, followed by dermatitis, blisters, and deep and painful desquamation that affects the areas covered by the bathing suit (in men, especially the scrotum, perineum, and perianal areas; occasionally, in women, the breasts). Patch tests with the alga are neither necessary nor helpful, since it is a potent irritant. Bathing in fresh water within 10 or 15 min of leaving the ocean may prevent the dermatitis. The Bermuda fire sponge may produce contact erythema multiforme. Trawler fishermen in the Dogger Bank area of the North Sea develop allergic dermatitis after contact with Alcyonidium hirsutum. This is a seaweed-like animal colony that becomes caught in the fishermen’s net and produces erythema, edema, and lichenification on the hands and wrists.
Plant-associated dermatitis Phototoxic contact dermatitis from plants is discussed in Chapter 3 (Fig. 6-12). The residua of various insecticides on plants may also produce dermatitis. This is especially true of arsenic- and malathion-containing sprays. Randox (2-chloro-N, N-diallylacetamide) has been reported as the cause of hemorrhagic bullae on the feet of farmers. Lawn-care companies spray herbicides and fungicides throughout the spring, summer, and fall. Dryene, thiuram, carbamates, and chlorothalonil are potential sensitizers in these workers, whose clothing frequently becomes wetted while spraying. Barbs, bristles, spines, thorns, spicules, and cactus needles are some of the mechanical accessories of plants that may produce dermatitis. Sabra dermatitis is an occupational dermatitis resembling scabies. It is seen among pickers of the prickly pear cactus plant. It also occurs in persons handling Indian figs in Israel, where the condition is seen from July to November. The penetration of minute, invisible thorns into the skin is the cause. Agave americana is a low-growing plant grown for ornamental purposes in many Southwestern communities. Trimming during landscaping can induce an irritant dermatitis caused by calcium oxalate crystals. The stinging
Pollens and seeds The pollens in ragweed are composed of two antigens. The protein fraction causes the respiratory symptoms of asthma and hay fever, and the oil-soluble portion causes contact dermatitis. Ragweed oil dermatitis is a seasonal disturbance seen mainly during the ragweed growing season from spring to fall. Contact with the plant or with wind-blown fragments of the dried plant produces the typical dermatitis. The oil causes swelling and redness of the lids and entire face, and a red blotchy eruption on the forearms that, after several attacks, may become generalized, with lichenification. It closely resembles chronic atopic dermatitis, with lichenification of the face, neck, and major flexures, and severe pruritus. The distribution also mimics that of photodermatitis, the differentiating point being that in ragweed dermatitis there is involvement of the upper eyelids and the retroauricular and submental areas. Chronic cases may continue into the winter; however, signs and symptoms are most severe at the height of the season. Sesquiterpene lactones are the cause. Coexistent sensitization to pyrethrum may account for prolongation of ragweed dermatitis. Men outnumber women in hypersensitivity reactions; farmers outnumber patients of all other occupations.
Marine plants Numerous aquatic plants are toxic or produce contact dermatitis. Algae are the worse offenders. Freshwater plants are rarely of concern. Seaweed dermatitis is a type of swimmer’s 96
Fig. 6-12 Photosensitivity caused by dripping fruit juice.
Plant derivatives Sensitizing substances derived from plants are found in the oleoresin fractions that contain camphors, essential oils, phenols, resins, and terpenes. The chief sensitizers are the essential oils. They may be localized in certain parts of the plant, such as in the peel of citrus fruits, leaves of the eucalyptus tree, and bark of the cinnamon tree. Aromatherapy, an increasingly popular treatment for relief of stress, involves either inhaling or massaging with essential oils; this may cause allergic contact dermatitis in therapists or clients. Exposure to botanical extracts through many cosmetics and homeopathic remedies has resulted in an increasing number of reports of allergic contact sensitivity to individual ingredients, especially tea tree oil. Cinnamon oil (cassia oil) is a common flavoring agent, especially in pastries. Hand dermatitis in pastry bakers is often caused by cinnamon. It is also used as a flavor for lipstick, bitters, alcoholic and nonalcoholic beverages, toothpaste, and chewing gum. Perioral dermatitis may be caused by cinnamon in chewing gum. A 5% cinnamon solution in olive oil is used for patch testing. Eugenol, clove oil, and eucalyptus oil are used by dentists, who may acquire contact dermatitis from them. Anise, peppermint, and spearmint oils may cause sensitization. Nutmeg, paprika, and cloves are causes of spice allergy. Fragrance-mix is a useful indicator allergen. Lemon oil from lemon peel or lemon wood may cause sensitization in the various handlers of these substances. Citric acid may cause dermatitis in bakers. Lime oil in lime-scented shaving cream or lotion may cause photoallergy. Myroxylon pereirae contains numerous substances, among which are essential oils similar to the oil of lemon peel. It is known to cross-react with vanilla and cinnamon, among many others. Vanillin is derived from the vanilla plant and frequently produces contact dermatitis, vanillism, in those connected with its production and use. Turpentine frequently acts as an irritant and as an allergic sensitizer (carene). It is contained in paints, paint thinners, varnishes, and waxes.
Testing for plant allergens The method of testing for plant hypersensitivity is the application of the crushed plant leaf, stem, and petal, and then covering with micropore tape. The plant should be washed thoroughly as infection with fungi from the soil may complicate testing. A test should also be performed on several controls to make sure that the leaf is not an irritant. It must be remembered that some of the plants are photosensitizers. Test sites for these must be done in duplicate, with one set kept covered and the other exposed to artificial light or sunlight for the detection of photosensitivity. Anderson BE, et al: Stinging nettle dermatitis. Am J Contact Dermat 2003; 14:44. Arberer W: Contact allergy and medicinal plants. J Dtsch Dermatol Ges 2008; 6:15. Bedi MK, et al: Herbal therapy in dermatology. Arch Dermatol 2002; 138:232. Crawford GH, et al: Tea tree oil. Am J Contact Dermat 2004; 15:59. Crawford GH, et al: Use of aromatherapy products and increased risk of hand dermatitis in massage therapists. Arch Dermatol 2004; 140:991. Gladman AC: Toxicodendron dermatitis. Wilderness Environ Med 2006; 17:120. Gordon LA: Compositae dermatitis. Australas J Dermatol 1999; 40:123. Guanche AD, et al: Generalized eczematous contact dermatitis from cocobolo wood. Am J Contact Dermat 2003; 14:90. Gutman AB, et al: Liverworts—Frullania species. Cutis 2005; 75:262.
Hamilton TK, et al: Systemic contact dermatitis to raw cashew nuts in a pesto sauce. Am J Contact Dermat 1998; 9:51. Hershko K, et al: Exploring the mango–poison ivy connection. Contact Dermatitis 2005; 52:3. High WA: Agave contact dermatitis. Am J Contact Dermat 2003; 14:213. Kurlan JG, et al: Black spot poison ivy. J Am Acad Dermatol 2001; 45:246. LeSuer BW, et al: Necrotizing cellulites caused by Apophysomyces elegans at a patch test site. Am J Contact Dermat 2002; 13:140. Marks JG Jr, et al: Prevention of poison ivy and poison ash allergic contact dermatitis by quaternium-18 bentonite. J Am Acad Dermatol 1995; 33:212. McGovern TW, et al: Is it, or isn’t it? Poison ivy look-a-likes. Am J Contact Dermat 2000; 11:104. Paulsen E: Contact sensitisation from Compositae-containing herbal remedies and cosmetics. Contact Dermatitis 2002; 47:189. Rutherford T, et al: Allergy to tea tree oil. Australas J Dermatol 2007; 48:83. Sharma VK, et al: Parthenium dermatitis. Dermatitis 2007; 18:183. Simpson EL, et al: Prevalence of botanical extract allergy in patients with contact dermatitis. Am J Contact Dermat 2004; 15:67.
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nettle is a common weed that bears tiny spines with biologically active substances such as histamine that produce itching and urticaria within minutes of contact.
Dermatitis from clothing A predisposition to contact dermatitis from clothing occurs in persons who perspire freely or who are obese and wear clothing that tends to be tight. Depending on the offending substance, various regions of the body will be affected. Regional location is helpful in identifying the sensitizing substance. The axillary folds are commonly involved; the vaults of the axillae are usually spared. Sites of increased perspiration and sites where evaporation is impeded, such as the intertriginous areas, will tend to leach dyes from fabrics to produce dermatitis. Areas where the material is tight against the skin, such as the waistband or neck, are frequently involved (Fig. 6-13). The thighs are commonly affected when pants contain the offending allergen. Sparing of the hands, face, and undergarment sites is usual, but otherwise these reactions may be scattered and generalized. Secondary changes of lichenification and infection occur frequently because of the chronicity of exposure. Cotton, wool, linen, and silk fabrics were used exclusively before the advent of synthetic fabrics. Most materials are now blended in definite proportions with synthetics to produce superior lasting and esthetic properties. Dermatitis from cotton is virtually nonexistent. In most instances there is no true sensitization to wool. Wool acts as an irritant because of the barbs on its fibers. These barbs may produce severe
Fig. 6-13 Waistband clothing dermatitis.
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pruritus at points of contact with the skin, especially in the intertriginous areas. In sensitive-skinned persons, such as those with atopic dermatitis, the wearing of wool is not advisable because of its mechanical irritative properties. Silk is a sensitizer, but rarely; the nature of the allergen is not known. Many patients believe their detergent is the source of a dermatitis, but this is rarely the case. Numerous synthetic fibers are available for clothing and accessory manufacture, all of which again are remarkably free of sensitizing properties. Polyvinyl resins are the plastics used in such apparel as raincoats, rainhoods, wristbands, suspenders, plastic mittens, and gloves. These again are only infrequently found to be causes of contact dermatitis. The most common causes of clothing dermatitis are the fabric finishers, dyes, and rubber additives. Fabric finishers are used to improve the durability, appearance, and feel of a mat erial. Antiwrinkling and crease-holding chemicals are mostly resins, which are incorporated into the fibers as they are being manufactured or applied to the completed (finished) fabric. Fabrics are treated to make them less vulnerable to the effects of perspiration and ironing. Clothing may be treated with these substances to make it dry rapidly after washing. They are used to make clothing fabrics shrink-resistant, and waterand stain-repellent. When all these uses are taken into consideration, the low incidence of dermatitis from these formaldehyde resin materials is remarkable. Ethylene urea melamine formaldehyde resin and dimethylol dihydroxyethylene urea formaldehyde resin are the best screening agents. Many also react to formaldehyde and the formaldehyde-releasing preservatives such as quaternium-15. Avoidance of exposure of the skin to formaldehyde resin is most difficult. New clothes should be thoroughly washed twice before wearing the first time. Even with this precaution, however, allergens may still be present in sufficient quantities to continue the dermatitis. Jeans, Spandex, silk, 100% linen, 100% nylon, and 100% cotton that is not wrinkle-resistant or colorfast are best tolerated. T-shirts, sweat shirts, sweat pants, white underclothes suitable for bleaching, and any type of mixed synthetic fibers with cotton fibers that are added to make them drip-dry are most likely to cause problems in these patients. An increasing number of patients allergic to clothing dye are being reported. Synthetic fabrics such as polyester and acetate liners in women’s clothing are prime causes, and affected patients are more commonly women than men. Even infants may be affected, however, with dyes in diapers accounting for five cases reported by Alberta et al. In many cases patients do not react to paraphenylene diamine, but only to the disperse dye allergens. The best screening agents are disperse blue 106 and 124. Suspected fabrics may be soaked in water for 15 min and applied under a patch for 72–96 h. Spandex is a nonrubber (but elastic) polyurethane fiber. It is widely used for garments such as girdles, brassieres, and socks, but is generally safe in the US, as it is free of rubber additives. Alberta L, et al: Diaper dye dermatitis. Pediatrics 2005; 116:e450. Carlson RM, et al: Diagnosis and treatment of dermatitis due to formaldehyde resin in clothing. Dermatitis 2004; 15:169. Cohen D, et al: Clothes make the woman: diagnosis and management of clothing dermatitis. Am J Contact Dermat 2001; 12:229. Donovan J, et al: Allergic contact dermatitis from formaldehyde textile resins in surgical uniforms and nonwoven textile masks. Dermatitis 2007; 18:40. Hatch K, et al: Textile dye dermatitis. J Am Acad Dermatol 1995; 32:631. Hatch KL, et al: Disperse dyes in fabrics of patients patch-test-positive to disperse dyes. Am J Contact Dermat 2003; 14:205. Nedorost S, et al: Allergens retained in clothing. Dermatitis 2007; 18:212.
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Reich HC, et al: Allergic contact dermatitis from formaldehyde textile resins. Dermatitis 2010; 21:65. Ryberg K, et al: Contact allergy to textile dyes in southern Sweden. Contact Dermatitis 2006; 54:313. Zug KA, et al: The value of patch testing patients with a scattered generalized distribution of dermatitis. J Am Acad Dermatol 2008; 59:426.
Shoe dermatitis Footwear dermatitis may begin on the dorsal surfaces of the toes and may remain localized to that area indefinitely (Fig. 6-14). There is erythema, lichenification, and, in severe cases, weeping and crusting. Secondary infection is frequent. In severe cases an id reaction may be produced on the hands similar to the reaction from fungus infection of the feet. A diagnostic point is the normal appearance of the skin between the toes, which has no contact with the offending substance. In fungus infections the toe webs are usually involved. Another pattern seen is involvement of the sole with sparing of the instep and flexural creases of the toes. Also purpuric reactions to components of black rubber mix may occur. Hyperhidrosis and atopy predispose to the development of shoe allergy. Shoe dermatitis is most frequently caused by the rubber accelerators mercaptobenzothiazole, carbamates, and tetra methylthiuram disulfide. Potassium dichromate in leather and the adhesives used in synthetic materials (especially p-tertbutylphenol formaldehyde resin) are also common shoe allergens. Diisocyanates are used in making foam rubber padding for athletic shoes and may cause allergy. Other causative agents are felt, cork liners, formaldehyde, dyes, asphalt, dimethyl fumarate and tar. Patch testing with pieces of various shoe parts may be done by soaking them for 15 min in water and applying them to the back for 72–96 h. Once the allergen has been identified, selection of shoes without the offending substance will lead to resolution. This is, unfortunately, a difficult process, as most shoes are made in areas without mandatory labeling requirements, and plastic, wooden, or fabric shoes which contain fewer allergens are often impractical. Castando-Tardan MP, et al: Allergic contact dermatitis to Crocs. Contact Dermatitis 2008; 58:248. Chowdhuri S, et al: Epidemio-allergological study in 155 cases of footwear dermatitis. Indian J Dermatol Venereol Leprol 2007; 73:319. Fraga A, et al: Allergic contact dermatitis to dimethyl fumarate in footwear. Contact Dermatitis 2010; 62:121. Oztas P, et al: Shoe dermatitis from para-tertiary butylphenol formaldehyde. Contact Dermatitis 2007; 56:294. Van Coevorden AM, et al: Contact allergens in shoe leather among patients with foot eczema. Contact Dermatitis 2002; 46:145. Washaw EM, et al: Shoe allergens. Dermatitis 2007; 18:191.
Fig. 6-14 Shoe dermatitis.
Contact dermatitis Fig. 6-15 Nickel dermatitis from earring.
Dermatitis from metals and metal salts Metal dermatitis is most frequently caused by nickel and chromates. Usually, with the exception of nickel, the pure metals generally do not cause hypersensitivity; it is only when they are incorporated into salts that they cause reactions. Most objects containing metal or metal salts are combinations of several metals, some of which may have been used to plate the surface, thereby enhancing its attractiveness, durability, or tensile strength. For this reason suspicion of a metal-caused dermatitis should be investigated by doing patch tests to several of the metal salts. Patients have been reported who developed a variety of dermatoses, most often eczematous in type, after placement of an orthopedic implant or an endovascular device. Reed et al and Honari et al have published recent reviews of these two situations. In general, patch testing prior to placement may help guide the specific type of device to be utilized. However, patch testing after placement to evaluate a new eruption is rarely useful. A positive diagnosis of allergy requires at a minimum the appearance of a chronic dermatitis after placement, no other cause, a positive patch test for the suspected metal (or in the case of drug-eluting stents, the drug), and healing after removal. This scenario is exceedingly uncommon; removal of a foreign material rarely results in cure.
Fig. 6-16 Jeans button nickel dermatitis.
Black dermatographism Black or greenish staining under rings, metal wristbands, bracelets, and clasps is caused by the abrasive effect of cosmetics or other powders containing zinc or titanium oxide on gold jewelry. This skin discoloration is black because of the deposit of metal particles on skin that has been powdered and that has metal, such as gold, silver, or platinum, rubbing on it. Abrasion of the metal results from the fact that some powders are hard (zinc oxide) and are capable of abrading the metal.
Nickel Because we are all constantly exposed to nickel, nickel dermatitis is a frequent occurrence. While still most frequent among women, sensitization is increasing among men. A direct relationship between prevalence of nickel allergy and number of pierced sites has been documented. Nickel produces more cases of allergic contact dermatitis than all other metals combined. Erythematous and eczematous eruptions, sometimes with lichenification, appear beneath earrings (Fig. 6-15), bracelets, rings, wrist watches, clasps, and blue-jeans buttons (Figs 6-16 and 6-17). The snaps on clothing have been implicated in producing allergy in children; nickel is the most common cause of allergic contact dermatitis in children as well as
Fig. 6-17 Close-up of Fig. 6-16.
adults. Several patients with dermatitis on one ear or the preauricular area have been reported to be allergic to their cell phone. The metal portion is often nickel-containing, with this being the implicated allergen. Euro coins have enough nickel in them to elicit allergic responses in nickel-sensitive individuals; however, coins are rarely a cause of hand dermatitis. Nickel ranks highly on lists of occupationally induced allergic contact dermatitis. Nickel dermatitis is seen most frequently on the earlobes. Piercing the earlobes with nickel-plated instruments or wearing nickel-plated jewelry readily induces nickel sensitivity. Earlobes should be pierced only with stainless steel instruments, and only stainless steel earrings should be worn until the ears have healed. Exposure to the metal may not be readily 99
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apparent most of the time. Even in gold jewelry the clasps and solder may contain nickel. Nickel objects may be plated with chrome and yet cause nickel dermatitis through the leaching of some of the nickel through the small pores of the chromium plating. Nickel oxides in green paints may produce nickel dermatitis. Homeopathic and complementary medicaments may also contain enough nickel to produce a contact allergy. Sweat containing sodium chloride may combine with nickel to form nickel chloride. This affects the degree of nickel dermatitis, it being more severe in persons who perspire profusely. The diagnosis is established by a positive patch-test reaction to nickel sulfate. Nickel may be detected by applying a freshly prepared 1% alcohol solution of dimethylglyoxime and a 10% aqueous solution of ammonia separately in equal amounts to the test object. In the presence of nickel, the cotton swab used to apply the solution will turn orange–pink. A positive test always means that nickel is present, but a negative test does not rule out its presence. Sweat, blood, or saline may leach nickel from stainless steel. Prophylactic measures should include the reduction of perspiration in those sensitive to nickel. Topical corticosteroids applied before exposure to nickel, such as before putting on a wrist band, may be successful. Clasps and other objects are available in plastic material so that some of the exposure to nickel may be decreased. Polyurethane varathane 91 (Flecto) applied in three coats will give protection for several months. Treatment of nickel dermatitis consists of the application of topical corticosteroids. In Europe laws regulating the maximum content of nickel in jewelry are in force; this has led to a marked decrease in sensitization. Efforts to enact a similar standard in the US are under way. Hand eczema and pompholyx in nickel- or cobalt-sensitive patients has rarely been aggravated by orally ingested metals in the diet. In severe, treatment-resistant dermatitis a specific diet low in nickel and cobalt may be tried.
Chromium The chromates are strongly corrosive and irritating to the skin; they may act as primary irritants or as sensitizers to produce allergic contact dermatitis. Aside from occurrence among employees in chromate works, chrome dermatitis is encountered among tanners, painters, dyers, photographers, polishers, welders, aircraft workers, diesel engine workers, and those involved with the bleaching of crude oils, tallows, and fats. Traces of dichromates in shoe leather and gloves may cause eczema of the feet and hands. Many zippers are chromium-plated, and the nickel underneath the plate may be the causative agent. Chromium metal and stainless steel do not produce contact dermatitis. Zinc chromate paint is a source of dermatitis. Matches, hide glues, chrome alloys, cigarette lighters, and leather hatbands, sandals, or camera cases may cause chrome dermatitis. Anticorrosion solutions used for refrigeration and other recirculation systems often contain chromates that produce dermatitis. Most individuals in the cement industry suffering from cement eczema show positive patch tests to dichromates. Cement eczema is often a primary irritant dermatitis complicated by allergic contact dermatitis to the hexavalent chromates. The incidence of cement dermatitis has decreased significantly over the years, which is believed to be because of the addition of ferrous sulfate, delivery of premixed cement to the job site, and improved education. The skin changes are multiform, ranging from a mild follicular dermatitis to widespread nodular and crusted eruptions, all being worse on exposed parts. Often they are slow to clear up, lasting from a few weeks to 6 months after contact has 100
ceased. Heavy exposure of industrial workers to chromates may produce chrome ulcers on the backs of the hands and forearms, usually beginning around a hair follicle, or in the creases of the knuckles or finger webs. The hole begins as a small abrasion that deepens and widens as its edges grow thick, eventually forming a conical indolent ulceration. Chrome ulcers may also arise on—and perforate—the nasal septum. Arsenic exposure may result in similar ulcers. Diagnosis of chrome sensitivity is made by a positive patch test to potassium dichromate in petrolatum. The hexavalent chrome compounds are the most frequent cause of chrome dermatitis since they penetrate the skin more easily than the trivalent form. Both forms are sensitizers. Even with avoidance of chromate-containing materials, chromate-induced dermatitis is often persistent.
Mercury The mercurials may act not only as irritants but also as sensitizers. Thimerosal is a mercuric-containing preservative; it is an allergen that is rarely relevant. Allergy to this compound is likely to have been caused by exposure during childhood vaccinations and to tincture of merthiolate antiseptic. In general, these patients tolerate repeated vaccinations well. Most individuals are sensitized to the ethyl mercuric component of thimerosal; however, those who react to the thiosalicylic acid portion develop photodermatitis to piroxicam. Mercury in amalgam dental fillings has been shown in multiple large studies to cause oral lichoid eruptions. The relationship is especially strong when the oral lesion, often with a painful erosion present, is apposed to a gold or amalgam filling. In many cases where sensitivity is proven by patch testing and fillings are replaced, involution of the oral findings occurs.
Cobalt Cobalt is frequently combined with nickel as a contaminant and patients allergic to cobalt are commonly also allergic to nickel. The metals have similar properties but do not produce cross-reactions. Cobalt dermatitis may occur in those involved in the manufacture of polyester resins and paints, in the manufacture of hard metal used for cutting and drilling tools, and in the manufacture and use of cement. Cobalt dermatitis may also occur in producers of pottery, ceramics, metal alloys, glass, carbides, and pigments. Individuals may be exposed to cobalt in hair dye, flypaper, and vitamin B12. Blue tattoo pigment contains cobalt oxide. Rarely, cobalt chloride may cause nonimmunologic local release of vasoreactive materials, with a local urticarial response.
Gold Gold dermatitis may rarely occur from the wearing of gold jewelry. A predisposing factor in such patients is the presence of dental gold. Oral lichoid eruptions have also been reported with gold, similar to the situation with mercury-containing amalgams. It is not uncommon to see positive reactions to gold when patch-testing patients with facial, eyelid, or widespread dermatitis of unknown cause. Although it is difficult to make a direct clinical correlation with any one piece of jewelry, occasional patients will clear if they stop wearing all gold jewelry. However, in most patients there is a lack of relevance. A number of cases of dermatitis resulting from gold jewelry, especially gold rings, contaminated with radon and its decay products have been reported. This may eventuate in radiation dermatitis and squamous cell carcinoma of the finger. Evidently, the source of contaminated gold for the rings had been reclaimed decayed radon gold seeds.
Most other commonly used metals are not important in causing contact dermatitis. Platinum dermatitis may occur from exposure to platinum salts and sprays in industry. Platinum rings, earrings, white gold spectacles, clasps, and other jewelry cause eruptions resembling those caused by nickel. Zinc, aluminum, copper sulfate, titanium, and antimony dermatitis rarely occur; these metals may, however, act as irritants. Belsito DV: Thimerosal: contact (non)allergen of the year. Am J Contact Dermat 2002; 13:1. De Medeiros LM, et al: Complementary and alternative remedies: an additional source of potential systemic nickel exposure. Contact Dermatitis 2008; 58:97. Filan FL, et al: Sensitization to palladium chloride. Am J Contact Dermat 2003; 14:78. Fowler J Jr, et al: Gold. Am J Contact Dermat 2001; 12:1. Fowler J Jr, et al: Gold allergy in North America. Am J Contact Dermat 2001; 12:3. Freiman A, et al: Patch testing with thimerosal in a Canadian center. Am J Contact Dermat 2003; 14:138. Heim KE, et al: Children’s clothing fasteners as a potential source of exposure to releasable nickel ions. Contact Dermatitis 2009; 60:100. Honari G, et al: Hypersensitivity reactions associated with endovascular devices. Contact Dermatitis 2008; 59:7. Kornick R, et al: Nickel. Dermatitis 2008; 19:3. Reed KB, et al: Retrospective evaluation of patch testing before or after metal device implantation. Arch Dermatol 2008; 144:999. Seishma M, et al: Cellular phone dermatitis with chromate allergy. Dermatology 2003; 207:48. Shah M, et al: Nickel as an occupational allergen. Arch Dermatol 1998; 134:1231. Stuckert J, et al: Low cobalt diet for dyshidrotic eczema. Contact Dermatitis 2008; 59:361. Suneja T, et al: Blue-jean button nickel. Dermatitis 2007; 18:208. Thyssen JP, et al: Patch test reactivity to metal allergens following regulatory intervention. Contact Dermatitis 2010; 63:102. Thyssen JP, et al: The outcome of dimethylglyoxime testing in a sample of cell phones in Denmark. Contact Dermatitis 2008; 59:38. Torgerson RR, et al: Contact allergy in oral disease. J Am Acad Dermatol 2007; 57:315. Wong L, et al: Oral lichenoid lesions and mercury in amalgam fillings. Contact Dermatitis 2003; 48:74.
Contact stomatitis The role of contact allergy in oral symptomatology is significant. Approximately 30% of patients with oral symptoms will have relevant allergens; these are most commonly metals used in dental fillings, food additives (flavorings and antioxidants), and dental products such as acrylic monomers, epoxy resins, and hardeners used in prosthedontics and dental impression materials. Chewing gums and dentifrices may also produce contact stomatitis. Ingredients responsible for this are hexylresorcinol, thymol, dichlorophen, oil of cinnamon, and mint. Clinical signs may be bright erythema of the tongue and buccal mucosa with scattered erosions. Angular cheilitis may also develop. Oral lichenoid lesions may be caused by sensitization to metals in dental fillings or gold caps or crowns. Ditrichova D, et al: Oral lichenoid lesions and allergy to dental materials. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2007; 151:333. Kanerva L, et al: A multicenter study of patch test reactions with dental screening series. Am J Contact Dermat 2001; 12:83. Torgerson RR, et al: Contact allergy in oral disease. J Am Acad Dermatol 2007; 57:315. Zug KA, et al: Patch-testing North American lip dermatitis patients. Dermatitis 2008; 19:202.
Rubber dermatitis Rubber dermatitis generally occurs on the hands from wearing rubber gloves (surgeons, nurses, homemakers). The eruption
is usually sharply limited to the gloved area but may spread up the forearms. Rubber dermatitis also develops from exposure to condoms, diaphragms, swim goggles, caps and scuba masks, wet suits, bandages for chronic leg ulcers, respirators, gas masks, rubber sheets, and cosmetic sponges. Shoe dermatitis may be caused by rubber allergy to insoles or sneakers (see above). Natural and synthetic rubbers are used separately or in combination to make the final rubber product. It is the chemicals added in the rubber manufacturing process, most importantly the accelerators and antioxidants, which are the common causes of allergic contact dermatitis. A similar list of additives is present in neoprene, a synthetic rubber. One particular class of additive in neoprene is causing an increasing number of reactions: the dialkyl thioureas. These are not in the standard patch trays and thus may escape detection unless they are applied as a supplemental allergen. Elastic in underwear is chemically transformed by laundry bleach, such as Clorox, into a potent sensitizing substance. The allergen is permanent and cannot be removed by washing. The offending garments must be thrown out and the use of bleaches interdicted.
Contact dermatitis
Other metals
Accelerators During the manufacturing process, chemicals are used to hasten the vulcanization of rubber. Among the numerous chemicals available, tetramethylthiuram disulfide, mercaptobenzothiazole, and diphenylguanidine are frequently used. Tetramethylthiuram disulfide and its analogs, known as disulfiram and thiuram, may produce contact dermatitis when moist skin is exposed to the finished rubber product. In one 10-year study of 636 cases of allergy to rubber additives, thiuram mix was by far the most common sensitizer. Mercaptobenzothiazole is most often the cause in shoe allergy and thiuram in glove allergy.
Antioxidants Antioxidants are used to preserve rubber. Among antioxidants the amine type, such as phenyl-α-naphthylamine, is most effective. Hydroquinone antioxidants may cause depigmentation of the skin, as well as allergic contact dermatitis. A frequent antioxidant sensitizer, propyl p-phenylenediamine, is used in tires, heavy-duty rubber goods, boots, and elastic underwear. Adams AK, et al: Allergic contact dermatitis from mercapto compounds. Dermatitis 2006; 17:56. Cravo M, et al: Allergic contact dermatitis to rubber-containing bandages in patients with leg ulcers. Contact Dermatitis 2008; 58:371. Gibbon KL, et al: Changing frequency of thiuram allergy in healthcare workers with hand dermatitis. Br J Dermatol 2001; 144:347. Militello G, et al: Dialkyl thioureas. Dermatitis 2008; 19:E42. Warshaw EM, et al: Positive patch-test reactions to mixed dialkyl thioureas. Dermatitis 2008; 19:190. Woo DK, et al: Neoprene. Dermatitis 2004; 15:206.
Adhesive dermatitis Cements, glues, and gums may cause adhesive dermatitis. Formaldehyde resin adhesives contain free formaldehyde, naphtha, glue, and disinfectants. Synthetic resin adhesives contain plasticizers; hide glues may contain chromates from the tanned leather while other glues incorporate preservatives such as formaldehyde. Dental bonding adhesives may contain acrylic monomers and epoxy resins and hardeners. Pressuresensitive adhesives contain rubber and acrylates, and anaerobic adhesives primarily acrylates. Vegetable gums, such as gum tragacanth, gum arabic, and karaya, may be used in denture adhesives, hair wave lotions, topical medications, toothpastes, and depilatories, and many 101
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cause contact dermatitis. Resins are used in adhesive tapes and in various adhesives such as tincture of benzoin. Turpentine is frequently found in rosin; abietic acid in the rosin is the causative sensitizer. Adhesive tape reactions are frequently irritant in nature. Allergic reactions to adhesive tape itself are caused by the rubber components, accelerators, antioxidants, and various resins or turpentine. Some adhesive tapes contain acrylate polymers rather than rubber adhesives. These acrylates may cause allergic contact dermatitis. Pressure-sensitive adhesives are in widespread use in the tape and label industries. Allergens present in these adhesives include rosin, rubber accelerators, antioxidants, acrylates, hydroquinones, lanolin, thiourea compounds, and N-dodecylmaleamic compounds. Howard BK, et al: Contact dermatitis from Dermabond. Contact Dermatitis 2010; 62:314. Kanerva L, et al: Patch-test reactions to plastic and glue allergens. Acta Dermatol Venereol 1999; 79:296. Sharma PR: Allergic contact stomatitis from colophony. Dent Update 2006; 33:440. Volz A, et al: Mastix, a known herbal allergen, as a causative agent in occupation-related dermatitis. Contact Dermatitis 2006; 54:346. Widman TJ, et al: Allergic contact dermatitis from medical adhesive bandages in patients who report having a reaction to medical bandages. Dermatitis 2008; 19:32.
Synthetic resin dermatitis The many varieties of synthetic resins preclude adequate discussion of each. The reactions incurred during the manufacture of these substances are more frequent than those encountered in their finished state.
Epoxy resins The epoxy resins in their liquid (noncured, monomer) form may produce severe dermatitis, especially during the manufacturing process. The fully polymerized or cured product is nonsensitizing. Nonindustrial exposure is usually to epoxy resin glues, nail lacquers, and artificial nails. Epoxy resins are used in the home as glues and paints (bathtub and refrigerator). Artists and sculptors frequently use epoxy resins. Epoxy resins consist of two or more components, the resin and the curing agent. Approximately 90% of allergic reactions are to the resin and 10% to the hardener. There are numerous curing agents such as the amines, phenolic compounds, peroxides, and polyamides. These may be irritants and/or allergens. The resin, based on an acetone and phenol compound known as bisphenol A, in its raw state may cause allergic contact dermatitis. BIS-GMA, a combination of bisphenol A and glycidyl methacrylate, is the main allergen in dental bonding agents. Epoxy resins are used also as stabilizers and plasticizers. Their use in the manufacture of polyvinyl chloride (plastic) film has caused dermatitis from plastic handbags, beads, gloves, and panties.
Polyester resins Ordinarily, completely cured or polymerized resins are not sensitizers. The unsaturated polyester resins are dissolved and later copolymerized with vinyl monomers. Such polyester resins are used for polyester plasticizers, polyester fibers (Dacron), and polyester film (Mylar). The unsaturated polyester resins, on the other hand, will produce primary irritation in their fabrication or among sculptors. The dermatitis occurs typically as an eczematous eruption on the back of the hands, wrists, and forearms. Polyester resins are commonly incorporated into other plastic material as laminates to give them strength; applications include boat hulls, automobile body putty, safety helmets, fuel tanks, lampshades, and skylights. 102
Acrylic monomers Cyanoacrylates are used widely as adhesives in a variety of home and commercial products. They are generally a rare cause of contact dermatitis. With the advent of skin bonding agents, reports of allergy may increase. Multifunctional acrylic monomers may produce allergic or irritant contact dermatitis. Pentaerythritol triacrylate, trimethylolpropane triacrylate, and hexanediol diacrylate are widely used acrylic monomers. Printers handling multifunctional acrylic monomers in printing inks and acrylic printing plates may present with an erythematous, pruritic eruption, mainly of the hands and arms, swelling of the face, and involvement of the eyelids. Orthopedic surgeons experience contact dermatitis from the use of acrylic bone cement (methyl methacrylate monomer) used in mending hip joints. Dentists and dental technicians are exposed when applying this to teeth. The sensitizer passes through rubber and polyvinyl gloves and may additionally cause paresthesias. In patients who are allergic to their acrylate dental prosthesis, coating this with UV light-cured acrylate lacquer may allow it to be worn without adverse effects. Benzoyl peroxide is a popular acne remedy. It is also used for bleaching flour and edible oils, and for curing plastics, such as acrylic dentures. Infrequently, an allergic contact dermatitis may be caused. Aalto-Korte K, et al: Methacrylate and acrylate allergy in dental personnel. Contact Dermatitis 2007; 57:324. Hivnor CM, et al: Allergic contact dermatitis after postsurgical repair with 2-octylcyanoacrylate. Arch Dermatol 2008; 144:814. Lazarov A: Sensitization to acrylates is a common adverse reaction to artificial fingernails. J Eur Acad Dermatol Venereol 2007; 21:169. Militello G, et al: Allergic contact dermatitis from isocyanates among sculptors. Dermatitis 2004; 15:150.
Cosmetic dermatitis Cutaneous reactions to cosmetics may be divided into irritant, allergic hypersensitivity, and photosensitivity reactions. More than half of the reactions occur on the face and are due pri marily to skin-care products, nail cosmetics, shaving preparations, and deodorants. The leading cause of allergic contact dermatitis associated with cosmetics is from fragrance. A close second is preservatives, such as Bronopol (2-bromo-2nitropropane-1-3-diol), Kathon CG, quarternium-15, Euxyl K 400, and imidazolidinyl urea. Third is p-phenylenediamine in hair dye. It is recommended that patch testing with the patient’s own product, as long as it is applied to the skin as a leave-on product, be part of the evaluation.
Fragrances Almost all cosmetic preparations, skin-care products, and many medications contain fragrance; even those labeled nonscented often contain a “masking” fragrance that may be a sensitizer. Even “fragrance-free” products have been documented to contain the raw fragrance ingredients, e.g. rose oil in “all-natural” products. Fragrances are the most common cosmetic ingredient causing allergic contact dermatitis. Photodermatitis, irritation, contact urticaria, and dyspigmentation are other types of reactions they may produce. The most common individual allergens identified are cinnamic alcohol, oak moss, cinnamic aldehyde, hydroxy citronellal, musk ambrette, isoeugenol, geraniol, coumarin, lyral, and eugenol. Frequently, unspecified allergens are the cause, as they are not listed on labels and fragrances are combinations of many different ingredients. Myroxylon pereirae (balsam of Peru) will identify approximately half of those often unsuspected cases of allergic dermatitis, and additional testing with the fragrance mixes will identify over 90%. Additionally, a natural fragrance mixture of jasmine absolute, ylang-ylang oil, narcissus absolute, spearmint oil, and sandalwood oil is
Hair dyes Permanent hair dyes incorporate p-phenylenediamine (PPDA), a popular but potent sensitizer that may cross-react with many chemicals. In rinses and tints the azo dyes, acid violet 6B, water-soluble nigrosine, and ammonium carbonate may sensitize and cross-react with PPDA. Those engaged in the manufacture of PPDA, furriers, hairdressers, and those in the photographic and rubber vulcanization industries develop eruptions at first on the backs of the hands, wrists, forearms, eyelids, and nose, consisting of an eczematous, erythematous, oozing dermatitis. Lichenification and scaling are seen in the chronic type. In those whose hair has been dyed, sensitivity is manifested by itching, redness, and puffiness of the upper eyelids, tops of the ears, temples, and back of the neck. Beard dermatitis may be due to coloring of the facial hair and eyelid dermatitis from dying eyelashes. PPDA added to temporary henna tattoos to make them darker has resulted in a large number of acute vesicular allergic reactions, some with scarring and hyperpigmentation. Kumkum is a commonly used cosmetic in India, primarily smeared on the forehead of women to denote their marital status; one of many reported allergens in the product is PPDA. For those sensitive to this type of hair dye, use of semipermanent or temporary dyes might be the solution. In the case of sensitivity to the latter, vegetable dyes such as henna may be tried. Metallic dyes are usually not favored by women but are frequently used by men as “hair color restorers.” The metallic hair dyes may contain nickel, cobalt, chromium, or lead. Hair dyes containing FD&C and D&C dyes often do not cross-react with PPDA.
Other hair products Hair bleach products incorporate peroxides, persulfates, and ammonia, which may act as primary irritants. Hair bleaches that contain ammonium persulfate, a primary irritant, may produce a local urticarial and a generalized histamine reaction. Several types of permanent wave preparations exist. The alkaline permanent wave preparations, which use ammonium thioglycolate, are rarely, if ever, sensitizers, and usually cause only hair breakage and irritant reactions. The hot type, or acid perm, is a common sensitizer, the allergen being glyceryl monothioglycolate. Cosmetologists are at risk for development of hand dermatitis. The glyceryl monothioglycolate persists in the hair for at least 3 months after application and may cause a long-lasting dermatitis. It readily penetrates rubber and vinyl gloves. A more neutral pH permanent wave solution is less allergenic than the acid perms; however, allergy to cysteamine hydrochloride found in neutral permanent wave products may occur. This allergen does not penetrate household-weight latex gloves and hair waved with it does not produce allergic reactions in sensitized individuals. Also, it is an amine salt and not a thioglycolate, so cross-reactivity is unlikely. Hair straighteners using greases and gums are not sensitizers; however, the perfume incorporated in these preparations
can be. Thioglycolates are also used, and hair breakage may occur with these products. Hair sprays may contain shellac, gum arabic, sunscreens, and synthetic resins as sensitizers, and allergic reactions occur infrequently. Lanolin is frequently incorporated into aerosol sprays. Chemical depilatories containing calcium thioglycolate and the sulfides and sulfhydrates may cause primary irritant dermatitis. Mechanical hair removers are the mercaptans, waxes, and resins. The latter may produce allergic dermatitis. Hair tonics and lotions with tincture of cinchona produce allergic sensitization; tincture of cantharidin and salicylic acid, primary irritation. Resorcin, quinine sulfate, and perfumes such as bay rum are also sensitizers.
Contact dermatitis
recommended. New products should be tested for tolerance in those with a history of fragrance sensitivity. Around 1% of the population has fragrance sensitivity. Women still outnumber men, but as the frequency of fragrance contact reactions has increased over the years, men have shown a steeper increase in sensitivity. Ingestion of balsamrelated foods, such as tomatoes, citrus fruits, and spices, may cause a flare in some sensitive patients. In particularly difficultto-treat patients, balsam-restricted diets may be beneficial but are not easy to follow.
Nail products Nail lacquers may contain tosylamide/formaldehyde resin and are a frequent cause of eyelid and neck dermatitis. Polishes free of this resin are available. Nail polish removers are solvents such as acetone, which can cause nail brittleness. The acrylic monomers in artificial nails, as well as the ethyl cyanoacrylate glue required to attach the prosthetic nail, may produce allergic sensitivity. Photoinitiating agents, such as benzophenone, used in photobonded acrylic sculptured nails are other potential allergens.
Lipsticks Various R and C dyes, sunscreens, shellac, flavoring agents, preservative, and lipstick perfumes may cause sensitization reactions. Lipsticks are tested as is. Lip plumpers may cause contact urticaria in those being kissed. Propolis is found in many so-called natural products, including lip balms, toothpastes, lotions, shampoos, and other cosmetics. Its main allergens are two types of caffeates.
Eye make-up In mascara, eye shadow, and eyeliners, the preservative, shellac, metals, base wax, and perfumes are the components that may produce sensitization, but this occurs rarely. Falsepositive reactions to some mascaras occur when a closed patch test is used. This is caused by the irritative qualities of the solvents. An open or nonocclusive patch test is recommended. A provocative use test in the antecubital fossae may ultimately be necessary. The rubber sponges used to apply eye make-up also cause eyelid dermatitis.
Sunscreens p-Aminobenzoic acid (PABA) and its derivatives, such as padimate O, padimate A, and glycerol PABA, and dibenzoylmethanes, salicylates, cinnamates, and benzophenones are photosensitizers as well as sensitizers. If allergy to PABA exists, its derivatives should be avoided and there should be an awareness that thiazides, sulfonylurea antidiabetic medication, azo dyes, p-aminosalicylic acid, benzocaine, and p-phenylenediamine all may cause dermatitis from crossreactions. Oxybenzone is the most common sunscreen allergen.
Bleaching creams Hydroquinones are occasional sensitizers. Ammoniated mercury is a sensitizing agent formerly used in bleaching creams.
Lanolin The fatty alcohol lanolin is rarely a sensitizer on normal skin and most cosmetic and skin-care products do not cause dermatitis. It provokes allergic reactions more frequently in 103
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therapeutic agents used by atopic patients and in emollient products which may be used postsurgically.
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Dentifrices and mouthwashes contain sensitizers, such as the essential oils used as flavoring agents, preservatives, formalin, antibiotics, and antiseptics. Beacham et al reported 20 women who developed circumoral dermatitis and cheilitis from tartarcontrol types of dentifrice.
Dentifrices and mouthwashes
Axillary antiperspirants Aluminum salts, such as aluminum chloride and chlorhydroxide, and zinc salts, such as zinc chloride, act as primary irritants, and may rarely produce a folliculitis. Aluminum chlorhydrate is considered to be the least irritating antiperspirant. Zirconium salt preparations, now removed from all antiperspirants, produced a granulomatous reaction. Zirconium–aluminum complexes, however, are commonly used as the active ingredient in topical antiperspirants and may produce granulomas. Quaternary ammonium compounds in some roll-on deodorants may produce allergic contact dermatitis.
Axillary deodorants and feminine hygiene sprays Fragrances, bacteriostats, and propellants cause the majority of the reactions seen with these products. Deodorants that contain cinnamic aldehyde can induce irritation on axillary skin even when tolerated on healthy skin in other sites.
Cosmetic intolerance syndrome Occasionally, a patient will complain of intense burning or stinging after applying any cosmetic. Usually there are only subjective symptoms, but objective inflammation may also be present. The underlying cause may be difficult to document, even though thorough patch testing, photopatch testing, and contact urticaria testing are completed. Endogenous disease, such as seborrheic dermatitis, rosacea, or atopic dermatitis, may complicate the assessment. Avoidance of all cosmetics, with only glycerin being allowed, for 6–12 months is often necessary to calm the reactive state. Adding back cosmetics one at a time, no more frequently than one a week, may then be tolerated. Baran R: Nail cosmetics: allergies and irritations. Am J Clin Dermatol 2002; 3:547. Beacham BE, et al: Circumoral dermatitis and cheilitis caused by tartar control dentifrices. J Am Acad Dermatol 1990; 22:1029. Biebl KA, et al: Allergic contact dermatitis to cosmetics. Dermatol Clin 2006; 24:215. Bruze M, et al: Deodorants. J Am Acad Dermatol 2003; 48:194. Castanedo-Tardan MP, et al: Patterns of contact allergy. Dermatol Clin 2009; 27:265. Diepgen TL, et al: Contact dermatitis: epidemiology and frequent sensitizers to cosmetics. J Eur Acad Dermatol Venereol 2007; 21(Suppl 2):9. Firoz EF, et al: Lip plumper contact urticaria. J Am Acad Dermatol 2009; 60:861. Francalanci S, et al: Multicentre study of allergic contact cheilitis from toothpastes. Contact Dermatitis 2000; 43:216. Hartford O, et al: Tea tree oil. Cutis 2005; 76:178. Jacob SE, et al: Benzyl alcohol: a covert fragrance. Dermatitis 2007; 18:232. Jacob SE, et al: Sensitivity to para-phenylenediamine and intolerance to hydrochlorothiazide. Dermatitis 2008; 19:E44. Jovanovic DL, et al: Allergic contact dermatitis from temporary henna tattoo. J Dermatol 2009; 36:63. Khumalo NP, et al: Prevalence of cutaneous adverse effects of hairdressing. Arch Dermatol 2006; 142:377. Landers MC, et al: Permanent wave dermatitis. Am J Contact Dermat 2003; 14:157. LeCoz CJ, et al: Allergic contact dermatitis to shellac in mascara. Contact Dermatitis 2002; 46:149.
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Lee B, et al: Lanolin allergy. Dermatitis 2008; 19:63. Militello G: Contact and primary irritant dermatitis of the nail unit. Dermatol Ther 2007; 20:47. Militello G, et al: Lyral: a fragrance allergen. Dermatitis 2005; 16:41. Nath AK, et al: Kumkum-induced dermatitis. Clin Expert Dermatol 2007; 32:385. Nguyen JC, et al: Allergic contact dermatitis caused by lanolin (wool) alcohol contained in an emollient in three post surgical patients. J Am Acad Dermatol 2010; 62:1064. Salam TN, et al: Balsam-related systemic contact dermatitis. J Am Acad Dermatol 2002; 45:377. Scheuer E, et al: Sunscreen allergy. Dermatitis 2006; 17:3. Thyssen JP, et al: Epidemiological data on consumer allergy to p-phenylenediamine. Contact Dermatitis 2008; 59:327. Turchin I, et al: Cross-reactions among parabens, para-phenyldiamine, and benzocaine. Dermatitis 2006; 17:192. Uter W, et al: Contact allergy to fragrances. Contact Dermatitis 2010; epub. Valks R, et al: Contact dermatitis in hairdressers, ten years later. Dermatitis 2005; 16:28. Walgrave SE, et al: Allergic contact dermatitis from propolis. Dermatitis 2005; 16:209. Warshaw EM, et al: Positive patch test reactions to lanolin. Dermatitis 2009; 20:79. Waters AJ, et al: Photocontact allergy to PABA in sunscreens: the need for continued vigilance. Contact Dermatitis 2009; 60:172.
Preservatives Preservatives are added to any preparation that contains water to kill microorganisms and prevent spoilage. Such products include moist materials such as baby wipes, which when used in either infants or adults can produce reactions caused by preservatives. The most important class is formaldehyde and the formaldehyde-releasing compounds, including quaternium-15 (the leading preservative sensitizer in the US), imidazolidinyl urea, diazolidinyl urea, DMDM hydantoin, and 2-bromo-2 nitropropane-1,3-diol. Kathon CG or methylchloroisothiazolinone/methyl isothiazolinone (MCI/MI) and Euxyl K 400 (methyldibromoglutaronitrile and phenoxyethanol in a 1:4 ratio) are other important preservative allergens. In the latter it is the methyldibromoglutaronitrile component that produces the allergic response. This preservative may produce false-negatives on testing, so repeat open testing is indicated if a specific leave-on product is suspected of causing allergy. Methyldibromoglutaronitrile has been the subject of a European regulation limiting exposure to it. As with similar laws regulating nickel in Europe, allergy to this preservative is also lowering in incidence over time. Tea tree oil is an additive to some natural products that may serve as an antimicrobial. Developing data show it to be a sensitizer as well. Sorbic acid is a rare sensitizer among the preservatives; however, it is a cause of facial flushing and stinging through its action as an inducer of nonimmunologic contact urticaria. Benzalkonium chloride is widely used but a rare sensitizer. Finally, triclosan and benzyl alcohol are weak sensitizers. Thimerosal is discussed above.
Formaldehyde and formaldehyde-releasing agents Formaldehyde is used rarely, primarily in shampoos. Because it is quickly diluted and washed away, sensitization through this exposure is rare. Formaldehyde releasers are polymers of formaldehyde that may release small amounts of formaldehyde under certain conditions. Allergy may be to the formaldehyde-releasing preservatives (which act as antibacterial and antifungal agents in their own right) and/or to the released formaldehyde. Cross-reactivity among them is common, so when allergy is proven to one compound and avoidance does not clear the eruption, screening for clinically relevant reactions to the others is indicated. This may be done
Parabens Allergic contact dermatitis may develop from parabens, which are used in cosmetics, foods, drugs, dentifrices, and suppositories. The paraben esters (methyl, ethyl, propyl, and butyl p-hydroxybenzoates) are used in low concentrations in cosmetics and rarely cause dermatitis. They are found in higher concentration in topical medicaments and may be the cause of allergic reactions. Perpetuation of a dermatitis, despite effective topical medication, suggests the possibility of paraben or corticosteroid sensitivity, or that another sensitizer may be present. Parabens, which are frequently used as bacteriostatic agents, are capable of producing immunologically mediated immediate systemic hypersensitivity reactions. Crossreactivity to para-phenylenediamine and benzocaine occurs in some individuals.
p-Chloro-meta-xylenol (PCMX) This chlorinated phenol antiseptic is used in many over-thecounter products with the disinfectant properties of p-chlorometacresol. Sensitization occurs primarily through exposure to betamethasone-containing cream. There is cross-reactivity to p-chloro-metacresol. Askari SK, et al: Parabens. Dermatitis 2006; 17:215. Berthelot C, et al: Allergic contact dermatitis to choroxylenol. Dermatitis 2006; 17:156. Campbell L, et al: Triclosan. Dermatitis 2006; 17:204. Cashman AL, et al: Parabens. Dermatitis 2005; 16:57. Curry EJ, et al: Benzyl alcohol allergy. Dermatitis 2005; 16:203. Fields KS, et al: Contact dermatitis caused by baby wipes. J Am Acad Dermatol 2006; 54(Suppl):S230. Isaksson M, et al: Repeated open application tests with methyldibromoglutaronitrile in dermatitis patients with and without hypersensitivity to methyldibromoglutaronitrile. Dermatitis 2007; 18:203. Johansen JD, et al: Decreasing trends in methyldibromoglutaronitrile contact allergy following regulatory intervention. Contact Dermatitis 2008; 59:48. Jong CT, et al: Contact sensitivity to preservatives in the UK 2004–2005. Contact Dermatitis 2007; 57:165. Marcano ME, et al: Occupational allergic contact dermatitis to methyldibromoglutaronitrile in hand degreasing toilet paper. Contact Dermatitis 2007; 57:126. Sanchez-Perez J, et al: Allergic and systemic contact dermatitis to methylparaben. Contact Dermatitis 2006; 54:117. Williams JD, et al: Dermatologically tested baby toilet tissues: a cause of allergic contact dermatitis in adults. Contact Dermatitis 2007; 57:97. Wilson M, et al: Chloroxylenol. Dermatitis 2007; 18:120. Zug KA, et al: Patch-test results of the North American Contact Dermatitis Group 2005–2006. Dermatitis 2009; 20:149.
Vehicles Formulation of topically applied products is complex and additives are blended to make a pleasing base for carriage of the active ingredient to the skin. Various emulsifiers, humectants, stabilizers, surfactants, and surface active agents are used to make esthetically pleasing preparations. These may cause irritation, erythema, and allergy. The surfactant cocamidopropyl betaine produces dermatitis of the head and neck in consumers and the hands in hairdressers, often due to its presence in shampoos. Propolis and lanolin are discussed within the cosmetic portion above.
Propylene glycol Propylene glycol is widely used as a vehicle for topical medications, cosmetics (especially antiperspirants), and various emollient lotions. It is used in the manufacture of automobile brake fluid and alkyd resins, as a lubricant for food machinery, and as an additive for food colors and flavoring agents.
Propylene glycol must be considered as a sensitizer able to produce contact dermatitis, and it can cause a flare of the contact dermatitis when ingested. It is tested as a 4% aqueous solution, but irritant reactions or false-negatives are common. A use test of the implicated propylene glycol-containing products may be required.
Ethylenediamine Ethylenediamine is used as a stabilizer in medicated creams. It may cause contact dermatitis and cross-react with internally taken aminophylline, which consists of theophylline and ethy lenediamine. Hydroxyzine is a piperazine derivative that is structurally based on a dimer of ethylenediamine, to which patients sensitive to the stabilizer may develop a generalized itchy, red eruption that recurs each time hydroxyzine is taken orally.
Contact dermatitis
by repetitive open application testing to the leave-on product, or by extended patch testing.
Ash S, et al: Systemic contact dermatitis to hydroxyzine. Am J Contact Dermat 1997; 8:2. Jacob SE, et al: Cocamidopropyl betaine. Dermatitis 2008; 19:157. Lessman H, et al: Skin-sensitizing and irritant properties of propylene glycol. Contact Dermatitis 2005; 53:247. Lowther A, et al: Systemic contact dermatitis from propylene glycol. Dermatitis 2008; 19:105. Pereira F, et al: Contact dermatitis due to emulsifiers. Contact Dermatitis 1997; 36:114.
Topical drug contact dermatitis Drugs, in addition to their pharmacologic and possible toxic action, also possess sensitizing properties. Sensitization may occur not only from topical application but also from ingestion, injection or inhalation. Some, such as the antihistamines, including topical doxepin, sensitize much more frequently when applied topically than when taken orally. With the advent of transdermal patches for delivery of medications such as nitroglycerin, hormones, nicotine, clonidine, fentanyl, lidocaine, and scopolamine, reports of sensitization are increasing. Clonidine induces the highest rate of allergic reactions. At times erythema multiforme-like reactions may occur with transdermally applied drugs. Some drugs may produce sensitization of the skin when applied topically; if the medication is taken later internally, an acute flare at the site of the contact dermatitis may result. This so-called anamnestic (recalled) eruption or systemic contact dermatitis can occur with antihistamines, sulfonamides, and penicillin. The same is true of the local anesthetic ointments containing “caine” medications. Usually, if sensitization occurs when using transdermal patches, the drugs do not cause systemic contact dermatitis when taken orally. Although it is impossible to mention all topical medications that cause irritation or allergic contact dermatitis, some are important enough to be dealt with individually.
Local anesthetics Physicians and dentists may develop allergic contact dermatitis from local anesthetics. In addition, the continued use of these local anesthetics as antipruritic ointments and lotions causes sensitization of the skin. Benzocaine is a frequently used topical antipruritic and is the most common topical sensitizer of this group. Itchy dermatitis of the anogenital area may be due to a topically applied anesthetic. Local anesthetics may be divided into two groups. The first includes the p-aminobenzoic acid esters, such as benzocaine, butethamine, chloroprocaine, procaine (Novacaine), and tetracaine (Pantocaine). The second, which sensitizes much less frequently, includes the amides, such as dibucaine (Nupercainal), lidocaine (Lido-Mantle, EMLA, Lidoderm patch, LMX, Xylocaine), mepivacaine (Carbocaine), and prilocaine (Citanest). In addition, the preservative methylparaben, 105
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frequently found in these prepared solutions, may cause hypersensitivity reactions that can easily be misattributed to the local anesthetics. It should be kept in mind that numerous cross-reactions are seen in benzocaine-sensitive individuals. These are discussed in the section on sunscreens and preservatives. Lidocaine can induce contact urticaria as well.
Antimicrobials Physicians, dentists, nurses, and other medical personnel, as well as patients, especially those suffering from chronic leg ulcers, may develop contact dermatitis from various antibiotics. Neomycin and bacitracin are only behind nickel, fragrances (and the related Myroxylon pereirae), and quaternium-15 as the most frequent sensitizers in the US. As a topical antibiotic, neomycin sulfate has been incorporated into innumerable ointments, creams, and lotions. It is present in such preparations as underarm deodorants, otic and ophthalmologic preparations, and antibiotic creams and ointments available without prescription. The signs of neomycin sensitivity may be those of a typical contact dermatitis but are often those of a recalcitrant skin eruption that has become lichenified and even hyperkeratotic. This may be because many topical agents contain several types of antibiotic but also often have cortico steroids present. This picture may be seen in persistent external otitis, lichen simplex chronicus of the nuchal area, or dermatophytosis between the toes. A late-appearing reaction on patch testing is not uncommon, so an assessment at day 7 is recommended. There has been a dramatic rise in allergy to bacitracin. Its use after minor surgical procedures may account for this. After clean surgical procedures white petrolatum is as effective in aiding wound healing as antibiotic ointment, allows no more infection, and of course does not carry the allergenic potential. Petrolatum should be used after clean cutaneous surgery; antibiotic ointments are not necessary and contribute to the overall increasing problem of allergy to these medications. There is a high rate of coreaction (not cross-reaction) with neomycin because of simultaneous exposures. Contact urticaria and anaphylaxis are reported more often with bacitracin than with other antibiotics. Mafenide acetate, the topical antimicrobial found in Sulfamylon, a burn remedy, may cause allergic contact dermatitis, as can metronidazole.
Antifungal agents Allergic contact dermatitis to imidazole and other antifungal agents may occur. There is a high cross-reactivity rate between miconazole, isoconazole, clotrimazole, and oxiconazole because of their common chemical structure.
Phenothiazine drugs Handling injectable solutions and tablets may produce dermatitis in those sensitized to chlorpromazine and other phenothiazine derivatives. The reactions may be photoallergic or nonphotoallergic.
Corticosteroids Numerous reports of large series of patients who have developed allergy to these commonly used preparations emphasize the need for a high index of suspicion when treating patients with chronic dermatitis who fail to improve, or who worsen, when topical steroidal agents are used. Once sensitized to one type of corticosteroid, cross-sensitization may occur. The corticosteroids have been separated into four structural classes: • Class A is the hydrocortisone, tixocortol pivalate group. • Class B is the triamcinolone acetonide, budesonide group. 106
• Class C is the betamethasone group. • Class D is the hydrocortisone-17-butyrate group. There are frequent cross-reactions between classes B and D. Tixocortol pivalate and budesonide have been found to be the best screening agents, finding 93% of steroid allergies. In the absence of having these materials, patch testing to the implicated product may be useful. An empiric trial of desoximetasone (Topicort) or mometasone (Elocon) in the absence of patch testing will give the best chance of selecting a topical steroid with an extremely low risk of sensitization. Cronin H, et al: Anaphylactic reaction to bacitracin ointment. Cutis 2009; 83:127. Chaudari PR, et al: Allergic contact dermatitis from ophthalmics. Contact Dermatitis 2007; 57:11. Firoz EF: Allergic contact dermatitis to mafenide acetate. J Drug Dermatol 2007; 6:825. Foti C, et al: Allergic contact dermatitis from ciclopirox olamine. Australas J Dermatol 2001; 42:145. Foti C, et al: Contact allergy to topical corticosteroids. Recent Pat Inflamm Allergy Drug Discov 2009; 3:33. Gehrig KA, et al: Allergic contact dermatitis to topical antibiotics. J Am Acad Dermatol 2008; 58:1. Green CM, et al: Contact allergy to topical medicaments becomes more common with advancing age. Contact Dermatitis 2007; 56:229. Isaksson M: Systemic contact allergy to corticosteroids revisited. Contact Dermatitis 2007; 57:368. Javanovic M, et al: Contact urticaria and allergic contact dermatitis to lidocaine in a patient sensitive to benzocaine and propolis. Contact Dermatitis 2006; 54:124. Mackley CL, et al: Delayed type hypersensitivity to lidocaine. Arch Dermatol 2003; 139:343. Madsen JT, et al: Allergic contact dermatitis to topical metronidazole. Contact Dermatitis 2007; 56:364. Musel AL, et al: Cutaneous reactions to transdermal therapeutic systems. Dermatitis 2006; 17:109. Sidhu SK, et al: A 10-year retrospective study on benzocaine allergy in the UK. Am J Contact Dermat 1999; 10:57. Smack DP, et al: Infection and allergy incidence in ambulatory surgery patients using white petrolatum vs. bacitracin ointment. JAMA 1996; 276:972. Sood A, et al: Bacitracin: allergen of the year. Am J Contact Dermat 2003; 14:3. Warshaw EM, et al: Patch-test reactions to topical anesthetics. Dermatitis 2008; 19:81.
Occupational contact dermatitis Workers in various occupations are prone to contact dermatitis from primary irritants and allergic contactants. In certain occupations it is a common occurrence. Irritant contact dermatitis is more frequent in the workplace, but it tends to be less severe and less chronic than allergic contact dermatitis. Occupational skin disease has declined over the past 30 years but still constitutes approximately 10% of all occupational disease cases. Agriculture, forestry, and fishing have the highest incidence of occupational skin disease, with the manufacturing and healthcare sectors contributing many cases as well. Irritant contact dermatitis is commonly present in wet-work jobs, and allergy occurs in hairdressers, machinists, and many others with unique exposures to multiple sensitizing chemicals. The hands are the parts most affected, being involved in 60% of allergic reactions and 80% of irritant dermatitis. Epoxy resin is an allergen overrepresented when evaluating occupational patients. The allergens most frequently encountered in occupational cases are carba mix, thiuram mix, epoxy resin, formaldehyde, and nickel.
Management Occupational contact dermatitis is managed by eliminating contact of the skin with irritating and sensitizing substances.
Adisesh A, et al: Prognosis and work absence due to occupational contact dermatitis. Contact Dermatitis 2002; 46:273. Bauer A, et al: Intervention for preventing occupational irritant hand dermatitis. Cochrane Database Syst Rev 2010; 6:CD004414. Belsito DV: Occupational contact dermatitis. J Am Acad Dermatol 2005; 53:303. Bourrain JL: Occupational contact urticaria. Clin Rev Allergy Immunol 2006; 30:39. Diepgen TL, et al: Management of chronic hand eczema. Contact Dermatitis 2007; 57:203. Elsner P: Skin protection in the prevention of skin diseases. Curr Probl Dermatol 2007; 34:1. Emmitt EA: Occupational contact dermatitis. Am J Contact Dermat 2003; 14:21. Mai Konen T, et al: Long-term follow-up study of occupational hand eczema. Br J Dermatol 2010; epub. Marks JG Jr, et al: Contact and Occupational Dermatology, 3rd edn. St Louis: Mosby, 2002. Meding B: Differences between the sexes with regard to work-related skin disease. Contact Dermatitis 2000; 42:65. Nettis E, et al: Occupational irritant and allergic contact dermatitis among healthcare workers. Contact Dermatitis 2002; 46:101. Rietschel RL, et al: Relationship of occupation to contact dermatitis. Am J Contact Dermat 2002; 13:170. Rietschel RL, Fowler JF Jr: Fisher’s Contact Dermatitis, 6th edn. Hamilton: Lippincott, BC Decker, 2008. Saary J, et al: A systematic review of contact dermatitis treatment and prevention. J Am Acad Dermatol 2005; 53:845. Shalock PC, et al: Protection from occupational allergens. Curr Probl Dermatol 2007; 34:58. Slodownik D, et al: Occupational factors in skin diseases. Curr Prob Dermatol 2007; 35:173.
Sohrabian S, et al: Contact dermatitis in agriculture. J Agromedicine 2007; 12:3. Suneja T, et al: Occupational dermatoses in health care workers evaluated for suspected allergic contact dermatitis. Contact Dermatitis 2008; 58:285. Uter W, et al: Contact allergy to hairdressing allergens in female hairdressers and clients. J Dtsch Dermatol Ges 2007; 5:993. Zhai H, et al: Protection from irritants. Curr Prob Dermatol 2007; 34:47.
Contact urticaria Contact urticaria may be defined as a wheal and flare reaction occurring when a substance is applied to the intact skin. Urticaria is only one of a broad spectrum of immediate reactions, including pruritus, dermatitis, local or general urticaria, bronchial asthma, orolaryngeal edema, rhinoconjunctivitis, gastrointestinal distress, headache, or an anaphylactic reaction. Any combination of these is subsumed under the expression “syndrome of immediate reactions.” It may be nonimmunologic (no prior sensitization), immunologic, or of unknown mechanism. The nonimmunologic type is the most common, and may be caused by direct release of vasoactive substances from mast cells. The allergic type tends to be the most severe, as anaphylaxis is possible. The third type has features of both.
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The work environment should be carefully controlled, with use of all available protective devices to prevent accidental and even planned exposures. Personal protective measures, such as frequent clothing changes, cleansing showers, protective clothing, and protective barrier creams should be used as appropriate. Hand-cleansing procedures should be thoroughly surveyed, with particular attention paid to the soaps available and also what solvents may be used. Treatment of the dermatitis follows closely that recommended for toxicodendron dermatitis. Topical corticosteroid preparations are especially helpful in the acute phase. For dry, fissured hands, soaking them in water for 20 min at night followed immediately upon removing (without drying them) with triamcinolone 0.1% ointment will help hydrate and heal them. Topical tacrolimus ointment and pimecrolimus cream may assist in maintenance therapy. When rubber and poly vinyl gloves cannot be used against irritant and allergenic substances, skin protective creams may offer a solution, although they are often impractical. A wide variety is available, but two main types are used. One is for “wet work”—to protect against acids, alkalis, water-base paints, coolants, and cutting oils with water; and the other type is for “dry work”— to protect against oils, greases, cutting oils, adhesive, resins, glues, and wood preservatives. Unfortunately, despite the best efforts at treatment and prevention, the prognosis for occupational skin disease is guarded. One-third to one-quarter heal, and another one-third to onehalf improve, with the remainder the same or worse. A change or discontinuance of the job does not guarantee relief, as many individuals continue to have persistent postoccupational dermatitis. The importance of thorough patient education cannot be overemphasized. Atopics, males with chromate allergy, females with nickel allergy, those with a delay in diagnosis before institution of treatment, and construction industry workers fare the worst, while irritation from metalworking fluids, reactions to urushiols in foresters, and allergic contact dermatitis to acrylic monomers or amine-curing agents is usually short-lived.
Nonimmunologic mechanism This type of reaction occurs most frequently and may produce contact urticaria in almost all exposed individuals. Examples of this type of reaction are seen with nettle rash (plants), di methyl sulfoxide (DMSO), sorbic acid, benzoic acid, cinnamic aldehyde, cobalt chloride, and Trafuril.
Immunologic mechanism This reaction is of the immediate (IgE-mediated) hypersensitivity type. Latex, potatoes, phenylmercuric propionate, and many other allergens have been reported to cause this.
Uncertain mechanism This type of reaction occurs with those agents that produce contact urticaria and a generalized histamine type of reaction but lack a direct or immunologic basis for the reaction.
Substances causing contact urticaria Many different substances can elicit such a reaction. It is seen in homemakers and food handlers who handle raw vegetables, raw meats and fish, shellfish, and other foods. Raw potatoes have been shown to cause not only contact urticaria but also asthma at the same time. It has been seen in hairdressers who handle bleaches and hair dyes containing ammonium persulfate, in whom the contact urticaria is accompanied by swelling and erythema of the face, followed by unconsciousness. Caterpillars, moths, and hedgehogs may cause contact urticaria just by touching the skin. Additional substances inducing this reaction are oatmeal, flour, meat, turkey skin, calf liver, banana, lemon, monoamylamine, benzophenone, nail polish, tetanus antitoxin, streptomycin, cetyl alcohol, stearyl alcohol, estrogenic cream, cinnamic aldehyde, sorbic acid, benzoic acid, castor bean, lindane, carrots, spices, wool, silk, dog and cat saliva, dog hairs, horse serum, ammonia, sulfur dioxide, formaldehyde, acrylic monomers, exotic woods, wheat, cod liver oil, and aspirin. Bacitracin ointment may cause anaphylactic reactions when applied topically, especially to chronic leg ulcers; however, it may rarely occur after application to acute wounds. Universal precautions not only led to a marked increase in delayed-type hypersensitivity reaction to rubber additives, but also to a large number of reports of contact urticaria and 107
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anaphylaxis to latex. Most of these reactions occur in health professionals. Reactions are characterized by itching and swelling of the hands within a few minutes of donning the gloves, and will usually resolve within an hour after removing them. In patients with continued exposures the eruption may eventually appear as chronic eczema. Glove powder may aerosolize the allergen and produce more generalized reactions. While these reactions may occur on the job, many cases present as death or near-death events when sensitized individuals undergo operations or other procedures, especially when there is mucosal exposure (dental care, rectal examination, childbirth). In addition to healthcare workers, who have a reported incidence of between 3% and 10%, atopics and spina bifida patients are other risk groups for the development of type I allergy to latex protein. The sensitized individual should also be aware that up to 50% of them will have a concomitant fruit allergy to foods such as banana, avocado, kiwi, chestnut, and passion fruit.
Testing The usual closed patch tests do not show sensitivity reactions. Instead, open patch tests are performed for eliciting immediatetype hypersensitivity. The substance is applied to a 1 cm2 area on the forearm and observed for 20–30 min for erythema that evolves into a wheal and flare response. When foods are tested, a small piece of the actual food is placed on the skin. Rubber glove testing can be done by applying one finger of a latex glove to a moistened hand for 15 min. If no reaction is observed, the entire glove is worn for another 15–20 min. Radioallergosorbent testing (RAST) detects 75% of latexallergic individuals. There is no standard allergen available for prick testing. Prick, scratch, or intradermal testing is resorted to only when there are problems of interpretation of the open patch tests. These tests have produced anaphylactic reactions and should only be attempted when support for this complication is available.
Management Avoidance of the offending substance is best, but if this is not possible, antihistamines are of benefit. If generalized urticaria or asthmatic reactions occur, then systemic glucocorticoids are best. For anaphylaxis, epinephrine and supportive measures are needed. Adachi A, et al: Anaphylaxis to polyvinylpyrrolidone after vaginal application of povidone-iodine. Contact Dermatitis 2003; 48:133. Bourrain JL: Occupational contact urticaria. Clin Rev Allergy Immunol 2006; 30:39. Bourrain JL, et al: Contact urticaria photoinduced by benzophenones. Contact Dermatitis 2003; 48:45. Bousquet J, et al: Natural rubber latex allergy among health care workers. J Allergy Clin Immunol 2006; 118:447. Cronin H, et al: Anaphylactic reaction to bacitracin ointment. Cutis 2009; 83:127. Doutre MS: Occupational contact urticaria and protein contact dermatitis. Eur J Dermatol 2005; 15:419. Fairley JA, et al: Hedgehog hives. Arch Dermatol 1999; 135:561. Firoz EF, et al: Lip plumper contact urticaria. J Am Acad Dermatol 2009; 60:861. Kim KT, et al: Prevalence of food allergy in 137 latex-allergic patients. Allergy Asthma Proc 1999; 20:95. Konstantinou GN, et al: Food contact hypersensitivity syndrome. Clin Exp Dermatol 2008; 33:383. Stutz N, et al: Anaphylaxis caused by contact urticaria because of epoxy resins. Contact Dermatitis 2008; 58:307. Tan BM, et al: Severe food allergies by skin contact. Ann Allergy Asthma Immunol 2001; 86:583. Williams JD, et al: Occupational contact urticaria. Br J Dermatol 2008; 159:125.
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Drug reactions Epidemiology Adverse drug reactions (ADRs) are a common cause of dermatologic consultation. In a large French study, about 1 in 200 inpatients on medical services developed a drug eruption, as compared to 1 in 10 000 on surgical services. In the US, similar studies have shown a reaction rate of 2–3 in 100 for medical inpatients. In only about 55% of patients who were carefully evaluated was it possible to attribute a specific medication definitely as the cause of the eruption. Simple exanthems (75– 95%) and urticaria (5–6%) account for the vast majority of drug eruptions. The risk for development of a drug eruption is related to the following factors: age, gender, dose, and the nature of the medication itself. Females are 1.3–1.5 times more likely to develop drug eruptions, except in children under the age of 3 where boys are more likely to be affected. Not all drugs cause reactions at the same rate. Aminopenicillins cause drug eruptions in between 1.2% and 8% of exposures, and the combination of trimethoprim–sulfamethoxazole at a rate of 2.8–3.7%. About 20% of emergency room (ER) visits for adverse events due to medications were caused by antibiotics, largely penicillins and cephalosporins. This is estimated to have accounted for more than 28 000 visits annually in the US. Up to 20 ER visits occurred per 10 000 prescriptions written for certain antibiotics. Nonsteroidal anti-inflammatory drugs (NSAIDs) have a reaction rate of about 1 in 200. In contrast, reaction rates for digoxin, lidocaine, prednisone, codeine, and acetaminophen are less than 1 in 1000. In addition, the immune status and genetic make-up of the patient strongly determine the risk of developing certain drug eruptions. For example, patients with human immunodeficiency virus (HIV) infection and Epstein–Barr virus (EBV) infection have dramatically increased rates of exanthematous reactions to certain antibiotics. Hypersensitivity syndromes from multiple drug classes have been associated with reactivation of latent viral infections, primarily human herpes virus (HHV)-6 and 7, but also EBV and cytomegalovirus. In addition, the status of the immune system, as measured by helper T-cell count in the case of HIV, defines a window of immune dysfunction in which this enhanced risk for ADRs occurs. Certain hypersensitivity syndromes are closely associated with genetic differences in the ability of the patient to metabolize a specific medication or a toxic metabolite of the medication. In addition, HLA type, in a race-specific manner, may increase risk for drug reactions for specific medications. Therefore, drug eruptions are not simply drug “allergy,” but result from variations in drug metabolism, immune status, coexistent viral disease, the patient’s racial background, the patient’s HLA status, and the inherent chemical structure (allergenicity) and dosage of the medication itself (see below).
Evaluation Four basic rules should always be applied in evaluating the patient with a suspected drug reaction. • First, the patient is probably on unnecessary medications, and all of these should be stopped. Pare down the medication list to the bare essentials. • Second, the patient must be asked about non-prescription medications and pharmaceuticals delivered by other means (eye drops, suppositories, implants, injections, patches, and recreational drugs). • Third, no matter how atypical the patient’s cutaneous reaction, always consider medication as a possible cause. In patients with unusual reactions, searching the medical
An important step in evaluating a patient with a potential drug reaction is to diagnose the cutaneous eruption by clinical pattern (e.g. urticaria, exanthem, vasculitis, hypersensitivity syndrome, etc.). In determining whether the patient’s current eruption could be related to a specific medication, two basic questions should be asked. Which of this patient’s medications cause this pattern of reaction? How commonly does this medication cause this reaction pattern? Bigby reviewed how to use this information to make clinical decisions about stopping possible reaction-inducing medications. A regularly updated manual (such as Litt) or similar databases on the web are strongly recommended as ready reference sources for this information. An algorithm by which the likelihood can be evaluated of a certain medication causing a particular reaction has been developed. This algorithm, summarized below, can be used as a framework for the evaluation of a given patient: 1. Previous general experience with the drug: Has the suspected medication been reported to cause the reaction the patient is experiencing? If so, how commonly? Also ask the patient if he/she has had a previous reaction to any medications, as the current eruption may represent a cross-reaction from a prior exposure. 2. Alternative etiologic candidates: What are other possible causes of the patient’s eruption? An exanthem, for instance, could be related to an associated viral illness, not the medication. 3. Timing of events: When did the eruption appear relative to the administration of the suspected medication? A detailed history from the patient and a careful review of the patient record, including the nursing notes, are useful to establish the chronologic sequence of all drug therapy. A drug chart as described above is very useful 4. Drug levels and evidence of overdose: Certain reactions are known to be related to rate of administration (vancomycin red man syndrome) or cumulative dose (lichenoid reactions to gold). 5. Response to discontinuation (dechallenge): Does the eruption clear when the suspected medication is stopped? Because certain eruptions may clear in the face of continuation, this is a useful, but not irrefutable criterion to ascribe a specific reaction to a medication. 6. Rechallenge: If the offending medication reproduces the reaction on readministration, this is strong evidence that the medication did indeed cause the reaction. Reactions associated with an increase in dosage may also be considered in this category. In certain reaction patterns (e.g. exanthems), even a fraction of the original dose may reproduce the reaction. It may be impossible to rechallenge if the reaction was severe. In addition to the clinical evaluations noted above, complete evaluation may include special testing for confirmation. Skin testing is most useful in evaluating type I (immediate) hypersensitivity. It is most frequently used in evaluating adverse
reactions to penicillin, local anesthetics, insulin, and vaccines. RAST has a 20% false-negative rate in penicillin type I allergy, so it must be followed by skin testing. In their current form, RAST tests cannot replace skin testing. Intradermal, prick skin, and patch testing are also reported to be beneficial in some cases of morbilliform reactions or fixed drug reaction. The patient’s metabolism of certain drugs in lymphocytotoxicity assays may be associated with an adverse reaction. Such testing is commercially available, but is expensive and timeconsuming, and its value is limited to certain situations such as anticonvulsant or sulfonamide hypersensitivity reactions. The patient should be given concrete advice about his/her reaction. What was the probability that the patient’s reaction was caused by the medication? Can the patient take the medication again, and if so, what may occur? What cross-reactions are known? What other medications must the patient avoid? Unusual reactions should be reported to regulatory agencies and the manufacturer.
Drug reactions
literature and calling the manufacturer for prior reports may be very useful. • Fourth, the timing of drug administration must correlate with the appearance of the eruption. A drug chart lists all the drugs given to the patient in the left column, with the dates along the lower axis, and the course of the drug eruption at the top. Lines extend from left to right for the dates of administration of each medication. These are directly below the course of the eruption. This graphic representation of the timing of medication administration and eruption is a very handy tool in assigning plausibility to a certain medication causing an eruption. The nurses’ notes and patient history are most useful in determining exactly when the eruption first appeared.
Pathogenesis T cells, specifically Th1 cells, are felt to be important inducers of ADRs. These T cells act in two ways to induce reactions. They can directly secrete biologically active molecules, resulting in direct tissue effects (epidermal necrosis, for example), or they can act by secreting chemokines that recruit the effector cells (eosinophils or neutrophils, for example). In biopsies from ADRs, the cytokines produced by helper T cells in the skin parallel the reaction pattern observed. For example, T cells in the dermis in acute generalized exanthematous pustulosis (AGEP) secrete interleukin (IL)-8, a neutrophil-attracting chemokine. In drug rash with eosinophils and systemic symptoms (DRESS), they secrete IL-5 and eotaxin, recruiting eosino phils. As a consequence of helper T-cell activation, memory T cells are produced, resulting in recurrence of the eruption upon rechallenge. Since Th1 cells are mediators of these eruptions, interferon (IFN)-γ release assays using peripheral blood lymphocytes are being evaluated for confirming the inciting medication in ADRs. The sensitivity appears to be drug classdependent, and specifically of low sensitivity for ADRs induced by anticonvulsants, antibiotics, and cardiovascular medications. The medications that induce ADRs can create immunemediated reactions by several mechanisms. Large molecules, such as rat- or mouse-derived antibodies, can be immunogenic. Most medications, however, are too small to be recognized as antigens by immunologically active cells. They must bind to a larger molecule, usually a protein, to form an immunogenic product. The medication is the hapten, and the immunologically active molecule is a medication–protein complex, or hapten–carrier complex. Some medications, such as penicillin, are active enough to bind directly to proteins. Most, however, need to be metabolized to more active or more immunogenic forms in order to bind to proteins and cause an immunologic reaction. The drug metabolites can also be toxic to cells, causing direct cell damage. This metabolism occurs in the cytochrome P450 system in the liver, and perhaps in lower amounts in other organs. These active immunogenic molecules are inactivated through metabolism. This model of immune-mediated ADR explains why the drug itself, the metabolism and breakdown of the medication by the patient, and the patient’s immune status all determine the likelihood of developing an ADR. There has also been a proposed model for ADRs in which the drug or a metabolite binds directly to T cells or Langerhans cells in close opposition to sentinel T cells in the skin. This direct binding could activate the T cell–Langerhans cell interactive unit, resulting in the production of biologically active
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molecules. This would explain how some drug eruptions occur soon after exposure or with the first exposure to a medication. It could also explain a dose-dependent effect in drug eruptions. Also, a systemic viral infection would have already activated the immune cells in the skin, reducing their threshold for activation by drug binding. This could also explain why many drug eruptions occur only on the skin, apparently sparing other organs. The skin may uniquely have T cells that are sensitive to activation corresponding to a “sentinel” activity appropriate for cells residing on a surface that interacts with the environment. Since the avidity with which drugs directly bind to T cells would vary considerably, this could account for the wide variation in the rate of exanthems from different medications (from 30% for gemifloxacin to 2 weeks) after the discontinuation of the causative drug. 3. Fever (over 38°C). 4. Multiorgan involvement. 5. Eosinophilia (>1500 absolute eosinophilia). 6. Lymphocyte activation (lymphocytosis, atypical lymphocytosis, lymphadenopathy). 7. Frequent reactivation of herpesviruses HHV-6, HHV-7, EBV, and cytomegalovirus.
Drug reactions
true radiation recall (see adverse reactions to chemotherapy below). In the case of simple exanthems, treatment is supportive. The eruption will clear within 2 weeks of stopping the offending medication, and may clear even if it is continued. Topical steroids and antihistamines may benefit and allow the course of therapy to be completed. Rechallenge usually results in the reappearance of the eruption, except in the setting of HIV. In many HIV-infected patients with simple reactions to trimethoprim–sulfamethoxazole, re-exposure by slow introduction or full-dose re-exposure may be tolerated. Uncommonly in HIV infection, however, and rarely in persons with normal immune function, rechallenge may result in a more severe blistering reaction. The use of patch and intradermal testing for the confirmation of the incriminated drug in morbilliform exanthems is not standardized. Only between 2% and 10% of patients who experience the eruption on rechallenge will have a positive patch or intradermal test, making such testing not very useful clinically. Cutaneous findings identical to simple exanthems may occur as part of DIHS or DRESS. As opposed to simple exanthems, in complex exanthems the inciting agent must be stopped immediately and rechallenge should rarely be undertaken.
The vast majority of DRESS cases are caused by a limited number of medications, although more than 200 medications have been incriminated. Only 7 medications/classes of medication are implicated: 1. anticonvulsants (phenobarbital, lamotrigine, and phenytoin) 2. long-acting sulfonamides (sulfamethoxazole, sulfadiazine, and sulfasalazine but NOT related medications—sulfonylureas, thiazine diuretics, furosemide, and acetazolamide) 3. allopurinol 4. nevirapine 5. abacavir 6. dapsone 7. minocycline. Vancomycin has also recently been recognized as a cause. The skin eruption accompanying DRESS (DIHS) is typically morbilliform and can vary from faint and mild to severe with exfoliative erythroderma. Facial edema often accompanies the skin eruption, and the eruption may evolve to demonstrate superficial pustules (especially on the face). Some patients with Stevens–Johnson syndrome (SJS)/TEN may have some of the features of DRESS, specifically fever, eosinophilia, and internal organ involvement. How to classify these cases is controversial, but from a pragmatic point of view, the management is that of SJS/TEN and they are best given that diagnosis. The relative frequency of internal organ involvement and other features of DRESS differs depending on the medication which causes the reaction. The variants of DRESS/DIHS are outlined below. The internal organ involvement described in DRESS can be divided into two types: organ dysfunction occurring during or immediately associated with the acute episode; and late sequelae, possibly with an autoimmune basis. The first category includes colitis/intestinal bleeding, encephalitis/aseptic meningitis, hepatitis, interstitial nephritis, interstitial pneumonitis/ respiratory distress syndrome, sialadenitis, and myocarditis. Late sequelae include syndrome of inappropriate secretion of antidiuretic hormone (ADH), thyroiditis/Graves’ disease, and diabetes mellitus. Systemic lupus erythematosus (SLE) can rarely occur. In one series, 5% of patients with DRESS died, usually due to complications of liver or renal involvement. 111
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The pathogenesis of DRESS has been studied extensively. Three factors appear to play a role, to various degrees depending on the medication class inducing the DRESS. These are: 1. Certain HLA types put individuals from specific genetic backgrounds at risk of developing DRESS from specific medications. 2. Genetic or acquired inadequate metabolism of toxic or immunogenic breakdown products of certain classes of medication increases the risk for DRESS. 3. Reactivation of herpes viruses (especially HHV-6, but also cytomegalovirus, EBV, and HHV-7) is associated with the development of DRESS. HHV-6 may reactivate during the transient hypogammaglobulinemia that often accompanies DRESS. The mononucleosis-like syndrome accompanying DRESS could be analogous to the mononucleosis-like syndrome accompanying primary HHV-6 infection. In severe DRESS cases, HHV-6 can also be found in the liver and cerebrospinal fluid associated with hepatitis and encephalitis. Certain drugs known to induce DRESS, e.g. sodium valproate, directly induce HHV-6 replication. In one series all fatal cases of DRESS were associated with HHV-6 reactivation. During the acute phase of DRESS, regulatory T cells (T-regs) are expanded and functionally more robust. T-regs become functionally deficient as DRESS resolves, perhaps allowing for the development of autoimmune disease.
Anticonvulsant hypersensitivity syndrome Anticonvulsant hypersensitivity syndrome can be seen with phenytoin, phenobarbital, carbamazepine, lamotrigine, zonisamide, and other anticonvulsants, so the general term “anticonvulsant hypersensitivity syndrome” is preferred to the original descriptive term “dilantin hypersensitivity syndrome.” The incidence of this condition has been estimated at between 1 in 1000 and 1 in 10 000 patients treated with these medications, but is ten times that rate for lamotrigine. Carbamazepine is currently the most common anticonvulsant causing DRESS, because it is also used to treat neuropathic pain, bipolar disorder, and schizophrenia. Medication dosage does not determine risk for this syndrome. HHV-6 and 7 reactivation are observed in about 30% of anticonvulsant hypersensitivity syndrome patients, much more commonly in carbamazepineinduced cases. The DRESS begins on average 30–40 days after starting the anticonvulsant. Low-grade fever and pharyngitis may precede the eruption by a few days. The skin eruption is typically morbilliform initially, and associated with marked facial and neck edema (Fig. 6-19). The eruption begins on the trunk and face, spreading centrifugally. As the eruption becomes more severe, it may evolve to confluent plaques with purpura. The intense dermal edema accompanying the eruption may lead to bulla formation. Commonly associated findings include fever (in more than 50%), adenopathy (in about 20% of cases), and elevated liver function tests (in between two-thirds and three-quarters of cases). Atypical lymphocytosis can occur, completing a mononucleosis-like picture. Lung and renal involvement is uncommon. Lamotrigine DRESS is somewhat different than that induced by the other anticonvulsants. It has eosinophilia in only 19% of cases, lymphadenopathy in only 12%, and multiorgan involvement in only 45%—lower rates than seen with the other anticonvulsants. Lamotrigine DRESS occurs within 4 weeks in most patients, but may not occur for up to 6 months in 10% of cases. Coadministration of valproate increases the risk of lamotrigine DRESS. Slow introduction reduces the risk for lamotrigine DRESS. In anticonvulsant hypersensitivity syndrome, as the eruption evolves, it is typical for widespread pinpoint pustules to 112
Fig. 6-19 Erythroderma with papulopustules and lymphadenopathy, dilantin-induced hypersensitivity syndrome. (Courtesy of Dr L Lieblich)
appear on the face, trunk, and extremities, especially in darkskinned patients. The syndrome may continue to progress, even after the inciting medication has been stopped. The associated hepatitis can be life-threatening. Because many of the anticonvulsants are metabolized through the same pathway, cross-reactions are frequent, making selection of an alternative agent quite difficult. The rate of cross-reactivity between phenytoin, phenobarbital, and carbamazepine is 70%. In vitro tests are commercially avail able and may aid in selecting an agent to which the patient will not cross-react. Valproate is a safe alternative. The management of anticonvulsant hypersensitivity syndrome begins with considering it in the appropriate setting and ruling out other possible explanations for the patient’s findings. The offending medication must be immediately discontinued. Because cross-reactivity among these drugs is high, the therapeutic benefit of a medication from this class must be carefully reconsidered. If the treatment is for depression, prophylaxis after closed head injury, or atypical pain syndromes, medication from another class can often be substituted. Treatment is initially supportive until the extent and severity of the syndrome are assessed. Some patients clear if the medication is simply discontinued. If there is liver or renal involvement, or if the patient appears ill or requires hospitalization, and there is no contraindication, systemic steroids are given. The usually starting dose is between 1 and 1.5 mg/kg/ day. N-acetylcysteine may be added if hepatitis is present. Steroid therapy is continued at doses required for control then gradually tapered. It may require months to wean the patient off steroids successfully. If steroids are tapered too rapidly, the syndrome may recur. Intravenous immunoglobulin (IVIG) and other immunosuppressives, such as azathioprine or cyclosporine, have been successfully used in steroid-refractory cases.
Allopurinol hypersensitivity syndrome Allopurinol hypersensitivity syndrome typically occurs in persons with preexisting renal failure. Often, affected patients are treated unnecessarily for asymptomatic hyperuricemia, with clear indications for therapy present in only about onethird of patients suffering this syndrome. They are often given
Drug reactions
syndrome are often slow acetylators unable to detoxify the toxic and immunogenic metabolites generated during the metabolism of the sulfonamides. Patients with sulfonamide hypersensitivity syndrome may develop antibodies that recognize microsomal proteins to which the reactive metabolite of the sulfonamides binds. Hepatitis, nephropathy, pneumonitis, pericarditis, myocarditis, pancreatitis, and pleural effusion can all occur as a part of the syndrome. The hepatitis can be life-threatening. Sulfonamide hypersensitivity syndrome is treated with topical treatments appropriate for the skin eruption, and systemic steroids for systemic complications. Zonisamide, a sulfonamide anticonvulsant, cross-reacts with sulfonamides but not other anticonvulsants.
Minocycline hypersensitivity syndrome
Fig. 6-20 Allopurinol hypersensitivity syndrome.
a dose not adjusted for their coexisting renal disease. They are frequently on a thiazide diuretic. Weeks to many months (average 7 weeks) after the allopurinol is begun, the patient develops a morbilliform eruption (50% of cases) that often evolves to an exfoliative erythroderma (20%) (Fig. 6-20). Bullae as a consequence of severe dermal edema may occur, especially on the palms and soles. Occasional oral ulcers may occur. Associated with the dermatitis are fever, eosinophilia, sometimes hepatitis (70% of cases), and typically worsening of renal function (40–80% of cases, the higher percentage in those with pre-existing renal disease). Lung involvement and adenopathy are uncommon. About 25% of patients die as a consequence of this syndrome, often from cardiovascular complications of the syndrome. Pancreatitis and subsequent insulin-dependent diabetes may occur as a complication. Dialysis does not appear to accelerate the resolution of the eruption, suggesting that if a drug metabolite is responsible, it is not dialyzable. It has been suggested that adjusting the allopurinol dose to compensate for the patient’s impaired renal function might reduce the risk of developing this reaction. There is a strong association between HLA-B-5801 and the development of allopurinol hypersensitivity syndrome in the Han Chinese, but not in other races. HHV-6 reactivation may be associated. This syndrome may be steroid-responsive, but is extremely slow to resolve, frequently lasting for months after allopurinol has been stopped. Very gradual tapering of systemic steroids with monitoring of eosinophil count and renal function is essential. Too rapid tapering may lead to relapse of the syndrome.
Sulfonamide hypersensitivity syndrome Fewer than 0.1% of treatment courses with sulfonamides are complicated by a hypersensitivity syndrome. Sulfonamide hypersensitivity syndrome is similar to that seen with the anticonvulsants, including the characteristic facial and periorbital edema. It typically begins 3 weeks after starting the medication, but may occur as soon as 1 week after. The skin eruption is usually morbilliform or an erythroderma. Patients with this
Minocycline hypersensitivity syndrome occurs in young adults, usually in the context of acne therapy. Females are favored, as are those of Afro-Caribbean ancestry. Deficiency of glutathione S-transferases is common in affected individuals, and is more common in persons of Afro-Caribbean descent. In patients with minocycline hypersensitivity syndrome, minocycline may be detected in the blood up to 17 months after discontinuation of the medication, suggesting that slow metabolism and persistent levels of medication may play a role. The syndrome begins usually 2–4 weeks after starting the minocycline. Fever, a skin eruption, and adenopathy occur in more than 80% of cases. Headache and cough are common complaints. The eruption can be morbilliform, erythrodermic, or pustular. Facial edema is common. Liver involvement occurs in 75% of cases, and renal disease in 17%. Minocycline hypersensitivity is particularly associated with interstitial pneumonia with eosinophilia. This may progress to respiratory distress syndrome. It can be life-threatening, but most patients survive. Myocarditis has also been reported. Treatment is systemic steroids.
Dapsone hypersensitivity syndrome Dapsone hypersensitivity syndrome occurs in 38°C) 3. Erythrocyte sedimentation rate >20 mm; C-reactive protein positive; peripheral leukocytosis, and left shift 4. Excellent response to treatment with systemic corticosteroids *Both major and two minor criteria are needed for diagnosis.
Neutrophilic dermatosis of the dorsal hands Lesions of neutrophilic dermatosis of the dorsal hands present as edematous, pustular, or ulcerative nodules or plaques localized to the dorsal hands (Fig. 7-12). Histologically, papillary dermal edema and a nodular and diffuse neutrophilic infiltrate with karyorrhexis are noted. As in Sweet syndrome, leukocytoclastic vasculitis may be present focally. Individual flares respond to prednisone and dapsone, but recurrences are common. As the clinical appearance, tendency to relapse, response to treatment, and histologic features overlap with those of Sweet syndrome and pyoderma gangrenosum, this condition illustrates the close relationship of the various neutrophilic dermatoses. It is best considered a localized variant of Sweet syndrome.
Neutrophilic eccrine hidradenitis Neutrophilic eccrine hidradenitis is discussed in Chapter 33.
Marshall syndrome This rare syndrome is characterized by skin lesions resembling Sweet syndrome, which are followed by acquired cutis laxa. Cases occur primarily in children. Small red papules expand
Fig. 7-12 Neutrophilic dermatosis of the dorsal hands.
to urticarial, targetoid plaques with hypopigmented centers. Histologic evaluation of the skin lesions usually shows a neutrophilic dermatosis virtually identical to Sweet syndrome. Occasionally, an eosinophilic infiltrate will be found. The lesions resolve with destruction of the elastic tissue at the site, producing soft, wrinkled, skin-colored, protuberant plaques that can be pushed into the dermis. Elastic tissue in other organs may also be affected, especially the heart and lungs. Some cases may be associated with α1-antitrypsin deficiency. Cohen PR: Sweet’s syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis 2007 Jul 26; 2:34. Cook-Norris RH, et al: Neutrophilic dermatosis of the hands: an under-recognized hematological condition that may result in unnecessary surgery. Am J Hematol 2009; 84(1):60. Del Pozo J, et al: Neutrophilic dermatosis of the hands: presentation of eight cases and review of the literature. J Dermatol 2007 Apr; 34(4):243–247. Glendenning J, et al: Sweet’s syndrome in prostate cancer. Prostate Cancer Prostatic Dis 2008 Jan 29 (Epub). Gottlieb CC, et al: Ocular involvement in acute febrile neutrophilic dermatosis (Sweet syndrome): new cases and review of the literature. Surv Ophthalmol 2008 May–June; 53(3):219–226. Kaune KM, et al: Bullous sweet syndrome in a patient with t(9; 22)(q34; q11)-positive chronic myeloid leukemia treated with the tyrosine kinase inhibitor nilotinib: interphase cytogenetic detection of BCR-ABL-positive lesional cells. Arch Dermatol 2008 Mar; 144(3):361–364. Magro CM, et al: Clonality in the setting of Sweet’s syndrome and pyoderma gangrenosum is not limited to underlying myeloproliferative disease. J Cutan Pathol 2007 Jul; 34(7):526–534. Malone JC, et al: Sweet’s syndrome: a disease in histologic evolution? Arch Dermatol 2005; 141:893. Neoh CY, et al: Sweet’s syndrome: a spectrum of unusual clinical presentations and associations. Br J Dermatol 2007 Mar; 156(3):480–485. Ratzinger G, et al: Acute febrile neutrophilic dermatosis: a histopathologic study of 31 cases with review of literature. Am J Dermatopathol 2007 Apr; 29(2):125–133. Requena L, et al: Histiocytoid Sweet syndrome: a dermal infiltration of immature neutrophilic granulocytes. Arch Dermatol 2005; 141:837. Tabanlioğlu D, et al: Sweet’s syndrome and erythema nodosum: a companionship or a spectrum?—a case report with review of the literature. Int J Dermatol 2010 Jan; 49(1):62–66. Thompson DF, et al: Drug-induced Sweet’s syndrome. Ann Pharmacother 2007 May; 41(5):802–811. Wallach D, et al: From acute febrile neutrophilic dermatosis to neutrophilic disease: forty years of clinical research. J Am Acad Dermatol 2006 Dec; 55(6):1066–1071.
Reactive neutrophilic dermatoses
Bowel bypass syndrome has skin lesions that, on histologic examination, are identical to those of Sweet syndrome; fever and arthritis also accompany this condition. Although it is easy to distinguish classic EN from Sweet syndrome, these two conditions share many features. They occur most often in young adult women and frequently follow upper respiratory infections. They may be associated with pregnancy, underlying malignancy, and inflammatory bowel disease. In both, fever and arthritis may occur, along with leukocytosis with neutrophilia. There are many reports of simultaneous or sequential EN and Sweet syndrome in the same patient. Leukemia-associated Sweet syndrome may overlap with pyoderma gangrenosum. A search for an underlying cause should be undertaken, especially in persons over the age of 50 and those with anemia, thrombocytopenia, or lesions that are bullous or necrotic. The standard treatment is systemic cor ticosteroids (approximately 1 mg/kg/day oral prednisone). This will result in resolution of fever and skin lesions within days. Potassium iodide has been reported to be effective. Colchicine, dapsone, doxycycline, clofazimine, cyclosporine, and NSAIDs may be helpful in chronic or refractory disease. Medication should be continued for several weeks to prevent relapse.
Pyoderma gangrenosum Brunsting is credited with the initial clinical description of pyoderma gangrenosum (PG) in 1930. Classic PG begins as an inflammatory pustule with a surrounding halo that enlarges and begins to ulcerate. A primary lesion may not always be seen, and a substantial proportion of lesions appear at sites of trauma (pathergy). Satellite violaceous papules may appear just peripheral to the border of the ulcer and break down to fuse with the central ulcer. Fully developed lesions are painful ulcers with sharply marginated, undermined, blue to purple borders (Fig. 7-13). PG most commonly occurs in adults aged 40–60 years, and typically presents on the lower extremities and trunk. Lesions heal with characteristic thin, atrophic scars. “Malignant pyoderma” is no longer used as a diagnosis, according to the investigators at the Mayo Clinic who originally described it. Although ulcerative PG may occur on the head and neck, most cases described originally as malignant pyoderma are c-ANCA (antibodies to neutrophilic cytoplasmic antigens)-positive, and represent cutaneous presentations of Wegener’s granulomatosis. Pustular PG consists of pustular lesions that generally do not progress to ulcerative lesions. 145
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Fig. 7-13 Enlarging ulcer of pyoderma gangrenosum.
This forme fruste of PG is often seen in patients with inflammatory bowel disease. Pyostomatitis vegetans and subcorneal pustular dermatosis are two other pustular neutrophilic diseases reported in association with PG, sometimes in patients with IgA gammopathy. “Bullous” PG is more superficial and less destructive than the ulcerative type. These lesions have considerable overlap with what has been called bullous Sweet syndrome, and are usually seen in patients with leukemia or polycythemia vera. These red plaques become dusky and develop superficial erosions. They are not deep, usually are not undermined, and are less painful than ulcerative PG. “Vegetative” PG is the least aggressive form of PG. It is synonymous with “superficial granulomatous pyoderma.” Lesions present as cribriform chronic superficial ulcerations usually of the trunk. They enlarge slowly and have elevated borders and clean bases. They are rarely painful, generally respond to relatively conservative treatments, and are usually not associated with underlying systemic disease. PG is rare in children. More than 40% of these patients have underlying inflammatory bowel disease, and another 18% have leukemia. An association of childhood acquired immunodeficiency syndrome (AIDS) and PG has been documented. About onequarter of children with PG have no underlying disease. Genital and head and neck lesions are not uncommon in children. Overall, approximately 50% of patients with PG have an associated disease. The most common is inflammatory bowel disease, both Crohn’s and ulcerative colitis. Between 1.5% and 5% of patients with inflammatory bowel disease develop PG. The two diseases may flare together or run an independent course. Surgical removal of the diseased intestine may lead to complete remission of PG, or lesions may persist or first appear after removal of the affected bowel. Most patients with PG and inflammatory bowel disease have involvement of the colon. The ulcerative and pustular types of PG are most commonly seen in patients with associated inflammatory bowel disease. Many other associated conditions have been reported. Leukemia (chiefly acute or chronic myelogenous leukemia), myeloma, monoclonal gammopathy (chiefly IgA), polycythemia vera, myeloid metaplasia, chronic active hepatitis, hepatitis C, human immunodeficiency virus (HIV) infection, systemic lupus erythematosus, pregnancy, PAPA syndrome, and Takayasu arteritis are among the many diseases seen in conjunction with PG. PAPA syndrome is discussed with the other autoinflammatory disorders (see below). More than onethird of PG patients have arthritis, most commonly an asymmetrical, seronegative, monoarticular arthritis of the large joints. Monoclonal gammopathy, usually IgA, is found in 10% of PG patients. Children with congenital deficiency of 146
leukocyte-adherence glycoproteins (LAD) develop PG-like lesions. Early biopsies of PG show a suppurative folliculitis. The affected follicle is often ruptured. As the lesions evolve, they demonstrate suppurative inflammation in the dermis and subcutaneous fat. Massive dermal edema and epidermal neutrophilic abscesses are present at the violaceous undermined border. These features are not diagnostic and infectious causes must still be excluded. The clinical picture of PG, in the classic ulcerative form, is very characteristic. Because there are no diagnostic serologic or histologic features, however, PG remains a diagnosis of exclusion. Multiple infections, including mycobacteria, deep fungi, gummatous syphilis, synergistic gangrene, and amebiasis, must be excluded with cultures and special studies. Other disorders frequently misdiagnosed as PG include vascular occlusive or chronic venous disease, vasculitis, cancer, and exogenous tissue injury including factitial disease. PG may be misdiagnosed as a spider bite if there is only a solitary lesion on an extremity. Spider bites tend to evolve more rapidly and may be associated with other systemic symptoms or findings, such as disseminated intravascular coagulation. Various forms of cutaneous large-vessel vasculitis may produce similar clinical lesions; they are excluded by histologic evaluation and ancillary studies, such as ANCA and antiphospholipid antibody tests. The most difficult diagnosis to exclude is factitial disease. The clinical lesions may be strikingly similar, evolving from small papulopustules to form ulcerations that do not heal. Histologic evaluation will often simply show suppurative dermatitis, since the injected or applied caustic substance may not be identifiable (urine, disinfectants, drain cleaner). Even the most experienced clinician may misdiagnose factitial disease as PG. Management of PG is challenging. The initial step is to classify the lesion by type. Underlying conditions should be sought, even if no symptoms are found. Treatment of underlying inflammatory bowel disease may lead to improvement. In general, the vegetative type will respond to topical or local measures. The treatment is determined by the severity of the disease and by its rate of progression. In rapidly progressive cases, aggressive early management may reduce morbidity. Local treatment includes compresses or whirlpool baths, followed by the use of ointment or hydrophilic occlusive dressings. In mild cases, application of potent topical steroidal medications, intralesional steroid injections, or topical 4% cromolyn or tacrolimus may be beneficial, although pathergy may sometimes be seen at sites of injection. Hyperbaric oxygen therapy has been successful in some patients. Systemic steroids can be very effective. Initial doses are in the range of 1 mg/kg or higher. If control is achieved, the dose may be rapidly tapered. If steroid reduction is not possible, a steroidsparing agent may be added. In cases that are unresponsive to oral corticosteroids, the use of pulse methylprednisolone may be beneficial. In general, when the disease is aggressive and use of steroidal medications does not lead to rapid resolution, an immunosuppressive agent is added. Azathioprine, cyclophosphamide, and chlorambucil have been used effectively; however, cyclosporine and infliximab result in faster healing and are the immunosuppressives of choice for PG. The lesions often respond dramatically to these agents, including many that have not responded adequately to corticosteroid therapy. Initial doses of cyclosporine of approximately 5 mg/kg/day are effective in most cases. In failures, the dose can be raised to 10 mg/kg/day. The response is independent of any underlying cause. Infliximab is given as intravenous infusions in doses of about 5 mg/kg every few weeks. In very aggressive,
Adis¸en E, et al: Treatment of idiopathic pyoderma gangrenosum with infliximab: induction dosing regimen or on-demand therapy? Dermatology 2008; 216(2):163–165. Callen JP, et al: Pyoderma gangrenosum: an update. Rheum Dis Clin North Am 2007 Nov; 33(4):787–802. Hubbard VG, et al: Systemic pyoderma gangrenosum responding to infliximab and adalimumab. Br J Dermatol 2005; 152:1059. Kikuchi N, et al: Pyoderma gangrenosum following surgical procedures. Int J Dermatol 2010 Mar; 49(3):346–348. Miller J, et al: Pyoderma gangrenosum: a review and update on new therapies. J Am Acad Dermatol 2010 Apr; 62(4):646–654. Reichrath J, et al: Treatment recommendations for pyoderma gangrenosum: an evidence-based review of the literature based on more than 350 patients. J Am Acad Dermatol 2005; 53:273. Rogge FJ, et al: Treatment of pyoderma gangrenosum with the anti-TNFalpha drug—etanercept. J Plast Reconstr Aesthet Surg 2008; 61(4):431–433. Turner RB, et al: Rapid resolution of pyoderma gangrenosum after treatment with intravenous cyclosporine. J Am Acad Dermatol 2010 Sep; 63(3):e72–e74. Zaccagna A, et al: Anti-tumor necrosis factor alpha monoclonal antibody (infliximab) for the treatment of pyoderma gangrenosum associated with Crohn’s disease. Eur J Dermatol 2003; 13:258.
Autoinflammatory syndromes The autoinflammatory syndromes are a group of inherited disorders characterized by bouts of inflammation and periodic fevers. Inflammatory skin lesions are often prominent manifestations, especially acne, PG, and erysipelas- and urticarialike lesions. Familial Mediterranean fever (FMF) is an autosomalrecessive syndrome characterized by recurrent attacks of fever, peritonitis, pleuritis, arthritis, and erysipelas-like erythema. It is caused by mutation in the MEFV gene, which produces pyrin, but a significant number of patients with a similar phenotype lack a detectable gene defect. Incomplete penetrance is common and many patients with paired mutations lack symptoms or have attenuated symptoms. Colchicine is the mainstay of treatment for these patients and it can reduce the risk of associated amyloidosis. Thalidomide was reported as successful in a colchicine-resistant patient. An herbal remedy (a combination of Andrographis paniculata Nees with Eleutherococcus senticosus Maxim, Schizandra chinensis Bail, and Glycyrrhiza glabra L extracts) was shown to be effective in a small double-blind, randomized, placebo-controlled study. The PAPA syndrome is an autosomal-dominant syndrome characterized by pyogenic arthritis, PG, and acne, and is caused by proline serine threonine phosphatase-interacting protein 1 (PSTPIP1) or CD2-binding protein 1 (CD2BP1) mutations. PSTPIP1/CD2BP1, a tyrosine-phosphorylated protein involved in cytoskeletal organization, interacts with pyrin, the gene product important in the pathogenesis of FMF. The TNF receptor-associated periodic syndrome (TRAPS) is similar to FMF, but shows autosomal-dominant inheritance,
longer attacks, and a lack of response to colchicine. TRAPS is associated with mutations in the TNFRSF1A gene, resulting in decreased serum-soluble TNF receptor. The hyper-IgD syndrome (HIDS), associated with mutations in the mevalonate kinase (MVK) gene, leading to MVK deficiency, also presents with hereditary periodic fever. Cryopyrin, the product of the CAIS1 locus, is associated with familial cold urticaria (familial cold autoinflammatory syndrome), an autosomal-dominant syndrome characterized by fever, rash, conjunctivitis, and arthralgia elicited by generalized exposure to cold. The defect has been mapped to a 10-cM region on chromosome 1q44. The same gene and product are associated with the Muckle–Wells syndrome and chronic infantile neurologic cutaneous and articular syndrome/ neonatal-onset multisystem inflammatory disease (CINCA/ NOMID). The Muckle–Wells syndrome is an autosomaldominant syndrome associated with acute febrile inflammatory episodes comprising abdominal pain, arthritis, urticaria, and multiorgan amyloidosis. The cryopyrin-related diseases often respond to anakinra, a recombinant human IL-1 receptor antagonist that appears promising for other autoinflammatory diseases. Patients with the CINCA syndrome have fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial rash, and a deforming arthritis. They may also have dysmorphic facial appearance, clubbing of the fingers, mild mental retardation, and papilledema. The Blau syndrome, an autosomal-dominant syndrome with arthritis, uveitis, granulomatous inflammation, and camptodactyly, is associated with mutations in the NOD2/CARD15 gene, which also predisposes to Crohn’s disease. Schnitzler syndrome (urticaria, periodic fever, bone pain, and monoclonal gammopathy) may respond to anakinra and is classified by some as an auto inflammatory syndrome.
Urticaria (hives)
rapidly progressive cases, consideration should be given to starting cyclosporine or infliximab treatment early to gain control of the disease. Etanercept, adalimumab, and alefacept have also been used. Tacrolimus and mycophenolate mofetil are also effective in some cases, but experience with these agents is much more limited. Sulfapyridine, sulfasalazine, salicylazosulfapyridine, and dapsone may be helpful, either as single agents or in combination with corticosteroids. Clofazimine, in doses of 200–400 mg/day, has been useful in some patients. Minocycline and rarely other antibiotics have anecdotally been successful. Epidermal allografts or autografts may be applied soon after the disease is controlled. Pathergy is rarely noted at the donor site when patients are on adequate immunosuppressive therapy.
Farasat S, et al: Autoinflammatory diseases: clinical and genetic advances. Arch Dermatol 2008 Mar; 144(3):392–402. Jéru I, et al: Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A 2008 Feb 5; 105(5):1614–1619. Jesus AA, et al: Phenotype-genotype analysis of cryopyrin-associated periodic syndromes (CAPS): description of a rare non-exon 3 and a novel CIAS1 missense mutation. J Clin Immunol 2008 Mar; 28(2):134–138. Kanazawa N, et al: Autoinflammatory syndromes with a dermatological perspective. J Dermatol 2007 Sep; 34(9):601–618. Maksimovic L, et al: New CIAS1 mutation and anakinra efficacy in overlapping of Muckle–Wells and familial cold autoinflammatory syndromes. Rheumatology (Oxford) 2008 Mar; 47(3):309–310. Ross JB, et al: Use of anakinra (Kineret) in the treatment of familial cold autoinflammatory syndrome with a 16-month follow-up. J Cutan Med Surg 2008 Jan–Feb; 12(1):8–16. Shinkai K, et al: Cryopyrin-associated periodic syndromes and autoinflammation. Clin Exp Dermatol 2008 Jan; 33(1):1–9. Stankovic K, et al: Autoinflammatory syndromes: diagnosis and treatment. Joint Bone Spine 2007 Dec; 74(6):544–550. Yamazaki T, et al: Anakinra improves sensory deafness in a Japanese patient with Muckle–Wells syndrome, possibly by inhibiting the cryopyrin inflammasome. Arthritis Rheum 2008 Mar; 58(3):864–868.
Urticaria (hives) Urticaria is a vascular reaction of the skin characterized by the appearance of wheals (Fig. 7-14), generally surrounded by a red halo or flare and associated with severe itching, stinging, or pricking sensations. These wheals are caused by localized edema. Clearing of the central region may occur and lesions may coalesce, producing an annular or polycyclic pattern. Subcutaneous swellings (angioedema) may accompany the wheals. Angioedema may target the gastrointestinal and respiratory tracts, resulting in abdominal pain, coryza, asthma, and respiratory problems. Respiratory tract involvement can 147
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Fig. 7-14 Annular and polycyclic urticaria.
produce airway obstruction. Anaphylaxis and hypotension may also occur.
Classification Acute urticaria evolves over days to weeks, producing evanescent wheals that individually rarely last more than 12 h, with complete resolution of the urticaria within 6 weeks of onset. Daily episodes of urticaria and/or angioedema lasting more than 6 weeks are designated chronic urticaria. Chronic urticaria predominantly affects adults and is twice as common in women as in men. Nonimmunologic mechanisms can produce mast cell degranulation. Common triggers include opiates, polymyxin B, tubocurarine, radiocontrast dye, aspirin, other NSAIDs, tartrazine, and benzoate. More than 50% of chronic urticaria is idiopathic. Physical stimuli may produce urticarial reactions and represent 7–17% of cases of chronic urticaria. The physical urticarias include dermatographic, cold, heat, cholinergic, aquagenic, solar, vibratory, and exercise-induced cases. Physical urticaria commonly occurs in patients with chronic urticaria.
Food additives
Etiologic factors
Fewer than 10% of cases of chronic urticaria are caused by food additives. Natural food additives that may be implicated in urticaria include yeasts, salicylates, citric acid, egg, and fish albumin. Synthetic additives include azo dyes, benzoic acid derivatives, sulfite, and penicillin. Yeast is widely used in foods. When it is suspected of being the causative agent, bread and breadstuffs, sausages, wine, beer, grapes, cheese, vinegar, pickled foods, catsup, and yeast tablets should be avoided. Foods containing azo dyes and benzoic acid include candy, soft drinks, jelly, marmalade, custards, puddings, various cake and pancake mixes, mayonnaise, ready-made salad dressings and sauces, packaged soups, anchovies, and colored toothpastes. With the exception of sulfite and penicillin, most food additives can be avoided by eating only meat, produce, and dairy products (the outer aisles of the grocery store). Packaged foods found in the interior aisles are largely off limits.
Drugs
Infections
Drugs are probably the most frequent cause of acute urticaria. Penicillin and related antibiotics are the most frequent offenders (see Chapter 6). A frequently overlooked factor is that penicillin sensitivity may become so exquisite that reactions can occur from penicillin in dairy products. The incidence of aspirin-induced urticaria has fallen, most likely related to the availability of alternative anti-inflammatory agents. Aspirin-sensitive persons tend to have cross-sensitivity with tartrazine, the yellow azo-benzone dye, and other azo dyes, natural salicylates, and benzoic acid and its derivatives. These are common food additives and preservatives. Aspirin exacerbates chronic urticaria in at least 30% of patients. Patients may have allergic rhinitis or asthma, nasal polyps, and foodinduced anaphylaxis. Mite-contaminated wheat flour has been implicated as an allergen. The nature of the association between aspirin intolerance and mite-induced respiratory allergies is unknown.
Emotional stress
Food Foods are a frequent cause of acute urticaria, whereas in chronic urticaria food is a less frequent factor. The most aller148
genic foods are chocolate, shellfish, nuts, peanuts, tomatoes, strawberries, melons, pork, cheese, garlic, onions, eggs, milk, and spices. Food allergens that may cross-react with latex include chestnuts, bananas, passion fruit, avocado, and kiwi. Exposure to safely cooked fish and shellfish parasitized by Anisakis simplex can result in angioedema and urticaria, suggesting that some seafood allergies may be related to exposure to parasite antigens. If the urticaria is acute and recurrent, food allergy may be suggested by a food diary. Serum radioallergosorbent tests (RASTs) can be used to detect specific IgE, and elimination diets can be of benefit in some patients. One such diet permits inclusion of the following: lamb, beef, rice, potatoes, carrots, string beans, peas, squash, apple sauce, tapioca, preserved pears, peaches, or cherries, Ry-Krisp crackers, butter, sugar, tea without milk or lemon, and coffee without cream. This diet is followed for 3 weeks. If urticaria does not occur, then suspected foods are added one by one and reactions observed. It should be noted that potatoes often contain sulfites, and that some patients may be allergic to the foods contained in the above diet. It is best tried only after a careful history. The use of food challenges and of scratch and intradermal tests can be misleading. False-positive food challenges are common and an offending food may give a negative prick or intradermal test. Moreover, food additives and preservatives may be responsible.
Acute urticaria may be associated with upper respiratory infections, especially streptococcal infections. The incidence of streptococcal infection in pediatric cases of acute urticaria varies greatly in reported series. The possibility of localized infection in the tonsils, a tooth, the sinuses, gallbladder, prostate, bladder, or kidney should be considered as a possible cause in cases of acute or chronic urticaria. In some patients, treatment with antibiotics for Helicobacter pylori has led to resolution of the urticaria. Chronic viral infections, such as hepatitis B (Fig. 7-15) and C, may cause urticaria. Acute infectious mononucleosis and psittacosis may also be triggering conditions. Helminths may cause urticaria. Among these are Ascaris, Ankylostoma, Strongyloides, Filaria, Echinococcus, Schistosoma, Trichinella, Toxocara, and liver fluke. Persons under severe emotional stress may have more marked urticaria, no matter what the primary cause is. In cholinergic urticaria emotional stress is a particularly well-documented inciting stimulus.
Fig. 7-15 Urticaria secondary to hepatitis B.
Menthol Rarely, menthol may cause urticaria. It is found in mentholated cigarettes, candy and mints, cough drops, aerosol sprays, and topical medications.
Neoplasms Urticaria has been associated with carcinomas and Hodgkin disease. Cold urticaria with cryoglobulinemia has been reported as being associated with chronic lymphocytic leukemia.
Inhalants
Diagnosis
Grass pollens, house dust mites, feathers, formaldehyde, acrolein (produced when frying with lard or by smoking cigarettes containing glycerin), castor bean or soybean dust, cooked lentils, cottonseed, animal dander, cosmetics, aerosols, pyrethrum, and molds have been known to cause urticaria.
Diagnosis of urticaria and angioedema is usually made on clinical grounds. Lesions in a fixed location for more than 24 h suggest the possibility of urticarial vasculitis, the urticarial phase of an immunobullous eruption, EM, granuloma annulare, sarcoidosis, or cutaneous T-cell lymphoma. If individual wheals last for longer than 24 h, a skin biopsy should be performed.
Alcohol Urticaria may be induced by the ingestion of alcohol. The mechanism of alcohol-induced indirect mast cell stimulation is unknown. Wines generally contain sulfites, which may produce flushing or urticaria.
Hormonal imbalance Chronic urticaria is approximately twice as common among women than men and low levels of dehydroepiandrosterone (DHEA)-S have been noted, suggesting a possible role for hormone imbalance.
Genetics Polymorphisms in the β2 adrenergic receptor (ADRB2) gene have been identified in aspirin-intolerant acute urticaria.
Pathogenesis/histopathology Capillary permeability results from the increased release of histamine from the mast cells situated around the capillaries. The mast cell is the primary effector cell in urticarial reactions. Other substances besides histamine may cause vasodilation
Urticaria (hives)
and capillary permeability, and thereby may possibly become mediators of urticaria and angioedema. These include sero tonin, leukotrienes, prostaglandins, proteases, and kinins. The major basic protein of eosinophil granules is abnormally high in the blood of more than 40% of patients with chronic urticaria, even when peripheral blood eosinophil counts are normal, and there are extracellular deposits of it in the skin in about the same proportion of patients. About one-third of patients with chronic idiopathic urticaria have circulating functional histamine-releasing IgG autoantibodies that bind to the high-affinity IgE receptor. Some patients have IgG that does not bind the IgE receptor, but causes mastcell degranulation. Thyroid autoantibodies are often present in women with chronic idiopathic urticaria, but clinically relevant thyroid disease is seldom present. Even in those with thyroid disease, treatment of the thyroid disorder generally does not affect the course of the urticaria. The histopathologic changes in acute urticaria include mild dermal edema and margination of neutrophils within postcapillary venules. Later, neutrophils migrate through the vessel wall into the interstitium, and eosinophils and lymphocytes are also noted in the infiltrate. Karyorrhexis and fibrin deposition within vessel walls are absent, helping to differentiate urticaria from vasculitis. A subset of patients has long-lasting, refractory lesions and this has been dubbed “neutrophilic urticaria.” Lesions in these patients often persist for longer than 24 h, and biopsies demonstrate a neutrophil-rich perivascular infiltrate that lacks karyorrhexis or fibrin deposition within vessels walls. Eosinophils and mononuclear cells are noted in varying proportions. Patients with neutrophilic urticaria may present with acute urticaria, chronic urticaria, or physical urticaria. Lesional skin demonstrates increased expression of TNF-α and IL-3, whereas IL-8 expression is only minor. As neutrophils are commonly present in urticaria in general, it is likely that cases of neutrophilic urticaria simply represent urticaria with upregulation of some mast cell-derived cytokines.
Clinical evaluation Laboratory evaluation should be driven by associated signs and symptoms. Random tests in the absence of a suggestive history or physical findings are rarely cost-effective. A practical evaluation is limited to a detailed history (foods, drugs, including aspirin, physical causes) and physical examination. Angioedema in the absence of urticaria may be related to hereditary angioedema or an angiotensin-converting enzyme (ACE) inhibitor. C1 esterase deficiency does not cause hives, only angioedema. If there is a history of sinus difficulties, particularly if there is palpable tenderness over the maxillary or ethmoid sinuses, radiologic sinus evaluation is recommended. In areas where parasitic disease is common, a blood count to detect eosinophilia is an inexpensive screening test with a fair yield. The blood count may be unreliable if the patient has been on a systemic corticosteroid. In patients with chronic urticaria, a review of medications, including over-the-counter products, supplements, aspirin, and other NSAIDs, should be obtained. If the history suggests 149
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a physical urticaria, then the appropriate challenge test should be used to confirm the diagnosis. Lesions that burn rather than itch, resolve with purpura, or last longer than 24 h should prompt a biopsy to exclude urticarial vasculitis. A directed history and physical examination should elicit signs or symptoms of thyroid disease, connective tissue disease, changes in bowel or bladder habits, vaginal or urethral discharge, other localized infection, jaundice, or risk factors for hepatitis or Lyme disease. Positive findings should prompt appropriate screening tests. Although sinus x-ray films, a Panorex dental film, a streptococcal throat culture, abdominal ultrasonography, and urinalysis with urine culture (in men, with prostatic massage) may reveal the most common occult infections triggering urticaria, positive cases are almost always associated with some signs or symptoms suggestive of the diagnosis. In patients with chronic angioedema, without classic wheals or symptoms of pruritus, a careful drug history and evaluation of C4 level should be ordered. If C4 is low, an evaluation of C1 esterase inhibitor is appropriate.
Anaphylaxis Anaphylaxis is an acute and often life-threatening immunologic reaction, frequently heralded by scalp pruritus, diffuse erythema, urticaria, or angioedema. Bronchospasm, laryngeal edema, hyperperistalsis, hypotension, and cardiac arrhythmia may occur. Antibiotics, especially penicillins, other drugs, and radiographic contrast agents are the most common causes of serious anaphylactic reactions. Hymenoptera stings are the next most frequent cause, followed by ingestion of crustaceans and other food allergens. Atopic dermatitis is commonly associated with anaphylaxis regardless of origin. Causative agents can be identified in up to two-thirds of cases and recurrent attacks are the rule. Exercise-induced anaphylaxis is often dependent on priming by prior ingestion of a specific food, or food in general, and aspirin may be an additional exacerbating factor.
Treatment Acute urticaria The mainstay of treatment of acute urticaria is administration of antihistamines. In adults, nonsedating antihistamines pose a lower risk of psychomotor impairment. If the cause of the acute episode can be identified, avoiding that trigger should be stressed. In patients with acute urticaria that does not respond to antihistamines, systemic corticosteroids are generally effective. Less rebound is seen with a 3-week tapered course of systemic corticosteroid therapy as compared with shorter courses. For severe reactions, including anaphylaxis, respiratory and cardiovascular support is essential. A 0.3 mL dose of a 1 : 1000 dilution of epinephrine is administered every 10–20 min as needed. In young children, a half-strength dilution is used. In rapidly progressive cases, intubation or tracheotomy may be required. Adjunctive therapy includes intramuscular antihistamines (25–50 mg hydroxyzine or diphenhydramine every 6 h as needed) and systemic corticosteroids (250 mg hydrocortisone or 50 mg methylprednisolone intravenously every 6 h for 2–4 doses).
Chronic urticaria The mainstay of treatment for chronic urticaria is, again, administration of antihistamines. These should be taken on a daily basis; they should not be prescribed to be taken only as needed. The patient should be warned about driving an automobile when first-generation antihistamines are used. 150
Second-generation H1 antihistamines (cetirizine, levocetirizine, famotidine, loratadine, acrivastine, and azelastine) are large, lipophilic molecules with charged side chains that bind extensively to proteins, preventing the drugs from crossing the blood–brain barrier; thus they produce less sedation in most patients. Long-acting forms are available, and the long half-life of these antihistamines and reduced sedation result in improved compliance and efficacy. Cetirizine (Zyrtec) and some of the other second-generation antihistamines can cause drowsiness in some individuals, particularly in higher doses or when combined with other antihistamines. Doxepin, a tricyclic antidepressant with potent H1 antihistaminic activity, may be useful and can be added to the existing antihistamine. Doxepin is frequently dosed at bedtime, so much of the drowsiness and dry mouth are gone by morning. In stubborn cases, dosages of antihistamines that exceed drug labeling are sometimes required. Even second-generation antihistamines may become sedating at higher doses. Fexofenadine is generally well tolerated, even at doses that exceed product labeling. The authors have found escalating doses of antihistamines to be helpful in management, but in one published study of 22 adult patients with refractory urticaria, tripling the dose of cetirizine resulted in adequate control in only one patient. The others required alternate systemic agents such as cyclosporine. The combination of H1 and H2 antihistamines, such as hydroxyzine and cimetidine or ranitidine, may be effective in some cases. Cimetidine or ranitidine should not be used alone for treatment of urticaria, as they may interfere with feedback inhibition of histamine release. Other second-line treatments include phototherapy, calcium channel antagonists (nifedipine), antimalarial medications, leukotriene and 5-lipoxygenase inhibitors, gold, azathioprine, low-dose cyclosporine, terbutaline, omalizumab, and methotrexate. Dapsone and colchicines may be helpful in neutrophil-rich urticaria. Unfortunately, although systemic corticosteroids are effective in suppressing most cases of chronic urticaria, their long-term side effects make their extended use impractical. As soon as the corticosteroid is stopped, hives recurs. In addition, if an infection is the trigger, this could be exacerbated by long-term steroid therapy. Topical corticosteroids, topical antihistamines, and topical anesthetics have no role in the management of chronic urticaria. For local treatment, tepid or cold tub baths or showers may be freely advocated. Topical camphor and menthol can provide symptomatic relief. Sarna lotion contains menthol, phenol, and camphor. In about one-third of cases of chronic idiopathic urticaria, patients have autoantibodies that bind to high-affinity IgE receptors. Such patients may require more aggressive management to include chronic immunosuppressive therapy, plasmapheresis, or intravenous immunoglobulin (IVIG).
Other urticarial variants Angioedema Angioedema is an acute, evanescent, circumscribed edema that usually affects the most distensible tissues, such as the eyelids, lips (Fig. 7-16), lobes of the ears, and external genitalia, or the mucous membranes of the mouth, tongue, or larynx. The swelling occurs in the deeper parts of the skin or in the subcutaneous tissues and as a rule is only slightly tender, with the overlying skin unaltered, edematous, or, rarely, ecchymotic. There may be a diffuse swelling on the hands, forearms, feet, and ankles. Frequently, the condition begins during the night and is found on awakening. There are two distinct subsets of angioedema. The first is considered a deep form of urticaria and may be observed as solitary or multiple sites of angioedema alone or in
Urticaria (hives)
activation and consumption. In addition to depressed C4 levels, patients with types I and II also have low C1, C1q, and C2 levels. If the clinical picture and screening tests are positive, a titer of C1-EI should be ordered. C1-EI is a labile protein and sample decay is common. A low C1-EI in the presence of normal C4 levels should raise the suspicion of sample decay, rather than true HAE. The treatment of choice for acute HAE types I and II is replacement therapy with concentrates or fresh frozen plasma. Short-term prophylaxis (e.g. for patients undergoing dental care, endoscopy, or intubation for surgery) can be obtained from stanozolol, an attenuated androgen. Estrogens in oral contraceptives, in contrast, may precipitate attacks. Antifibrinolytic tranexamic acid, a drug related to e-aminocaproic acid, has been used to treat acute and chronic disease. Type III does not respond to C1-EI replacement, but may respond to danazol.
Acquired C1 esterase inhibitor deficiency Fig. 7-16 Angioedema of the lips.
combination with urticaria. The action of histamine or similar substances creates vasomotor lability, and pruritus may be a significant feature. The second, angioedema associated with C1 esterase inhibitor deficiency, is not associated with hives and there is no pruritus. Symptoms of pain predominate. Angioedema may be related to ACE inhibitors.
Hereditary angioedema Also known as Quincke edema, hereditary angioedema (HAE) was originally described and named by Osler in 1888. HAE characteristically appears in the second to fourth decade. Sudden attacks of angioedema occur as frequently as every 2 weeks throughout the patient’s life, lasting for 2–5 days. Swelling is typically asymmetrical, and urticaria or itching does not occur. The presentation may overlap with that of the autoinflammatory syndromes. Patients may experience local swelling in subcutaneous tissues (face, hands, arms, legs, genitals, and buttocks); abdominal organs (stomach, intestines, bladder), mimicking surgical emergencies; and the upper airway (larynx), which can be lifethreatening. There is little response to antihistamines, epi nephrine, or steroids. The mortality rate is high, with death often caused by laryngeal edema. Gastrointestinal edema is manifested by nausea, vomiting, and severe colic, and it may simulate appendicitis so closely that appendectomy is mistakenly performed. The factors that trigger attacks are minor trauma, surgery, sudden changes of temperature, or sudden emotional stress. Inherited in an autosomal-dominant fashion, HAE is estimated to occur in 1 in 50 000–150 000 persons. There are three phenotypic forms of the disease. Type I is characterized by low antigenic and functional plasma levels of a normal C1 esterase inhibitor protein (C1-EI). Type II is characterized by the presence of normal or elevated antigenic levels of a dysfunctional protein. Type III demonstrates normal C1-EI function and normal complement. It has been described only in female members of affected families. Criteria for type III include a long history of recurrent attacks of skin swelling, abdominal pain, or upper airway obstruction; absence of urticaria; familial occurrence; normal C1-EI and C4 concentrations; and failure of treatment with antihistamines, corticosteroids, and C1-EI concentrate. The screening test of choice for types I and II is a C4 level. C4 will be low (0.5 g/day or casts • neurologic disorders (seizures or psychosis in the absence of other known causes) • pleuritis/pericarditis • blood abnormalities (including hemolytic anemia, leukopenia, thrombocytopenia) • immunologic disorders such as anti-dsDNA antibody, anti-Sm, antiphospholipid antibodies (based on IgG or IgM anticardiolipin antibodies, lupus anticoagulant or a false-positive serologic test for syphilis known for at least 6 months) • positive ANA blood test. 159
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Fig. 8-10 Bullous lupus erythematosus.
Fig. 8-11 Oral lesions of systemic lupus erythematosus.
For identification of patients in clinical studies, a patient may be said to have SLE if four or more of the above criteria are satisfied, serially or simultaneously. It is important to note that many patients present with autoantibodies, arthralgia, and constitutional signs, but do not meet ACR criteria for SLE. With time, patients may evolve to meet all criteria.
Weber–Rendu syndrome demonstrate ectasia of half of the capillary loop. Erythema multiforme-like lesions may predominate; this has been termed Rowell syndrome. Rarely, toxic epidermal necrolysis may be associated with lupus. In addition to periungual telangiectasia, red or spotted lunulae may be present in patients with SLE. The palms, soles, elbows, knees, or buttocks may become persistently erythematous or purplish, sometimes with overlying scale. Diffuse, nonscarring hair loss is common. Short hairs in the frontal region are referred to as lupus hairs. These hairs result from a combination of chronic telogen effluvium and increased hair fragility. Mucous membrane lesions are seen in 20–30% of SLE patients, and chronic cutaneous lupus may be localized to the eyelid or oral mucosa. Conjunctivitis, episcleritis, and nasal and vaginal ulcerations may occur. Oral mucosal hemorrhages, erosions, shallow angular ulcerations (Fig. 8-11) with surrounding erythema, and gingivitis occur commonly. Erythema, petechiae, and ulcerations may occur on the hard palate. Multiple eruptive dermatofibromas have been described in SLE. Leg ulcers, typically deeply punched out and with very little inflammation, may be seen on the pretibial or malleolar areas. Many of these patients present with a livedoid pattern and many have an antiphospholipid antibody. Sneddon syndrome is composed of livedo reticularis and strokes related to a hyalinizing vasculopathy. Both erythema multiforme-like and toxic epidermal necrolysis-like presentations have been described. Calcinosis cutis is uncommon but may be dramatic. Also seen infrequently are plaque-like or papulonodular depositions of mucin. These reddish-purple to skin-colored lesions are often present on the trunk and arms or head and neck (Fig. 8-12). Finally, a symmetrical papular eruption of the extremities may occur (Fig. 8-13). These skin-colored to erythematous lesions with a smooth, ulcerated, or umbilicated surface may show vasculitis or, in older lesions, a palisaded granulomatous inflammation. These occur in patients with SLE, rheumatoid arthritis, or other immune complex-mediated disease. This eruption has been referred to as palisaded neutrophilic and granulomatous dermatitis of immune complex disease.
Cutaneous manifestations The characteristic butterfly facial erythema seen in patients with SLE is a common manifestation of acute cutaneous LE. The eruption usually begins on the malar area and the bridge of the nose. There may be associated edema. The ears and chest may also be the sites of early lesions. Biopsies at all sites show interface dermatitis and a scant perivascular lymphoid infiltrate. The eruption may last from a day to several weeks, and resolves without scarring. There may be more widespread erythema in some cases. Bullous lesions of LE (BLE) (Fig. 8-10) occur as single or grouped vesicles or bullae, often widespread, with a predilection for sun-exposed areas. Rarely, they may itch. Most sets of published criteria require that patients with BLE meet ACR criteria for SLE, but patients exist who have identical bullous lesions and fewer than four ACR criteria. ACR criteria are critical to ensure that patients with similar severity are enrolled in clinical trials, but they sometimes fall short in the evaluation of a given patient. Histologically, neutrophils accumulate at the dermoepidermal junction and within dermal papillae. In bullous lesions, there is a subepidermal bulla containing neutrophils. Fluorescence with IgG, IgM, IgA, or C3 is commonly present in a continuous granular pattern at the basement membrane zone on DIF testing. They are found in or below the lamina densa on immunoelectron microscopy. Most of these patients are HLA-DR2-positive. The recognition of this subset as a distinct one is made clear by its often dramatic therapeutic response to dapsone. Epidermolysis bullosa acquisita is histopathologically and immunopathologically identical since both diseases are mediated by circulating antibodies against type VII collagen. Dapsone is usually ineffective in epidermolysis bullosa acquisita. Bullous lesions may also occasionally arise as a result of liquefactive degeneration of the basal cell layer or full-thickness epidermal necrosis resembling toxic epidermal necrolysis. A variety of vascular lesions occur in 50% of cases of SLE. Often the fingertips or toes show edema, erythema, or telangiectasia. Nailfold capillary loops in LE are more likely to show wandering glomeruloid loops, whereas dermatomyositis and scleroderma capillary loops demonstrate symmetrical dilatation and dropout of vessels. Capillary loops in the Osler– 160
Systemic manifestations Most organs can be involved; the symptoms and findings are often due to immune complex disease, especially vasculitis. The earliest changes noted may be transitory or migratory arthralgia, often with periarticular inflammation. Fever, weight loss, pleuritis, adenopathy, or acute abdominal pain
Lupus erythematosus Fig. 8-12 Papulonodular mucinosis.
Fig. 8-14 Cutaneous thrombosis in antiphospholipid antibody syndrome.
Fig. 8-13 Palisaded neutrophilic granulomatous dermatitis.
may occur. Arthralgia is often the earliest abnormality and may remain the sole symptom for some time. Around 95% of SLE patients will manifest this symptom. Arthralgia, deforming arthropathy, and acute migratory polyarthritis resembling rheumatoid arthritis may all occur as manifestations of SLE. Avascular necrosis of the femoral head has been observed. Although this is a known complication of systemic corticosteroid therapy, it has also occurred in patients with SLE who have never had corticosteroids. Thrombosis in vessels of various sizes and thromboembolism may be a recurring event (Fig. 8-14). It may be attributed to a plasma constituent paradoxically called lupus anticoagulant (LA) because it causes prolonged coagulation studies in vitro, but thrombosis in vivo. The finding of a lupus anticoagulant is usually associated with antiphospholipid antibodies. These may be anticardiolipin antibodies, but other types of
antiphospholipid antibody (antiphosphatidylserine, anti phosphatidylinositol, and antiphosphatidylethanolamine) may occur. Antiphospholipid antibodies and elevated homocysteine may each increase the risk of thrombosis. Antiphospholipid antibodies are associated with early-onset organ damage. Many, but not all, patients have a false-positive blood test for syphilis. In one study, inflammatory lesions of SLE and infections were the most common causes of death during the initial 5 years of disease, while thromboses were the most common cause of death after the first 5 years. Renal involvement may be of either nephritic or nephrotic type, leading in either case to chronic renal insufficiency with proteinuria and azotemia. Active nephritis is unlikely in the absence of anti-dsDNA. Both anti-dsDNA antibody and antiC1q antibody are of relatively high specificity for active nephritis. Hypercholesterolemia and hypoalbuminemia may occur. Immunoglobulin and complement components have been found localized to the basement membrane of glomeruli, where vasculitis produces the characteristic “wire-loop” lesion. Myocarditis is indicated by cardiomegaly and gallop rhythm, but the electrocardiographic changes are usually not specific. Pericarditis (the most frequent cardiac manifestation) and endocarditis also occur. Raynaud phenomenon occurs in about 15% of patients; these individuals have less renal disease and consequently lower mortality. The CNS may be involved with vasculitis, manifested by hemiparesis, convulsions, epilepsy, diplopia, retinitis, choroiditis, psychosis, and other personality disorders. Livedo reticularis is a marker for patients at risk for CNS lesions (Sneddon syndrome, see above). Idiopathic thrombocytopenic purpura is occasionally the forerunner of SLE. Coombs-positive hemolytic anemia, neutropenia, and lymphopenia are other hematologic findings. Gastrointestinal involvement may produce symptoms of nausea, vomiting, and diarrhea. Frequently, the intestinal wall and the mesenteric vessels show vasculitis. Pulmonary involvement with pleural effusions, interstitial lung disease, 161
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and acute lupus pneumonitis may be present. Sjögren syndrome (keratoconjunctivitis sicca) and Hashimoto thyroiditis are associated with SLE. Overlap with any of the connective tissue diseases may be seen, and occurs in approximately 25% of patients. Muscular atrophy may accompany extreme weakness so that dermatomyositis may be suspected. Myopathy of the vacuolar type may produce muscular weakness, myocardial disease, dysphagia, and achalasia of the esophagus. Steroid myopathy may also occur. The serum aldolase level may be elevated with a normal creatine phosphokinase. Type B insulin resistance syndrome with insulin receptor antibodies accompanied by pancytopenia has been reported in the setting of chronic discoid LE evolving to SLE. A history of exposure to excessive sunlight before the onset of the disease or before an exacerbation is sometimes obtained. Some patients may suffer only mild constitutional symptoms for weeks or months, but immediately after exposure to strong sunlight they may develop the facial eruption and severe disease complications. Hydralazine, procainamide, sulfonamides, penicillin, anticonvulsants, minocycline, and isoniazid have been implicated as causes of drug-induced LE. Most drug-induced lupus is associated with a positive ANA test, antihistone antibodies, and sometimes serositis. Penicillamine induces (or unmasks) true SLE, and etanercept has produced a range of findings, including SLE. Anti-tumor necrosis factor (TNF) agents have produced a shift to a lupus profile of autoantibodies in patients with rheumatoid arthritis.
Childhood systemic lupus erythematosus The onset of childhood SLE occurs between the ages of 3 and 15, with girls outnumbering boys 4:1. The skin manifestations may be the typical butterfly eruption on the face and photosensitivity. In addition, there may be morbilliform, bullous, purpuric, ulcerating, or nodose lesions. The oral mucosa is frequently involved. Skin eruptions may be associated with joint, renal, neurologic, and gastrointestinal disease. Weight loss, fatigue, hepatosplenomegaly, lymphadenopathy, and fever are other manifestations. Pediatric patients with SLE and antiphospho lipid antibodies, specifically lupus anticoagulants, are at high risk of developing thromboembolic events.
Pregnancy Women with LE may have successful pregnancies, although there might be difficulty in conceiving, and miscarriages occur with greater frequency, especially among those with antiphospholipid antibodies. The course of pregnancy may be entirely normal, with remission of the LE, or the symptoms of LE may become worse. Risk of fetal death is increased in women with a previous history of fetal loss and anticardiolipin or anti-Ro antibodies. Low-dose aspirin is often used in the former instance. For the patient with these antibodies but without a history of previous fetal loss, the risk of fetal loss or neonatal lupus is low. In most cases, the pregnancy itself is well tolerated, although a flare of SLE may occur during the postpartum period. Several studies have failed to demonstrate a clinically significant association between oral contraceptive use and flares of SLE. There is a high incidence of thromboses in women with antiphospholipid antibodies, and oral contraceptives containing second- or third-generation progestogens may induce a higher risk.
Etiology A family history of connective tissue disease is a strong risk factor for all forms of LE. HLA and gene linkage studies suggest a strongly heritable component, and some skin lesions 162
of LE follow lines of Blaschko, suggesting postzygotic mutation or loss of heterozygosity for a genetic locus. The C-reactive protein (CRP) response is defective in patients with flares of SLE, and the gene locus for CRP maps to 1q23.2 within an interval linked with SLE. Gene polymorphisms in APRIL, a member of the TNF family, have also been linked with SLE. Increased expression of TNF-α and IFN-inducible protein myxovirus protein A is noted in cutaneous LE. Polymorphisms of the C1qA gene are associated with both systemic and cutaneous LE. Strong linkage has been found with SLE at 5p15.3, 1q23, 1q31, 11q14, 12q24, and 16q12, as well as other candidate sites. Linkage varies in different ethnic groups and different clinical subsets of lupus. Taken together, these data suggest polygenetic susceptibility to LE. Both ultraviolet (UV) B and UVA can upregulate antigen expression and cytokines, and cause release of sequestered antigens and free radical damage. All of these mechanisms may contribute to photosensitivity and UV-induced flares of systemic disease. Several aspects of the altered immune response are worth particular attention. T-suppressor cell function is reduced in patients with LE. Overproduction of γ-globulins by B cells and reduced clearance of immune complexes by the reticulo endothelial system may contribute to complement-mediated damage. Externalization of cellular antigens, such as Ro/SSA in response to sunlight, may lead to cell injury by way of antibody-dependent cellular cytotoxicity. Abnormal apoptosis or reduced clearance of apoptotic cells may lead to increased exposure of nucleosome antigens and antinucleosome antibodies. HLA-DR4 individuals, who are slow acetylators, are predisposed to develop hydralazine-induced LE. Antibody to the histone complex H2A–H2B is closely associated with disease. In most drug-induced LE, antibodies are directed against histones. Exceptions include penicillamine and etanercept, which may induce or unmask native disease with antidsDNA antibodies. Pegylated IFN-α and ribavirin have also produced systemic LE during treatment for chronic hepatitis C. Drugs implicated in SCLE are listed earlier in this chapter. L-Canavanine, an amino acid found in alfalfa sprouts and tablets, can also induce or worsen SLE. There is little credible data regarding other possible aggravating dietary factors, but some reports have implicated excess calories, excess protein, high fat (especially saturated and ω-6 polyunsaturated fatty acids), excess zinc, and excess iron. Well-designed studies are needed. Cigarette smoking is associated with increased disease activity in SLE, and can interfere with the effects of antimalarial drugs.
Laboratory findings There may be hemolytic anemia, thrombocytopenia, lymphopenia, or leukopenia; the ESR is usually markedly elevated during active disease, Coombs test may be positive, there is a biologic false-positive test for syphilis, and a rheumatoid factor may be present. Levels of IgG may be high, the albumin to globulin ratio is reversed, and the serum globulin is increased, especially the γ-globulin or α2 fraction. Albumin, red blood cells, and casts are the most frequent findings in the urine.
Immunologic findings 1. ANA test. This is positive in 95% of cases of SLE. Human substrates, such as Hep-2 or KB tumor cell lines, are far more sensitive than mouse substrates. ANA pattern has some correlation with clinical subsets, such as a shrunken peripheral pattern in SLE with renal disease, a fine particulate pattern in subacute cutaneous LE, and a homogeneous pattern with antihistone antibodies.
Differential diagnosis SLE must be differentiated from dermatomyositis, erythema multiforme, polyarteritis nodosa, acute rheumatic fever, rheumatoid arthritis, pellagra, pemphigus erythematosus (Senear– Usher syndrome), drug eruptions, hyperglobulinemic purpura, Sjögren syndrome, necrotizing angiitis, and myasthenia gravis. In SLE there may be fever, arthralgia, weakness, lassitude, diagnostic skin lesions, an increased ESR, cytopenias, proteinuria, immunoglobulin deposition at the dermoepidermal junction, and a positive ANA test. Biopsies of skin lesions and involved kidney may also be diagnostic.
Treatment Some general measures are important for all patients with LE. Exposure to sunlight must be avoided, and a high sunprotection factor (SPF) sunscreen should be used daily. Photosensitivity is frequently present even if the patient denies
it, and all patients must be educated about sun avoidance and sunscreen use. The patient should also avoid exposure to excessive cold, to heat, and to localized trauma. Biopsies and scar revision will often provoke a flare of the disease. Women with SLE have an increased risk of osteoporosis, independent of the use of corticosteroids. Bone density should be monitored, and calcium and vitamin D supplementation should be considered. Some women will benefit from bisphosphonate therapy, especially if corticosteroids are used. The most rapid bone loss with corticosteroid therapy occurs at the onset of treatment, so bisphosphonate therapy should not be delayed. Patients who will be treated with immunosuppressive agents should receive a tuberculin skin test as well as a thorough physical examination. Aggressive treatment is often necessary for discoid lesions and scarring alopecia. The slowly progressive nature of these lesions, and the lack of systemic involvement, may lead to inappropriate therapeutic complacency. The result is slow, progressive disfigurement.
Lupus erythematosus
2. Lupus erythematosus cell test. This is specific but not very sensitive and has been deleted from the ACR criteria. 3. Double-stranded DNA. Anti-dsDNA, anti-native DNA. This is specific, but not very sensitive. It indicates a high risk of renal disease, and correlates with a shrunken peripheral ANA pattern and positive DIF in sun-protected skin. 4. Anti-Sm antibody. Sensitivity is less than 10% but there is very high specificity. 5. Antinuclear ribonucleic acid protein (anti-nRNP). Very high titers are present in mixed connective tissue disease. Lower titers may be seen in SLE. 6. Anti-La antibodies. These are common in SCLE and Sjögren syndrome, and occasionally found in SLE. 7. Anti-Ro antibodies. These are found in about 25% of SLE and 40% of Sjögren cases. They are more common in patients with SCLE (70%), neonatal LE (95%), C2- and C4-deficient LE (50–75%), late-onset LE (75%), and Asian patients with LE (50–60%). Photosensitivity may be striking, and externalization of the antigen is seen after UV exposure. 8. Serum complement. Low levels indicate active disease, often with renal involvement. 9. Lupus band test. Direct cutaneous immunofluorescence. Continuous granular deposits of immunoglobulins and complement along the dermoepidermal junction occur in more than 75% of well-established lesions of DLE. In SLE, it is commonly positive in sun-exposed skin. A positive test in normal protected skin correlates with the presence of anti-dsDNA antibodies and renal disease. The test is seldom performed, as the same population of patients can be detected with anti-dsDNA antibodies. 10. Anti-ssDNA antibody. This test is sensitive but not specific. Many are photosensitive. An IgM isotope seen in DLE may identify a subset of patients at risk for developing systemic symptoms. 11. Antiphospholipid antibodies. Both the anticardiolipin antibody and the lupus anticoagulant are subtypes of these. They are associated with a syndrome that includes venous thrombosis, arterial thrombosis, spontaneous abortions, and thrombocytopenia. Livedo reticularis is a frequent skin finding and nonfading acral microlivedo, small cyanotic pink lesions on the hands and feet, is a subtle clue to the presence of these antibodies. Antiphospholipid antibodies may occur in association with lupus and other connective tissue disease, or as a solitary event. In the latter case it is referred to as the primary antiphospholipid syndrome.
Local treatment The application of potent or superpotent topical corticosteroids is beneficial. Occlusion may be necessary and may be enhanced by customized vinyl appliances (especially for oral lesions) or surgical dressings. Tape containing corticosteroid (Cordran) is sometimes helpful. The single most effective local treatment is the injection of corticosteroids into the lesions. Triamcinolone acetonide, 2.5–10 mg/mL, is infiltrated into the lesion through a 30-gauge needle at intervals of 4–6 weeks. No more than 40 mg of triamcinolone should be used at one time. Steroid atrophy is a valid concern, but so are the atrophy and scar produced by the disease. The minimal intralesional dose needed to control the disease should be used; when the response is poor, however, it is generally better to err on the slightly more aggressive side of treatment than to undertreat. Topical calcineurin inhibitors (topical macrolactams) may also be useful as second-line topical therapy. Photodynamic therapy has been reported as effective.
Systemic treatment The safest class of systemic agent for LE is the antimalarials. Retinoids are second-line agents and are particularly helpful in treating hypertrophic LE. Systemic immunosuppressive agents are often required to manage the systemic manifestations of LE, and are third-line systemic agents for cutaneous LE. Thalidomide can be effective but its use is limited by the risk of teratogenicity and neuropathy. Dapsone is the drug of choice for bullous systemic LE, and may be effective in some cases of SCLE and DLE. Oral prednisone is generally reserved for acute flares of disease. Antimalarials Hydroxychloroquine (Plaquenil), at a dose equal to or less than 6.5 mg/kg/day, has an excellent safety profile and is generally used as first-line systemic therapy in most forms of cutaneous LE. If no response occurs after 3 months, another agent should be considered. Chloroquine (Aralen) is effective in a dose of 250 mg/day for an average adult, but is difficult to procure. Quinacrine (Atabrine), 100 mg/day, may be added to hydroxychloroquine, since this adds no increased risk of retinal toxicity. Quinacrine is also difficult to procure and carries a higher risk of disfiguring pigmentation than the other antimalarials. Systemic treatment can sometimes be reduced or stopped during the winter months. A Cochrane group review of randomized controlled trials concluded that hydroxychloroquine and acitretin appear to be of similar efficacy, although adverse effects are more severe and occur more commonly with acitretin. Ocular toxicity is rare with doses of hydroxychloroquine equal to or less than 6.5 mg/kg/day. Ophthalmologic consultation should be obtained before, and at 4- to 6-month intervals 163
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during, treatment. Constriction of visual fields to a red object and paracentral scotomas are rare at the recommended dose, but even a small risk of loss of vision must be taken seriously. The finding of any visual field defect or pigmentary abnormality is an indication to stop antimalarial therapy. Other reported side effects with antimalarials include ery throderma, erythema multiforme, purpura, urticaria, nervousness, tinnitus, abducens nerve paralysis, toxic psychoses, leukopenia, and thrombocytopenia. Antimalarials, except in very small doses, will exacerbate skin disease or cause hepatic necrosis in patients with porphyria cutanea tarda. They may also worsen or induce psoriasis. Quinacrine produces a yellow discoloration of the skin and conjunctivae. Quinacrine has also been known to produce blue–black pigmentation of the hard palate, nailbeds, cartilage of the ears, alae nasi, and sclerae. Other antimalarials may also rarely produce a blue–black pigmentation of skin. Bullous erythema multiforme, lichenoid drug eruption, nausea, vomiting, anorexia, and diarrhea may develop. Aplastic anemia has rarely been noted in longterm therapy. A patient’s brown or red hair may turn light blond. Corticosteroids Systemic corticosteroids are highly effective for widespread or disfiguring lesions, but disease activity often rebounds quickly when the drug is discontinued. Because of long-term side effects, corticosteroid treatment should be limited to short (generally 3 weeks or less) courses to treat flares of disease or to obtain initial control while antimalarial therapy is being initiated. In cases with renal or neurologic involvement, corticosteroids should be administered in doses adequate to control the disease, while treatment with a steroidsparing regimen is initiated. Treatment with 1000 mg/day intravenous methylprednisolone for 3 days, followed by oral prednisone, 0.5–1 mg/kg/day, is effective in quickly reversing most clinical and serologic signs of activity of lupus nephritis. In general, the corticosteroid dose should be optimized to the lowest possible that controls symptoms and laboratory abnormalities. Immunosuppressive therapy Aggressive treatment protocols with agents such as pulse cyclophosphamide (with hydration and MESNA to prevent bladder toxicity) have greatly improved the outcome of renal LE. Other immunosuppressive agents, including azathioprine, methotrexate, and mycophenolate mofetil, are often employed as steroid-sparing agents for refractory cutaneous disease. Some authorities have suggested that azathioprine is inferior to mycophenolate mofetil in the treatment of cutaneous lesions. IL-6 receptor inhibition with tocilizumab appears promising but may cause neutropenia.
Other therapy Isotretinoin therapy, in doses of 1 mg/kg/day may be effective, especially in hypertrophic or lichenoid lesions of LE. Rapid relapse may be noted when the drug is discontinued. Dapsone, clofazimine, acitretin, IFN-α 2a, auranofin (oral gold), high-dose intravenous γ-globulin, efalizumab, and thalidomide have all been reported as effective in anecdotal use or limited trials. Pulsed dye laser has been shown to be effective for some erythematous lesions of cutaneous LE, but should be used cautiously, as it may also cause flares of disease. Flares of disease are also common with surgical modalities used to improve scarring or alopecia. Anti-CD20 monoclonal antibody (rituximab) has been used successfully to treat life-threatening refractory SLE with renal and CNS involvement, as well as for hypocomplementemic urticarial vasculitis and refractory cutaneous lesions. Although lupus is a photosensitive disorder, UVA-1 therapy appears to be a useful adjuvant treatment modality in some patients, and photodynamic therapy has been effective in some patients. 164
Albrecht J, et al: Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus. Lupus 2004; 13:839. Bonilla-Martinez ZL, et al: The cutaneous lupus erythematosus disease area and severity index: a responsive instrument to measure activity and damage in patients with cutaneous lupus erythematosus. Arch Dermatol 2008 Feb; 144(2):173–180. Cavazzana I, et al: Treatment of lupus skin involvement with quinacrine and hydroxychloroquine. Lupus 2009 Jul; 18(8):735–739. Cervera R, et al: Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003; 82:299. Costa MF, et al: Drug-induced lupus due to anti-tumor necrosis factor alpha agents. Semin Arthritis Rheum 2008 Jun; 37(6):381–387. Fusconi M, et al: Etanercept and infliximab induce the same serological autoimmune modifications in patients with rheumatoid arthritis. Rheumatol Int 2007 Nov; 28(1):47–49. Garcia-Carrasco M, et al: Anti-CD20 therapy in patients with refractory systemic lupus erythematosus: a longitudinal analysis of 52 Hispanic patients. Lupus 2010 Feb; 19(2):213–219. Hamprecht A, et al: Successful treatment of recalcitrant malar rash in a patient with cutaneous lupus erythematosus with efalizumab. Clin Exp Dermatol 2008 May; 33(3):347–348. Hivnor CM, et al: Terbinafine-induced subacute cutaneous lupus erythematosus. Cutis 2008 Feb; 81(2):156–157. Ho V, et al: Severe systemic lupus erythematosus induced by antiviral treatment for hepatitis C. J Clin Rheumatol 2008 Jun; 14(3):166–168. Illei GG, et al: Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum 2010 Jan 28; 62(2):542–552. Jessop S, et al: Drugs for discoid lupus erythematosus. Cochrane Database Syst Rev 2009 Oct 7; (4):CD002954. Kalia S, et al: New concepts in antimalarial use and mode of action in dermatology. Dermatol Ther 2007 Jul–Aug; 20(4):160–174. Kallel-Sellami M, et al: Pediatric systemic lupus erythematosus with C1q deficiency. Ann N Y Acad Sci 2007 Jun; 1108:193–196. Kuhn A, et al: Cutaneous lupus erythematosus: molecular and cellular basis of clinical findings. Curr Dir Autoimmun 2008; 10:119–140. Kuhn A, et al: Pathogenesis of cutaneous lupus erythematosus. Lupus 2008; 17(5):389–393. Kuhn A, et al: Photosensitivity, phototesting, and photoprotection in cutaneous lupus erythematosus. Lupus 2010 Aug; 19(9):1036–1046. Kuhn A, et al: Treatment of cutaneous lupus erythematosus. Lupus 2010 Aug; 19(9):1125–1136. Lin JH, et al: Pathophysiology of cutaneous lupus erythematosus. Clin Rev Allergy Immunol 2007 Oct; 33(1–2):85–106. Lourenço SV, et al: Lupus erythematosus: clinical and histopathological study of oral manifestations and immunohistochemical profile of the inflammatory infiltrate. J Cutan Pathol 2007 Jul; 34(7):558–564. Marzano AV, et al: Drug-induced lupus: an update on its dermatologic aspects. Lupus 2009 Oct; 18(11):935–940. Mok CC: Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a systematic review. Scand J Rheumatol 2007 Sep–Oct; 36(5):329–337. Muller S, et al: Pathogenic anti-nucleosome antibodies. Lupus 2008; 17(5):431–436. Obermoser G, et al: Overview of common, rare and atypical manifestations of cutaneous lupus erythematosus and histopathological correlates. Lupus 2010 Aug; 19(9):1050–1070. Paradela S, et al: Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus. Lupus 2007; 16(9):741–745. Park HS, et al: Lupus erythematosus panniculitis: clinicopathological, immunophenotypic, and molecular studies. Am J Dermatopathol 2010; 32(1):24–30. Petri M, et al: Classification criteria for systemic lupus erythematosus: a review. Lupus 2004; 13:829. Saarialho-Kere U: Clinical and laboratory characteristics of Finnish lupus erythematosus patients with cutaneous manifestations. Lupus 2008;17(4): 337–347. Saito K, et al: Successful treatment with anti-CD20 monoclonal antibody (rituximab) of life-threatening refractory systemic lupus erythematosus with renal and central nervous system involvement. Lupus 2003; 12:798.
Dermatomyositis Dermatomyositis (DM) is typically characterized by inflammatory myositis and skin disease, although amyopathic DM (DM with subclinical or absent myopathy) also occurs. Muscle involvement without skin changes is called polymyositis (PM). With or without skin lesions, weakness of proximal muscle groups is characteristic.
Skin findings
terized by pruritic and scaly pink patches, edema, and pinkishviolet (heliotrope) discoloration or bullae. Pruritic scaly pink patches are often seen in amyopathic DM. Edema and pinkishviolet discoloration are often signs of inflammation in the underlying striated orbicularis oculi muscle, rather than the skin itself. In such cases, the eyelids may be tender to the touch. Bullous DM may portend a poor prognosis, and patients often have severe inflammatory myopathy or lung disease. Other skin changes include erythema, scaling, and swelling of the upper face, often with involvement of the hairline and eyebrows. Extensor surfaces of the extremities are often pink, red or violaceous with an atrophic appearance or overlying scale. The similarity to psoriasis can be striking, and patients may suffer severe flares of DM if they are inappropriately treated with phototherapy for presumed psoriasis. Photo sensitivity to natural sunlight is common as well. Firm, slightly pitting edema may be seen over the shoulder girdle, arms, and neck. Associated erythema and scale (with or without poikiloderma) over the shoulder regions is known as the shawl sign. Pruritus may be severe in some cases, and is much more common in DM than in psoriasis or LE. Over time, more widespread skin changes are typically seen. Skin lesions become more prominent on the neck, thorax, shoulders, and arms. Characteristic areas include nape of the neck, upper chest (V) pattern, and upper back, neck, and shoulder (shawl) pattern (Fig. 8-16). Occasionally, a flagellate pattern mimicking bleomycin-induced linear edematous streaks or erythroderma may be seen. On the hands, telangiectatic vessels often become prominent in the proximal nailfolds. Enlarged capillaries of the nailfold appear as dilated, sausage-shaped loops with adjacent avascular regions (Fig. 8-17), similar to those changes observed in scleroderma. There may be cuticular overgrowth with an irregular frayed appearance. A pink to reddish-purple atrophic (Fig. 8-18) or scaling eruption often occurs over the knuckles, knees, and elbows (Gottron’s sign). Flat-topped, polygonal, violaceous papules over the knuckles (Gottron’s papules) are less common, but are highly characteristic of DM. Hyperkeratosis, scaling, fissuring, and hyperpigmentation over the fingertips, sides of the thumb, and fingers with occasional involvement of the palms is referred to as mechanic’s hands (Fig. 8-19) and has been reported in 70% of patients with antisynthetase antibodies. Intermittent fever, malaise, anorexia, arthralgia, and marked weight loss are commonly present at this stage. Telangiectasia and erythema may become more pronounced with time. Mottled hyperpigmentation and hypopigmentation, atrophy, and telangiectasia (poikiloderma) eventually develop in many patients. In some patients with disease remission, the residual hyperpigmentation simulates the bronze
Dermatomyositis
Sampaio MC, et al: Discoid lupus erythematosus in children—a retrospective study of 34 patients. Pediatr Dermatol 2008 Mar–Apr; 25(2):163–167. Sato N, et al: Type B insulin resistance syndrome with systemic lupus erythematosus. Clin Nephrol 2010; 73(2):157–162. Sfikakis PP, et al: Rituximab anti-B-cell therapy in systemic lupus erythematosus: pointing to the future. Curr Opin Rheumatol 2005; 17:550. Shadid NH, et al: Lupus erythematosus associated with erythema multiforme: Rowell’s syndrome. Int J Dermatol 2007 Nov; 46(Suppl 3):30–32. Sticherling M, et al: Diagnostic approach and treatment of cutaneous lupus erythematosus. J Dtsch Dermatol Ges 2008 Jan; 6(1):48–59. Uthman I, et al: Successful treatment of refractory skin manifestations of systemic lupus erythematosus with rituximab: report of a case. Dermatology 2008; 216(3):257–259. Walling HW, et al: Cutaneous lupus erythematosus: issues in diagnosis and treatment. Am J Clin Dermatol 2009; 10(6):365–381. Weide R, et al: Successful long-term treatment of systemic lupus erythematosus with rituximab maintenance therapy. Lupus 2003; 12:779. Wenzel J, et al: Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients. Br J Dermatol 2005; 153:157. Wenzel J, et al: Pathogenesis of cutaneous lupus erythematosus: common and different features in distinct subsets. Lupus 2010 Aug; 19(9):1020–1028. Werth VP: Cutaneous lupus: insights into pathogenesis and disease classification. Bull NYU Hosp Jt Dis 2007; 65(3):200–204. Wollina U, et al: The use of topical calcineurin inhibitors in lupus erythematosus: an overview. J Eur Acad Dermatol Venereol 2008 Jan; 22(1):1–6. Wozniacka A, et al: Optimal use of antimalarials in treating cutaneous lupus erythematosus. Am J Clin Dermatol 2005; 6:11. Wozniacka A, et al: Chloroquine treatment reduces the number of cutaneous HLA-DR+ and CD1a+ cells in patients with systemic lupus erythematosus. Lupus 2007; 16(2):89–94. Yang Y, et al: Complete complement components C4A and C4B deficiencies in human kidney diseases and systemic lupus erythematosus. J Immunol 2004; 173:2803. Zuppa AA, et al: Infants born to mothers with anti-SSA/Ro autoantibodies: neonatal outcome and follow-up. Clin Pediatr (Phila) 2008 Apr; 47(3):231–236.
Usually the disease begins with erythema and edema of the face and eyelids. Eyelid involvement (Fig. 8-15) may be charac-
Fig. 8-15 Heliotrope rash in a patient with dermatomyositis.
Fig. 8-16 “V” of neck with poikiloderma in dermatomyositis.
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Fig. 8-19 Mechanic’s hands.
and its severity. Calcinosis of the dermis, subcutaneous tissue, and muscle occurs mostly on the upper half of the body around the shoulder girdle, elbows, and hands. Ulcerations and cellulitis are frequently associated with this debilitating and disabling complication of DM. Fig. 8-17 Dilated vessels and avascular regions of the proximal nailfold.
Muscle changes In severe cases, early and extensive muscular weakness occurs, with acute swelling and pain. The muscle weakness is seen symmetrically, most frequently involving the shoulder girdle and sometimes the pelvic region, as well as the hands. The patients may notice difficulty in lifting even the lightest objects. They may be unable to raise their arms to comb their hair, and rising from a chair may be impossible without “pushing off” with the arms. Patients often complain of pain in the legs when standing barefoot or of being unable to climb stairs. Difficulty in swallowing, talking, and breathing, caused by weakness of the involved muscles, may be noted early in the disease. Some patients with severe diaphragmatic disease require mechanical ventilation. Cardiac failure may be present in the terminal phase of the disease. Skin involvement commonly precedes muscle involvement, but some patients have typical skin findings of DM but never develop clinically apparent muscle involvement. These cases have been termed amyopathic DM or DM sine myositis. It is common, however, for muscle inflammation to be present but not symptomatic. Muscle enzymes (to include both creatine kinase and aldolase), electromyogram (EMG), and magnetic resonance imaging (MRI) may be required to detect subtle involvement.
Diagnostic criteria Fig. 8-18 Gottron’s papules of dermatomyositis involving the knuckles.
discoloration of Addison’s disease. Rarely, large, persistent ulcerations in flexural areas or over pressure points may develop. Ulceration in the early stages of disease has been reported to be associated with a higher incidence of cancer and a poor prognosis, but the authors have seen many patients with ulcerative DM without associated cancer. In later stages, ulceration may merely be a manifestation of pressure or trauma to atrophic areas. Rarely, DM may be associated with clinical findings of pityriasis rubra pilaris (Wong variant of DM) or generalized subcutaneous edema. Calcium deposits in the skin and muscles occur in more than half of children with DM; they are found rather infrequently in adults. Calcification is related to duration of disease activity 166
The following criteria are commonly used to define DM/PM: • skin lesions • heliotrope rash (red–purple edematous erythema on the upper palpebra) • Gottron’s papules or sign (red–purple flat-topped papules, atrophy, or erythema on the extensor surfaces and finger joints) • proximal muscle weakness (upper or lower extremity and trunk) • elevated serum creatine kinase or aldolase level • muscle pain on grasping or spontaneous pain • myogenic changes on EMG (short-duration, polyphasic motor unit potentials with spontaneous fibrillation potentials)
Dermatomyositis
• positive anti-Jo-1 (histadyl tRNA synthetase) antibody • nondestructive arthritis or arthralgias • systemic inflammatory signs (fever >37°C at axilla, elevated serum CRP level or accelerated ESR of >20 mm/h by the Westergren method) • pathologic findings compatible with inflammatory myositis. Patients with the first criterion and four of the remaining criteria have DM. Patients lacking the first criterion but with at least four of the remaining criteria have PM. Some patients with DM have little evidence of myopathy, and drug eruptions may mimic the characteristic rash. In particular, hydroxyurea has been associated with a DM-like eruption.
Associated diseases DM may overlap with other connective tissue diseases. Sclerodermatous changes are the most frequently observed. This is called sclerodermatomyositis. Antibodies such as anti-Ku and anti-PM/scl may be present in this subgroup. Mixed connective tissue disease (associated with high antiribonucleoprotein [RNP]), rheumatoid arthritis, LE, and Sjögren syndrome may occur concomitantly. DM may be associated with interstitial lung disease, which is frequently the cause of death. The presence of anti-Jo-1 antibody, as well as other antisynthetase antibodies, such as anti-PL-7, anti-PL-12, anti-DJ, and anti-EJ, correlates well with the development of pulmonary disease. Even those patients without anti-Jo-1 should routinely be screened for interstitial lung disease, as up to 69% of patients with interstitial lung disease are seronegative for the anti-Jo-1 antibody in published reports.
Neoplasia with dermatomyositis In adults, malignancy is frequently associated with DM. The malignancy is discovered before, simultaneously, or after the DM in almost equal proportions. The highest probability of finding an associated tumor occurs within 2 years of the diagnosis. Factors associated with malignancy include age, constitutional symptoms, rapid onset of DM, the lack of Raynaud phenomenon, and a grossly elevated ESR or creatine kinase level. Malignancy is most frequently seen in patients in the fifth and sixth decades of life. Routine “age-appropriate screening” may be inadequate to uncover a significant number of malignancies. In addition to history and physical examination, a stool hemoccult test, mammography, pelvic examination, chest x-ray, and computed tomographic (CT) scans of the abdominal, pelvic, and thoracic areas may be indicated. Periodic rescreening may be of value, but the appropriate interval for screening has not been established. The presence of leukocytoclastic vasculitis might indicate a higher potential for malignancy.
Childhood dermatomyositis Several features of childhood dermatomyositis differ from the adult form. Two childhood variants exist. The more common Brunsting type has a slow course, progressive weakness, calcinosis, and steroid responsiveness (Fig. 8-20). Calcinosis may involve intermuscular fascial planes or be subcutaneous. The second type, the Banker type, is characterized by a vasculitis of the muscles and gastrointestinal tract, rapid onset of severe weakness, steroid unresponsiveness, and a high death rate. Internal malignancy is seldom seen in children with either type, but insulin resistance may be present. Calcinosis cutis is more common in children with severe disease.
Fig. 8-20 Childhood DM.
Etiology There is mounting evidence that muscle findings in DM are related to humoral immunity, a vasculopathy mediated by complement deposition, lysis of endomysial capillaries, and resulting muscle ischemia. In contrast, PM and inclusion-body myositis are related to clonally expanded CD8+ cytotoxic T cells invading muscle fibers and causing necrosis via the perforin pathway. The initial immune response in DM is an IFNα/β-induced cascade with secondary stimulation of IFN-γ. Many autoantibodies may be present in DM, some of which are disease-specific and can identify specific subgroups. In addition to the antisynthetase antibodies previously discussed, the anti-Mi-2 antibody is present in some patients with acute onset of classic DM and a good prognosis. An association with bovine collagen dermal implants has been reported but may reflect a referral bias, rather than a true statistical association. Both healthy individuals and children with juvenile DM may demonstrate persistence of maternal microchimerism, but the incidence is higher in children with juvenile DM. This has also been demonstrated in patients with other connective tissue diseases such as scleroderma. The finding may be an epiphenomenon, or may be part of a pathogenic alloimmune response. An inherited predisposition has been demonstrated, and studies of juvenile DM gene expression have shown DQA1*0501 in 85% of patients. Viral or bacterial infections may produce an abnormal immune response. Fulminant disease may be related to an endotheliotropic viral infection. Epitopes of group A β-hemolytic streptococcal M protein have sequence homology with myosin, and can elicit both cell-mediated cytotoxicity and TNF-α production when incubated with mononuclear cells from children with active juvenile DM. The TNF-α-308A allele is associated with increased TNF-α synthesis in juvenile DM patients, and with increased thrombospondin-1 (an antiangio genic agent) and small vessel occlusion. In adults with PM and DM, endothelial damage occurs early. Pathogenic factors in adults include IL-1α, transforming growth factor (TGF)-β, and myoblast production of IL-15. Cases associated with terbinafine may be related to apoptosis induced by the drug.
Incidence DM is relatively rare. It is twice as prevalent in women as in men and four times as common in black as in white patients. 167
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There is a bimodal peak, the smaller one seen in children and the larger peak in adults between the ages of 40 and 65.
Histopathology The histologic changes in DM are similar to those of LE. The two may be indistinguishable, although lesions of DM have more of a tendency to become atrophic. Lesions typically demonstrate thinning of the epidermis, hydropic degeneration of the basal layer, basement membrane thickening, papillary dermal edema, and a perivascular and periadnexal lymphocytic infiltrate in the superficial and deep dermis with increased dermal mucin. Scattered melanophages are present in the superficial dermis. As compared with LE, DM shows less eccrine coil involvement and fewer vertical columns of lymphocytes in fibrous tract remnants. Subcutaneous lymphoid nodules and panniculitis are rarely seen in DM. Characteristic changes are found in the muscles. The deltoid, trapezius, and quadriceps muscles seem to be almost always involved, and are good biopsy sites. Muscle bundles demonstrate lymphoid inflammation and atrophy, which preferentially affects the periphery of the muscle bundle. Muscle biopsy is directed to those areas found to be most tender or in which EMG demonstrates myopathy. MRI is a useful aid in identifying active sites for muscle biopsy, and may obviate the need for biopsy in some cases. The MRI short transition interval recovery (STIR) images are best. They can be used to localize disease and longitudinally assess results of treatment.
Laboratory findings The serum levels of creatine kinase are elevated in most patients. Aldolase, lactic dehydrogenase, and transaminases are other indicators of active muscle disease. There may be leukocytosis, anemia with low serum iron, and an increased ESR. Positive ANA tests are seen in 60–80% of patients if a human diploid substrate is used; 35–40% have myositisspecific antibodies. Cutaneous DIF is positive in at least one-third of cases, with a higher yield in well-established (at least 3–6 months old) lesions. Cytoid bodies are commonly seen, although continuous granular staining with IgG, IgM, and IgA may be seen. X-ray studies with barium swallow may show weak pharyngeal muscles and a collection of barium in the pyriform sinuses and valleculae. MRI of the muscles is an excellent way to assess activity of disease noninvasively. EMG studies for diagnosis show spontaneous fibrillation, polyphasic potential with voluntary contraction, short duration potential with decreased amplitude, and salvos of muscle stimulation.
Differential diagnosis DM must be differentiated from erysipelas, SLE, angioedema, drug eruptions, trichinosis, and erythema multiforme. Aldosteronism, with adenoma of adrenal glands and hypo kalemia, may also cause puffy heliotrope eyelids and face. Hydroxyurea may produce an eruption resembling DM.
Treatment Prednisone is the mainstay of acute treatment, at doses beginning with 1 mg/kg/day until the severity decreases and muscle enzymes are almost normal. The dosage is reduced with clinical response. The aspartate aminotransferase (AST)/ serum glutamic-oxaloacetic transaminase (SGOT) and creatine 168
phosphokinase return to normal levels as remission occurs. Methotrexate and mycophenolate mofetil are commonly used as steroid-sparing agents, and should be started early in the course of treatment to reduce steroid side effects. Some data favor methotrexate as a steroid-sparing agent, but because of the increased risk of interstitial lung disease with methotrexate, some authors avoid this agent in patients with pulmonary disease or anti-Jo-1 antibodies. Azathioprine is less expensive than mycophenolate mofetil, but skin disease may not respond as well. If patients do not respond adequately to the combination of prednisone and methotrexate, mycophenolate mofetil, or azathioprine, a trial of intravenous immunoglobulin (IVIG) (1 g/kg/day for 2 days each month), cyclosporine, or tacrolimus may be beneficial. IVIG has been associated with thromboembolic events, including deep venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, and this risk must be weighed against the benefits of the drug. Anti-TNF-α treatment with infliximab has proved a rapidly effective therapy for some patients with myositis. Etanercept and infliximab have also been used, but some studies have found little improvement or flares of muscle disease. Because anti-TNF therapy has resulted in a shift to a lupus antibody profile in some patients, patients should be monitored carefully. Cyclophosphamide is generally reserved for refractory cases. Leflunomide, an immunomodulatory drug used to treat rheumatoid arthritis, has been effective as adjuvant therapy. In severe juvenile DM, pulse intravenous methylprednisone (30 mg/kg/day) or high-dose prednisone has been reported as highly effective. Patients who fail to respond within 6 weeks should be started on an alternative agent such as methotrexate. IVIG has been reported as effective, but products with a high level of immunoglobulin A are less well tolerated. A retrospective study of 38 patients treated at a tertiary care children’s hospital suggested that corticosteroids may not be necessary in many children treated with IVIG or methotrexate. Rituximab appears promising in the treatment of refractory disease. Onset of calcinosis is associated with delays in diagnosis and treatment, as well as longer disease duration. Calcinosis related to DM has been treated with aluminum hydroxide, diphosphonates, diltiazem, probenecid, colchicine, low doses of warfarin, and surgery with variable, but usually poor, results. Autologous stem cell transplantation has been reported as successful. The skin lesions may respond to systemic therapy; however, response is unpredictable and skin disease may persist despite involution of the myositis. Because DM is photosensitive, sunscreens with high SPF (>30) should be used daily, and patients should be counseled about sun avoidance. Topical steroids may be helpful in some patients. Antimalarials, such as hydroxychloroquine given in doses of 200–400 mg/day (2–5 mg/kg/day in children), have been shown to be useful in abating the eruption of DM; however, adverse cutaneous reactions are common. Non-life-threatening cutaneous reactions occur in approximately one-third of patients, and up to one-half of those who react to hydroxychloroquine will also react to chloroquine.
Prognosis Major causes of death are cancer, ischemic heart disease, and lung disease. Independent risk factors include failure to induce clinical remission, white blood cell count above 10 000/mm3, temperature greater than 38°C at diagnosis, older age, shorter disease history, and dysphagia. Early aggressive therapy in juvenile cases is associated with a lower incidence of disabling calcinosis cutis.
Wedderburn LR, et al: Juvenile dermatomyositis: new developments in pathogenesis, assessment and treatment. Best Pract Res Clin Rheumatol 2009 Oct; 23(5):665–678.
Scleroderma Scleroderma is characterized by the appearance of circumscribed or diffuse, hard, smooth, ivory-colored areas that are immobile and give the appearance of hidebound skin. It occurs in both localized and systemic forms. Cutaneous types may be categorized as morphea (localized, generalized, profunda, atrophic, and pansclerotic types) or linear scleroderma (with or without melorheostosis or hemiatrophy). Progressive systemic sclerosis and the Thibierge–Weissenbach syndrome (commonly referred to as the CREST syndrome) are the two types of systemic scleroderma.
Scleroderma
András C, et al: Dermatomyositis and polymyositis associated with malignancy: a 21-year retrospective study. J Rheumatol 2008 Mar; 35(3):438–444. Boswell JS, et al: Leflunomide as adjuvant treatment of dermatomyositis. J Am Acad Dermatol 2008 Mar; 58(3):403–406. Callen JP: Cutaneous manifestations of dermatomyositis and their management. Curr Rheumatol Rep 2010 Jun; 12(3):192–197. Choy E, et al: Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis. Cochrane Database Syst Rev 2005; 3:CD003643. Chung L, et al: A pilot trial of rituximab in the treatment of patients with dermatomyositis. Arch Dermatol 2007 Jun; 143(6):763–767. Cooper MA, et al: Rituximab for the treatment of juvenile dermatomyositis: a report of four pediatric patients. Arthritis Rheum 2007 Sep; 56(9):3107–3111. Dastmalchi M, et al: A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies. Ann Rheum Dis 2008 Feb 13 (Epub ahead of print). Fisler RE, et al: Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. J Am Acad Dermatol 2002; 47:505. Franks AG Jr: Skin manifestations of internal disease. Med Clin North Am 2009 Nov; 93(6):1265–1282. Hengstman GJ, et al: Open-label trial of anti-TNF-alpha in dermato- and polymyositis treated concomitantly with methotrexate. Eur Neurol 2008; 59(3–4):159–163. Holzer U, et al: Successful autologous stem cell transplantation in two patients with juvenile dermatomyositis. Scand J Rheumatol 2010; 39(1):88–92. Krathen MS, et al: Dermatomyositis. Curr Dir Autoimmun 2008; 10:313–332. Lee KH, et al: Acute dermatomyositis associated with generalized subcutaneous edema. Rheumatol Int 2008 Jun; 28(8):797–800. Levy DM, et al: Favorable outcome of juvenile dermatomyositis treated without systemic corticosteroids. J Pediatr 2010 Feb; 156(2):302–307. Lobo IM, et al: Calcinosis cutis: a rare feature of adult dermatomyositis. Dermatol Online J 2008 Jan 15; 14(1):10. Lyons R, et al: Effective use of autoantibody tests in the diagnosis of systemic autoimmune disease. Ann NY Acad Sci 2005; 1050:217. Magro CM, et al: Terbinafine-induced dermatomyositis: a case report and literature review of drug-induced dermatomyositis. J Cutan Pathol 2008 Jan; 35(1):74–81. Magro CM, et al: Fulminant and accelerated presentation of dermatomyositis in two previously healthy young adult males: a potential role for endotheliotropic viral infection. J Cutan Pathol 2009; 36:853–858. Manlhiot C, et al: Safety of intravenous immunoglobulin in the treatment of juvenile dermatomyositis: adverse reactions are associated with immunoglobulin A content. Pediatrics 2008 Mar; 121(3):e626–630. Mendese G, et al: Histopathology of Gottron’s papules: utility in diagnosing dermatomyositis. J Cutan Pathol 2007 Oct; 34(10):793–796. Pelle MT, et al: Adverse cutaneous reactions to hydroxychloroquine are more common in patients with dermatomyositis than in patients with cutaneous lupus erythematosus. Arch Dermatol 2002; 138:1231. Polat M, et al: Dermatomyositis with a pityriasis rubra pilaris-like eruption: an uncommon cutaneous manifestation in dermatomyositis. Pediatr Dermatol 2007 Mar–Apr; 24(2):151–154. Reed AM: Microchimerism in children with rheumatic disorders: what does it mean? Curr Rheumatol Rep 2003; 5:458. Riley P, et al: Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcinosis. Rheumatology (Oxford) 2008 Jun; 47(6):877–880. Rouster-Stevens KA, et al: Pharmacokinetic study of oral prednisolone compared with intravenous methylprednisolone in patients with juvenile dermatomyositis. Arthritis Rheum 2008 Feb 15; 59(2):222–226. Saito E, et al: Efficacy of high-dose intravenous immunoglobulin therapy in Japanese patients with steroid-resistant polymyositis and dermatomyositis. Mod Rheumatol 2008; 18(1):34–44. Schmidt E, et al: Rituximab in treatment-resistant autoimmune blistering skin disorders. Clin Rev Allergy Immunol 2008 Feb; 34(1):56–64. Sparsa A, et al: Routine vs extensive malignancy search for adult dermatomyositis and polymyositis: a study of 40 patients. Arch Dermatol 2002; 138:885.
Cutaneous types Localized morphea This form of scleroderma is twice as common in women as in men and occurs in childhood as well as in adult life. It presents most often as macules or plaques a few centimeters in diameter, but also may occur as bands or in guttate lesions or nodules. Rose or violaceous macules may appear first, followed by smooth, hard, somewhat depressed, yellowish-white or ivory lesions. They are most common on the trunk but also occur on the extremities. The margins of the areas are generally surrounded by a light violaceous zone or by telangiectases. Within the patch skin elasticity is lost, and when it is picked up between the thumb and index finger it feels rigid. The follicular orifices may be unusually prominent, leading to a condition that resembles pigskin. In guttate morphea multiple small, chalk-white, flat or slightly depressed macules occur over the chest, neck, shoulders, or upper back. The lesions are not very firm and may be difficult to separate clinically from guttate lichen sclerosus et atrophicus.
Morphea–lichen sclerosus et atrophicus overlap There are patients who present with lesions of both morphea and lichen sclerosus et atrophicus (LSA). They are commonly women with widespread morphea who have typical LSA lesions either separated from morphea or overlying morphea. When the changes are seen above dermal changes of morphea, the characteristic inflammatory lymphoid band of LSA is lacking, suggesting that the superficial homogenization is really a manifestation of morphea rather than representing a separate disease process.
Generalized morphea Widespread involvement by indurated plaques with pigmentary change characterizes this variety. Muscle atrophy may be present, but there is no visceral involvement (Fig. 8-21). Patients may lose their wrinkles as a result of the firmness and contraction of skin. Spontaneous involution is less common with generalized morphea than with localized lesions.
Atrophoderma of Pasini and Pierini In 1923, Pasini described a peculiar form of atrophoderma now thought to be in the spectrum of morphea. The disease consists of brownish-gray, oval, round or irregular, smooth atrophic lesions depressed below the level of the skin with a welldemarcated, sharply sloping border. Some of the appearance of depression is an optical illusion related to the color change. Atrophoderma occurs mainly on the trunk of young individuals, predominately females (Fig. 8-22). The lesions are usually 169
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Fig. 8-21 Generalized morphea. Fig. 8-23 En coup de sabre.
eosinophilia myalgia syndrome, and the Spanish toxic oil syndrome. The latter two conditions were related to contaminants found in batches of tryptophan or cooking oil. Unlike eosino philic fasciitis, morphea profunda shows little response to corticosteroids and tends to run a more chronic debilitating course.
Linear scleroderma
Fig. 8-22 Atrophoderma of Pasini and Pierini.
asymptomatic, and may measure 20 cm or more in diameter. Linear atrophoderma of Moulin is a related condition that follows lines of Blaschko. Biopsies of atrophoderma demonstrate a reduction in the thickness of the dermal connective tissue. Some widening and hyalinization of collagen bundles may be noted. Because the changes may be subtle, a biopsy should include normalappearing skin so that a comparison may be made.
Pansclerotic morphea This variant is manifested by sclerosis of the dermis, panniculus, fascia, muscle, and at times, bone. There is disabling limitation of motion of joints.
Morphea profunda Morphea profunda involves deep subcutaneous tissue, including fascia. There is clinical overlap with eosinophilic fasciitis, 170
These linear lesions may extend the length of the arm or leg, and may follow lines of Blaschko. The condition often begins during the first decade of life. Lesions may also occur para sagittally on the frontal scalp and extend part way down the forehead (en coup de sabre) (Fig. 8-23). The Parry–Romberg syndrome, which manifests as progressive hemifacial atrophy, epilepsy, exophthalmos, and alopecia, may be a form of linear scleroderma. When the lower extremity is involved, there may be associated spina bifida, faulty limb development, hemiatrophy, or flexion contractures. Melorheostosis, seen in roentgenograms as a dense linear cortical hyperostosis, may occur. At times linear lesions of the trunk merge into more generalized involvement. Generally, the only type that shows spontaneous improvement is the childhood type involving the extremities. Physical therapy of the involved limb is of paramount importance to prevent contractures and frozen joints.
Systemic types CREST syndrome This variant of systemic scleroderma has the most favorable prognosis, owing to the usually limited systemic involvement. Patients with the syndrome develop calcinosis cutis (Fig. 8-24), Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. Patients may present with sclerodactyly, severe heartburn, or telangiectatic mats. The mats tend to have a smooth outline, in contrast to the mats of the Osler– Weber–Rendu syndrome, which tend to exhibit an irregular outline with more radiating vessels. This form of scleroderma generally lacks serious renal or pulmonary involvement. Anticentromere antibodies are highly specific for the CREST syndrome, being positive in 50–90% of cases and only 2–10% of patients with progressive sclerosis.
Scleroderma Fig. 8-24 Calcinosis in CREST syndrome.
Fig. 8-26 Facial involvement in scleroderma.
Fig. 8-25 Sclerodactyly.
Progressive systemic sclerosis Progressive systemic sclerosis (PSS) is a generalized disorder of connective tissue in which there is thickening of dermal collagen bundles, and fibrosis and vascular abnormalities in internal organs. Raynaud phenomenon is the first manifestation of PSS in more than half the cases. Other patients present with “woody edema” of the hands. The heart, lungs, gastro intestinal tract, kidney, and other organs are frequently involved. Women are affected three times more commonly than men, with the peak age of onset being between the third and fifth decades. Classic criteria include either proximal sclerosis or two or all of the following: 1. sclerodactyly (Fig. 8-25) 2. digital pitting scars of the fingertips or loss of substance of the distal finger pad 3. bilateral basilar pulmonary fibrosis. Localized forms of scleroderma must be excluded. These criteria have been shown to be 97% sensitive and 98% specific for the diagnosis. The ACR has proposed an expanded list of criteria, including: 1. Skin changes: tightness, thickening, and nonpitting induration, sclerodactyly, proximal scleroderma; changes proximal to the metacarpophalangeal or
metatarsophalangeal joints, and affecting other parts of the extremities, face, neck, or trunk (thorax or abdomen), digital pitting, loss of substance from the finger pad, bilateral firm but pitting finger or hand edema, abnormal skin pigmentation (often “pepper and salt”). The changes are usually bilateral and symmetrical, and almost always include sclerodactyly. 2. Raynaud phenomenon: at least two-phase color change in fingers and often toes consisting of pallor, cyanosis, and reactive hyperemia. 3. Visceral manifestations: bibasilar pulmonary fibrosis not attributable to primary lung disease, lower (distal) esophageal dysphagia, lower (distal) esophageal dysmotility, colonic sacculations.
Skin findings In the earlier phases of scleroderma the affected areas are erythematous and swollen. Patients are frequently misdiagnosed as having carpal tunnel syndrome and may even have positive EMGs. Raynaud phenomenon is often present, and suggests the correct diagnosis. Over time, sclerosis supervenes. The skin becomes smooth, yellowish, and firm, and shrinks so that the underlying structures are bound down. The earliest changes often occur insidiously on the face and hands, and in more advanced stages these parts become hidebound, so that the face is expressionless, the mouth is constricted (Fig. 8-26), and the hands are clawlike. The skin of the face appears drawn, stretched, and taut, with loss of lines of expression. The lips are thin, contracted, and radially furrowed, the nose appears sharp and pinched, and the chin may be puckered. Barnett described the “neck sign” as a ridging and tightening of the neck on extension, which occurs in 90% of patients with scleroderma. The disease may remain localized to the hands and feet for long periods (acrosclerosis). The fingers become semiflexed, immobile, and useless, the skin over them being hard, inelastic, incompressible, and pallid. The terminal phalanges are boardlike and indurated. Mizutani described the “round finger-pad sign.” The fingers lose the normal peaked contour, but rather appear as a rounded hemisphere when viewed from the side. This process may lead to loss of pulp on the distal 171
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digit. Trophic ulcerations and gangrene may occur on the tips of the fingers and knuckles, which may be painful or insensitive. Pterygium inversum unguis, in which the distal part of the nailbed remains adherent to the ventral surface of the nail plate, may be seen in scleroderma and LE, or may be idiopathic. Dilated nailfold capillary loops are present in 75% of systemic scleroderma patients. Symmetrically dilated capillaries are seen adjacent to avascular areas. This differs from the nailfold capillaries of the Osler–Weber–Rendu syndrome, which typically have dilatation of only one-half of the loop and no avascular areas. Nailfold capillary hemorrhage in two or more fingers is highly specific for scleroderma and correlates with the anticentromere antibody. Keloid-like nodules may develop on the extremities or the chest, and there may be a widespread diffuse calcification of the skin, as shown by radiographs. A diffuse involvement of the chest may lead to a cuirasse-like restraint of respiration. Late in the course of the disorder, hyperpigmented or depigmented spots or a diffuse bronzing may be present. The most characteristic pigmentary change is a loss of pigment in a large patch with perifollicular pigment retention within it. Perifollicular pigmentation may appear in response to UV light exposure. Pigment may also be retained over superficial blood vessels. The affected areas become hairless, and atrophy is often associated with telangiectasia. Bullae and ulcerations may develop, especially on the distal parts of the extremities.
Internal involvement PSS may involve most of the internal organs. Esophageal involvement is seen in more than 90% of patients. The distal two-thirds are affected, leading to dysphagia and reflux esophagitis. Small intestinal atonia may lead to constipation, malabsorption, or diarrhea. Pulmonary fibrosis with arterial hypoxia, dyspnea, and productive cough may be present. Progressive nonspecific interstitial fibrosis, with bronchiectasis and cyst formation, is the most frequent pathologic change. Pulmonary hypertension and right-sided heart failure are ominous signs, occurring in 5–10% of patients. The cardiac involvement produces dyspnea and other symptoms of congestive heart failure. Sclerosis of the myocardium also produces conduction changes and may result in arrhythmia. Pericarditis, hypertension, and retinopathy may be present. The skeletal manifestations include articular pain, swelling, and inflammation. Polyarthritis may be the first symptom in systemic sclerosis. There is limitation of motion, as a result of skin tautness, followed by ankylosis and severe contractual deformities. The hand joints are involved most frequently. There may be resorption and shortening of the phalanges, and narrowing of the joint spaces. Osteoporosis and sclerosis of the bones of the hands and feet may occur, as well as decalcification of the vault of the skull. Childhood PSS has identical cutaneous manifestations. Raynaud phenomenon is less frequent, while cardiac wall involvement is more common and is responsible for half the deaths. Renal disease is unusual. Familial scleroderma rarely occurs.
Prognosis The course of PSS is variable. Renal disease accounts for some early mortality, but pulmonary disease remains the major cause of death. The patient’s age at disease onset is a significant risk factor for pulmonary arterial hypertension. Cardiac disease also correlates with a poor prognosis, while gastro intestinal involvement contributes mainly to morbidity. ANA patterns predict different subsets of disease with varying prognosis. Anticentromere antibodies correlate with CREST syndrome and a good prognosis, while Scl-70 and ANA correlate with a poorer prognosis. Malignancy may be associated 172
with systemic sclerosis in up to 10% of patients, with lung and breast cancer as the most frequent associated malignancies. The presence of many telangiectases is strongly associated with the presence of pulmonary vascular disease.
Laboratory findings ANA testing is positive in more than 90% of patients with systemic scleroderma. As noted above, several of these antibodies identify specific clinical subsets of patients. The anti nucleolar pattern is considered most specific for scleroderma, and when present as the only pattern, it is highly specific for scleroderma. When antibodies to such nucleolar antigens as RNA polymerase t and fibrillarin are present, diffuse sclerosis, generalized telangiectasia, and internal organ involvement are often seen. The homogeneous ANA pattern is seen in those patients with PM–Scl antibodies, the marker for PM– scleroderma overlap. The true speckled or anticentromere pattern is sensitive and specific for the CREST variant. Patients with antibodies to Scl-70 tend to have diffuse truncal involvement, pulmonary fibrosis, and digital pitted scars, but a lower incidence of renal disease. Antibodies to nuclear RNP are found in patients with Raynaud phenomenon, polyarthralgia, arthritis, and swollen hands. Very high RNP titers define mixed connective tissue disease. These patients are fairly homogeneous and the term is not synonymous with connective tissue overlap. Anti-ssDNA antibodies are common in linear scleroderma.
Radiographic findings The gastrointestinal tract is commonly involved. The esophagus may have decreased peristalsis and dilation. Esophagograms and esophageal manometry may be helpful. In early esophageal involvement, a barium swallow in the usual upright position may be reported as normal. If the patient is supine, however, barium will often be seen to pool in the flaccid esophagus. The stomach may be dilated and atonic, resulting in delayed emptying time. Involvement of the small intestine may cause extreme dilation of the duodenum and jejunum, producing a characteristic roentgenographic picture of persistently dilated intestinal loops long after the barium has passed through. Colonic or small intestinal sacculations may be present.
Histology Systemic and localized forms of scleroderma show similar histologic changes, although lymphoid infiltrates tend to be heavier in the acute phase of morphea. In the acute phase there is a perivascular lymphocytic infiltrate with plasma cells that is heaviest at the junction of the dermis and subcutaneous fat. Collagen bundles become hyalinized and the space between adjacent bundles is lost. Loss of CD34+ dermal dendritic cells is an early finding. Dermal sclerosis typically results in a rectangular punch biopsy specimen. As the dermis replaces the subcutaneous tissue, eccrine glands appear to be in the midportion of the thickened dermis. The subcutaneous fat is quantitatively reduced and adventitial fat (the fat that normally surrounds the adnexal structures on the trunk) is lost. Collagen abuts directly on the adnexal structures. Elastic fibers in the reticular dermis may be prominent and stain bright red, and the papillary dermis may appear pale and edematous. In advanced lesions, the inflammatory infiltrate may be minimal. Pilosebaceous units are absent, and eccrine glands and ducts are compressed by surrounding collagen. On DIF testing of skin the nucleolus may be stained in the keratinocytes if antinucleolar circulating antibodies are
Differential diagnosis Myxedema is softer and associated with other signs of hypothyroidism. Diabetic scleredema tends to be erythematous and affects the central back in a pebbly pattern. Scleromyxedema begins with discrete papules, but may assume an appearance very similar to systemic sclerosis. A paraprotein is typically present. Sclerodactyly may be confused with digital changes of Hansen’s disease and syringomyelia. Eosinophilic fasciitis is more steroid-responsive. The skin is thickened, edematous, and erythematous, and has a coarse peau d’orange appearance, as opposed to its sclerotic, taut appearance in scleroderma. The hands and face are usually spared in eosinophilic fasciitis, and when the arms are involved, the blood vessels draw inward when the arms are raised, producing a “dry riverbed appearance.” In vitiligo the depigmentation is the sole change in the skin, and sclerosis is absent. Scleroderma in the atrophic stage may closely resemble acrodermatitis chronica atrophicans (ACA), but ACA shows more attenuation of collagen fibers and a diffuse lymphohistiocytic infiltrate. Lyme titers may be positive. Dermal fibrosis is a major feature of chronic sclerodermoid graft versus host disease, porphyria cutanea tarda, phenyl ketonuria, carcinoid syndrome, juvenile-onset diabetes, pro geria, and the Werner, Huriez, and Crow–Fukase (POEMS) syndromes. Occupational exposure to silica, epoxy resins, polyvinyl chloride, and vibratory stimuli (jackhammer or chain saw) may produce sclerodermoid conditions. Chemicals such as polyvinyl chloride, bleomycin, isoniazid, pentazocine, valproate sodium, epoxy resin vapor, vitamin K (after injection), contaminated Spanish rapeseed oil (toxic oil syndrome), contaminated tryptophan (eosinophilia–myalgia syndrome), nitrofurantoin, and hydantoin may also induce various patterns of fibrosis. The “stiff skin syndrome,” also known as congenital fascial dystrophy, is characterized by stony-hard induration of the skin and deeper tissues of the buttocks, thighs, and legs, with joint limitation and limb contractures. The disease begins in infancy. Scleroderma-like symptoms may be the presenting features of multiple myeloma and amyloidosis.
Pathogenesis The pathogenesis of scleroderma and morphea involves vascular damage, autoimmune mechanisms, and possibly microchimerism resulting in alloimmune graft versus host reactions. Both anticardiolipin and anti-β(2) glycoprotein I antibodies appear to play roles in pathogenesis. The plasma D-dimer concentration correlates with macrovascular complications. Borrelia afzelii and Borrelia garinii are related to the development of morphea-like lesions in some cases. Other environmental agents may be involved. Epidemiologic studies support the role of organic solvents and certain chemicals. In women, there is an association with teaching and working in the textile industry. The immune mechanisms involved are complex. Upregulated proteins and mRNAs include monocyte chemoattractant protein-1, pulmonary and activation-regulated chemokine, macrophage inflammatory protein-1, IL-8, platelet-derived growth factor receptor β-subunit (PDGFR-β), and TGF-β (although the latter has not correlated well in some studies).
These factors may stimulate extracellular matrix production, TGF-β production and activation, and chemoattraction of T cells. Various target antigens have been proposed, including a protein termed “protein highly expressed in testis” (PHET), which is ectopically overexpressed in scleroderma dermal fibroblasts. Serum antibodies to a recombinant PHET fragment have been detected in 9 (8.4%) of 107 scleroderma patients, but in none of 50 SLE patients or 77 healthy controls. The presence of anti-PHET antibodies was associated with diffuse cutaneous scleroderma and lung involvement. Expression of CD40 is increased on fibroblasts in lesional skin, and ligation of CD40 by recombinant human CD154 results in increased production of IL-6, IL-8, and monocyte chemoattractant protein-1 in a dose-dependent manner. These phenomena are not shown in normal fibroblasts with the addition of CD154. Lesion skin of early-stage scleroderma contains T cells preferentially producing high levels of IL-4. CD4+ Th2like cells can inhibit collagen production by normal fibroblasts and the inhibition is mediated by TNF-α. The inhibition is dominant over the enhancement induced by IL-4 and TGF-β. To be inhibitory, Th2 cells require activation by CD3 ligation. Th2 cells are less potent than T-helper 1 (Th1) cells in inhibiting collagen production by normal fibroblasts, and fibroblasts from involved skin are resistant to inhibition. Etanercept has been shown to decrease serum TGF-β1, tissue hydroxyproline, dermal fibrosis, and the number of α-SMA-positive cells. However, because Th2 cells reduce type I collagen synthesis through the effect of TNF-α, TNF-α blockade by new biologics should be approached with caution. Drug-induced morphea has been related to the cathepsin K inhibitor balicatib used for osteoporosis. Capecitabine, an oral prodrug of 5-fluorouracil used in the treatment of metastatic colon and breast carcinoma, has been associated with a hand-foot syndrome with sclerodactyly. Onset of systemic sclerosis with digital ulcers has been reported during IFN-β therapy for multiple sclerosis.
Scleroderma
present, and a “pepper-dot” epidermal nuclear reaction pattern may be seen in CREST patients who have anticentromere antibodies in their serum.
Treatment Although effective treatment is available for many of the visceral complications of scleroderma, treatment for the skin disease remains unsatisfactory. Spontaneous improvement may be seen in some children and in some cases of localized scleroderma. Physical therapy emphasizing range of motion for all joints as well as the mouth is important. Exposure to cold is to be avoided, and smoking is forbidden. Among patients with scleroderma, smokers are 3–4 times more likely than never-smokers to incur digital vascular complications. Vasodilating drugs (calcium-channel blockers, angiotensin II receptor antagonists, topical nitrates, and prostanoids) remain the mainstay of medical therapy for Raynaud phenomenon. Antioxidants, such as vitamin C, have been used, but the data are mixed. Both sildenafil (Viagra) and intravenous or inhaled iloprost are useful in the treatment of both pulmonary hypertension and Raynaud phenomenon. Ginkgo biloba has been shown to have some efficacy in a double-blinded trial. Oral L-arginine has reversed digital necrosis in some patients with Raynaud phenomenon and improved symptoms in others. Calcium-channel blockers, such as nifedipine (Procardia XL), 30–60 mg/day, are commonly used as firstline therapy. Some patients who experience worsening of esophageal reflux with nifedipine do better with diltiazem (Cardizem CD), 120–180 mg/day. Botulinum toxin, topical nitroglycerin, and simple hand warming on a regular basis may also be effective. Cyclophosphamide has shown some promising results in the treatment of cutaneous disease, improving skin scores, 173
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maximal oral opening, flexion index, forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO). Results with cyclophosphamide have been superior to those obtained with D-penicillamine. Oral methotrexate or cyclophosphamide has been used with prednisolone in some trials. Oral cyclophosphamide must be given in the morning with vigorous hydration. Many rheumatologists prefer intravenous pulse cyclophosphamide with MESNA and hydration to reduce bladder toxicity. Cyclophosphamide has been used together with antithymocyte globulin and hematopoietic stem cell infusion. Other evolving therapies include agents that target TGF-β1 signaling, tyrosine kinase inhibitors including imatinib, and inhibitors of histone deacetylase. Phototherapy and photochemotherapy, especially with UVA1, have also shown some efficacy. Methotrexate may have some efficacy for the skin thickening of diffuse scleroderma, although better trials are needed. Widespread morphea has been treated with oral calcitriol, and calcipotriene may have some efficacy as a topical agent. Halofuginone, an inhibitor of collagen type I synthesis, can decrease collagen synthesis in the tight skin mouse and murine graft versus host disease. Application of halofuginone caused a reduction in skin scores in a pilot study with scleroderma patients. CO2 laser vaporization has produced remission of symptoms in cutaneous calcinosis of CREST syndrome. Some data suggest that minocycline may be effective in the control of calcinosis in systemic sclerosis. Oral type I collagen has been disappointing overall, but may be of some limited benefit for skin findings in late-phase disease. Although there is strong evidence that the ACE inhibitors are disease-modifying for scleroderma renal crisis, better randomized controlled trials are still needed. Epoprostenol is used to treat pulmonary hypertension in scleroderma, based largely on evidence that it can be life-saving in the treatment of primary pulmonary hypertension. Other pro mising drugs for visceral involvement include bosentan (for pulmonary hypertension and ischemic ulcers), cyclophosphamide (for alveolitis), IFN-γ (for interstitial pulmonary fibrosis), intravenous prostaglandins (for vascular disease), and sildenafil (for pulmonary hypertension and Raynaud phenomenon). The future lies with early aggressive intervention before the development of fibrosis and organ damage. Bone marrow and nonmyeloablative allogeneic hematopoietic stem cell transplantation has shown dramatic and sustained benefits in some patients. It should be noted that increased renal and pulmonary toxicity, as well as parenchymal fibrosis, has been reported in some patients with scleroderma, and this treatment should still be considered experimental. Objective measures of improvement of skin sclerosis can be obtained by means of durometer measurements and high-resolution ultrasound. The course of microangiopathic changes can be evaluated with serial nailfold videocapillaroscopy. Arkachaisri T, et al: Development and initial validation of the localized scleroderma skin damage index and physician global assessment of disease damage: a proof-of-concept study. Rheumatology (Oxford) 2010; 49(2):373–381. Boin F, et al: Scleroderma-like fibrosing disorders. Rheum Dis Clin North Am 2008 Feb; 34(1):199–220. Brenner M, et al: Phototherapy and photochemotherapy of sclerosing skin diseases. Photodermatol Photoimmunol Photomed 2005; 21:157. Diab M, et al: Treatment of recalcitrant generalized morphea with infliximab. Arch Dermatol 2010 Jun; 146(6):601–604. Distler J, et al: Novel treatment approaches to fibrosis in scleroderma. Rheum Dis Clin North Am 2008 Feb; 34(1):145–159; vii. García de la Peña-Lefebvre P, et al: Long-term experience of bosentan for treating ulcers and healed ulcers in systemic sclerosis patients. Rheumatology (Oxford) 2008 Apr; 47(4):464–466. Gilliam AC: Scleroderma. Curr Dir Autoimmun 2008; 10:258–279.
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Hachulla E, et al: Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J Rheumatol 2007 Dec; 34(12):2423–2430. Hasegawa M, et al: The roles of chemokines in leukocyte recruitment and fibrosis in systemic sclerosis. Front Biosci 2008 May 1; 13:3637–3647. Henness S, et al: Current drug therapy for scleroderma and secondary Raynaud’s phenomenon: evidence-based review. Curr Opin Rheumatol 2007 Nov; 19(6):611–618. Hesselstrand R, et al: High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease. Rheumatology (Oxford) 2008 Jan; 47(1):84–87. Hudson M, et al: Improving the sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis. Clin Exp Rheumatol 2007 Sep–Oct; 25(5):754–757. Koca SS, et al: Effectiveness of etanercept in bleomycin-induced experimental scleroderma. Rheumatology (Oxford) 2008 Feb; 47(2):172–175. Kreuter A, et al: Pulsed high-dose corticosteroids combined with low-dose methotrexate in severe localized scleroderma. Arch Dermatol 2005; 141:847. Marie I, et al: Anticardiolipin and anti-beta2 glycoprotein I antibodies and lupus-like anticoagulant: prevalence and significance in systemic sclerosis. Br J Dermatol 2008 Jan; 158(1):141–144. Marie I, et al: Plasma D-dimer concentration in patients with systemic sclerosis. Br J Dermatol 2008 Feb; 158(2):392–395. (Epub 2007 Nov 19) Moore SC, et al: Treatment of complications associated with systemic sclerosis. Am J Health Syst Pharm 2008 Feb 15; 65(4):315–321. Neumeister MW, et al: Botox therapy for ischemic digits. Plast Reconstr Surg 2009; 124:191. Nihtyanova SI, et al: Autoantibodies as predictive tools in systemic sclerosis. Nat Rev Rheumatol 2010 Feb; 6(2):112–116. Pendergrass SA, et al: Understanding systemic sclerosis through gene expression profiling. Curr Opin Rheumatol 2007 Nov; 19(6):561–567. Peroni A, et al: Drug-induced morphea: report of a case induced by balicatib and review of the literature. J Am Acad Dermatol 2008 Apr 12 (Epub ahead of print). Pines M, et al: Halofuginone to treat fibrosis in chronic graft-versus-host disease and scleroderma. Biol Blood Marrow Transplant 2003; 9:417. Poole JL: Musculoskeletal rehabilitation in the person with scleroderma. Curr Opin Rheumatol 2010 Mar; 22(2):205–212. Postlethwaite AE, et al: A multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen treatment in patients with diffuse cutaneous systemic sclerosis: I. Oral type I collagen does not improve skin in all patients, but may improve skin in late-phase disease. Arthritis Rheum 2008 May 31; 58(6):1810–1822. Rembold CM, et al: Oral L-arginine can reverse digital necrosis in Raynaud’s phenomenon. Mol Cell Biochem 2003; 244:139. Reyes CM, et al: Scleroderma-like illness as a presenting feature of multiple myeloma and amyloidosis. J Clin Rheumatol 2008 Jun; 14(3):161–165. Rombold S, et al: Efficacy of UVA1 phototherapy in 230 patients with various skin diseases. Photodermatol Photoimmunol Photomed 2008 Feb; 24(1):19–23. Rosenkranz S, et al: Sildenafil improved pulmonary hypertension and peripheral blood flow in a patient with scleroderma-associated lung fibrosis and the Raynaud phenomenon. Ann Intern Med 2003; 139:871. Shah AA, et al: Telangiectases in scleroderma: a potential clinical marker of pulmonary arterial hypertension. J Rheumatol 2010; 37(1):98–104. Shiratsuchi M, et al: Long-term follow-up after nonmyeloablative allogeneic hematopoietic stem cell transplantation for systemic sclerosis. Clin Rheumatol 2008 May 16 (Epub ahead of print). Soria A, et al: The effect of imatinib (Glivec) on scleroderma and normal dermal fibroblasts: a preclinical study. Dermatology 2008; 216(2):109–117. Steen VD: Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005; 35:35. Steen VD: The many faces of scleroderma. Rheum Dis Clin North Am 2008 Feb; 34(1):1–15. Sulli A, et al: Scoring the nailfold microvascular changes during the capillaroscopic analysis in systemic sclerosis patients. Ann Rheum Dis 2008 Jun; 67(6):885–887.
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Tehlirian CV, et al: High-dose cyclophosphamide without stem cell rescue in scleroderma. Ann Rheum Dis 2008 Jun; 67(6):775–781. Trindade F, et al: Hand-foot syndrome with sclerodactyly-like changes in a patient treated with capecitabine. Am J Dermatopathol 2008 Apr; 30(2):172–173. Valentini G, et al: Disease-specific quality indicators, guidelines and outcome measures in scleroderma. Clin Exp Rheumatol 2007 Nov–Dec; 25(6 Suppl 47):159–162. Varga JA, et al: Fibrosis in systemic sclerosis. Rheum Dis Clin North Am 2008 Feb; 34(1):115–143. Villela R, et al: Assessment of unmet needs and the lack of generalizability in the design of randomized controlled trials for scleroderma treatment. Arthritis Rheum 2008 May 15; 59(5):706–713. Walker JG, et al: Update on autoantibodies in systemic sclerosis. Curr Opin Rheumatol 2007 Nov; 19(6):580–591. Wooten M: Systemic sclerosis and malignancy: a review of the literature. South Med J 2008 Jan; 101(1):59–62. Review. Zulian F: Systemic sclerosis and localized scleroderma in childhood. Rheum Dis Clin North Am 2008 Feb; 34(1):239–255; ix.
Eosinophilic fasciitis In 1974, Lawrence Shulman described a disorder that he called diffuse eosinophilic fasciitis. Classically, patients had engaged in strenuous muscular activity for a few days or weeks before the acute onset of weakness, fatigability, and pain and swelling of the extremities. The prodrome was followed by severe induration of the skin and subcutaneous tissues of the forearms and legs. A favorable response to corticosteroids was noted. Since the initial description, environmental exposures have been reported as possible triggers for the syndrome, including L-tryptophan contaminated with 1,1′-ethylidenebis, Borrelia, and exposure to trichloroethylene. Alterations in L-tryptophan metabolism have been described with elevated levels of L-kynurenine and quinolinic acid. Some consider this disease to be a variant of scleroderma. Polycythemia vera, metastatic colorectal carcinoma, and multiple myeloma have been associated in a limited number of patients, suggesting that some cases may represent a paraneoplastic phenomenon. The skin is commonly edematous and erythematous, with a coarse peau d’orange appearance, most noticeable inside the upper arms, thighs, or flanks. The hands and face are usually spared. When the patient holds the arms laterally or vertically, linear depressions occur within the thickened skin. This “groove sign” or “dry riverbed sign” (Fig. 8-27) follows the course of underlying vessels. This contrasts with scleroderma, in which the skin remains smooth and taut. Limitation of flexion and extension of the limbs and contracture may develop, and patients are often unable to stand fully erect. In contrast to scleroderma, Raynaud phenomenon is usually absent. Associated systemic abnormalities have included carpal tunnel syndrome, peripheral neuropathy, seizures, posterior ischemic optic neuropathy, pleuropericardial effusion, pancytopenia, anemia, antibody-mediated hemolytic anemia, thrombocytopenia, Sjögren syndrome, lymphadenopathy, pernicious anemia, and IgA nephropathy. Detected cytokine abnormalities are similar to those in atopic patients, but with a striking elevation of TGF-β1. Considerable evidence supports a Th17-mediated pathway. The ESR is generally increased and hypergammaglobulinemia is common. Increased production of IL-5 and clonal populations of circulating T cells have been reported. Biopsy shows a patchy lymphohistiocytic and plasma cell infiltrate in the fascia and subfascial muscle with massive thickening of the fascia and deep subcutaneous septae. Peripheral blood eosinophilia of 10–40% is the rule, but eosino phils may or may not be present in the affected fascia. The inflammatory infiltrate is mainly composed of macrophages
Fig. 8-27 Dry riverbed sign in eosinophilic fasciitis.
and lymphocytes, often with a CD8+ T lymphocyte predominance. Few eosinophils are typically present in tissue, although they may be numerous in some cases. Cytotoxic CD8+ T lymphocytes may be demonstrated by granzyme B staining. Major histocompatibility complex (MHC) class I antigens are upregulated in muscle fibers, but MHC class II antigens are not usually expressed by muscle fibers. C5b9 membrane attack complex (MAC) deposits are generally not detected. CT and MRI have both been used to demonstrate fascial thickening, and may obviate the need for biopsy in some cases. The response to systemic corticosteroids is generally excellent. In responders, complete recovery is usual within 1–3 years. Some patients have also demonstrated a response to histamine blockers, including hydroxyzine and cimetidine. Patients with a prolonged course unresponsive to systemic steroids are being recognized with increasing frequency. Many of these poorly responsive cases overlap with morphea profunda. In refractory cases, plaquenil, cyclosporine, methotrexate, azathioprine, psoralen + UVA (PUVA), bath PUVA, extracorporeal photochemotherapy, IVIG, rituximab, and other immunosuppressive regimens have been used with variable success. The increased synthesis of IL-5 may be blocked by IFN-α, suggesting a possible role for IFN in the treatment of this disorder. Both infliximab and intravenous cyclophosphamide used with moderate- to high-dose prednisolone have been reported as effective in refractory cases. Al Hammadi A, et al: Groove sign and eosinophilic fasciitis. J Cutan Med Surg 2008 Jan–Feb; 12(1):49. Bischoff L, et al: Eosinophilic fasciitis: demographics, disease pattern and response to treatment: report of 12 cases and review of the literature. Int J Dermatol 2008 Jan; 47(1):29–35. Kato T, et al: Therapeutic efficacy of intravenous cyclophosphamide concomitant with moderate- to high-dose prednisolone in two patients with fasciitis panniculitis syndrome. Mod Rheumatol 2008 Apr; 18(2):193–199. Khanna D, et al: Infliximab may be effective in the treatment of steroid-resistant eosinophilic fasciitis: report of three cases. Rheumatology (Oxford) 2010 Jun; 49(6):1184–1188.
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Philpott H, et al: Eosinophilic fasciitis as a paraneoplastic phenomenon associated with metastatic colorectal carcinoma. Australas J Dermatol 2008 Feb; 49(1):27–29. Pimenta S, et al: Intravenous immune globulins to treat eosinophilic fasciitis: a case report. Joint Bone Spine 2009 Oct; 76(5):572–574. Ronneberger M, et al: Can MRI substitute for biopsy in eosinophilic fasciitis? Ann Rheum Dis 2009 Oct; 68(10):1651-1652. Silny W, et al: Eosinophilic fasciitis: a report of two cases treated with ultraviolet A1 phototherapy. Photodermatol Photoimmunol Photomed 2009 Dec; 25(6):325–327. Tahara K, et al: Long-term remission by cyclosporine in a patient with eosinophilic fasciitis associated with primary biliary cirrhosis. Clin Rheumatol 2008 Sep; 27(9):1199–1201. Tzaribachev N, et al: Infliximab effective in steroid-dependent juvenile eosinophilic fasciitis. Rheumatology (Oxford) 2008 Jun; 47(6):930–932.
Mixed connective tissue disease Mixed connective tissue disease (MCTD) has overlapping features of scleroderma, SLE, and DM, and high U1RNP antibodies in the absence of anti-Sm antibodies. Patients often have severe arthralgia, swelling of the hands, tapered fingers, Raynaud phenomenon, abnormal esophageal motility, pulmonary fibrosis, and muscle pain, weakness, and tenderness. Occasionally, mucosal lesions occur, Pulmonary arterial hypertension is the major life-threatening complication. Hyperglobulinemia and lymphadenopathy are present in some cases. MCTD is a distinct disorder with a characteristic serologic marker. The term is not synonymous with “overlap syndrome,” a combination of diseases where each disease complies with the diagnostic criteria for that disorder. MCTD is also not synonymous with undifferentiated connective tissue disease (UCTD)—patients with connective tissue disease who have not yet developed a defined disease. Only about 4% of patients with UCTD go on to develop MCTD. The ANA test typically demonstrates a particulate pattern in MCTD, reflecting the high titers of nuclear RNP antibodies (anti-RNP antibodies). This ANA pattern generally persists through periods of remission and is a valuable diagnostic test. In addition, particulate epidermal nuclear IgG deposition on DIF study of skin is a distinctive finding in MCTD. Anti-TS1RNA antibodies appear to define a subpopulation with predominance of lupus-like clinical features. Lung disease may be a cause of death in patients with MCTD. The pulmonary disease has many similarities to that seen in DM or scleroderma, but differences in pathogenesis may exist. Pulmonary lavage usually demonstrates a significantly higher CD4 : CD8 ratio, with more CD4+ lymphocytes in MCTD patients than in PM–DM patients. MCTD patients have a significantly lower percentage of CD71+ alveolar macrophages as compared with scleroderma patients. For acute treatment, corticosteroids (like prednisone at a daily dose of 1 mg/kg) are effective for inflammatory features such as arthritis and myositis. Like LE, MCTD may be associated with an independent risk of osteoporosis, and the long-term morbidity associated with corticosteroid treatment can be significant. Bisphosphonate therapy and therapy with a steroid-sparing agent should be considered early. In general, the LE features of MCTD are the most likely to improve with therapy, while the scleroderma features are the least likely to improve. Generally, the prognosis is better than that of scleroderma, largely related to the lower incidence of renal disease. Small-molecule tyrosine kinase inhibitors such as imatinib, dasatinib, and nilotinib target TGF-β and PDGF signaling and are being investigated as therapeutic options. Aringer M, et al: Mixed connective tissue disease: what is behind the curtain? Best Pract Res Clin Rheumatol 2007 Dec; 21(6):1037–1049.
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Distler JH, et al: Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. Ann Rheum Dis 2010 Jan; 69(Suppl 1):i48–51. Greidinger EL, et al: CD4+ T cells target epitopes residing within the RNA-binding domain of the U1-70-kDa small nuclear ribonucleoprotein autoantigen and have restricted TCR diversity in an HLA-DR4transgenic murine model of mixed connective tissue disease. J Immunol 2008 Jun 15; 180(12):8444–8454. Kim P, et al: Treatment of mixed connective tissue disease. Rheum Dis Clin N Am 2005; 31:549. Lage LV, et al: Proposed disease activity criteria for mixed connective tissue disease. Lupus 2010 Feb; 19(2):223–224. Lundberg IE: The prognosis of mixed connective tissue disease. Rheum Dis Clin N Am 2005; 31:535. Perkins K, et al: A Rasch analysis for classification of systemic lupus erythematosus and mixed connective tissue disease. J Appl Meas 2008; 9(2):136–150.
Nephrogenic systemic fibrosis Nephrogenic systemic fibrosis (NSF) is a recently recognized fibrosing skin condition that resembles scleromyxedema histologically. It usually develops in patients with renal insufficiency on hemodialysis, although it has been noted in patients with acute renal failure who had never undergone dialysis. Epidemiologic and x-ray emission spectroscopic studies have implicated gadolinium-containing MRI contrast agents and the incidence of disease has decreased since their use has been limited in patients with renal failure. Concurrent infection, increased serum phosphate and calcium concentrations, and acidosis may play important roles in pathogenesis of the disease. Clinical findings include thickened sclerotic or edema tous papules and plaques involving the extremities (Fig. 8-28) and trunk. Yellow scleral plaques and scleral telangiectasia resembling conjunctivitis have been described. Soft tissue calcification is rare, but may be extensive when it occurs. Clinically, the condition differs from scleromyxedema by the lack of involvement of the face, absence of plasma cells, and lack of paraproteinemia. Systemic involvement is generally absent, but may occur with fibrosis and calcification of the diaphragm, psoas muscle, renal tubules, and rete testes.
Fig. 8-28 Hyperpigmented sclerotic plaques of nephrogenic fibrosing dermopathy.
Abraham JL, et al: Tissue distribution and kinetics of gadolinium and nephrogenic systemic fibrosis. Eur J Radiol 2008 May; 66(2):200–207. Chen AY, et al: Nephrogenic systemic fibrosis: a review. J Drugs Dermatol 2010 Jul; 9(7):829–834. Cowper SE: Nephrogenic systemic fibrosis: an overview. J Am Coll Radiol 2008 Jan; 5(1):23–28. Golding LP, et al: Nephrogenic systemic fibrosis: possible association with a predisposing infection. AJR Am J Roentgenol 2008 Apr; 190(4):1069–1075. Kallen AJ, et al: Gadolinium-containing magnetic resonance imaging contrast and nephrogenic systemic fibrosis: a case-control study. Am J Kidney Dis 2008 Jun; 51(6):966–975. Knopp EA, et al: Nephrogenic systemic fibrosis: early recognition and treatment. Semin Dial 2008 Mar–Apr; 21(2):123–128. Kucher C, et al: Histopathologic comparison of nephrogenic fibrosing dermopathy and scleromyxedema. J Cutan Pathol 2005; 32:484. High WA, et al: Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007 Apr; 56(4):710–712. Idée JM, et al: Possible involvement of gadolinium chelates in the pathophysiology of nephrogenic systemic fibrosis: a critical review. Toxicology 2008 Jun 27; 248(2–3):77–88. Linfert DR, et al: Treatment of nephrogenic systemic fibrosis: limited options but hope for the future. Semin Dial 2008 Mar–Apr; 21(2):155–159. Marckmann P: Nephrogenic systemic fibrosis: epidemiology update. Curr Opin Nephrol Hypertens 2008 May; 17(3):315–319. Martin DR, et al: Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols. J Magn Reson Imaging 2010 Feb; 31(2):440–446. Shabana WM, et al: Nephrogenic systemic fibrosis: a report of 29 cases. AJR Am J Roentgenol 2008 Mar; 190(3):736–741. Swaminathan S, et al: Rapid improvement of nephrogenic systemic fibrosis with rapamycin therapy: possible role of phospho-70ribosomal-S6 kinase. J Am Acad Dermatol 2010; 62(2):343–345.
Sjögren syndrome (sicca syndrome) Keratoconjunctivitis sicca and xerostomia (mouth dryness) are commonly associated with rheumatoid arthritis and other connective tissue diseases. Dry eyes and mouth may occur as primary Sjögren syndrome. Most patients are aged 50 or older and more than 90% are women. Sjögren syndrome is a chronic
autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands, particularly the salivary and lacrimal glands. One-third of patients present with extraglandular manifestations, such as vasculitis. Xerostomia may produce difficulty in speech and eating, increased tooth decay, thrush, and decreased taste (hypogeusia). Patients frequently suck on sour candies to stimulate what little salivary secretions remain, and those unfamiliar with the condition may blame the habit of sucking lemon drops for the ensuing tooth decay. Sjögren syndrome alters the composition of saliva, producing a decrease in salivary amylase and carbonic anhydrase, along with an increase in lactoferrin, β(2)microglobulin, cystatin C, sodium, and lysozyme C. Rhinitis sicca (dryness of the nasal mucous membranes) may induce nasal crusting and decreased olfactory acuity (hyposmia). Vaginal dryness and dyspareunia may develop. Dry eyes are painful, feel gritty or scratchy, and produce discharge and blurry vision. Fatigue is a prominent symptom. In addition, there may be laryngitis, gastric achlorhydria, thyroid enlargement resembling Hashimoto thyroiditis, malignant lymphoma, thrombotic thrombocytopenic purpura, painful distal sensory axonal neuropathy, and splenomegaly. Skin manifestations of Sjögren syndrome include vasculitis, xerosis, pruritus, and annular erythema. Decreased sweating occurs. Asian patients have been described who develop erythematous, indurated, annular dermal plaques primarily on the face. This is different from the annular lesions of SCLE, which show epidermal change and histologic changes of lupus. Patients may also present with an overlap of Sjögren syndrome and LE. A common finding in these patients is Ro/ SSA antibody positivity. SCLE patients with Sjögren syndrome have a worse prognosis than patients with SCLE unassociated with Sjögren syndrome. Patients with Sjögren syndrome and cutaneous vasculitis also have a significant incidence of peripheral, renal, or CNS vasculitis. Cutaneous vasculitis may present as purpura of the legs, which may be palpable or nonpalpable. Sjögren vasculitis accounts for most patients with Waldenström benign hypergammaglobulinemic purpura. Approximately 30% of benign hypergammaglobulinemic purpura patients will have or will develop Sjögren syndrome, and a high percentage have SSA and SSB antibodies. Other cutaneous vascular manifestations are urticarial vasculitis, digital ulcers, and petechiae. Histologically, a leukocytoclastic vasculitis is found at the level of the postcapillary venule with expansion of the vascular wall, fibrin deposition, and karyorrhexis, but no necrosis of the endothelium. Labial salivary gland biopsy from inside the lower lip is regarded by many as the most definitive test for Sjögren syndrome. Typically, there is a dense lymphocytic infiltrate with many plasma cells and fewer histiocytes in aggregates within minor salivary glands. More than one focus of 50 or more lymphocytes is typically present per 4 mm2 of the tissue biopsy. Lymphoepithelial islands predominate early, while glandular atrophy predominates in the late stages. At this stage, few lymphoid aggregates are present. Xerostomia is diagnosed by the Schirmer test and reflects diminished glandular secretion from the lacrimal glands. Imaging studies are also helpful. Classically, the diagnosis is made when there is objective evidence for two of the following three major criteria:
Sjögren syndrome
Circulating antiphospholipid antibodies have been noted in some patients. Histologic sections demonstrate plump bipolar CD34+ spindle cells with dendrites extending along both sides of elastic fibers (tram track sign), many new collagen bundles, and increased mucin. With time, thickened collagen bundles become prominent in the reticular dermis. Myofibroblasts have been noted in lesional skin. Immunohistochemical staining for CD34 and procollagen I in the spindle cells of NFD suggests that many of the dermal cells of NFD may represent circulating fibrocytes recruited to the dermis. The CD34 positivity in NFD contrasts with the loss of CD34+ cells in morphea. Effective therapy remains elusive. Topical retinoids, steroids, and vitamin D analogs are not effective. Immuno suppressive therapy appears to be of little benefit. In three cases that have evolved after liver transplantation, treatment with basiliximab, mycophenolate mofetil, calcineurin inhibitor, and prednisone did not stop the development of “woody” skin induration of the distal extremities, erythematous papules, and contractures. The most effective treatment strategy appears to be optimization of renal function through medical therapy or transplantation. Some data support a beneficial effect from phototherapy, extracorporeal photopheresis, or intravenous sodium thiosulfate tyrosine kinase inhibitors, and rapamycin. The proliferating fibrocytes of NSF express phospho-70-S6 kinase, a protein downstream from the mammalian target of rapamycin. All patients should be referred for physical therapy.
1. xerophthalmia 2. xerostomia 3. an associated autoimmune, rheumatic, or lymphoproliferative disorder. These criteria may be too restrictive, as patients are increasingly being identified with predominantly extraglandular 177
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disease. The lack of sicca symptoms or anti-SSA or SSB antibodies does not exclude Sjögren syndrome. Numerous serologic abnormalities are associated with Sjögren syndrome or its associated conditions. Antibodies to fodrin, a major component of the membrane cytoskeleton of most eukaryotic cells, are present in some populations with primary and secondary Sjögren syndrome. IgA and IgG antibodies against α-fodrin are detected in 88% and 64% respectively in some studies. In other populations, fodrin antibodies are less helpful. Around 80% of patients have anti-Ro/SSA antibodies; half as many have anti-La/SSB antibodies. The rheumatoid factor is commonly positive, and an elevated ESR, serum globulin, and CRP, and high titers of IgG, IgA, and IgM are common. Cryoglobulins may be demonstrated. Dendritic cells are increased in tissue during the early phases of the disease. The aquaporin family of water channels (proteins freely permeated by water but not protons) appears to be an important target in the pathogenesis of Sjögren syndrome. Both duct and secretory cells are targets for the activation of CD4+ T cells. IL-12 and IFN-γ are upregulated. It appears that Th1 cytokines mediate the functional interactions between antigen-presenting cells and CD4+ T cells in early lesions. Patients with Sjögren syndrome are predisposed to the development of lymphoreticular malignancies, especially nonHodgkin B-cell lymphoma. Both malignant and nonmalignant extraglandular lymphoproliferative processes occur. Cases of pseudolymphoma have the potential for regression, or for progression to overt B-cell lymphoma. Patients with palpable purpura, low C4, and mixed monoclonal cryoglobulinemia are at higher risk for lymphoma. The differential diagnosis of Sjögren syndrome includes sarcoidosis, lymphoma, amyloidosis, and human immunodeficiency virus (HIV) disease. The latter produces diffuse infiltrative lymphocytosis syndrome (DILS), which is characterized by massive parotid enlargement; prominent renal, lung, and gastrointestinal manifestations; and a low frequency of autoantibodies. Treatment for Sjögren syndrome has largely been symptomatic, but disease-modifying therapy is also becoming a reality. Artificial lubricants are helpful for eye symptoms, as well as oral, nasal, and vaginal dryness. Topical lubricants are useful for xerosis. In hot climates, patients with impaired sweating must be counseled to avoid heat stroke. Pharmacologic agents, such as pilocarpine and cevimeline, are helpful to stimulate salivation. These agents may also have a role in the treatment of dry eyes. Topical cyclosporine A looks promising for local treatment of Sjögren syndrome, as does topical human IFN therapy for oral lesions. In all trials, the mechanical stimulation by the lozenge may play a significant role in the improvement of symptoms. This is reflected in a high placebo response. Acid maltose lozenges are cheaper and remain useful for symptomatic relief. For patients with systemic disease, biologic TNF inhibitors such as infliximab show some promise. Pilocarpine, in doses of 10 mg/day, has been shown to have a beneficial effect on subjective eye symptoms, as well as improvement of rose bengal staining. An increase in tear production, as measured by the Schirmer-I test, was not substantiated. Gene therapy also looks promising, at least in animal models. IL-10 genes can be transferred via adenovirus vectors, and can have disease-modifying effects in the salivary glands of a mouse model. Severe systemic vasculitis causing renal disease has responded to corticosteroids with or without cyclophosphamide. Mycophenolate sodium and rituximab have both been used to treat severe manifestations associated with Sjögren syndrome. Rituximab has proved effective in double-blind, placebo-controlled, randomized studies, and rituximab plus cyclophosphamide, vincristine, and prednisone
have been used to treat Sjögren syndrome-associated B-cell non-Hodgkin lymphoma. Atkinson JC, et al: Salivary hypofunction and xerostomia: diagnosis and review. Dent Clin North Am 2005; 49:309. Carbone J, et al: Combined therapy with rituximab plus cyclophosphamide/vincristine/prednisone for Sjögren’s syndromeassociated B-cell non-Hodgkin’s lymphoma. Clin Rev Allergy Immunol 2008 Feb; 34(1):80–84. Dass S, et al: Reduction of fatigue in Sjögren’s syndrome with rituximab: results of a randomised, double-blind, placebo controlled pilot study. Ann Rheum Dis 2008 Feb 14 (Epub ahead of print). Fox RI: Sjögren’s syndrome. Lancet 2005; 366:321. Hansen A, et al: Immunopathogenesis of primary Sjögren’s syndrome: implications for disease management and therapy. Curr Opin Rheumatol 2005; 17:558. Jain AK, et al: Effect of topical cyclosporine on tear functions in tear-deficient dry eyes. Ann Ophthalmol 2007 Spring; 39(1):19–25. Kagami H, et al: Restoring the function of salivary glands. Oral Dis 2008 Jan; 14(1):15–24. Mavragani CP, et al: Conventional therapy of Sjögren’s syndrome. Clin Rev Allergy Immunol 2007 Jun; 32(3):284–291. Meijer JM, et al: The future of biologic agents in the treatment of Sjögren’s syndrome. Clin Rev Allergy Immunol 2007 Jun; 32(3):292–297. Ng KP, et al: Sjögren’s syndrome: diagnosis and therapeutic challenges in the elderly. Drugs Aging 2008; 25(1):19–33. Ozaki Y, et al: Decrease of blood dendritic cells and increase of tissue-infiltrating dendritic cells are involved in the induction of Sjögren’s syndrome but not in the maintenance. Clin Exp Immunol 2010; 159(3):315–326. Pers JO, et al: B-cell depletion and repopulation in autoimmune diseases. Clin Rev Allergy Immunol 2008 Feb; 34(1):50–55. Voulgarelis M, et al: Clinical, immunologic, and molecular factors predicting lymphoma development in Sjögren’s syndrome patients. Clin Rev Allergy Immunol 2007 Jun; 32(3):265–274. Willeke P, et al: Mycophenolate sodium treatment in patients with primary Sjögren syndrome: a pilot trial. Arthritis Res Ther 2007; 9(6):R115. Yilmaz I, et al: Parotid magnetic resonance imaging, sialography, and parotid biopsy for diagnosis of Sjögren’s syndrome in a patient with negative serology. J Otolaryngol 2005; 37:199.
Rheumatoid arthritis The majority of skin manifestations of rheumatoid arthritis (RA) are consequences of neutrophil-mediated injury. There may be annular erythemas, purpura, bullae, shallow ulcers, and gangrene of the extremities. Many diseases have been reported to occur in association with RA, such as erythema elevatum diutinum, pyoderma gangrenosum, Felty syndrome, IgA vasculitis, linear IgA disease, Sjögren syndrome, bullous pemphigoid, and yellow nail syndrome. Treatment of RA with disease-modifying drugs has reduced the burden of destructive disease for patients with this disorder. Biologic agents are being used with increasing frequency, although older drugs like methotrexate still have a role. Methotrexate-treated patients with RA have an increased incidence of melanoma, as well as non-Hodgkin lymphoma, and lung cancer. They should be followed for the development of cutaneous lesions. Of interest to dermatologists, extracts from the Rhus family of plants have been shown to have some benefit in limited studies. Ofatumumab, a new anti-CD20 human monoclonal antibody, shows promise in early clinical trials.
Rheumatoid nodules Subcutaneous nodules (Fig. 8-29) are seen in 20–30% of patients. They may arise anywhere on the body but most frequently are found over the bony prominences, especially on the extensor surface of the forearm just below the elbow and
Rheumatoid arthritis Fig. 8-29 Rheumatoid nodules.
Fig. 8-30 Rheumatoid neutrophilic dermatosis presents with urticarial plaques.
the dorsal hands. The lesions are nontender, firm, skin-colored, round nodules, which may or may not be attached to the underlying tissue. Frequently, they are attached to the fibrous portions of the periarticular capsule, or they may be free in the subcutaneous tissue. Rheumatoid nodules can easily be mistaken for xanthomas because of a yellow color (pseudoxanthomatous variant). They also occur in 5–7% of patients with SLE, especially around small joints of the hands. Rheumatoid factor may or may not be present. Histologic examination of the rheumatoid nodule shows intensely staining foci of fibrin surrounded by histiocytes in palisade arrangement. Neutrophils and neutrophilic debris may be noted in association with the fibrin, and with time, the surrounding histiocytes are replaced by fibrosis. Rheumatoid nodules are differentiated from Heberden nodes, which are tender, hard, bony exostoses on the dorso lateral aspects of the distal interphalangeal joints of patients with degenerative joint disease. Nodules or tophi of gout are characterized by masses of feathery urate crystals surrounded by a chronic inflammatory infiltrate often containing foreign body giant cells. Rare patients present with multiple ulcerated nodules and high rheumatoid factors, but no active joint disease. This variant of rheumatoid disease without destructive joint disease is designated rheumatoid nodulosis.
diagnosis includes erythema elevatum diutinum and Sweet syndrome.
Rheumatoid vasculitis Peripheral vascular lesions appear as typical features of RA. These are localized purpura, cutaneous ulceration, and gangrene of the distal parts of the extremities. Additionally, papular lesions located primarily on the hands have been described as rheumatoid papules. These show a combination of vasculitis and palisading granuloma formation. A rheumatoid factor is typically present. Peripheral neuropathy is frequently associated with the vasculitis. The presence of rheumatoid nodules may help to distinguish these lesions of vasculitis from SLE, polyarteritis nodosa, Buerger’s disease, and the dysproteinemias. Prednisone and cytotoxic agents are commonly used as in other forms of vasculitis. Rituximab has also been used successfully.
Rheumatoid neutrophilic dermatosis Chronic urticaria-like plaques (Fig. 8-30) characterized histologically by a dense neutrophilic infiltrate have been described in patients with debilitating RA. The differential
Related palisading granulomas Interstitial granulomatous dermatitis with arthritis is a condition that most commonly presents with symmetrical round-tooval erythematous or violaceous plaques on the flanks, axillae, inner thighs, and lower abdomen. Linear, slightly red or skincolored cords extending from the upper back to the axilla may occur. The presence of these linear bands has been called the rope sign. When the lesions resolve they may leave behind hyperpigmentation and a slightly wrinkled appearance. Arthritis may occur before, concurrently, or after the eruption, and tends to affect multiple joints of the upper extremities. While serologic findings of connective tissue disease are common, most patients do not have a well-defined associated condition. A moderate to dense inflammatory infiltrate is seen through the reticular dermis, composed mostly of histiocytes distributed interstitially around discrete bundles of sclerotic collagen. Variable numbers of neutrophils and/or eosinophils are seen. Mucin, necrobiosis, vasculitis, and vacuolar change are usually absent or mild. The eruption is usually asymptomatic and may spontaneously involute after many months or years. If therapy is required, methotrexate, etanercept, cyclosporine, or a steroid is needed. Palisaded neutrophilic and granulomatous dermatitis is usually associated with a well-defined connective tissue disease (LE or RA, most commonly). It often presents with eroded or ulcerated symmetrically distributed umbilicated papules or nodules on the elbows, knuckles, and knees. The biopsy may reveal leukocytoclastic vasculitis and collagen degeneration in early lesions, or palisaded granulomatous infiltrates with dermatofibrosis and scant neutrophilic debris in older lesions. Interstitial granulomatous dermatitis has been reported in RA during treatment with etanercept but has also been reported to respond to etanercept. Methotrexate-induced papular eruption appears in patients with rheumatic diseases during treatment with this medication. They present with erythematous indurated papules, usually located on the proximal extremities. Histopathologic examination reveals an inflammatory infiltrate composed of histiocytes interstitially arranged between collagen bundles of the dermis, intermingled with few neutrophils. At times, small rosettes composed of clusters of histiocytes surrounding a thick central collagen bundle are present in the deep reticular dermis. 179
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Buchbinder R, et al: Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum 2008 May 30; 59(6):794–799. Hellmann M, et al: Successful treatment of rheumatoid vasculitisassociated cutaneous ulcers using rituximab in two patients with rheumatoid arthritis. Rheumatology (Oxford) 2008 Jun; 47(6):929–930. Hu S, et al: Interstitial granulomatous dermatitis in a patient with rheumatoid arthritis on etanercept. Cutis 2008 Apr; 81(4):336–338. Navarro-Sarabia F, et al: Adalimumab for treating rheumatoid arthritis. Cochrane Database Syst Rev 2005; 3:CD005113. Robak T: Ofatumumab, a human monoclonal antibody for lymphoid malignancies and autoimmune disorders. Curr Opin Mol Ther 2008 Jun; 10(3):294–309. Sacre SM, et al: Molecular therapeutic targets in rheumatoid arthritis. Expert Rev Mol Med 2005; 7:1. Sanchez E, et al: Polymorphisms of toll-like receptor 2 and 4 genes in rheumatoid arthritis and systemic lupus erythematosus. Tissue Antigens 2004; 63:54. Zoli A, et al: Interstitial granulomatous dermatitis in rheumatoid arthritis responsive to etanercept. Clin Rheumatol 2010 Jan; 29(1):99–101.
Adams A, et al: Update on the pathogenesis and treatment of systemic onset juvenile rheumatoid arthritis. Curr Opin Rheumatol 2005; 17:612. Dyer JA, et al: Neutrophilic panniculitis in infancy: a cutaneous manifestation of juvenile rheumatoid arthritis. J Am Acad Dermatol 2007 Nov; 57(5 Suppl):S65–68. Lequerré T, et al: Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 2008 Mar; 67(3):302–308.
Relapsing polychondritis
Juvenile RA is not a single disease but a group of disorders characterized by arthritis and young age of onset. The subset called Still’s disease accounts for only 20% of the patients. It shows skin manifestations in some 40% of young patients ranging in age from 7 to 25 years. An eruption consisting of evanescent, non-pruritic, salmon-pink, macular, or papular lesions on the trunk and extremities (Fig. 8-31) may precede the onset of joint manifestations by many months. Neutrophilic panniculitis has been described. The systemic symptoms of fever and serositis usually recur over weeks each afternoon. Most remit permanently by adulthood. IL-1β, IL-6, and IL-18 are implicated in the pathogenesis of the disease, as are phagocyte-specific S100-proteins, such as S100A8, S100A9, and S100A12. Steroid-sparing agents are useful to decrease steroid-associated toxicity. The dose–response curve for methotrexate plateaus with parenteral administration of 15 mg/m2/week. The full therapeutic effect may not be
Relapsing polychondritis is characterized by intermittent episodes of inflammation of the articular and nonarticular cartilage eventuating in chondrolysis and collapse of the involved cartilage. The course of the disease is chronic and variable, with episodic flares. Both sexes are equally affected, with the usual age at onset being in the fourth to fifth decade. Dissolution of the cartilage involves the ears, nose, and respiratory tract. During bouts of inflammation, the bright red involvement of the ears is confined to the cartilaginous portion while the ear lobes remain conspicuously normal (Fig. 8-32). The affected areas are swollen and tender. There may be conductive deafness as a result of the obstruction produced by the swollen cartilage. The nasal septal cartilage is similarly involved to produce rhinitis, with crusting and bleeding, and, eventually, a saddle-nose deformity. Involvement of the bronchi, larynx, and epiglottis produces hoarseness, coughing, and dyspnea. Migratory arthralgia and atypical chest pain are often present. Patients evaluated for chest pain are often released without treatment and with a diagnosis of costochondritis. Ocular disease most often presents as conjunctivitis, scleritis, or iritis. Perforation of the globe may occur. Complete heart block has been reported as a presenting sign. The MAGIC syndrome is a combination of Behçet’s disease and relapsing polychondritis (mouth and genital ulcers with inflamed cartilage).
Fig. 8-31 Evanescent eruption of Still’s disease.
Fig. 8-32 Relapsing polychondritis characteristically involves cartilaginous portions of the ear but spares the lobe.
Juvenile rheumatoid arthritis (juvenile idiopathic arthritis)
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evident for 12 months. Refractory disease has been treated with pulse methylprednisolone and cyclophosphamide. Anakinra has shown modest efficacy.
infliximab. Endobronchial ultrasonography has been used to facilitate the diagnosis and estimate the size of the involved airway for placement of stents. Carter JD: Treatment of relapsing polychondritis with a TNF antagonist. J Rheumatol 2005; 32:1413. Gergely P Jr, et al: Relapsing polychondritis. Best Pract Res Clin Rheumatol 2004; 18:723. Goldenberg G, et al: Successful treatment of relapsing polychondritis with mycophenolate mofetil. J Dermatolog Treat 2006; 17(3):158–159. Hojaili B, et al: Relapsing polychondritis presenting with complete heart block. J Clin Rheumatol 2008 Feb; 14(1):24–26. Marie I, et al: Sustained response to infliximab in a patient with relapsing polychondritis with aortic involvement. Rheumatology (Oxford) 2009 Oct; 48(10):1328–1329. Mark KA, et al: Colchicine and indomethacin for the treatment of relapsing polychondritis. J Am Acad Dermatol 2002; 46(2 Suppl Case Reports):S22. McCarthy EM, et al: Treatment of relapsing polychondritis in the era of biological agents. Rheumatol Int 2010 Apr; 30(6):827–828. Subrahmanyam P, et al: Sustained response to etanercept after failing infliximab, in a patient with relapsing polychondritis with tracheomalacia. Scand J Rheumatol 2008 May–Jun; 37(3):239–240. Terrier B, et al: Complete remission in refractory relapsing polychondritis with intravenous immunoglobulins. Clin Exp Rheumatol 2008 Jan–Feb; 26(1):136–138. Vounotrypidis P, et al: Refractory relapsing polychondritis: rapid and sustained response in the treatment with an IL-1 receptor antagonist (anakinra). Rheumatology (Oxford) 2006 Apr; 45(4):491–492. Yanagi T, et al: Relapsing polychondritis and malignant lymphoma: is polychondritis paraneoplastic? Arch Dermatol 2007 Jan; 143(1):89–90.
Relapsing polychondritis
Autoimmune mechanisms appear to be responsible for this disease. Cell-mediated immunity to cartilage has been demonstrated in vitro, with a degree of response correlated with disease activity. IgG anti-type II collagen antibodies have been documented, again in titers corresponding with disease activity. Elevations in ESR, CRP levels, and urinary type II collagen neoepitope levels correlate with disease activity. A second connective tissue disease or other autoimmune disease is present in about one-third of patients, and some cases appear to be paraneoplastic, occurring in association with hematopoietic malignancies. Limited data suggest that serum levels of Th1 cytokines (IFN-γ, IL-12, and IL-2) may correlate better with disease activity than those of Th2 cytokines (IL-4, IL-5, IL-6, and IL-10). Histologically, a predominantly neutrophilic infiltrate is noted in the perichondrium. Varying degrees of chondrolysis may be present. DIF often demonstrates a lupus-like continuous granular band of immunoglobulin and complement in the perichondrium. Dapsone, 100 mg once or twice a day for an adult, reduces the frequency of flares, but is usually inadequate to control the disease. Colchicine, leflunomide, or hydroxychloroquine may also be helpful. Systemic corticosteroids should be used to treat acute flares, but most patients require a steroid-sparing immunosuppressive drug. Azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, IVIG, anakinra, and TNF-α inhibitors have been used. Sustained response to etanercept has been reported, even after failure to respond to
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 8-1 Discoid lupus erythematosus. Fig. 8-2 Ear involvement with discoid lupus erythematosus. Fig. 8-3 Lower eyelid lesion of discoid lupus erythematosus. Fig. 8-4 Scarring alopecia in discoid lupus erythematosus. Fig. 8-5 Hypertrophic lupus erythematosus, indurated hyperkeratotic plaques with ulceration. Fig. 8-6 Characteristic palmar involvement in lupus:lichen planus overlap syndrome. Fig. 8-7 Annular lesions of subacute cutaneous lupus erythematosus. Fig. 8-8 Psoriasiform subacute cutaneous lupus erythematosus. Fig. 8-9 Annular erythematous lesions of neonatal lupus erythematosus. Fig. 8-10 Indurated coalescing lesions of neonatal lupus erythematosus.
Fig. 8-11 Palmar erythema in systemic lupus erythematosus. Fig. 8-12 Lupus hair, short miniaturized hairs affecting the anterior hairline. Fig. 8-13 Scalp erythema in dermatomyositis. Fig. 8-14 Erythema in trunk in dermatomyositis. Fig. 8-15 Cuticular fraying in dermatomyositis. Fig. 8-16 Gottron’s sign. Fig. 8-17 Calcinosis cutis in long-standing DM. Fig. 8-18 Vasculitis in childhood DM. Fig. 8-19 Morphea. Fig. 8-20 Linear scleroderma presents with induration and pigmentary change. Fig. 8-21 Telangiectases in CREST syndrome. Fig. 8-22 Scarring, loss of finger pad substance, and pterygium inversum unguis. Fig. 8-23 Ulceration of the fingertip. Fig. 8-24 Eosinophilic folliculitis. Fig. 8-25 Mucosal ulcerations in mixed connective tissue disease.
Fig. 8-26 Rheumatoid vasculitis frequently results in ulceration. Fig. 8-27 Palisaded neutrophilic and granulomatous dermatitis often involves the extensor surfaces with erosion or ulceration of the lesions. Fig. 8-28 Dyspigmentation and scarring of discoid lupus erythematosus. Fig. 8-29 Bullous lupus erythematosus. Fig. 8-30 Heliotrope rash in a patient with dermatomyositis. Fig. 8-31 Atrophic coalescing lesions of dermatomyositis on the arm. Fig. 8-32 Atrophic lesions of dermatomyositis involving the knuckles. Fig. 8-33 Pterygium inversum unguis in progressive systemic sclerosis. Fig. 8-34 Rheumatoid neutrophilic dermatosis presents with urticarial plaques.
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9
Mucinoses
Within the dermis is a fibrillar matrix, termed ground substance, which is composed of proteoglycans and glycosaminoglycans. These acid mucopolysaccharides, produced by fibroblasts, are highly hygroscopic, binding about 1000 times their own volume in water. They are critical in holding water in the dermis and are responsible for dermal volume and texture. Normally, the sulfated acid mucopolysaccharide chondroitin sulfate and heparin are the primary dermal mucins. In certain diseases, fibroblasts produce abnormally large amounts of acid mucopolysaccharides, usually hyaluronic acid. These acid mucopolysaccharides (mucin) accumulate in large amounts in the dermis, and may be visible as pale blue granular or amorphous material between collagen bundles. They are often not visualized with hematoxylin eosin stains, since the water they bind is removed in processing, so the presence of increased mucin is suspected by the presence of large empty spaces between the collagen bundles. They can be detected by special stains, such as colloidal iron, alcian blue, and toluidine blue. Incubation of the tissue with hyaluronidase eliminates the staining, confirming the presence of hyaluronic acid. Increased dermal mucin may result from many diseases and is a normal component of wound healing. The mucinoses are those diseases in which the production of increased amounts of mucin is the primary process. Mucin may also accumulate in the skin as a secondary phenomenon, such as when it is present in lupus erythematosus, dermatomyositis, Degos’ disease, granuloma annulare, and cutaneous tumors, or after therapies such as psoralen and ultraviolet A (PUVA) or retinoids. The genetic diseases in which mucin accumulates as a result of inherited metabolic abnormalities are termed the mucopolysaccharidoses (see Chapter 26). Myxedema and pretibial myxedema are reviewed in Chapter 24. Jackson EM, et al: Diffuse cutaneous mucinosis. Dermatol Clin 2002; 20:493. Rongioletti F, et al: The new cutaneous mucinoses. J Am Acad Dermatol 1991; 24:265. Rongioletti F, et al: Cutaneous mucinoses: microscopic criteria for diagnosis. Am J Dermatopathol 2001; 23:257.
Lichen myxedematosus The terminology used to describe disorders in this disease group has varied widely over the years. We will use the 1991 classification of Rongioletti and Rebora. A generalized form, scleromyxedema, is accompanied by a monoclonal gammopathy and may have systemic organ involvement. Five localized forms are recognized, these being characterized by a lack of a monoclonal antibody and systemic disease. Finally, patients may have disease that does not fit into these subsets, and their condition is termed atypical or intermediate in type. Thyroid disease should not account for the findings in any category.
Generalized lichen myxedematosus Scleromyxedema affects adults of both sexes and appears from ages 30 to 80. It is chronic and progressive. The primary lesions are multiple waxy, 2–4 mm, dome-shaped or flat-topped papules (Fig. 9-1). They may coalesce into plaques (Fig. 9-2) or be arranged in linear array. Less commonly, urticarial, nodular, or even annular lesions are seen. The dorsal hands, face, elbows, and extensor extremities are most frequently affected (Fig. 9-3). Mucosal lesions are absent. A diffuse infiltration develops, leading to woody sclerosis of the skin. A reduced range of motion of the mouth, hands, and extremities may follow. On the glabella and forehead, coalescence of lesions leads to the prominent furrowing of a “leonine facies”. At the proximal interphalangeal joint, induration surrounding a centrally depressed area has been termed the doughnut sign. Pruritus may occur. Scleromyxedema is often associated with visceral disease. Gastrointestinal findings are most frequent. Dysphagia resulting from involvement of the esophagus is most common, but the stomach or intestine may also be affected. Pulmonary complications with dyspnea caused by restrictive or obstructive disease are the second most common visceral problem. Proximal muscle weakness with an inflammatory myopathy or a nonspecific vacuolar change may occur. Carpal tunnel syndrome occurs in 10% of patients. Arthralgia or inflammatory arthritis is not uncommon. Peripheral neuropathies and central nervous system (CNS) disturbances, including confusion, dizziness, dysarthria, ascending paralysis, seizures, syncope, and coma, can occur. The latter has been termed the dermatoneuro syndrome. Visceral disease can be fatal. Criteria for inclusion in this disease category include mucin deposition, fibroblast proliferation and fibrosis, normal thyroid function tests, and the presence of a monoclonal gammopathy. Approximately 10% of patients do not have this latter finding on initial evaluation. The gammopathy is usually an IgG-λ type, suggesting an underlying plasma cell dyscrasia. Bone marrow examination may be normal or reveal increased numbers of plasma cells or frank myeloma. Clinical and histologic features are usually diagnostic. Skin biopsies of early papular lesions demonstrate a proliferation of fibroblasts with mucin and many small collagen fibers. The papules generally appear more fibrotic than mucinous. Over time, fibroblast nuclei become less numerous and collagen fibers become thickened. Many of the clinical findings seen in scleromyxedema are also found in systemic scleroderma, including cutaneous sclerosis, Raynaud phenomenon, dysphagia, and carpal tunnel syndrome. This distinction in some cases may be difficult without a biopsy. Other infiltrative disorders, such as amyloidosis, must be excluded. Association with hepatitis C has been reported frequently. Nephrogenic systemic fibrosis
Lichen myxedematosus Fig. 9-1 Shiny papules of early scleromyxedema.
Fig. 9-2 Scleromyxedema.
Fig. 9-4 Nephrogenic fibrosing dermopathy.
presents with skin thickening in the setting of renal failure (Fig. 9-4). In its earliest form, it includes mucin along with collagen deposition with a proliferation of CD34+ cells in the dermis. The histologic findings are identical to those of scleromyxedema, and the first report by Cowper et al was termed a scleromyxedema-like illness associated with renal failure. The clinical findings are dominated by fibrosis, so this entity is fully discussed in Chapter 8. Treatment of scleromyxedema is difficult and usually undertaken in concert with an oncologist. Many patients are treated with immunosuppressive agents, especially melphalan or cyclophosphamide with or without plasma exchange and prednisone. Temporary remission of progressive visceral disease may occur. These short-term benefits must be weighed against the increase in malignancies and sepsis complicating such therapy. Chances of remission are enhanced by the use of autologous stem cell transplantation with high-dose melphalan. Skin-directed therapy may also be utilized. Physical therapy is indicated. Moderate doses of systemic steroids are not usually helpful, but high doses alone may temporarily arrest progressive cutaneous and visceral disease. Retinoids, plasmapheresis, extracorporeal photochemotherapy, intravenous immunoglobulins, Grenz ray and electron beam therapy, PUVA, thalidomide, interferon (IFN)-α, cyclosporine, topical dimethyl sulfoxide, and topical and intralesional hyaluronidase and corticosteroids have all produced improvement in the skin of selected patients. Many others, however, have not benefited and visceral disease is usually not affected. UVB and IFN-α have exacerbated scleromyxedema. Occasional patients are reported who spontaneously remit even after many years of disease; however, scleromyxedema remains a therapeutic challenge, and the overall prognosis is poor.
Localized lichen myxedematosus
Fig. 9-3 Scleromyxedema. (Courtesy of Marshall Guill, MD)
The localized variants of lichen myxedematosus lack visceral involvement or an associated gammopathy. As a group, they are benign, but often persistent. No therapy is reliably effective in any of the localized forms of lichen myxedematosus. Since there is no gammopathy, visceral involvement, or associated thyroid disease in any of the variants, often no treatment is needed. Shave excision or CO2 ablation is an option for individual lesions, and spontaneous resolution may occur in all varieties. 183
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Fig. 9-5 Acral persistent papular mucinosis.
Discrete papular lichen myxedematosus Discrete papular lichen myxedematosus is characterized by the occurrence of waxy, 2–5 mm, firm, flesh-colored papules, usually confined to the limbs or trunk. The papules may have an erythematous or yellowish hue, may coalesce into nodules or plaques, and may number into the hundreds. Nodules may occasionally be the predominant lesion present, with few or absent papules. The underlying skin is not indurated and there is no associated gammopathy or internal involvement. Biopsy reveals the presence of mucin in the upper and mid-dermis. Fibroblast proliferation is variable, but collagen deposition is minimal. The slow accumulation of papules is the usual course, without the development of a gammopathy or internal manifestations. Occasional cases may spontaneously involute. Many patients with acquired immunodeficiency syndrome (AIDS) have been reported to develop mucinous papules, usually widespread, unassociated with a paraprotein. It is virtually always seen in advanced human immunodeficiency virus (HIV) disease, in patients with multiple infectious complications. These lesions may occur in association with an eczematous dermatitis or on normal skin. If associated with an eczematous dermatitis, the lesions often clear if the eczema is controlled. Those cases occurring on normal skin may respond to systemic retinoid therapy. At times spontaneous remission occurs. The authors have also seen one case of a patient with AIDS and true scleromyxedema with visceral involvement, and two patients have been reported with acral persistent papular mucinosis.
Acral persistent papular mucinosis Patients with acral persistent papular mucinosis have a few to over 100 bilaterally symmetrical, 2–5 mm, flesh-colored papules localized to the hands and wrists (Fig. 9-5). The knees, calves, or elbows may also be involved in a minority of patients. The face and trunk are spared. Women outnumber men by 5:1. The course is one of persistence and slow progression. Two involved sisters have been reported. Histologically, there is a collection of upper dermal mucin with minimal or no increase in fibroblasts.
Self-healing papular mucinosis Self-healing papular mucinosis occurs in a juvenile and an adult form. The juvenile variant, also called self-healing juvenile cutaneous mucinosis, is a rare, but distinct disorder, characterized by the sudden onset of skin lesions and polyarthritis. Children, most commonly between the ages of 5 and 15, are affected. Familial cases are reported. Skin lesions are ivorywhite papules of the head, neck, trunk, and typically the periarticular regions; deep nodules on the face and periarticular sites; and hard edema of the periorbital area and face. An acute arthritis affects the knees, elbows, and hand joints. In the adult form, papular lesions occur, usually without the associated 184
Fig. 9-6 Self-healing papular mucinosis.
joint symptoms (Fig. 9-6). Histology of the skin lesions reveals dermal mucin with little fibroblastic proliferation or collagen deposition. Although the initial presentation is worrisome, the prognosis is excellent. Spontaneous resolution without sequelae occurs over several months.
Papular mucinosis of infancy This is also referred to as cutaneous mucinosis of infancy and is a rare syndrome that occurs at birth or within the first few months of life. Skin-colored or translucent, grouped or discrete, 2–8 mm papules develop on the trunk or upper extremities, especially the back of the hands. Biopsies show very superficial upper dermal mucin without proliferation of fibroblasts. Existing lesions remain static; new lesions continue to accumulate gradually. Similar lesions may sometimes be noted in association with neonatal lupus erythematosus.
Atypical or intermediate lichen myxedematosus The cutaneous mucinoses are all relatively uncommon. In a literature dominated by case reports, individual patients have been found who do not fit well into the above scheme, e.g. patients exist with acral persistent papular mucinosis who have had a paraprotein, and others with apparently classic scleromyxedema with visceral lesions may not have a detectable circulating paraprotein. Berger JR, et al: The neurologic complications of scleromyxedema. Medicine 2001; 80:313. Blum M, et al: Scleromyxedema: a case series highlighting long-term outcomes of treatment with IVIG. Medicine (Baltimore) 2008; 87:10. Carder KR, et al: Self-healing juvenile cutaneous mucinosis. Pediatr Dermatol 2003; 20:35. Cheng T, et al: Complete and durable remission in a patient with life-threatening scleromyxedema treated with high-dose melphalan and BU with auto-SCT. Bone Marrow Transplant 2008 (Epub). Cokonis Georgakis CD, et al: Scleromyxedema. Clin Dermatol 2006; 24:493. Cowen EW, et al: Self-healing juvenile cutaneous mucinosis. J Am Acad Dermatol 2004; 50:S97. Cowper SE, et al: Scleromyxedema-like cutaneous diseases associated with renal failure. Lancet 2000; 356:1000. Donato ML, et al: Scleromyxedema: role of high-dose melphalan with autologous stem cell transplantation. Blood 2006; 107:463. Efthimiou P, et al: IVIG and thalidomide may be an effective therapeutic combination in refractory scleromyxedema. Semin Arthritis Rheum 2008 (Epub). Giron J, et al: Resolution of papular mucinosis in a person with HIV Infection. AIDS Read 2007; 17:418. Gonzalez J, et al: Scleromyxedema with dermato-neuro syndrome. J Am Acad Dermatol 2000; 42:927.
Scleredema Scleredema is a skin disease characterized by a stiffening and hardening of the subcutaneous tissues, as if they were infiltrated with paraffin. It occurs in two forms—with and without diabetes mellitus. In the more generalized, non-diabetic condition, a sudden onset following an infection, typically streptococcal in nature, may occur. This reactive variant may also present as a drug eruption. In others the onset is insidious and chronic in nature, and has no preceding infection. In the more common diabetes-associated disease, a long-lasting induration of the upper back is characteristic. In cases not associated with diabetes, females outnumber males by 2:1. The age at onset is from childhood through adulthood. Skin tightness and induration begins on the neck and/or face, spreading symmetrically to involve the arms, shoulders, back, and chest. The distal extremities are spared. There may be difficulty opening the mouth or eyes, and a masklike expression as a result of the infiltration. The involved skin, which is waxy and of woodlike consistency, gradually transitions into normal skin with no clear demarcation. Associated findings occur in variable numbers of patients and can include dysphagia caused by tongue and upper esophageal involvement, cardiac arrhythmias, and an associated paraprotein, usually an IgG type. Myeloma may be present. There may be pleural, pericardial, or peritoneal effusion. In about half the patients in whom the condition follows an infection, spontaneous resolution will occur in months to a few years. In one patient whose disease had a sudden onset after beginning infliximab treatment for rheumatoid arthritis, the condition resolved quickly after discontinuation of the medicine and did not recur after etanercept was initiated. The remaining patients with nondiabetic scleredema have a prolonged course. Therapy is generally of no benefit, but patients may live with the disease for many years. Cyclosporine, UVA1, pulsed dexamethasone, and extracorporeal photopheresis have been reported to be beneficial in individual patients. In the second group, which in most dermatologists’ experience is the more common, there is an association with lateonset, insulin-dependent diabetes. Men outnumber women by 10 : 1. Affected men tend to be obese. The lesions are of insidious onset and long duration, presenting as woody induration and thickening of the skin of the mid-upper back, neck, and shoulders (Fig. 9-7). There is a sharp step-off from the involved to the normal skin. Persistent erythema and folliculitis may involve the affected areas. The associated diabetes is of long duration and is difficult to control. Further, patients have fre-
Fig. 9-7 Scleredema.
Reticular erythematous mucinosis
Harris JE, et al: Acral persistent papular mucinosis. J Am Acad Dermatol 2004; 51:982. Horn KB, et al: A complete and durable clinical response to high-dose dexamethasone in a patient with scleromyxedema. J Am Acad Dermatol 2004; 51:S120. Illa I, et al: Steady remission of scleromyxedema 3 years after autologous stem cell transplantation. Blood 2006; 15:773. Nagaraj LV, et al: Self-healing juvenile cutaneous mucinosis. J Am Acad Dermatol 2006; 55:1036. Posswig A, et al: Discrete papular mucinosis—a rare subtype of lichen myxoedematosus. Clin Exp Dermatol 2000; 25:289. Rampino M, et al: Scleromyxedema: treatment of widespread cutaneous involvement by total skin electron beam therapy. Int J Dermatol 2007; 46:864. Rongioletti F, et al: Treatment of localized lichen myxedematosus of discrete type with tacrolimus ointment. J Am Acad Dermatol 2008; 58:530. Sansbury JG, et al: Treatment of recalcitrant scleromyxedema with thalidomide in three patients. J Am Acad Dermatol 2004; 51:126. Sperber BR, et al: Self-healing papular mucinosis in an adult. J Am Acad Dermatol 2004; 50:121.
quently suffered complications of their diabetes, such as nephropathy, atherosclerotic disease, retinopathy, and neuropathy. Control of the diabetes does not affect the course of the scler edema. No paraprotein is detected, and visceral involvement is not seen. Lesions are persistent and usually unresponsive to treatment. Intravenous penicillin, electron beam alone or in combination with photon irradiation, narrow-band UVB, and both bath and systemic PUVA have each been effective in individual patients. While low-dose methotrexate was successful in one patient, it was ineffective in a case series of seven patients. The histology of both forms is identical. The skin is dramatically thickened, with the dermis often expanded two- to threefold. There is no hyalinization such as that seen in scleroderma, but rather the thick dermal collagen bundles are separated by clear spaces that may contain visible mucin (hyaluronic acid). The amount of mucin is variable and usually only prominent in early lesions. In late lesions, slightly widened spaces between thick collagen bundles are the sole finding, as the amount of mucin is scant. Beers WH, et al: Scleredema adultorum of Buschke: a case report and review of the literature. Semin Arthritis Rheum 2006; 35:355. Bowen AF, et al: Scleredema adultorum of Buschke treated with radiation. Arch Dermatol 2003; 139:780. Dogra S, et al: Dexamethasone pulse therapy for scleredema. Pediatr Dermatol 2004; 21:280. Ioannidou DI, et al: Scleredema adultorum of Buschke presenting as periorbital edema. J Am Acad Dermatol 2005; 52:41. Malhotra AK, et al: Scleredema following scabies infestation. Pediatr Dermatol 2008; 25:136. Nakajima K, et al: Two cases of diabetic scleredema that responded to PUVA therapy. J Dermatol 2006; 33:820. Ranganathan P: Infliximab-induced scleredema in a patient with rheumatoid arthritis. J Clin Rheumatol 2005; 11:319. Stables GI, et al: Scleredema associated with paraproteinaemia treated by extracorporeal photopheresis. Br J Dermatol 2000; 142:781. Tamburin LM, et al: Scleredema of Buschke successfully treated with electron beam therapy. Arch Dermatol 1998; 134:419. Xiao T, et al: Scleredema adultorum treated with narrow-band ultraviolet B phototherapy. J Dermatol 2007; 34:270.
Reticular erythematous mucinosis (REM syndrome, plaque-like cutaneous mucinosis) Reticular erythematous mucinosis (REM) favors women in the third and fourth decades of life. The eruption frequently appears after intense sun exposure. Clinical lesions are erythematous plaques or reticulated patches that are several centimeters in diameter, and are most common in the midline of the chest and back (Fig. 9-8). Evolution is gradual, photosensitivity is common, and lesions may be induced with UVB. Onset or exacerbation with oral contraceptives, menses, and 185
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Fig. 9-8 Reticulated erythematous mucinosis.
Fig. 9-9 Alopecia mucinosa.
pregnancy is another feature. Serologic tests for lupus erythematosus are negative. Histologically, there are varying degrees of lymphocytic infiltration around dermal vessels, and deposits of mucin in the dermis. Direct immunofluorescence is negative, but focal vacuolar interface dermatitis is sometimes seen, suggesting a relationship to lupus erythematosus. Treatment with anti malarials is successful in most cases. The pulsed dye laser has led to resolution in two patients. Lesions of REM have also been reported to occur on the face, arms, abdomen, and groin. When evaluating patients with mucinous smooth-surfaced erythematous lesions it is important to consider the possibility of connective tissue disease. Plaque-like or papulonodular lesions in sites away from the central chest and back may infrequently herald the development of systemic lupus erythematosus, discoid lupus erythematosus, dermatomyositis or scleroderma. Tumid lupus erythematosus is a subset of chronic cutaneous lupus that is characterized by erythematous papules, nodules, and plaques that most often involve the face, extensor aspects of the arms, shoulders, V of the neck, and upper back. Histology is identical to REM. It is photoinducible and responsive to antimalarials. While serologic abnormalities occur in a small percentage of patients, this is usually a skin-limited condition. Thus, there is considerable overlap with REM and some authors consider the two to be closely related or identical.
posed of flesh-colored, follicular papules (Fig. 9-9). There may be only one lesion, especially on the head and neck, or multiple sites may be present. The plaques are firm and coarsely rough to the palpating finger. They are distributed mostly on the face, neck, and scalp but may appear on any parts of the body. Itching may or may not be present. Alopecia occurs regularly in lesions on the scalp and frequently in lesions located elsewhere. Some papules show a comedo-like black central dot that corresponds to a broken hair or the mucin itself. These may cause the surface of a patch to look like keratosis pilaris. Sensory dissociation, with hot–cold perception alterations or anesthesia to light touch, has been reported in some lesions, with a resultant misdiagnosis of Hansen’s disease. The term alopecia mucinosa may be used to describe the disease process, and follicular mucinosis to describe the histologic features. The disease may be skin-limited and benign (primary follicular mucinosis) or may be associated with follicular mycosis fungoides. When lesions are solitary or few in number and cluster on the head and neck of individuals younger than 40 years of age, the condition usually follows a benign, chronic course, even in cases where the infiltrate is found to be clonal in nature. Widespread lesions in an older patient, however, will usually be found to be cutaneous T-cell lymphoma (CTCL) at initial presentation or will progress to lymphoma within 5 years. These two subsets are not exclusive, however, and no clinical or histologic criteria absolutely distinguish them in the absence of diagnostic findings of CTCL. Histologically, follicular mucinosis demonstrates large collections of mucin within the sebaceous gland and outer root sheath. The mucin typically stains as hyaluronic acid. A mixed dermal infiltrate is present. When the condition occurs in association with CTLC, the perifollicular infiltrate is atypical but not generally epidermotropic, and a considerable admixture of eosinophils and plasma cells is present. The additional finding of the presence of syringolymphoid hyperplasia should raise concern that lymphoma is or will become evident. T-cell receptor gene rearrangement studies that indicate clonity are also supportive but do not alone predict an aggressive course. Spontaneous involution of primary follicular mucinosis may occur, especially in young children. Topical corticosteroids produce improvement. Hydroxychlorquine cured six patients. Dapsone, PUVA, radiation therapy, IFN-α 2b, minocycline, isotretinoin, photodynamic therapy, and indomethacin have been effective in individual cases. Follicular mycosis
Alexiades-Armenakas MR, et al: Tumid lupus erythematosus. Arthritis Rheum 2003; 49:494. Caputo R, et al: Reticular erythematous mucinosis occurring in a brother and sister. Dermatology 2006; 28:482. Greve B, et al: Treating REM syndrome with the pulsed dye laser. Lasers Surg Med 2001; 29:248. Kaufmann R, et al: Dermatomyositis presenting as plaque-like mucinosis. Br J Dermatol 1998; 138:889. Kuhn A, et al: Lupus erythematosus tumidus. Arch Dermatol 2000; 136:1033. Van Zander J, et al: Papular and nodular mucinosis as a presenting sign of progressive systemic sclerosis. J Am Acad Dermatol 2002; 46:304.
Follicular mucinosis (alopecia mucinosa) In 1957, Pinkus applied the name alopecia mucinosa to a series of patients with inflammatory plaques with alopecia characterized histologically by mucinous deposits in the outer root sheaths of the hair follicles. The plaques may be simply hypopigmented or erythematous and scaly, eczematous, or com186
Brown HA, et al: Primary follicular mucinosis. J Am Acad Dermatol 2002; 47:856. Ceroni L, et al: Follicular mucinosis. Arch Dermatol 2002; 138:182. Dalle S, et al: Neonatal follicular mucinosis. Br J Dermatol 2007; 157:609. Fernandez-Guarino M, et al: Primary follicular mucinosis. J Eur Acad Dermatol Venereol 2008; 22:393. Gerami P, et al: The spectrum of histopathologic and immunohistochemical findings in folliculotropic mycosis fungoides. Am J Surg Pathol 2007; 31:1430. Gibson LE, et al: Follicular mucinosis. Arch Dermatol 2002; 138:1615. Lehman JS, et al: Folliculotropic mycosis fungoides. Arch dermatol 2010; 146:662. Schneider SW, et al: Treatment of so-called idiopathic follicular mucinosis with hydroxychloroquine. Br J Dermatol 2010; 163:420. Van Doorn R, et al: Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis. Arch Dermatol 2002; 138:191.
Cutaneous focal mucinosis Focal mucinosis is characterized by a solitary nodule or papule. Lesions are asymptomatic and usually occur on the face, neck, trunk, or extremities. They appear in adulthood. Histologically, the lesion is characterized by a loose dermal stroma containing large quantities of mucin together with numerous dendriticshaped fibroblasts. The clinical appearance is not distinctive and may at times be suggestive of a cyst, a basal cell carcinoma, or a neurofibroma. The treatment is surgical excision. Chen HH, et al: A solitary soft fibroma-like polypoid mucinosis. Dermatol Surg 2004; 30:400. Takemura N, et al: Cutaneous focal mucinosis. J Dermatol 2005; 32:1051.
Myxoid cysts These lesions occur most commonly on the dorsal or lateral terminal digits of the hands but may also occur on the toes. They present as solitary, 5–7 mm, opalescent or skin-colored cysts. They may occur as asymptomatic swellings of the proximal nailfold, as subungual growths, or over the distal interphalangeal joint. Women are more frequently affected, and osteoarthritis is frequently present in the adjacent distal interphalangeal joint. Myxoid cysts that can be reduced with pressure communicate directly with the joint space. Multiple myxoid cysts are associated with connective tissue disease. Young children, even infants, may present with multiple myxoid cysts as the initial manifestation of juvenile rheumatoid arthritis. An adult with systemic sclerosis has also been reported. Two patients whose jobs entailed placing repeated pressure on the fingertips developed multiple myxoid cysts. When a myxoid cyst is present beneath the proximal nailfold, a characteristic groove may be formed in the nail plate by pressure of the lesion on the nail matrix (Fig. 9-10). Those located beneath the nail cause a transverse nail curvature, a red or blue discoloration of the lunula is common, and nail integrity is typically compromised, leading to distal or longi-
Myxoid cysts
fungoides, with or without associated mucin, is more refractory to treatment and has a worse prognosis than classic CTCL.
Fig. 9-10 Distortion of nail distal to a synovial cyst.
tudinal splitting or onycholysis. The diagnosis can be confirmed by magnetic resonance imaging (MRI) or surgical exploration. They contain a clear, viscous, sticky fluid that may spontaneously drain. These cysts do not have an epithelial lining but a compacted fibrous wall. Treatment depends on the site of the cyst. The repeated puncture technique for the two accessible types may achieve a cure rate of up to 70%, but multiple punctures (>40) may be required. This technique may be complicated by local tissue or joint infection. Steroids may be injected into the tissue after draining the cyst. Destruction by cryotherapy, CO2 laser ablation, curettage, and fulguration are alternatives with similar cure rates, but these result in scarring. Surgical approaches that reflect the skin overlying the cyst and either excise or tie off the communication to the joint, which may be visualized by injecting the cyst with methylene blue, have a cure rate of over 90%. Connolly M, et al: Multiple myxoid cysts secondary to occupation. Clin Exp Dermatol 2006; 31:404. de Berker DAR, et al: Treatment of myxoid cysts. Dermatol Surg 2001; 27:296. de Berker DAR, et al: Ganglion of the distal interphalangeal joint (myxoid cyst). Arch Dermatol 2001; 137:607. de Berker DAR, et al: Subungual myxoid cysts. J Am Acad Dermatol 2002; 46:394. Epstein E: A simple technique for managing digital mucous cysts. Arch Dermatol 1979; 115:1315.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. Fig. Fig. Fig. Fig.
9-1 9-2 9-3 9-4 9-5
Scleromyxedema. (Courtesy of Marshall Guill, MD) Scleromyxedema. (Courtesy of Marshall Guill, MD) Scleromyxedema. (Courtesy of Marshall Guill, MD) Alopecia mucinosa. Myxoid cyst.
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Seborrheic Dermatitis, Psoriasis, Recalcitrant Palmoplantar Eruptions, Pustular Dermatitis, and Erythroderma
Seborrheic dermatitis Clinical features Seborrheic dermatitis is common, occurring in 2–5% of the population. It is a chronic, superficial, inflammatory disease with a predilection for the scalp, eyebrows, eyelids, nasolabial creases, lips, ears (Fig. 10-1), sternal area, axillae, submammary folds, umbilicus, groins, and gluteal crease. The disease is characterized by scaling on an erythematous base. The scale often has a yellow, greasy appearance. Itching may be severe. Dandruff (pityriasis sicca) represents a mild form of seborrheic dermatitis. An oily type, pityriasis steatoides, is accompanied by erythema and an accumulation of thick crusts. Other types of seborrheic dermatitis on the scalp include arcuate, polycyclic, or petaloid patches, and psoriasiform, exudative, or crusted plaques. The disease frequently spreads beyond the hairy scalp to the forehead, ears, postauricular regions, and neck. On these areas the patches have convex borders and are reddish-yellow or yellowish. In dark-skinned individuals, arcuate and petaloid lesions commonly involve the hairline. In extreme cases the entire scalp is covered by a greasy, dirty crust with an offensive odor. In infants, yellow or brown scaling lesions on the scalp, with accumulated adherent epithelial debris, are called cradle cap. Erythema and scaling are often seen in the eyebrows. The lids may show yellowish-white, fine scales and faint erythema. The edges of the lids may be erythematous and granular (marginal blepharitis), and the conjunctivae may be injected. If the glabella is involved, fissures in the wrinkles at the inner end of the eyebrow may accompany the fine scaling. In the naso labial creases and on the alae nasi, there may be yellowish or reddish-yellow scaling macules, sometimes with fissures. In men, folliculitis of the beard area is common. In the ears, seborrheic dermatitis may be mistaken for an infectious otitis externa. There is scaling in the aural canals, around the auditory meatus, usually with marked pruritus. The postauricular region and skin under the lobe may be involved. In these areas the skin often becomes red, fissured, and swollen. In the axillae the eruption begins in the apices, bilaterally, and later progresses to neighboring skin. This pattern resembles that of allergic contact dermatitis to deodorant, but differs from that of clothing dermatitis (which involves the periphery of the axillae but spares the vault). The involvement may vary from simple erythema and scaling to more pronounced petaloid patches with fissures. The inframammary folds and the umbilicus may be involved. The presternal area is a favored site on the trunk. Seborrheic dermatitis is common in the groin and gluteal crease, where its appearance may closely simulate tinea cruris or candidiasis. In these areas, the appearance often overlaps with that of inverse psoriasis. In fact, many of these patients have an overlap of the two conditions (sebopsoriasis or sebor-
rhiasis) in the groin, as well as the scalp. The lesions may also become generalized and progress to a generalized exfoliative erythroderma (erythroderma desquamativum), especially in infants. A minority of these infants will have evidence of immunosuppression. In adults, generalized eruptions may be accompanied by adenopathy and may simulate mycosis fungoides or psoriatic erythroderma. Seborrheic dermatitis may be associated with several internal diseases. Parkinson’s disease is often accompanied by severe refractory seborrheic dermatitis involving the scalp and face, with waxy, profuse scaling. A unilateral injury to the innervation of the face, or a stroke, may lead to unilateral localized seborrheic dermatitis. Patients with acquired immuno deficiency syndrome (AIDS) have an increased incidence of seborrheic dermatitis. An increased incidence has also been noted in patients who are seropositive for human immuno deficiency virus (HIV), but have not developed other signs of clinical disease. Diabetes mellitus, especially in obese persons; sprue; malabsorption disorders; epilepsy; neuroleptic drugs, such as haloperidol; and reactions to arsenic and gold have all produced seborrheic dermatitis-like eruptions.
Etiology and pathogenesis The etiology of this common disorder is complex, but may be related to the presence of the lipophilic yeast Pityrosporum ovale, which produces bioactive indoles. The density of yeast has been correlated with the severity of the disease, and reduction of the yeast occurs with response to therapy. P. ovale may also be abundant on the scalps of patients who have no clinical signs of the disease, and the yeast may only be pathogenic in predisposed individuals. Patients with seborrheic dermatitis may show upregulation of interferon (IFN)-gamma, expressed interleukin (IL)-6, expressed IL-1β, and IL-4. Expression of cytotoxicity-activating ligands and recruitment of natural killer (NK) cells have also been noted.
Histology The epidermis demonstrates regular acanthosis with some thinning of the suprapapillary plates. Varying degrees of spongiosis and lymphocyte exocytosis are noted. A characteristic finding is the presence of a focal scale crust adjacent to the follicular ostia.
Differential diagnosis Some cases of seborrheic dermatitis bear a close clinical resemblance to psoriasis, and the two conditions may overlap. Psoriasis tends to have more pronounced erythema and heavier silvery scales that peel in layers. Removal of scales in psoriasis may disclose bleeding points (Auspitz sign). This sign is
Fig. 10-1 Seborrheic dermatitis.
common but lacks great specificity. Severe itching favors seborrheic dermatitis. Characteristic psoriasis elsewhere (nail pitting, balanitis) may resolve the question. Impetigo of the scalp, especially when associated with pediculosis, may cause difficulty in differentiation. Scalp impetigo can be an indolent crusted dermatosis associated with failure to thrive. Langerhans cell histiocytosis may also resemble seborrheic dermatitis, but typically demonstrates yellow–brown perifollicular papules and groin fissuring. Crusted scabies of the scalp can also be confused with seborrheic dermatitis, and Trichophyton tonsurans often produces a subtle seborrheic scale. In subtle cases of tinea, a moist gauze pad rubbed vigorously on the scalp will typically dislodge short, broken KOH-positive hairs. This can be the fastest way to make the diagnosis.
Treatment Agents suitable for use on glabrous skin include corticosteroid creams, gels, sprays and foam. Corticosteroids tend to produce a rapid effect, but on the face even mid-potency corticosteroids can produce steroid rosacea. For this reason, antifungal agents and topical calcineurin inhibitors are often preferred. Ketoconazole, ciclopirox, tacrolimus, zinc pyrithione, and pimecrolimus preparations are all effective alone and in combination. The antifungals are now available in a wide range of vehicles to include foams, gels, and liquids. Bifonazole shampoo has been shown to be effective in treating infants and small children. Topical calcineurin inhibitors may be associated with a burning sensation, especially on moist skin, and may produce flushing if patients consume alcohol. Patients generally tolerate these agents better after initial treatment with a corticosteroid. An open, randomized, prospective, comparative study of topical pimecrolimus 1% cream vs topical ketoconazole 2% cream found the two to be equally effective, but side effects were somewhat more common with pimecrolimus. Preliminary studies suggest oral itraconazole and oral terbinafine may show some efficacy. Oral fluconazole showed marginal benefit. Study results with topical metronidazole have been mixed. When secondary bacterial infection is present, a topical or oral antibiotic may be required. In patients infected with HIV,
Berk T, et al: Seborrheic dermatitis. P.T. 2010 Jun; 35(6):348–352. Cömert A, et al: Efficacy of oral fluconazole in the treatment of seborrheic dermatitis: a placebo-controlled study. Am J Clin Dermatol 2007; 8(4):235–238. Dawson TL Jr: Malassezia globosa and restricta: breakthrough understanding of the etiology and treatment of dandruff and seborrheic dermatitis through whole-genome analysis. J Investig Dermatol Symp Proc 2007; 12(2):15–19. Elewski B, et al: Efficacy and safety of a new once-daily topical ketoconazole 2% gel in the treatment of seborrheic dermatitis: a phase III trial. J Drugs Dermatol 2006; 5(7):646–650. Firooz A, et al: Pimecrolimus cream, 1%, vs hydrocortisone acetate cream, 1%, in the treatment of facial seborrheic dermatitis: a randomized, investigator-blind, clinical trial. Arch Dermatol 2006; 142(8):1066–1067. Food and Drug Administration, HHS: Dandruff, seborrheic dermatitis, and psoriasis drug products containing coal tar and menthol for over-thecounter human use; amendment to the monograph. Final rule. Fed Regist 2007; 72(43):9849–9852. Gaitanis G, et al: AhR ligands, malassezin, and indolo[3,2-b]carbazole are selectively produced by Malassezia furfur strains isolated from seborrheic dermatitis. J Invest Dermatol 2008; 128(7):1620–1625. Gee BC: Seborrhoeic dermatitis. Clin Evid 2004; 12:2344. High WA, et al: Pilot trial of 1% pimecrolimus cream in the treatment of seborrheic dermatitis in African American adults with associated hypopigmentation. J Am Acad Dermatol 2006; 54(6):1083–1088. Jackson WB: Blepharitis: current strategies for diagnosis and management. Can J Ophthalmol 2008; 43(2):170–179. Kircik L: The evolving role of therapeutic shampoos for targeting symptoms of inflammatory scalp disorders. J Drugs Dermatol 2010; 9(1):41–48. Koc E, et al: An open, randomized, prospective, comparative study of topical pimecrolimus 1% cream and topical ketoconazole 2% cream in the treatment of seborrheic dermatitis. J Dermatolog Treat 2008; 1:1–5. Ozcan H, et al: Is metronidazole 0.75% gel effective in the treatment of seborrhoeic dermatitis? A double-blind, placebo controlled study. Eur J Dermatol 2007; 17(4):313–316. Seckin D, et al: Metronidazole 0.75% gel vs. ketoconazole 2% cream in the treatment of facial seborrheic dermatitis: a randomized, doubleblind study. J Eur Acad Dermatol Venereol 2007; 21(3):345–350.
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lithium succinate ointment (Efalith) has been used for facial disease. Lithium gluconate 8% ointment has also been shown to compare favorably with ketoconazole 2% emulsion in healthy adults and was more effective in terms of control of scaling and symptoms. Sodium sulfacetamide products, with or without sulfur, are effective in some refractory patients. For scalp disease, selenium sulfide, ketoconazole, tar, zinc pyrithione, fluocinolone, and resorcin shampoos are effective. In many patients, these agents may be used 2–3 times a week, with a regular shampoo used in between as required. Antifungal foams and gels, as well as corticosteroid solutions, foams, gels, and sprays, are often preferred by Caucasian patients, while ointment or oil preparations are preferred by some black patients. Itching of the external ear canal usually responds to a topical corticosteroid, calcineurin inhibitors, or antifungals such as ketoconazole or ciclopirox. Some patients require the use of a class 1 corticosteroid on weekends to control refractory pruritus. Cortisporin otic suspension can bring about prompt clearing, but contact dermatitis to neomycin may complicate the use of some Cortisporin products. Desonide otic lotion (0.05% desonide and 2% acetic acid) is also effective and may be better tolerated than Domeboro otic solution. Sodium sulfacetamide drops or ointment may be effective for seborrheic blepharitis. Oral tetracyclines can also be effective, and have been shown to decrease the density of micro organisms in the affected follicles. Steroid preparations are suitable for short-term use, but may induce glaucoma and cataracts. Daily gentle cleansing with a cotton-tipped applicator and baby shampoo in water can reduce symptoms. In severe cases, oral antibiotics or oral antifungals may be combined with topical agents.
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Shemer A, et al: Treatment of moderate to severe facial seborrheic dermatitis with itraconazole: an open non-comparative study. Isr Med Assoc J 2008; 10(6):417–418. Siadat AH, et al: The efficacy of 1% metronidazole gel in facial seborrheic dermatitis: a double blind study. Indian J Dermatol Venereol Leprol 2006; 72(4):266–269. Tajima M, et al: Molecular analysis of Malassezia microflora in seborrheic dermatitis patients: comparison with other diseases and healthy subjects. J Invest Dermatol 2008; 128(2):345–351. Vena GA, et al: Oral terbinafine in the treatment of multi-site seborrheic dermatitis: a multicenter, double-blind placebo-controlled study. Int J Immunopathol Pharmacol 2005; 18(4):745–753. Waldroup W, et al: Medicated shampoos for the treatment of seborrheic dermatitis. J Drugs Dermatol 2008; 7(7):699–703. Warshaw EM, et al: Results of a randomized, double-blind, vehiclecontrolled efficacy trial of pimecrolimus cream 1% for the treatment of moderate to severe facial seborrheic dermatitis. J Am Acad Dermatol 2007; 57(2):257–264.
Psoriasis
dea, in which central involution does not occur and solid patches persist; and psoriasis rupioides, in which crusted lesions occur, resembling syphilitic rupia. The term chronic plaque psoriasis is often applied to stable lesions of the trunk and extremities. Inverse psoriasis predominates in intertriginous areas. Pustular variants of psoriasis may be chronic on the palms and soles (Fig. 10-3), or may be eruptive and accompanied by severe toxicity and hypocalcemia. Involved nails (Fig. 10-4) can demonstrate distal onycho lysis, random pitting (the result of parakeratosis from the proximal matrix), oil spots (yellow areas of subungual parakeratosis from the distal matrix), or salmon patches (nailbed psoriasis). Thick subungual hyperkeratosis may resemble onychomycosis.
Types Seborrheic-like psoriasis
Clinical features
Some cases of psoriasis overlap with seborrheic dermatitis. Seborrheic lesions may predominate on the face, under the
Psoriasis is a common, chronic, and recurrent inflammatory disease of the skin characterized by circumscribed, erythematous, dry, scaling plaques of various sizes. The lesions are usually covered by silvery white lamellar scales. The lesions have a predilection for the scalp, nails, extensor surfaces of the limbs, umbilical region, and sacrum. The eruption is usually symmetrical. It usually develops slowly but may be exanthema tous, with the sudden onset of numerous guttate (droplike) lesions (Fig. 10-2). Subjective symptoms, such as itching or burning, may be present and may cause extreme discomfort. The early lesions are small erythematous macules, which from the beginning are covered with dry, silvery scales. The lesions increase in size by peripheral extension and coalescence. The scales are micaceous, meaning that they peel in layers. They are looser toward the periphery and adherent centrally. When removed, bleeding points appear (Auspitz sign). Although plaques typically predominate, lesions may be annular or polycyclic. Old patches may be thick and covered with tough lamellar scales like the outside of an oyster shell (psoriasis ostracea). Various other descriptive terms have in the past been applied to the diverse appearances of the lesions: psoriasis guttata, in which the lesions are the size of water drops; psoriasis follicularis, in which tiny, scaly lesions are located at the orifices of hair follicles; psoriasis figurata, psoriasis annulata, and psoriasis gyrata, in which curved linear patterns are produced by central involution; psoriasis discoi-
Fig. 10-3 Pustular psoriasis of the hand.
Fig. 10-2 Psoriasis.
Fig. 10-4 Nail pitting and distal onycholysis in psoriasis.
Inverse psoriasis This form selectively and often exclusively involves folds, recesses, and flexor surfaces such as the ears, axillae, groins, inframammary folds, navel, intergluteal crease, penis (Fig. 10-5), lips, and web spaces. Other areas, such as the scalp and nails, may be involved.
“Napkin” psoriasis Napkin psoriasis, or psoriasis in the diaper area, is characteristically seen in infants between 2 and 8 months of age. Lesions appear as brightly erythematous, sharply demarcated patches of skin involving much of the diaper area. The lesions typically clear with topical therapy, but psoriasis may reappear in adulthood.
Psoriatic arthritis Five clinical patterns of arthritis occur: 1. asymmetrical distal interphalangeal joint involvement with nail damage (16%) 2. arthritis mutilans with osteolysis of phalanges and metacarpals (5%) (Fig. 10-6) 3. symmetrical polyarthritis-like rheumatoid arthritis, with claw hands (15%)
4. oligoarthritis with swelling and tenosynovitis of one or a few hand joints (70%) 5. ankylosing spondylitis alone or with peripheral arthritis (5%). Most radiographic findings resemble those in rheumatoid arthritis, but certain findings are highly suggestive of psoriasis. These include erosion of terminal phalangeal tufts (acrosteo lysis), tapering or “whittling” of phalanges or metacarpals with “cupping” of proximal ends of phalanges (pencil in a cup deformity), bony ankylosis, osteolysis of metatarsals, predilection for distal interphalangeal and proximal interphalangeal joints, relative sparing of metacarpal phalangeal and metatarsal phalangeal joints, paravertebral ossification, asymmetrical sacroiliitis, and rarity of “bamboo spine” when the spine is involved. Nearly half the patients with psoriatic arthritis have type human leukocyte antigen (HLA)-B27. Rest, splinting, passive motion, and nonsteroidal antiinflammatory drugs (NSAIDs) may provide symptomatic relief but do not prevent deformity. Methotrexate, cyclosporine, tacrolimus, and biologic agents are disease-modifying drugs that prevent deformity.
Psoriasis
breasts, and in the scalp, flexures, and axillae. Lesions in these areas are moist and erythematous, with yellow, greasy, soft scales, rather than dry and micaceous scales. Terms such as sebopsoriasis and seborrhiasis may be used to describe the condition of such patients.
Guttate psoriasis In this distinctive form of psoriasis typical lesions are the size of water drops, 2–5 mm in diameter. Lesions typically occur as an abrupt eruption following some acute infection, such as a streptococcal pharyngitis. Guttate psoriasis occurs mostly in patients under age 30. This type of psoriasis usually responds rapidly to broad-band ultraviolet (UV) B at erythemogenic doses. Suberythemogenic doses often have little impact on the lesions. This is one of the few forms of psoriasis where broadband UVB may have an advantage over narrow-band UVB. Minimal erythemogenic dose (MED) testing is recommended to allow for appropriately aggressive treatment. Recurrent episodes may be related to pharyngeal carriage of the responsible streptococcus by the patient or a close contact. A course of a semisynthetic penicillin (such as dicloxacillin, 250 mg four times a day for 10 days) with rifampin (600 mg/day for an adult) may be required to clear chronic streptococcal carriage.
Generalized pustular psoriasis (von Zumbusch)
Fig. 10-5 Penile psoriasis with erythema and silver scale.
Typical patients have had plaque psoriasis and often psoriatic arthritis. The onset is sudden, with formation of lakes of pus periungually, on the palms, and at the edge of psoriatic plaques. Erythema occurs in the flexures before the generalized eruption appears. This is followed by a generalized erythema and more pustules (Fig. 10-7). Pruritus and intense
Fig. 10-6 Psoriatic arthritis.
Fig. 10-7 Pustular psoriasis.
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Fig. 10-8 Geographic tongue in pustular psoriasis.
burning are often present. Mucous membrane lesions are common. The lips may be red and scaly, and superficial ulcerations of the tongue and mouth occur. Geographic or fissured tongue frequently occurs (Fig. 10-8). The patient is frequently ill with fever, erythroderma, hypo calcemia, and cachexia. A number of cases of acute respiratory distress syndrome associated with pustular and erythrodermic psoriasis have been reported. Other systemic complications include pneumonia, congestive heart failure, and hepatitis. Episodes are often provoked by withdrawal of systemic corticosteroids. The authors have also observed generalized pustular psoriasis as the presenting sign of Cushing’s disease. Other implicated drugs include iodides, coal tar, terbinafine, minocycline, hydroxychloroquine, acetazolamide, and salicylates. There is usually a strong familial history of psoriasis. Generalized pustular psoriasis may occur in infants and children with no implicated drug. It may also occur as an episodic event punctuating the course of localized acral pustular psoriasis. Acitretin is the drug of choice in this severe disease. The response is generally rapid. Isotretinoin is also effective. Cyclosporine, methotrexate, and biologicals are alternatives. Sometimes dapsone is effective in doses of 50–100 mg/day.
Fig. 10-9 Generalized pustular flare in a patient with acrodermatitis continua.
Acrodermatitis continua of Hallopeau Typical patients develop acral erythematous plaques studded with pustules. The nailbeds are heavily involved, and the fingernails float away on lakes of pus, resulting in anonychia. Hyperkeratosis often ensues, and the fingertips become increasingly painful, tapering to long keratotic points. Occasionally, patients may develop generalized pustular flares (Fig. 10-9). Acrodermatitis continua is discussed in more detail below.
Impetigo herpetiformis This term has been applied to generalized pustular psoriasis of pregnancy. Flexural erythema, studded with pustules, often occurs initially, followed by a generalized pustular flare and increasing toxicity. As the patients are pregnant, systemic retinoids are not appropriate. Many patients only respond to delivery, and early delivery should be strongly considered as soon as it is safe for the infant. Alternatively, patients may respond to prednisone at a dose of 1 mg/kg/day. The cortico steroid can also contribute to neonatal lung maturity.
Keratoderma blennorrhagicum (Reiter syndrome) Keratoderma blennorrhagicum resembles psoriasis both histologically and clinically, except for its tendency for thicker kera192
Fig. 10-10 Erythrodermic psoriasis.
totic lesions. Patients are often positive for HLA-B27 and develop reactive arthritis and skin disease after a bout of urethritis or enteritis.
Erythrodermic psoriasis Patients with psoriasis may develop a generalized erythroderma (Fig. 10-10). Erythrodermic psoriasis is covered in greater detail under exfoliative dermatitis.
Course The course of psoriasis is unpredictable. It usually begins on the scalp or elbows, and may remain localized in the original region for years. Chronic disease may also be almost entirely limited to the fingernails. Involvement over the sacrum may easily be confused with candidiasis or tinea. Onset may also be sudden and widespread.
Psoriasis
linked to psoriasis, including PSORS1 on chromosome 6 and within the MHC, and PSORS2 on chromosome 17q. It has also been shown that there are two subsets that differ in age of onset and in the frequency of HLA associations. Early onset is type I psoriasis and is associated mostly with Cw6, B57, and DR7. Late onset is type II and this predominantly features Cw2. PSORS9 has also been confirmed as a susceptibility locus for psoriasis. A variety of other HLA associations have been reported. It is believed that any individual who has B13 or B17 carries a five-fold risk of developing psoriasis. In pustular psoriasis HLA-B27 may be seen, whereas B13 and B17 are increased in guttate and erythrodermic psoriasis. In palmoplantar pustulosis, there is an association with HLA-B8, Bw35, Cw7, and DR3. HLA typing is a research tool for population-based studies, but is of limited value in assessing an individual patient.
Epidemiology
Fig. 10-11 Koebner phenomenon in psoriasis.
Two of the chief features of psoriasis are its tendency to recur and its persistence. The isomorphic response (Koebner phenomenon) is the appearance of typical lesions of psoriasis at sites of even trivial injury (Fig. 10-11). Lesions may occur at sites of scratches, incisions, and burns. Lesions may first appear after a viral exanthema or following pityriasis rosea. The isomorphic response may occur if psoriatic lesions are severely burned during phototherapy. With a reduction in light dosage, the erythema and burning resolve, and the plaques begin to clear. Woronoff’s ring is concentric blanching of the erythematous skin at or near the periphery of a healing psoriatic plaque. It is often the first sign that the patient’s psoriasis is responding to phototherapy. The palms and soles are sometimes exclusively affected, showing discrete erythematous dry scaling patches, circumscribed verrucous thickenings, or pustules on an erythematous base. The patches usually begin in the mid-portions of the palms or on the soles, and gradually expand. Psoriasis of the palms and soles is typically chronic and extremely resistant to treatment. Many studies report an association between hepatitis C and psoriasis, and hepatitis C has also been implicated in psoriatic arthritis. If treatment of psoriasis is to include a potentially hepatotoxic drug, such as methotrexate, a hepatitis C serology should be obtained. It should also be noted that interferon treatment of the hepatitis can further exacerbate or induce psoriasis. Anti-tumor necrosis factor (TNF)-α therapy shows promise in the treatment of psoriasis, even in the setting of chronic hepatitis C infection.
Inheritance In a large study of psoriasis in monozygotic twins, heritability was high and environmental influence low. Patients with psoriasis often have relatives with the disease, and the incidence typically increases in successive generations. Multifactorial inheritance is likely. Analysis of population-specific HLA haplotypes has provided evidence that susceptibility to psoriasis is linked to the class I and II major histocompatibility complex (MHC) on human chromosome 6. A number of genetic loci are
Psoriasis occurs with equal frequency in both sexes. Between 1 and 2% of the US population has psoriasis. It occurs less frequently in the tropics. It is less common in North American and West African black persons. Native Americans and native Fijians rarely have psoriasis. The onset of psoriasis is at a mean age of 27 years, but the range is wide, from the neonatal period to the seventies. Severe emotional stress tends to aggravate psoriasis in almost half of those studied. In pregnancy there is a distinct tendency for improvement or even temporary disappearance of lesions in the majority of women studied. After childbirth there is a tendency for exacerbation of lesions. Paradoxically, pregnancy is also the milieu for impetigo herpetiformis, and psoriasis may behave differently from one pregnancy to another in the same patient. A high prevalence of celiac disease has been noted in patients with psoriasis. Lymphoma also has an increased incidence in these patients, and psoriasis has been linked to the metabolic syndrome and a higher risk of cardiovascular disease.
Pathogenesis Psoriasis is a hyperproliferative disorder, but the proliferation is driven by a complex cascade of inflammatory mediators. Psoriasis appears to represent a mixed T-helper (Th)1 and Th17 inflammatory disease. Th17 cells appear to be more proximal in the inflammatory cascade. T cells and cytokines play pivotal roles in the pathophysiology of psoriasis. Overexpression of type 1 cytokines, such as IL-2, IL-6, IL-8, IL-12, IFN-γ and TNF-α, has been demonstrated, and overexpression of IL-8 leads to the accumulation of neutrophils. The main signal for Th1 development is IL-12, which promotes intracellular IFN-γ production. In animal models, shifting from Th1 to Th2 responses improves psoriasis. IL-4 is capable of inducing Th2 responses and improving psoriasis. Reduced expression of the anti-inflammatory cytokines IL-1RA and IL-10 has been found, and polymorphisms for IL-10 genes correlate with psoriasis. IL-10 is a type 2 cytokine with major influences on immuno regulation, inhibiting type 1 proinflammatory cytokine production. Patients on established traditional therapies show rising levels of IL-10 mRNA expression, suggesting that IL-10 may have antipsoriatic capacity. The response to biologic agents has demonstrated that CD2+ lymphocytes, CD-11a and TNF-α are important in the pathogenesis of psoriasis. IL-15 triggers inflammatory cell recruitment, angiogenesis, and production of inflammatory cytokines, including IFN-γ, TNF-α, and IL-17, all of which are upregulated in psoriatic lesions. The interplay is complex, but IL-17 193
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appears to be proinflammatory, while IL-22 may serve to retard keratinocyte differentiation. IL-23 stimulates survival, as well as proliferation of Th17 cells. Circulating NK cells are reduced in psoriasis. Specific targets for therapy include TNF-α, leukocyte function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) binding, and LFA-3/CD2 binding. An IL-15 monoclonal antibody has been shown to be effective in a mouse model of psoriasis.
Streptococci Streptococci play a role in some patients. Patients with psoriasis report sore throat more often than controls. Beta-hemolytic streptococci of Lancefield groups A, C, and G can cause exacerbation of chronic plaque psoriasis. Th1 cells recognize cellwall extract isolated from group A streptococci. HLA variation has a significant effect on the immune response to group A streptococci.
Stress Various studies have shown a positive correlation between stress and severity of disease. In almost half of patients studied, stress appears to play a significant role.
Drug-induced psoriasis Psoriasis may be induced by β-blockers, lithium, antimalarials, terbinafine, calcium channel blockers, captopril, glyburide, granulocyte colony-stimulating factor, interleukins, interferons, and lipid-lowering drugs. Systemic steroids may cause rebound or pustular flares. Antimalarials are associated with erythrodermic flares, but patients traveling to malaria-endemic regions should take appropriate prophylaxis. Often, drugs such as doxycycline or mefloquine are appropriate for the geographic area, but when a quinine derivative offers the best protection, it is generally better to take the prophylactic doses of a quinine derivative than to risk disease and full-dose treatment.
Pathology Histologically, all psoriasis is pustular. The microscopic pustules include spongiform intraepidermal pustules, and Munro microabscesses within the stratum corneum. In early guttate lesions, focal parakeratosis is noted within the stratum corneum. The parakeratotic focus typically has an outline resembling a child’s rendition of a seagull. Neutrophils are generally noted immediately above the focus of parakeratosis, but in some sections, the neutrophils will not be visible as a result of sampling error. In plaque psoriasis, neutrophilic foci are so numerous that they are rarely missed. Neutrophilic microabscesses are generally present at multiple levels in the stratum corneum, usually on top of small foci of parakeratosis. These foci generally alternate with areas of orthokeratotic stratum corneum, suggesting that the underlying spongiform pustules arise in a rhythmic fashion. The granular layer is absent focally, corresponding to areas producing foci of para keratosis. In well-developed plaques, there is regular epidermal acanthosis with long, bulbous rete ridges, thinning over the dermal papillae, and dilated capillaries within the dermal papillae. The last two findings correlate with the Auspitz sign. The stratum corneum may be entirely parakeratotic but still shows multiple small neutrophilic microabscesses at varying levels. Spongiosis is typically scant, except in the area immediately surrounding collections of neutrophils. In pustular psoriasis, geographic tongue, and Reiter syndrome, intraepidermal spongiform pustules tend to be much larger. Grossly pustular lesions often have little associated 194
acanthosis. In Reiter syndrome, the stratum corneum is often massively thickened, with prominent foci of neutrophils above parakeratosis, alternating with orthokeratosis. Acral lesions often demonstrate nondiagnostic features histologically. Spongiosis is typically prominent in these lesions and often leads to a differential diagnosis of psoriasis or chronic psoriasiform spongiotic dermatitis. Foci of neutrophils often contain serum and may be interpreted as impetiginized crusting. On direct immunofluorescence testing, the stratum corneum demonstrates intense fluorescence with all antibodies, complement, and fibrin. This fluorescence may be partially independent of the fluorescent label, as it has been noted in hematoxylin and eosin (H&E)-stained sections and frozen unstained sections. The same phenomenon of stratum corneum autofluorescence has been noted in some cases of candidiasis that demonstrate a psoriasiform histology. Psoriasis can generally be distinguished from dermatitis by the paucity of edema, the relative absence of spongiosis, the tortuosity of the capillary loops, and the presence of neutrophils above foci of parakeratosis. Neutrophils in the stratum corneum are commonly seen in tinea, impetigo, candidiasis, and syphilis, but rarely are found atop parakeratosis alternating with orthokeratosis in a rhythmic fashion. In psoriasiform syphilis the rete are typically long and slender, a vacuolar interface dermatitis is commonly present, dermal blood vessels appear to have no lumen because of endothelial swelling, and plasma cells are present in the dermal infiltrate. About onethird of biopsies of syphilis lack plasma cells, but the remaining characteristics still suggest the correct diagnosis. Psoriasiform lesions of mycosis fungoides exhibit epidermotropism of large lymphocytes with little spongiosis. The lymphocytes are typically larger, darker, and more angulated than the lymphocytes in the dermis. There is associated papillary dermal fibrosis, and the superficial perivascular infiltrate is asymmetrically distributed around the postcapillary venules, favoring the epidermal side (bare underbelly sign).
Clinical differential diagnosis Psoriasis must be differentiated from dermatomyositis, lupus erythematosus, seborrheic dermatitis, pityriasis rosea, lichen planus, eczema, and psoriasiform syphilid. The distribution in psoriasis is on the extensor surfaces, especially of the elbows and knees, and on the scalp; dermatomyositis shares this distribution, whereas lupus erythematosus generally lacks involvement of the extensor surfaces. Patients with dermatomyositis may exhibit a heliotrope sign, atrophy, poikiloderma, and nailfold changes. Advanced lesions of discoid lupus erythematosus often demonstrate follicular hyperkeratosis (carpet tack sign). Seborrheic dermatitis has a predilection for the eyebrows, nasolabial angle, ears, sternal region, and flexures. The scales in psoriasis are dry, white, and shiny, whereas those in seborrheic dermatitis are greasy and yellowish. On removal of the scales in psoriasis there is an oozing of blood from the capillaries (Auspitz sign), whereas this does not occur in seborrheic dermatitis. In pityriasis rosea the eruption is located on the upper arms, trunk, and thighs, and the duration is a matter of weeks. Lesions are typically oval and follow skin tension lines. Individual lesions show a crinkling of the epidermis and collarette scaling. A herald patch is frequently noted. Lichen planus chiefly affects the flexor surfaces of the wrists and ankles. Often the violaceous color is pronounced. In darkerskinned individuals, the lesions have a tendency to pronounced hyperpigmentation. The nails are not pitted as in psoriasis, but longitudinally ridged, rough, and thickened. Pterygium formation is characteristic of lichen planus.
Treatment Topical therapy is generally suitable for limited plaques. Localized treatments, such as the excimer laser or other forms of intense pulsed light, may be suitable for limited plaques. Phototherapy remains highly cost-effective for widespread psoriasis. Cyclosporine has a rapid onset of action, but is generally not suitable for sustained therapy. Methotrexate remains the systemic agent against which others are compared. Biologic agents can produce dramatic responses at dramatic expense. Rotating therapeutic agents that have varying toxicities have conceptual appeal, and combination therapy may reduce toxicity and reduce the incidence of neutralizing antibodies to agents such as infliximab. Attention should be paid to comorbidities including metabolic syndrome, cardiac risk, and joint manifestations.
Topical treatment Corticosteroids Topical application of corticosteroids in creams, ointments, lotions, foams, and sprays is the most frequently prescribed therapy for psoriasis. Class I steroids are suitable for 2-week courses of therapy on most body areas. Therapy can be continued with pulse applications on weekends to reduce the incidence of local adverse effects. On the scalp, corticosteroids in propylene glycol, gel, foam, and spray bases are preferred by most white patients. Black patients may find them drying, and may prefer oil and ointment preparations. Low to midstrength creams are preferred in the intertriginous areas and on the face. To augment effectiveness of topical corticosteroids in areas with thick keratotic scale, the area should be hydrated prior to application, and covered with an occlusive dressing of a polyethylene film (Saran wrap) or a sauna suit. Unfortunately, there is typically a rapid recurrence of disease when topical corticosteroid therapy is discontinued. Side effects include epidermal atrophy, steroid acne, miliaria, and pyoderma. Intralesional injections of triamcinolone are helpful for refractory plaques. Triamcinolone acetonide (Kenalog) suspension, 10 mg/mL, may be diluted with sterile saline to make a concentration of 2.5–5 mg/mL. Good results are also obtained in the treatment of psoriatic nails by injecting triamcinolone into the region of the matrix and the lateral nailfold. A digital block can be performed prior to injection to provide anesthesia. Injections are given once a month until the desired effect is achieved.
Tars Crude coal tar, and tar extracts such as liquor carbonis detergens, can be compounded into agents for topical use. Tar bath oils and shampoos are readily available. Oil of cade (pine tar) or birch tar in concentrations of 5–10% may also be incorporated into ointments. The odor of all tars may be offensive.
Anthralin Anthralin is effective, but is irritating and stains skin, clothing, and bedding. To avoid these drawbacks, short-contact anthra-
lin treatment (SCAT) can be helpful, with anthralin washed off after 15–30 min. In warmer climates, SCAT is often done outdoors to keep the mess out of the house. Anthralin exerts a direct effect on keratinocytes and leukocytes by suppressing neutrophil superoxide generation and inhibiting monocytederived IL-6, IL-8, and TNF-α.
Tazarotene
Psoriasis
Hand eczema may resemble psoriasis. In general, psoriatic lesions tend to be more sharply marginated, but at times the lesions are indistinguishable. Psoriasiform syphilid has infiltrated copper-colored papules, often arranged in a figurate pattern. Serologic tests for syphilis are generally positive, but prozone reactions may occur, and the serum may have to be diluted in order to obtain a positive test. Generalized lymph adenopathy and mucous patches may be present.
Tazarotene is a nonisomerizable retinoic acid receptor-specific retinoid. It appears to treat psoriasis by modulating keratinocyte differentiation and hyperproliferation, as well as by suppressing inflammation. Combining its use with a topical corticosteroid and weekend pulse therapy can decrease irritation.
Calcipotriene Vitamin D3 affects keratinocyte differentiation partly through its regulation of epidermal responsiveness to calcium. Treatment with the vitamin D analog calcipotriene (Dovonex) in ointment, cream, or solution form has been shown to be very effective in the treatment of plaque-type and scalp psoriasis. Combination therapy with calcipotriene and highpotency steroids may provide greater response rates, fewer side effects, and steroid-sparing. Calcipotriene is unstable in the presence of many other topical agents and degrades in the presence of UV light. Monitoring of serum calcium levels in adults is not required. Calcipotriene plus betamethasone dipropionate (Taclonex) is more effective than either agent alone.
Macrolactams (calcineurin inhibitors) Topical macrolactams such as tacrolimus and pimecrolimus are especially helpful for thin lesions in areas prone to atrophy or steroid acne. The burning commonly associated with these agents can be problematic, but may be avoided by prior treatment with a corticosteroid, and by application to dry skin, rather than after bathing.
Salicylic acid Salicylic acid is used as a keratolytic agent in shampoos, creams, and gels. It can promote the absorption of other topical agents. Widespread application may lead to salicylate toxicity manifesting with tinnitus, acute confusion, and refractory hypoglycemia, especially in patients with diabetes and those with compromised renal function.
Ultraviolet light Phototherapy is a cost-effective and underutilized modality for psoriasis. In most instances sunlight improves psoriasis. However, severe burning of the skin may cause the Koebner phenomenon and an exacerbation. Artificial UVB light is produced by fluorescent bulbs in broad-band or narrow-band spectrums. Maximal effect is usually achieved at MEDs. Although suberythemogenic doses can be effective, the response is slower than with erythemogenic regimens. With treatment, a tanning response occurs, and the dose must be increased to maintain efficacy. Maintenance UVB phototherapy after clearing contributes to the duration of remission and is justified for many patients. Using a monochromator, it has been shown that wavelengths of 254, 280, and 290 nm are ineffective; at 296, 300, 304, and 313 nm there is clearing. Narrow-band UVB (peak emission around 311 nm) has been shown to be more effective in treating psoriasis than broad-band UVB. Erythemogenic doses are not required in order to achieve a response. The response rates are better than 70% and close to those achievable with PUVA therapy. 195
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Goeckerman technique The Goeckerman technique remains an effective and costeffective method of treatment. In its modern form, a 2–5% tar preparation is applied to the skin, and a tar bath is taken at least once a day. The excess tar is removed with mineral or vegetable oil, and UV light is given. In psoriasis daycare centers, patients clear in an average of 18 days, and 75% remain free of disease for extended periods. The addition of a topical corticosteroid to the Goeckerman regimen shortens the time required for remission. Phototoxic reactions (tar smarts) may occur as a result of UVA generated by the predominantly UVB bulbs.
Methotrexate
Local hyperthermia can clear psoriatic plaques, but relapse is usually rapid. Microwave hyperthermia may produce significant complications, such as pain over bony prominences and tissue destruction.
This folic acid antagonist remains the standard against which other systemic treatments are measured. Methotrexate has a greater affinity for dihydrofolic acid reductase than has folic acid. The indications for the use of methotrexate include psoriatic erythroderma, psoriatic arthritis, acute pustular psoriasis (von Zumbusch type), or widespread body surface involvement. Localized pustular psoriasis or palmoplantar psoriasis that impairs normal function and employment may also require systemic treatment. It is important to make sure that the patient has no history of liver or kidney disease. Methotrexate can be toxic to the liver and decreased renal clearance can enhance toxicity. Other important factors to consider are alcohol abuse, cryptogenic cirrhosis, severe illness, debility, pregnancy, leukopenia, thrombocytopenia, active infectious disease, immunodeficiency, anemia, colitis, and ability to comply with directions. Hepatic enzymes, bilirubin, serum albumin, creatinine, alkaline phosphatase, complete blood count (CBC), platelet count, hepatitis serology (B and C), HIV antibody, and urinalysis should all be evaluated before starting treatment. Patients with hypoalbuminemia have a higher risk of developing pulmonary complications. The need for liver biopsy remains controversial. Biopsy is not without risks and is not commonly performed in the setting of methotrexate therapy for rheumatic disease. However, patients with psoriasis have a greater risk of liver disease than other patient populations. In most patients with no risk factors for liver disease, the first liver biopsy is commonly obtained at approximately 1.0–1.5 g of cumulative methotrexate and repeated every subsequent 1.5–2.0 g until a total of 4.0 g is reached. The frequency then changes to every 1.0–1.5 g cumulative intervals. These recommendations are likely to change as more data are evaluated. Weekly blood counts and monthly liver enzyme assessment are recommended at the onset of therapy or when the dosage is changed. Monitoring of aminoterminal procollagen III peptide and metabolic panels that predict the risk of fibrosis (NASH Fibrosure) may reduce the need for liver biopsy. Numerous treatment schedules have evolved. The authors recommend either three divided oral doses (12 h apart) weekly, weekly single doses orally, or single weekly subcutaneous injections. The weekly dose varies from 5 mg to more than 50 mg, with most patients requiring 15–30 mg a week. Once a single dose exceeds 25 mg, oral absorption is unpredictable and subcutaneous injections are recommended. Mid-week doses can result in severe toxicity and must be avoided. Oral or cutaneous ulceration may be a sign that the patient has taken a mid-week dose. Oral folic acid has been reported to decrease side effects, especially nausea, and doses of 1–4 mg/day are used. Oral folic acid is not adequate for the treatment of overdosage and leukovorin must be used in such cases.
Occlusive treatment
Cyclosporine
Ingram technique The Ingram technique consists of a daily coal tar bath in a solution such as 120 mL liquor carbonis detergens to 80 L of warm water. This is followed by daily exposure to UV light for increasing periods. An anthralin paste is then applied to each psoriatic plaque. Talcum powder is sprinkled over the lesions and stockinette dressings are applied. Modern versions of the technique employ SCAT.
PUVA therapy High-intensity longwave UV radiation (UVA) given 2 h after ingestion of 8-methoxypsoralen (Oxsoralen-Ultra), twice a week, is highly effective, even in severe psoriasis. Most patients clear in 20–25 treatments, but maintenance treatment is needed. Although PUVA therapy is highly effective, in patients with less than 50% of the skin surface affected, UVB may be as good. Polyethylene sheet bath PUVA is another therapeutic alternative to oral psoralen-UVA. The patient is immersed in a psoralen solution contained in plastic sheeting that conforms to the patient’s body. Oral psoralen can produce cataracts, and protective eyewear must be used. PUVA therapy is a risk factor for skin cancer, including squamous cell carcinoma and melanoma. Arsenic exposure is a more significant cofactor than prior exposure to methotrexate, UVB, or concomitant use of topical tar. Men treated without genital protection are at an increased risk of developing squamous cell carcinomas of the penis and scrotum. Although the risk of cancer is dose-related, there is no definitive threshold dose of cumulative PUVA exposure above which carcinogenicity can be predicted.
Surgical treatment In patients with pharyngeal colonization by streptococci, an excellent response has been reported after tonsillectomy. More effective antibiotic regimens, such as a 10-day course of dicloxacillin combined with rifampin (600 mg/day for an adult), have largely replaced tonsillectomy.
Hyperthermia
Occlusion with surgical tape or dressings can be effective as monotherapy or when combined with topical drugs.
Systemic treatment Corticosteroids The hazards of the injudicious use of systemic corticosteroids must be emphasized. There is great risk of “rebound” or induction of pustular psoriasis when therapy is stopped. 196
Corticosteroid use is generally restricted to unique circumstances, such as impetigo herpetiformis when expeditious delivery is not possible.
The therapeutic benefit of cyclosporine in psoriatic disease may be related to downmodulation of proinflammatory epidermal cytokines. The microemulsion formulation Neoral has greater bioavailability and is now standard. Doses of 2–5 mg/kg/day generally produce rapid clearing of psoriasis. Unfortunately, the lesions recur rapidly as well, and transition to another form of therapy is required. Treatment durations of up to 6 months are associated with a low incidence of renal complications, but blood pressure and serum creatinine must
Diet The anti-inflammatory effects of fish oils rich in n-3 polyunsaturated fatty acids have been demonstrated in rheumatoid arthritis, inflammatory bowel disease, psoriasis, and asthma. n-3 and n-6 polyunsaturated fatty acids affect a variety of cytokines, including IL-1, IL-6, and TNF. Herbal remedies have also been used with variable effects. Many of these products are unpalatable, and their efficacy does not compare favorably to pharmacologic agents.
Oral antimicrobial therapy The association of streptococcal pharyngitis with guttate psoriasis is well established. Staphylococcus aureus and streptococci secrete exotoxins that act as superantigens, producing massive T-cell activation. Oral antibiotic therapy for patients with psoriasis infected with these organisms is imperative. The efficacy of antimicrobial agents in other subsets of psoriasis is unclear. Oral bile acid supplementation has been shown to improve psoriasis, presumably by affecting the microflora and endotoxins in the gut. Oral ketoconazole, itraconazole, and other antibiotics have shown efficacy in a limited number of patients with psoriasis.
Retinoids Oral treatment with the aromatic retinoid ethylester, etretinate, was effective in many patients with psoriasis, especially in pustular disease. Because of its long half-life, the drug has been replaced by acitretin. Alcohol ingestion can convert acitretin to etretinate and is strongly discouraged. 13-Cisretinoic acid can also produce good results in some patients with pustular psoriasis. All of these drugs are potent teratogens and elevations in triglycerides may complicate therapy. Combinations of retinoic acids with photochemotherapy can be effective in chronic plaque psoriasis, resulting in lowered cumulative doses of light.
Dapsone Dapsone use is limited largely to palmoplantar pustulosis or other variants of pustular psoriasis. Even in this setting, it is a second- or third-line agent with limited efficacy.
Biologic agents A number of biologic agents are available that can produce dramatic responses in some patients with psoriasis; all are expensive. Three agents block TNF-α. Infliximab is a chimeric monoclonal antibody to TNF-α and requires intravenous infusion; etanercept is a fusion protein of human TNF type II receptor and the Fc region of IgG1; and adalimumab is a recombinant, fully human IgG1 monoclonal antibody to TNFα. Alefacept is a fusion protein of the external domain of LFA-3 and the Fc region of IgG1; it blocks T-cell activation and triggers apoptosis of pathogenic T cells. Efalizumab, a humanized monoclonal antibody to the CD11a portion of LFA-1, has been withdrawn from the market. Ustekinumab, a human monoclonal antibody against IL-12 and 23, is the first of a new class of agents that appear highly effective. They block the inflammatory pathway at a more proximal point than TNF agents. Neutralizing antibodies may decrease the effectiveness of many of the biologic agents.
Percentage of patients clearing with each drug Published data allow for various comparisons between biologic agents, but as trials are designed by the manufacturer to demonstrate the efficacy of the agent, the endpoints of some
trials differ. In controlled trials of infliximab, the percentage of patients reaching at least 75% improvement from baseline in the psoriasis area and severity index (PASI 75) at week 10 is about 70% with infliximab 3 mg/kg and 90% with 5 mg/ kg, as compared to 6% with placebo. About 35% of patients receiving etanercept, 25 mg subcutaneously twice a week, achieve PASI 75 at 12 weeks and 45% at 24 weeks. With the 50 mg induction dose administered twice a week, about 46% of patients achieve PASI 75 at 12 weeks and 50% at 24 weeks. About 14% of patients receiving 12 weekly intramuscular or intravenous injections of alefacept will achieve PASI 75, and about 38% PASI 50. After two 12-injection courses, about 26% of patients reach PASI 75 and 55% PASI 50. The onset of action is somewhat slower than with other agents, but ultimate clearing can be excellent. The data available suggest that about 53% of patients taking 40 mg of adalimumab every other week achieve PASI 75 by week 12, and about 80% of those taking 40 mg a week achieve PASI 75. An analysis of 24 randomized controlled trials including 9384 patients suggested that infliximab was superior to the other agents studied, and that adalimumab was superior to etanercept, 50 mg twice weekly, and cyclosporine. Ustekinumab was included in the study. A phase III, parallel, double-blind, placebo-controlled study of ustekinumab for moderate to severe psoriasis (45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks) showed that 67.1% of those who received 45 mg and 66.4% receiving 90 mg achieved PASI 75 at week 12. In a second multicenter, phase III, double-blind, placebo-controlled trial of ustekinumab in patients with moderate to severe psoriasis, 66.7% of patients receiving 45 mg and 75.7% receiving 90 mg achieved PASI 75.
Psoriasis
be monitored and doses adjusted accordingly. Usually, the dose is reduced if the baseline creatinine increases by one-third.
Rapidity of clearing and relapse The effects of infliximab are rapid and similar to those achieved with cyclosporine. In contrast to cyclosporine, clinical improvement after three intravenous infusions of infliximab is maintained for as long as 6 months in approximately half the patients. Adalimumab is also rapid in onset, with many patients demonstrating a response within the first week of treatment. About 15% of patients treated with alefacept will maintain benefits for more than 6 months.
Risks TNF agents may induce flares of psoriasis through upregulation of plasmacytoid dendritic cells. This may be a class effect. The biologic agents all suppress the normal immune response. Infliximab has been associated with reactivation of tuberculosis, demyelinating disease, and serious systemic opportunistic infection. It may also lose its effect because of neutralizing antibodies. Methotrexate or azathioprine may be needed as concomitant therapy to reduce the incidence of neutralizing antibodies and infusion reactions. Even though adalimumab is a fully human antibody, it may also induce an antibody response. Serious infections have been reported in patients with rheumatoid arthritis treated with this agent. Etanercept has been associated with infection, onset, or exacerbation of multiple sclerosis, vasculitis, and lupus erythematosus-like manifestations. All these manifestations are rare, and may not be statistically increased from the general population. A single 12-week course of alefacept does not appear to impair primary or secondary antibody responses to a neoantigen or memory responses to a recall antigen, but roughly 10% of patients have to interrupt therapy because CD4 counts fall below 250/mm3, and CD4 counts must be monitored with this agent. Many of the reported complications, such as lymphoma, demyelinating disease, and infection, are not unique to any one biologic agent. 197
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The National Psoriasis Foundation has endorsed a recommendation that all patients be screened for latent tuberculosis infection prior to any immunologic therapy. They recommend delaying immunologic therapy until prophylaxis for latent tuberculosis infection is completed, although they note that patients with severe disease may be treated after 1–2 months of prophylaxis. IFN-γ assays have greater specificity than tuberculin skin tests and are being used along with imaging studies to confirm tuberculosis in patients with positive skin tests.
Combination therapy In more severe forms of psoriasis a combination of treatment modalities may be employed. In treating patients with metho trexate, for example, concomitant topical agents may be used to minimize the dose. Methotrexate has been combined with infliximab to reduce the incidence of neutralizing antibodies, and has been used with acitretin in managing patients with severe, generalized pustular psoriasis. The use of PUVA and retinoids is called Re-PUVA and has been studied extensively. Acitretin has been combined with biologic agents to treat refractory psoriasis. Combination systemic therapy has the potential to reduce overall toxicity if the toxicities of each agent are different. However, new regimens should be used with caution because the potential for cumulative toxicity or drug interaction exists.
Alternative therapies Alternative therapies for psoriasis include mycophenolate mofetil, sulfasalazine, paclitaxel, azathioprine, fumaric acid esters, climatotherapy, and Grenz ray therapy. Nail disease can respond to systemic agents, topical retinoids, local triamcinolone injections, and topical 5-fluorouracil. The latter agent can cause onycholysis if applied to the free edge of the nail. Akaraphanth R, et al: Efficacy of a far erythemogenic dose of narrowband ultraviolet B phototherapy in chronic plaque-type psoriasis. J Dermatol 2010; 37(2):140–145. Asarch A, et al: Th17 cells: a new paradigm for cutaneous inflammation. J Dermatolog Treat 2008; 19(5):259–266. Bartlett BL, et al: Ustekinumab for chronic plaque psoriasis. Lancet 2008; 371(9625):1639–1640. Benoit S, et al: Childhood psoriasis. Clin Dermatol 2007; 25(6):555–562. Berends MA, et al: Reliability of the Roenigk classification of liver damage after methotrexate treatment for psoriasis: a clinicopathologic study of 160 liver biopsy specimens. Arch Dermatol 2007; 143(12):1515–1519. Berneburg M, et al: Phototherapy with narrowband vs. broadband UVB. Acta Derm Venereol 2005; 85:98. Beyer V, et al: Recent trends in systemic psoriasis treatment costs. Arch Dermatol 2010; 146(1):46–54. Blauvelt A: T-helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis. J Invest Dermatol 2008; 128(5):1064–1067. Boehncke WH, et al: Managing comorbid disease in patients with psoriasis. BMJ 2010 Jan 15; 340:b5666. Bos JD, et al: Topical treatments in psoriasis: today and tomorrow. Clin Dermatol 2008; 26(5):432–437. Brimhall AK, et al: Safety and efficacy of alefacept, efalizumab, etanercept and infliximab in treating moderate to severe plaque psoriasis: a meta-analysis of randomized controlled trials. Br J Dermatol 2008; 159(2):274–285. Cather JC, et al: Combining traditional agents and biologics for the treatment of psoriasis. Semin Cutan Med Surg 2005; 24:37. Conaghan PG, et al: Improving recognition of psoriatic arthritis. Practitioner 2009; 253(1724):15–18, 2–3. Davis MD, et al: Goeckerman treatment: neglected in the consensus approach for critically challenging case scenarios in moderate to severe psoriasis. J Am Acad Dermatol 2010; 62(3):508. Doherty SD, et al: National Psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis
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treated with systemic and biologic agents. J Am Acad Dermatol 2008; 59(2):209–217. Duffin KC, et al: Genetics of psoriasis and psoriatic arthritis: update and future direction. J Rheumatol 2008; 35(7):1449–1453. Evers AW, et al: Treatment nonadherence and long-term effects of narrowband UV-B therapy in patients with psoriasis. Arch Dermatol 2010; 146(2):198–199. Feuchtenberger M, et al: Psoriatic arthritis: therapeutic principles. Clin Dermatol 2008; 26(5):460–463. Fluhr JW, et al: Emollients, moisturizers, and keratolytic agents in psoriasis. Clin Dermatol 2008; 26(4):380–386. Gori A, et al: Unusual presentation of tuberculosis in an infliximabtreated patient—which is the correct TB screening before starting a biologic? Dermatol Ther 2010 Jan–Feb; 23(Suppl 1):S1–3. Gottlieb A, et al: Guidelines of care for the management of psoriasis and psoriatic arthritis: section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol 2008; 58(5):851–864. Gottlieb AB, et al: Psoriasis and the metabolic syndrome. J Drugs Dermatol 2008; 7(6):563–572. Halverstam CP, et al: Nonstandard and off-label therapies for psoriasis. Clin Dermatol 2008; 26(5):546–553. Hernandez C, et al: Tuberculosis in the age of biologic therapy. J Am Acad Dermatol 2008; 59(3):363–380. Heydendael VM, et al: Methotrexate versus cyclosporine in moderate-tosevere chronic plaque psoriasis. N Engl J Med 2003; 349:658. Homey B, et al: Chemokines and other mediators as therapeutic targets in psoriasis vulgaris. Clin Dermatol 2008; 26(5):539–545. Huang W, et al: To test or not to test? An evidence-based assessment of the value of screening and monitoring tests when using systemic biologic agents to treat psoriasis. J Am Acad Dermatol 2008; 58(6):970–977. Lebwohl M, et al: The evolving role of topical treatments in adjunctive therapy for moderate to severe plaque psoriasis. Cutis 2007; 80(5 Suppl):29–40. Lebwohl M, et al: From the Medical Board of the National Psoriasis Foundation: monitoring and vaccinations in patients treated with biologics for psoriasis. J Am Acad Dermatol 2008; 58(1):94–105. Lecluse LL, et al: Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. Arch Dermatol 2010; 146(2):127–132. Leonardi CL, et al: Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371(9625):1665–1674. Li YY, et al: Targeting leukocyte recruitment in the treatment of psoriasis. Clin Dermatol 2008; 26(5):527–538. MacDonald A, et al: Psoriasis: advances in pathophysiology and management. Postgrad Med J 2007; 83(985):690–697. Review. Maurice PD, et al: Monitoring patients on methotrexate: hepatic fibrosis not seen in patients with normal serum assays of aminoterminal peptide of type III procollagen. Br J Dermatol 2005; 152:451. Menter A, et al: Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008; 58(5):826–850. Mössner R, et al: Tumor necrosis factor antagonists in the therapy of psoriasis. Clin Dermatol 2008; 26(5):486–502. Neyns B, et al: Cetuximab treatment in a patient with metastatic colorectal cancer and psoriasis. Curr Oncol 2008; 15(4):196–197. Nolan BV, et al: A review of home phototherapy for psoriasis. Dermatol Online J 2010; 16(2):1. Papp KA: Monitoring biologics for the treatment of psoriasis. Clin Dermatol 2008; 26(5):515–521. Papp KA, et al: Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371(9625):1675–1684. Qureshi AA, et al: Psoriatic arthritis screening tools. J Rheumatol 2008; 35(7):1423–1425. Ritchlin CT: From skin to bone: translational perspectives on psoriatic disease. J Rheumatol 2008; 35(7):1434–1437. Schneider LA, et al: Phototherapy and photochemotherapy. Clin Dermatol 2008; 26(5):464–476.
Reactive arthritis with conjunctivitis/urethritis/ diarrhea (Reiter syndrome) Reiter syndrome is a characteristic clinical triad of urethritis, conjunctivitis, and arthritis. The disease occurs chiefly in young men of HLA-B27 genotype, generally following a bout of urethritis or diarrheal illness. Systemic involvement can include the gastrointestinal tract, kidneys, central nervous system, and cardiovascular system. As few patients present with the classic triad, the American College of Rheumatology recognizes criteria for limited manifestations of the syndrome, including peripheral arthritis of more than 1 month’s duration in association with urethritis, cervicitis, or bilateral conjunctivitis. Hans Reiter was a Nazi war criminal, involved with or having knowledge of involuntary sterilization, as well as a study of an experimental typhus vaccine that resulted in hundreds of deaths of concentration camp internees. Several authors have suggested that he no longer be afforded the recognition of using his name to designate the syndrome.
Fig. 10-12 Genital involvement in reactive arthritis.
Reactive arthritis with conjunctivitis/urethritis/diarrhea
Schön MP: Treatment of psoriasis: a journey from empiricism to evidence. Clin Dermatol 2008; 26(5):417–418. Singh SK, et al: Th17 cells in the pathogenesis of psoriasis. Curr Allergy Asthma Rep 2008; 8(5):382–385. Taylor WJ, et al: Drug use and toxicity in psoriatic disease: focus on methotrexate. J Rheumatol 2008; 35(7):1454–1457. Tesmer LA, et al: Th17 cells in human disease. Immunol Rev 2008; 223:87–113. Thaçi D: Long-term data in the treatment of psoriasis. Br J Dermatol 2008; 159(Suppl 2):18–24. Warren RB, et al: Systemic therapies for psoriasis: methotrexate, retinoids, and cyclosporine. Clin Dermatol 2008; 26(5):438–447. Weiss SC, et al: An assessment of the cost-utility of therapy for psoriasis. Ther Clin Risk Manag 2006; 2(3):325–328. Wozel G: Psoriasis treatment in difficult locations: scalp, nails, and intertriginous areas. Clin Dermatol 2008; 26(5):448–459. Zell D, et al: Genetic alterations in psoriasis. J Invest Dermatol 2008; 128(7):1614.
Clinical features Any part of the triad may occur first, often accompanied by fever, weakness, and weight loss. Although the inciting urethritis may be bacterial, later manifestations include a nonbacterial urethritis with painful urination and pyuria. Cystitis, prostatitis, and seminal vesiculitis may be accompaniments. Vulvar ulceration has been reported. About one-third of patients develop conjunctivitis, which may be bulbar, tarsal, or angular. Keratitis is usually superficial and extremely painful. Iritis is common, especially in recurrent cases. Infrequently, optic neuritis may occur. An asymmetric arthritis affects peripheral joints, especially those that are weightbearing. Its onset is usually sudden. Pain in one or both heels is a frequent symptom. Sacroiliitis may develop in up to twothirds of patients, most of whom are of HLA-B27 type. The skin involvement commonly begins with small, guttate, hyperkeratotic, crusted or pustular lesions of the genitals (Fig. 10-12), palms, or soles. Involvement of the glans penis (balanitis circinata) occurs in 25% of patients. Lesions on the soles and trunk often become thickly crusted or hyperkeratotic. The eruption on the soles is known as keratoderma blennorrhagicum (Fig. 10-13), and occurs in 10% of patients. The buccal, palatal, and lingual mucosa may show painless, shallow, red erosions. The nails become thick and brittle, with heavy subungual keratosis. Children are much more likely to have the post-dysenteric form, often with conjunctivitis and arthritis as the most prominent complaints.
Fig. 10-13 Keratoderma blennorrhagicum.
The syndrome generally follows an infectious urethritis or diarrheal illness. Implicated organisms include Chlamydia, Shigella, Salmonella, Yersinia, Campylobacter, Ureaplasma, Borrelia, Cryptosporidium, gonococci, and bacillus Calmette–Guérin (BCG). Chlamydia trachomatis and Ureaplasma urealyticum have been isolated from the synovial fluid of affected joints, and some patients respond to antibiotic therapy. Reiter syndrome has also been observed in HIV disease, but may not be directly related to the virus, as it frequently occurs under treatment as the immune response improves. The disease has also been triggered by adalimumab and leflunomide in the setting of ankylosing spondyloarthropathy and Crohn disease. The syndrome involves both infection and the resulting immunologically mediated tissue injury in a genetically predisposed patient. HLA-B27 is present in about 80% of cases. A positive family history is often noted. 199
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Peripheral leukocytosis of 10 000–20 000/mm3 and elevated sedimentation rate are the most consistent findings. There is no specific test for Reiter syndrome. The differential diagnosis includes rheumatoid arthritis, ankylosing spondylitis, gout, psoriatic arthritis, gonococcal arthritis, acute rheumatic fever, chronic mucocutaneous candidiasis, and serum sickness. The presence of associated mucocutaneous lesions establishes the diagnosis. Some cases of Lyme disease overlap with the syndrome. Individual skin lesions may be indistinguishable from those in psoriasis. Hyperkeratotic lesions generally have a thicker scale crust than most psoriatic plaques, but are otherwise identical. Mucocutaneous lesions are generally self-limited and clear with topical steroids. Joint disease is managed with rest and NSAIDs. Antibiotics, such as doxycycline, have been effective in some cases. Immunosuppressive agents, such as methotrexate, are commonly employed for refractory joint disease. Infliximab has been successful in treating severe disease. Refractory skin lesions are treated like refractory psoriasis, and severely affected patients have responded to acitretin or cyclosporine. Panush RS, et al: Retraction of the suggestion to use the term “Reiter’s syndrome” sixty-five years later: the legacy of Reiter, a war criminal, should not be eponymic honor but rather condemnation. Arthritis Rheum 2007; 56(2):693–694. Sampaio-Barros PD, et al: Frequency of HLA-B27 and its alleles in patients with Reiter syndrome: comparison with the frequency in other spondyloarthropathies and a healthy control population. Rheumatol Int 2008; 28(5):483–486. Thielen AM, et al: Reiter syndrome triggered by adalimumab (Humira) and leflunomide (Arava) in a patient with ankylosing spondylarthropathy and Crohn disease. Br J Dermatol 2007; 156(1):188–189. Townes JM: Reactive arthritis after enteric infections in the United States: the problem of definition. Clin Infect Dis 2010; 50(2):247–242. Wallace DJ, et al: The physician Hans Reiter as prisoner of war in Nuremberg: a contextual review of his interrogations (1945–1947). Semin Arthritis Rheum 2003; 32:208. Yu D, et al: Role of bacteria and HLA-B27 in the pathogenesis of reactive arthritis. Rheum Dis Clin North Am 2003; 29:21.
Subcorneal pustular dermatosis (Sneddon–Wilkinson disease) In 1956, Sneddon and Wilkinson described a chronic pustular disease, which occurred chiefly in middle-aged women. The pustules are superficial and arranged in annular and serpiginous patterns, especially on the abdomen, axillae, and groins. Cultures from the pustules are sterile. Oral lesions are rare. Some cases are associated with a monoclonal gammopathy (usually IgA). The condition is chronic, with remissions of variable duration. Histologically, the pustules form below the stratum corneum, as in impetigo. Acantholysis is absent, but spongiform pustules may be noted in the upper epidermis. The histologic differential diagnosis includes pustular psoriasis, and superficial fungal and bacterial infections. Some cases will show upper epidermal intercellular IgA staining. IgA pemphigus shows significant overlap with subcorneal pustular dermatosis. Presentations of IgA pemphigus include subcorneal pustular dermatosis and intraepidermal neutrophilic IgA dermatosis types. Using immunoblotting techniques, Hashimoto et al have shown that human desmocollin 1 is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. Localized cases may respond well to topical corticosteroids. Dapsone, 50–200 mg/day (for an adult), is effective for most 200
of the remaining cases. Some patients have responded better to sulfapyridine therapy. Acitretin, narrow-band UVB phototherapy, colchicine, azithromycin, biologicals, and tetracycline with niacinamide may also be effective. Bedi MKL: Successful treatment of long-standing, recalcitrant subcorneal pustular dermatosis with etanercept. Skinmed 2007 Sep–Oct; 6(5):245–247. Bliziotis I, et al: Regression of subcorneal pustular dermatosis type of IgA pemphigus lesions with azithromycin. J Infect 2005; 51:E31. Cheng S, et al: Subcorneal pustular dermatosis: 50 years on. Clin Exp Dermatol 2008; 33(3):229–233. Howell SM, et al: Rapid response of IgA pemphigus of the subcorneal pustular dermatosis subtype to treatment with adalimumab and mycophenolate mofetil. J Am Acad Dermatol 2005; 53:541.
Eosinophilic pustular folliculitis Eosinophilic pustular folliculitis (EPF) was first described in 1970 by Ofuji but is also referred to as sterile eosinophilic pustulosis. It occurs more commonly in males, and is mostly reported in Asia. The mean age of onset is 35. It is characterized by pruritic, follicular papulopustules that measure 1–2 mm. The lesions tend to be grouped and plaques commonly form. New lesions may form at the edges of the plaques, leading to peripheral extension, while central clearing takes place. The most frequent site is the face, particularly over the cheeks. The trunk and upper extremities are commonly affected, and 20% have palmoplantar pustules. The distribution is commonly asymmetrical, and the typical course is one of spontaneous remissions and exacerbations lasting several years. The condition must be distinguished from HIV-associated eosinophilic folliculitis, which is discussed in Chapter 19. A similar condition has occurred in association with hepatitis C virus infection, with allopurinol, and during pregnancy. Histologically, there is spongiosis and vesiculation of the follicular infundibulum and heavy infiltration with eosino phils. Follicular mucinosis may be present. There is a peripheral eosinophilia in half the cases, and pulmonary eosinophilia has been described. The cause is unknown; but numerous studies have implicated chemotactic substances, ICAM-1, and cyclooxygenase-generated metabolites. Tryptase-positive and chymase-negative mast cells have also been implicated. Indomethacin is effective in the vast majority of patients. Topical and intralesional corticosteroids, clofazimine, mino cycline, isotretinoin, UVB therapy, dapsone, colchicine, cyclosporine, and cetirizine have also been reported as effective. Childhood cases have been described. This subset differs from the typical cases in Asian males. Pediatric patients develop sterile pustules and papules preferentially over the scalp, although scattered clusters of pustules may occur over the trunk and extremities. Leukocytosis and eosinophilia are often present. Recurrent exacerbations and remissions usually occur, with eventual spontaneous resolution. Highpotency topical steroids are the treatment of choice in pediatric patients. Gul U, et al: Eosinophilic pustular folliculitis: the first case associated with hepatitis C virus. J Dermatol 2007; 34(6):397–399. Kus S, et al: Eosinophilic pustular folliculitis (Ofuji’s disease) exacerbated with pregnancies. J Eur Acad Dermatol Venereol 2006; 20(10):1347–1348. Sufyan W, et al: Eosinophilic pustular folliculitis. Arch Pathol Lab Med 2007; 131(10):1598–1601. Yoneda K, et al: Eosinophilic pustular folliculitis associated with pulmonary eosinophilia. J Eur Acad Dermatol Venereol 2007 Sep; 21(8):1122–1124.
Recalcitrant palmoplantar eruptions Dermatitis repens, also known as acrodermatitis continua and acrodermatitis perstans, is a chronic inflammatory disease of the hands and feet. It usually remains stable on the extremities, but in rare cases generalized pustular flares may occur. The disease usually begins distally on a digit, either as a pustule in the nailbed or as a paronychia. Extension takes place by eruption of fresh pustules with subsequent hyperkeratosis and crusting. The disease is usually unilateral in its beginning and asymmetrical throughout its entire course. As the disease progresses, one or more of the nails may become dystrophic or float away on lakes of pus. Anonychia is common in chronic cases. Some have used the term dermatitis repens to refer to more indolent involvement of the distal fingers. Involvement of the mucous membranes may occur, even when the eruption of the skin is localized. Painful, circular, white plaques surrounded by inflammatory areolae are found on the tongue and may form a fibrinous membrane. Fissured or geographic tongue may occur. Histologically, intraepithelial spongiform pustules identical to those of psoriasis are seen in the acute stage. Later stages show hyperkeratosis with parakeratosis or atrophy. Numerous treatment options have been used, including topical corticosteroids, calipotriene, dapsone, sulfapyridine, methotrexate, PUVA, acitretin, cyclosporine, and topical mechlorethamine. The decision regarding which agent to use should take into consideration the severity of disease, and the patient’s age and functional impairment.
Palmoplantar pustulosis (pustular psoriasis of the extremities) Chronic palmoplantar pustulosis is essentially a bilateral and symmetrical dermatosis (Fig. 10-14). The favorite locations are the thenar or hypothenar eminences or the central portion of the palms and soles. The patches begin as erythematous areas in which minute intraepidermal pustules form. At the beginning these are pinhead-sized; then they may enlarge and coalesce to form small lakes of pus. As the lesions resolve, denuded areas, crusts, or hyperkeratosis may persist. Palmoplantar pustulosis is strongly associated with thyroid disorders and cigarette smoking. Medications such as lithium, which aggravate psoriasis, have also been reported to induce palmoplantar pustular psoriasis. In 1968, Kato described the first case of bilateral clavicular osteomyelitis with palmar and plantar pustulosis. In 1974, Sonozaki described persistent palmoplantar pustulosis and sternoclavicular hyperostosis. These conditions belong to the spectrum of skin and joint involvement designated by Kahn as the SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis). Common features include palmoplantar pustulosis, acneiform eruption, and pain and swelling of a sternoclavicular joint, or sternomanubrial or costochondral junctions. There is shoulder, neck, and back pain, and limitation of motion of the shoulders and neck is common. Brachial plexus neuropathy and subclavian vein occlusion may occur. The lumbar spine and sacroiliac joints are usually spared. Chronic multifocal osteomyelitis in children may be a pediatric variant. Others have described an association between palmoplantar pustulosis and arthritis or osteitis. SAPHO syndrome may coexist with features of Behçet’s disease. The knees, spine, and ankles may be involved. Ivory vertebrae have been described.
A
Recalcitrant palmoplantar eruptions
Dermatitis repens
B
Fig. 10-14 A. Plantas pustulosis; B. Pustules and hyperkeratosis are typical.
The disease is commonly resistant to treatment. Topical steroids, retinoids, calcipotriene, or macrolactams are of some benefit. Acitretin is generally extremely effective at a dose of 1 mg/kg/day, although rebound occurs more quickly than with etretinate. Low-dose cyclosporine, in doses ranging from 1.25 to 5 mg/kg/day, has also been very effective, but it is not suitable for long-term treatment. Dapsone, colchicine, leflunomide, and mycophenolate mofetil may be effective. Oral 8-methoxypsoralen and high-intensity UVA irradiation or soak PUVA can both be helpful, and Grenz ray therapy can induce prolonged remissions in some patients. Chronic osteomyelitis in SAPHO syndrome has been reported to respond to bisphosphonates. Blanco JF, et al: Ivory vertebra and palmoplantar pustulosis. J Rheumatol 2007 Apr; 34(4):896–899. Hurtado-Nedelec M, et al: Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. Rheumatology (Oxford) 2008; 47(8):1160–1167. Nikkels AF, et al: Breaking the relentless course of Hallopeau’s acrodermatitis by dapsone. Eur J Dermatol 1999; 9:126. Piquero-Casals J, et al: Using oral tetracycline and topical betamethasone valerate to treat acrodermatitis continua of Hallopeau. Cutis 2002; 70:106. Proença NG: Acropustulosis repens. Int J Dermatol 2006; 45(4):389–393. Skov L, et al: IL-8 as antibody therapeutic target in inflammatory diseases: reduction of clinical activity in palmoplantar pustulosis. J Immunol 2008; 181(1):669–679. Yabe H, et al: Two cases of SAPHO syndrome accompanied by classic features of Behçet’s disease and review of the literature. Clin Rheumatol 2008; 27(1):133–135.
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Pustular bacterid Pustular bacterid was first described by George Andrews. It is characterized by a symmetric, grouped, vesicular, or pustular eruption on the palms and soles, marked by exacerbations and remissions over long periods. Andrews regarded the discovery of a remote focus of infection, and cure on its elimination, as crucial to the diagnosis. The primary lesions are pustules. Tiny hemorrhagic puncta intermingled with the pustules are frequently seen. When lesions are so numerous as to coalesce, they form a honeycomblike structure in the epidermis. The disease usually begins on the mid-portions of the palms or soles, from which it spreads outwardly until it may eventually cover the entire flexor aspects of the hands and feet. There is no involvement of the webs of the fingers or toes, as in tinea pedis. When the eruption is fully developed, both palms and soles are completely covered, and the symmetry is pronounced. During fresh outbreaks, the white blood count may show a leukocytosis that ranges from 12 000 to 19 000/mm3 with 65– 80% neutrophils. As a rule, scaling is present in fully evolved lesions, and the scales are adherent, tough, and dry. During exacerbations, crops of pustules or vesicles make their appearance, and there is often severe itching of the areas. Tenderness may be present. Many regard this condition as a variant of psoriasis, triggered by infection. Bacharach-Buhles M, et al: The pustular bacterid (Andrews): are there clinical criteria for differentiating from psoriasis pustulosa palmaris et plantaris? Hautarzt (Germany) 1993; 44:221. Worret WI: Pustular bacterid of Andrews. Am J Dermatopathol 1985; 7:200.
Infantile acropustulosis Infantile acropustulosis is an intensely itchy vesicopustular eruption of the hands and feet (Fig. 10-15). Most cases begin by 10 months of age. Lesions often predominate at the edges of the palms and soles. Individual crops of lesions clear in a few weeks, but recurrences may continue for months or years. Scabies, tinea, and herpetic infection can produce similar lesions, and must be excluded. Histologically, a subcorneal pustule with neutrophils is noted. Eosinophils may be numerous. As the lesions are easily punctured to produce smears of the inflammatory cells, biopsies are seldom employed.
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Fig. 10-15 Acropustulosis of infancy. (Courtesy of Curt Samlaska, MD)
Lesions often respond to topical corticosteroids. Refractory lesions may respond to dapsone at doses of 1–2 mg/kg/day. Vicente J, et al: Are eosinophilic pustular folliculitis of infancy and infantile acropustulosis the same entity? Br J Dermatol 1996; 135:807. Wagner A: Distinguishing vesicular and pustular disorders in the neonate. Curr Opin Pediatr 1997; 9:396.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 10-1 Seborrheic dermatitis. Fig. 10-2 Seborrheic dermatitis involving the chest and axillae. Fig. 10-3 Psoriasis. Fig. 10-4 Psoriasis plaque, red plaque with silver scale on the knee. Fig. 10-5 Inverse psoriasis. Fig. 10-6 Nail pitting and distal onycholysis in psoriasis. Fig. 10-7 Fissured and geographic tongue in a patient with generalized pustular psoriasis. Fig. 10-8 Nailbed involvement in acrodermatitis continua. Fig. 10-9 Anonychia in acrodermatitis continua. Fig. 10-10 Erythrodermic psoriasis. Fig. 10-11 Hyperkeratotic lesions of the reactive arthritis syndrome. Fig. 10-12 Plantar pustulosis. Fig. 10-13 Psoriasis.
Bonus images for this chapter can be found online at http://www.expertconsult.com
Pityriasis Rosea, Pityriasis Rubra Pilaris, and Other Papulosquamous and Hyperkeratotic Diseases Small plaque parapsoriasis Small plaque parapsoriasis (SPP) is characterized by hyperpigmented or yellowish-red scaling patches, round to oval in configuration, with sharply defined, regular borders. Most lesions occur on the trunk, and all are between 1 and 5 cm in diameter. In the digitate variant, yellowish-tan, elongated, fingerprint-like lesions are oriented along the cleavage lines, predominately on the flank (Fig. 11-1). These lesions may at times be longer than 5 cm. There is an absence of the induration, erythematous to purplish-red, large lesions, and poikiloderma that characterize small patches of cutaneous T-cell lymphoma in its early stages. The eruption may be mildly itchy or asymptomatic, and has a definite male preponderance. Typical SPP rarely progresses to mycosis fungoides (MF), although the histologic changes can overlap and clonality may be demonstrated. Debate continues on this issue. SPP has been reported in the setting of liposarcoma, with resolution of the eruption after resection of the tumor. The histologic findings of SPP are characterized by an infiltrate in the superficial dermis composed predominantly of lymphocytes. The overlying epidermis demonstrates mild acanthosis, spongiosis, and focal overlying parakeratosis. SPP is considered to be a type of chronic spongiotic dermatitis. Lesional skin also demonstrates an increase in CD1a(+), Langerhans cells, CD1a-positive dermal dendritic cells, and CD68(+) macrophages. SPP may be refractory to topical steroids alone, but usually responds to phototherapy. Treatment with ultraviolet (UV) B, narrow-band UVB, or natural sunlight, alone or in combination with a low-strength topical steroid or simple lubricant, will usually clear SPP. Without treatment, the patches of SPP may persist for years to decades and rarely, if ever, progress to lymphoma. Aydogan K: Narrowband UVB phototherapy for small plaque parapsoriasis. J Eur Acad Dermatol Venereol 2006 May; 20(5):573–577. Belousova IE, et al: A patient with clinicopathologic features of small plaque parapsoriasis presenting later with plaque-stage mycosis fungoides: report of a case and comparative retrospective study of 27 cases of “nonprogressive” small plaque parapsoriasis. J Am Acad Dermatol 2008 Sep; 59(3):474–482. Tartaglia F, et al: Retroperitoneal liposarcoma associated with small plaque parapsoriasis. World J Surg Oncol 2007 Jul 9; 5:76. Zeybek ND, et al: Immunohistochemical analysis of small plaque parapsoriasis: involvement of dendritic cells. Acta Histochem 2008; 110(5):380–387.
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patients, the lesions vary from skin-colored or faintly erythematous to hyperpigmented; in pigmented persons, lesions usually show hyperpigmentation, although a non-pigmenting form with fine white scale has been described. There may be severe itching or the lesions may be entirely asymptomatic. Familial cases have been reported. An actinomycete, dubbed Dietzia papillomatosis, has been isolated from lesional skin.
Fig. 11-1 Digitate parapsoriasis. (Courtesy of Thomas Nicotori, MD)
Confluent and reticulated papillomatosis (Gougerot and Carteaud) This eruption typically begins on the intermammary and upper lateral trunk as slightly scaly macules that slowly spread to involve the remainder of the trunk (Fig. 11-2). In white
Fig. 11-2 Confluent and reticulated papillomatosis.
Pityriasis Rosea, Pityriasis Rubra Pilaris, Other Papulosquamous Diseases
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Histologically, hyperkeratosis, acanthosis, and papillomatosis are generally seen. The histologic changes resemble those seen in acanthosis nigricans, and the two conditions may occur together. A variety of antibiotics have been successful in treating the disorder. Minocycline, 100 mg twice a day for 6 weeks, is used most commonly. Successful treatment has also been reported with oral fusidic acid, clarithromycin, amoxicillin, erythro mycin, azithromycin, and topical mupirocin. Topical and oral retinoids have also been used successfully, either alone or in combination with topical lactic acid or urea. Confluent and reticulated papillomatosis associated with polycystic ovarian syndrome has responded to contraceptive therapy. Low-dose isotretinoin has also been used. Pseudo-atrophoderma colli may be a related condition that occurs on the neck. It manifests as papillomatous, pigmented, and atrophic glossy lesions with delicate wrinkling. They tend to have a vertical orientation and may respond to minocycline. Cannavò SP: Confluent and reticulated papillomatosis and acanthosis nigricans in an obese girl: two distinct pathologies with a common pathogenetic pathway or a unique entity dependent on insulin resistance? J Eur Acad Dermatol Venereol 2006 Apr; 20(4):478–480. Davis MD, et al: Confluent and reticulate papillomatosis (Gougerot–Carteaud syndrome): a minocycline-responsive dermatosis without evidence for yeast in pathogenesis. A study of 39 patients and a proposal of diagnostic criteria. Br J Dermatol 2006 Feb; 154(2):287–293. Davis RF, et al: Confluent and reticulated papillomatosis successfully treated with amoxicillin. Br J Dermatol 2007 Mar; 156(3):583–584. Erkek E, et al: Confluent and reticulated papillomatosis: favourable response to low-dose isotretinoin. J Eur Acad Dermatol Venereol 2009; 23(11):1342–1343. Jones AL, et al: Dietzia papillomatosis sp. nov., a novel actinomycete isolated from the skin of an immunocompetent patient with confluent and reticulated papillomatosis. Int J Syst Evol Microbiol 2008 Jan; 58(Pt 1):68–72. Treat JR, et al: Nonpigmenting confluent and reticulated papillomatosis. Pediatr Dermatol 2006 Sep–Oct; 23(5):497–499.
finely crinkled, dry epidermis, which often desquamates, leaving a collarette of scaling. When stretched across the long axis, the scales tend to fold across the lines of stretch, the so-called “hanging curtain” sign. The disease most frequently begins with a single herald or mother patch (Fig. 11-4), usually larger than succeeding lesions, which may persist a week or longer before others appear. By the time involution of the herald patch has begun, the efflorescence of new lesions spreads rapidly (Fig. 11-5), and after 3–8 weeks they usually disappear spontaneously. Relapses and recurrences are observed infrequently. The incidence is highest between the ages of 15 and 40, and the disease is most prevalent in the spring and autumn. Women are more frequently affected than men. The fully developed eruption has a striking appearance because of the distribution and definite characteristics of the individual lesions. These are arranged so that the long axis of the macules runs parallel to the lines of cleavage. The eruption is usually generalized, affecting chiefly the trunk and sparing sun-exposed surfaces. At times it is localized to a certain area, such as the neck, thighs, groins, or axillae. In these regions confluent circinate patches with gyrate borders may be formed; these may strongly resemble tinea corporis. Rarely, the eyelids, palms and soles, scalp, or penis may be involved. Oral lesions are relatively uncommon. They are asymptomatic,
Pityriasis rosea Clinical features
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Pityriasis rosea is a mild inflammatory exanthem characterized by salmon-colored papular and macular lesions that are at first discrete but may become confluent (Fig. 11-3). The individual patches are oval or circinate, and are covered with
Fig. 11-4 Herald patch of pityriasis rosea.
Fig. 11-3 Pityriasis rosea.
Fig. 11-5 Pityriasis rosea.
Etiology Watanabe et al have provided evidence for the long-held belief that pityriasis rosea is a viral exanthem. They demonstrated active replication of human herpesvirus (HHV)-6 and 7 in mononuclear cells of lesional skin, as well as identifying the viruses in serum samples of patients. Although these viruses are nearly universally acquired in early childhood and remain in a latent phase as mononuclear cells, the eruption is likely secondary to reactivation leading to viremia. A pityriasis rosea-like eruption may occur as a reaction to captopril, imatinib mesylate, interferon, ketotifen, arsenicals, gold, bismuth, clonidine, methoxypromazine, tripelennamine hydrochloride, ergotamine, lisinopril, acyclovir, lithium, adalimumab, or barbiturates.
Histology The histologic features of pityriasis rosea include mild acanthosis, focal parakeratosis, and extravasation of erythrocytes into the epidermis. Spongiosis may be present in acute cases. A mild perivascular infiltrate of lymphocytes is found in the dermis. Histologic evaluation is especially helpful in excluding the conditions with which pityriasis rosea may be confused.
Differential diagnosis Pityriasis rosea may closely mimic seborrheic dermatitis, tinea corporis, macular syphilid, drug eruption, other viral exanthema, and psoriasis. In seborrheic dermatitis, the scalp and eyebrows are usually scaly; there is a predilection for the sternal and interscapular regions, and the flexor surfaces of the articulations, where the patches are covered with greasy scales. Tinea corporis is rarely so widespread. Tinea versicolor may also closely simulate pityriasis rosea. A positive KOH examination serves well to differentiate these last two. In macular syphilid, the lesions are of a uniform size and assume a brownish tint. Scaling and itching are absent or slight, and there are generalized adenopathy, mucous membrane lesions, palmoplantar lesions, positive nontreponemal and treponemal tests, and often the remains of a chancre. Scabies and lichen planus may be confused with the papular type.
Treatment Most patients require no therapy, as they are asymptomatic; however, the duration of the eruption may be notably reduced by several interventions. A Cochrane database review cited inadequate evidence for efficacy for most published treatments, but it should be noted that lack of evidence does not equate to lack of efficacy. They cited some evidence that oral erythromycin may be effective for both the rash and the itch, although this is based on only one small randomized controlled trial (see below). UVB in erythema exposures may be used to expedite the involution of the lesions after the acute inflammatory stage has passed. The erythema produced by UV treatment is succeeded by superficial exfoliation. In a comparison study by Leenutaphong et al, using a “placebo” of 1 J UVA on the untreated side compared with the UVB-treated side, there was significant improvement in the severity of the disease on the treated side. However, there was no difference in itchiness or the course of the disease. Corticosteroid lotions or creams provide some relief from itching. One study found erythro mycin, 250 mg four times a day for adults and 25–40 mg/kg in four divided doses a day for children, over a 2-week period resulted in complete clearance of all lesions. This response in 33 of 45 patients contrasted with the fact that none of the 45 placebo patients had the same response. Other studies have challenged the effectiveness of erythromycin, and more research is needed. For dryness and irritation, simple emollients are advised.
Pityriasis rubra pilaris
erythematous macules with raised borders and clearing centers or aphthous ulcer-like lesions. They involute simultaneously with the skin lesions. Moderate pruritus may be present, particularly during the outbreak, and there may be mild constitutional symptoms before the onset. Variations in the mode of onset, course, and clinical manifestations are extremely common. An unusual form, common in children under age 5, is papular pityriasis rosea, occurring in the typical sites and running a course similar to that of the common form of pityriasis rosea. Black children are particularly predisposed to this papular variant, and are also more prone to facial and scalp involvement. The lesions often heal, leaving hypopigmented macules. An inverse distribution, sparing covered areas, is not rare and is common in papular cases. A vesicular variant has also been described. Purpuric pityriasis rosea may manifest with petechiae and ecchymoses along Langer lines of the neck, trunk, and proximal extremities, and may occasionally be a sign of an underlying acute myeloid leukaemia. Pityriasis rosea occurring during pregnancy may be associated with premature delivery, neonatal hypotonia, and fetal loss, especially if the eruption occurs within the first 15 weeks of gestation.
Balci DD, et al: Vesicular pityriasis rosea: an atypical presentation. Dermatol Online J 2008 Mar 15; 14(3):6. Broccolo F, et al: Additional evidence that pityriasis rosea is associated with reactivation of human herpes 6 and 7. J Invest Dermatol 2005; 127:1234. Chuh AA, et al: Interventions for pityriasis rosea. Cochrane Database Syst Rev 2007 Apr 18; (2):CD005068. Drago F, et al: Pregnancy outcome in patients with pityriasis rosea. J Am Acad Dermatol 2008 May; 58(5 Suppl 1):S78–83. Drago F, et al: Pityriasis rosea: an update with a critical appraisal of its possible herpesviral etiology. J Am Acad Dermatol 2009; 61(2):303–318. Gündüz O, et al: Childhood pityriasis rosea. Pediatr Dermatol 2009; 26(6):750–751. Rajpara SN, et al: Adalimumab-induced pityriasis rosea. J Eur Acad Dermatol Venereol 2007 Oct; 21(9):1294–1296. Rasi A, et al: Oral erythromycin is ineffective in the treatment of pityriasis rosea. J Drugs Dermatol 2008 Jan; 7(1):35–38. Singal A, et al: Purpuric pityriasis rosea-like eruption: a cutaneous marker of acute myeloid leukaemia. J Eur Acad Dermatol Venereol 2007 Jul; 21(6):822–823.
Pityriasis rubra pilaris Clinical features Pityriasis rubra pilaris (PRP) is a chronic skin disease characterized by small follicular papules, disseminated yellowishpink scaling patches, and, often, solid confluent palmoplantar hyperkeratosis. The papules are the most important diagnostic feature, being more or less acuminate, reddish-brown, about pinhead-sized, and topped by a central horny plug (Fig. 11-6). A hair, or part of one, is usually embedded in the horny center. The highest incidence of onset is during the first 5 years of life or between the ages of 51 and 55. The classic disease generally manifests first by scaliness and erythema of the scalp. The eruption is limited in the beginning, having a predilection for the sides of the neck and trunk, and the extensor surfaces of the extremities, especially the backs of the first and second phalanges. Then, as new lesions occur, extensive areas are 205
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Fig. 11-6 Pityriasis rubra pilaris.
Fig. 11-8 Palmar hyperkeratosis in pityriasis rubra pilaris.
Fig. 11-7 Islands of sparing in pityriasis rubra pilaris.
converted into sharply marginated patches of various sizes, which look like exaggerated goose-flesh and feel like a nutmeg grater. Any part or the entire skin surface may be affected. The involvement is generally symmetrical and diffuse, with characteristic small islands of normal skin within the affected areas (Fig. 11-7). There is a hyperkeratosis of the palms (Fig. 11-8) and soles, with a tendency to fissures. On the soles especially, the hyperkeratosis typically extends up the sides, the so-called “sandal.” The nails may be dull, rough, thickened, brittle, and striated, and are apt to crack and break. They are rarely, if ever, pitted. The exfoliation may become generalized and the follicular lesions less noticeable, finally disappearing and leaving a widespread dry, scaly erythroderma. The skin becomes dull red, glazed, atrophic, sensitive to slight changes in temperature, and, over the bony prominences, subject to ulcerations. There are no subjective symptoms except itching in some cases. The Koebner phenomenon may be present. The general health of most patients is not affected, although occasionally arthritis may accompany the eruption. A number of cases of associated malignancy have recently been reported. It remains to be established whether these are true associations or chance 206
findings. Protein-losing enteropathy may occur. Both hypo thyroidism and hypoparathyroidism have been reported, as has the combination of sacroiliitis and autoimmune thyroiditis. PRP may be classified with respect to familial or acquired types, and to the onset of the disease in childhood or in adulthood. Griffith’s classification is useful in this regard. Type I, the classic adult type, is seen most commonly and carries a good prognosis, with 80% involuting over a 3-year period. Likewise, most patients with the classic juvenile type (type III) have clearing of the disease in 1 year, although it may recur, even into adulthood. The atypical adult and juvenile variants and the circumscribed juvenile-onset form account for up to 35% of cases and carry a poorer prognosis for spontaneous recovery. Human immunodeficiency virus (HIV) patients may develop PRP and have associated acne conglobata, hidradenitis suppurativa, or lichen spinulosus.
Etiology The etiology is unknown. Familial cases are uncommon. Either sex may be affected, with equal frequency. Both clinically and histologically, the disease has many features that suggest it is a vitamin deficiency disorder, particularly of vitamin A. Some reports of patients with low serum levels of retinolbinding protein have appeared, but this is not a reproducible finding.
Histology There is hyperkeratosis, follicular plugging, and focal para keratosis at the follicular orifice. Parakeratosis may alternate both vertically and horizontally, producing a checkerboard pattern. Acantholysis is an uncommon finding but may be present. The inflammatory infiltrate in the dermis is composed of mononuclear cells and is generally mild. Specimens should be obtained from skin sites where hair follicles are numerous. Although there may be difficulty in making an unequivocal histologic diagnosis of PRP, the findings of psoriasis, which is the most common clinical entity in the differential diagnosis, are not present.
The diagnosis of fully developed PRP is rarely difficult because of its distinctive features, such as the peculiar orange or salmon–yellow color of the follicular papules, containing a horny center, on the backs of the fingers, sides of the neck, and extensor surfaces of the limbs; the thickened, rough, and slightly or moderately scaly, harsh skin; the sandal-like palmo plantar hyperkeratosis; and the islands of normal skin in the midst of the eruption. It is distinguished from psoriasis by the scales, which in the latter are silvery and light, and overlap like shingles, and by the papules, which extend peripherally to form patches. Phrynoderma caused by vitamin A deficiency gives a somewhat similar appearance to the skin, as may eczematous eruptions caused by vitamin B deficiency. Rheumatologic disorders, such as subacute cutaneous lupus erythematosus and dermatomyositis, may present with similar cutaneous findings.
Treatment The management of PRP is generally with systemic retinoids, although topical tazarotene has also been reported to be of benefit. Isotretinoin, in doses of 0.5–1 mg/kg/day, may induce prolonged remissions or cures. It may take 6–9 months for full involution to occur, and tapering of the drug may prevent recurrence. Acitretin, in doses of 10–75 mg, is also effective over a course of several months. Methotrexate has been used with good results in doses of 2.5–30 mg, either alone or in combination with oral retinoids. UV light may flare some patients, but in others PUVA, UVA1, or narrow-band UVB, alone or in combination with retinoids, may be effective. Phototesting prior to instituting light treatment is recommended. Extracorporeal photochemotherapy, cyclosporine, anti-tumor necrosis factor (TNF) agents, and azathioprine have been reported to be effective in resistant and severe cases. Both improvement and flare have been reported with efalizumab. Topical applications of calcineurin inhibitors, lactic acid, or urea-containing preparations may be helpful. Responses to topical corticosteroids are not very effective as a rule. Systemic steroids are beneficial only for acute short-term management, but are not recommended for chronic use. In HIV-related disease, multiagent antiviral therapy may be useful alone or in combination with retinoids. Barth D, et al: Successful treatment of pityriasis rubra pilaris (type 1) under combination of infliximab and methotrexate. J Dtsch Dermatol Ges 2009; 7(12):1071–1073. Davis KF, et al: Clinical improvement of pityriasis rubra pilaris with combination etanercept and acitretin therapy. Arch Dermatol 2007 Dec; 143(12):1597–1599. Greene R: PRP support group. Dermatol Nurs 2006 Feb; 18(1):28. Gül U, et al: A case of pityriasis rubra pilaris associated with sacroileitis and autoimmune thyroiditis. J Eur Acad Dermatol Venereol 2008 Jul; 22(7):889–890. Hong JB, et al: Recurrence of classical juvenile pityriasis rubra pilaris in adulthood: report of a case. Br J Dermatol 2007 Oct; 157(4):842–844. Karimian-Teherani D, et al: Response of juvenile circumscribed pityriasis rubra pilaris to topical tazarotene treatment. Pediatr Dermatol 2008 Jan–Feb; 25(1):125–126. Klein A, et al: Exacerbation of pityriasis rubra pilaris under efalizumab therapy. Dermatology 2007; 215(1):72–75. Müller H, et al: Infliximab monotherapy as first-line treatment for adult-onset pityriasis rubra pilaris: case report and review of the literature on biologic therapy. J Am Acad Dermatol 2008; 59(Suppl):S65–70. Ruiz-Genao DP, et al: Pityriasis rubra pilaris successfully treated with infliximab. Acta Derm Venereol 2007; 87(6):552–553.
Ruzzetti M, et al: Type III juvenile pityriasis rubra pilaris: a successful treatment with infliximab. J Eur Acad Dermatol Venereol 2008 Jan; 22(1):117–118. Sato T, et al: Protein-losing gastroenteropathy in a patient with pityriasis rubra pilaris. Digestion 2007; 75(2–3):98. Seckin D, et al: Successful use of etanercept in type I pityriasis rubra pilaris. Br J Dermatol 2008 Mar; 158(3):642–644. Walling HW, et al: Pityriasis rubra pilaris responding rapidly to adalimumab. Arch Dermatol 2009; 145(1):99–101.
Palmoplantar keratoderma The term keratoderma is frequently used synonymously with keratosis palmaris et plantaris (KPP) and tylosis. This group of conditions is characterized by excessive formation of keratin on the palms and soles. Some varieties exist as part of a syndrome. Acquired types include keratoderma climactericum, arsenical keratoses, corns, calluses, porokeratosis plantaris discreta, porokeratotic eccrine ostial and dermal duct nevus, glucan-induced keratoderma in acquired immunodeficiency syndrome (AIDS), keratosis punctata of the palmar creases, and many skin disorders that are associated with palmoplantar keratoderma, such as psoriasis, paraneoplastic syndromes, PRP, lichen planus, and syphilis. A high incidence of melanoma has been noted in Japanese patients with palmoplantar keratoderma. Palmoplantar keratoderma has been described with sorafenib, an oral multikinase inhibitor used in the treatment of renal cell carcinoma. Arsenical keratoses can occur from tainted water supplies, intentional poisoning, and medications containing arsenic. Arsenical keratoses have been treated with a combination of keratolytics and low-dose acitretin. The hereditary types include hereditary palmoplantar keratoderma (Unna–Thost), punctate palmoplantar keratosis, Papillon–Lefèvre syndrome, mal de Meleda, familial keratoderma with carcinoma of the esophagus (Howell–Evans), autosomal-dominant hereditary punctate keratoderma associated with malignancy (Buschke–Fisher–Brauer), KPP of Sybert (palmoplantar hyperkeratosis with transgrediens, autosomaldominant inheritance, and a lack of associated systemic features), acrokeratoelastoidosis, focal acral hyperkeratosis, and several inherited disorders that have palmoplantar keratoderma as an associated finding, such as pachyonychia congenita, tyrosinemia II (Richner–Hanhart), Darier’s disease, Naxos syndrome (keratoderma, wooly hair, and cardio myopathy), and dyskeratosis congenita. Many disorders that have palmoplantar keratoderma as a feature will be discussed in other chapters. A number of mutations in keratin genes have been found. American patients with nonepidermolytic palmoplantar keratoderma associated with malignancy are linked to abnormalities of 17q24 distal to the keratin cluster. Pachyonychia congenita is associated with mutations in the helical initiation peptide of K6a, K16, or K17. Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal-dominant disease caused by mutations of the keratin 9 gene. The mutations localize to sequences encoding the highly conserved 1 A rod domain. Acantholysis of epidermal keratinocytes suggests the presence of desmoglein 1 mutations.
Palmoplantar keratoderma
Diagnosis
Keratolysis exfoliativa (lamellar dyshidrosis, recurrent palmar peeling) Keratolysis exfoliativa is a superficial exfoliative dermatosis of the palms and sometimes soles. Clinically, there is little to no inflammation, but white spots appear and gradually extend peripherally. The lesions rupture to produce an annular adherent collarette (Fig. 11-9), but remain largely asymptomatic. The 207
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Fig. 11-9 Keratolysis exfoliativa.
Fig. 11-10 Keratosis punctata of the palmar creases.
eruption is often exacerbated by environmental factors. Many patients have an atopic background and some have lesions of dyshidrotic eczema. Although some authors have suggested it is a disorder of cohesion of the stratum corneum, it is more likely that the condition represents subclinical eczema. The condition must be differentiated from dermatophytosis, and a KOH examination is recommended. Because the condition is generally asymptomatic, no treatment may be necessary. In some patients, spontaneous involution occurs in a few weeks. For patients who require treatment, emollients, corticosteroid preparations, tar, urea and lactic acid or ammonium lactate may be effective.
Keratosis punctata of the palmar creases Keratosis punctata of the palmar creases has also been referred to as keratotic pits of the palmar creases, punctate keratosis of the palmar creases, keratosis punctata, keratodermia punctata, hyperkeratosis penetrans, lenticular atrophia of the palmar creases, and hyperkeratosis punctata of the palmar creases. This common disorder occurs most often in black patients. The primary lesion is a 1–5 mm depression filled with a comedolike keratinous plug. The lesions localize to the creases of the palms or fingers (Fig. 11-10). The soles may be involved. An autosomal-dominant inheritance pattern has been suggested, but onset is often delayed until adulthood. Keratosis punctata of the palmar creases has been reported to be associated with atopic dermatitis, Dupuytren contractures, pterygium inversum unguis, dermatitis herpetiformis, knuckle pads, striate keratoderma, and psoriasis. Keratolytic agents and topical retinoids have provided temporary relief. Very painful lesions respond to punch excision.
Punctate keratoses of the palms and soles Punctate keratoses of the palms and soles has also been referred to as punctate keratoderma, keratodermia punctata, keratosis punctata palmaris et plantaris, keratoma hereditarium dissipatum palmare et plantare, keratoderma disseminatum palmaris et plantaris, palmar keratoses, and palmar and plantar seed dermatoses. Spiny keratoderma of the palms and soles, known as “music box spines,” is a distinct variant (Fig. 11-11). There may be from 1 to over 40 papules, with an average in one series of 8.3. The main symptom is pruritus. The onset is between ages 15 and 68. Black individuals predominate, and it most frequently afflicts men. There have been reports of 208
Fig. 11-11 “Music box” spine keratoderma.
autosomal-dominant inheritance. The histology demonstrates hyperkeratosis and parakeratosis, pyknotic, vacuolated epithelium, basal layer spongiosis, and dilated, occluded sweat ducts, blood vessels, and lymph vessels. Only mechanical de bridement and excision have achieved any permanent results.
Porokeratosis plantaris discreta Porokeratosis plantaris discreta occurs in adults, with a 4:1 female preponderance. It is characterized by a sharply marginated, rubbery, wide-based papule that on blunt dissection reveals an opaque plug without bleeding on removal. Lesions are multiple, painful, and usually 7–10 mm in diameter. They are usually confined to the weight-bearing area of the sole, beneath the metatarsal heads. Treatment may begin with fitted foot pads to redistribute the weight. Surgical excision, blunt dissection, and cryotherapy have been successful.
Keratoderma climactericum Keratoderma climactericum is characterized by hyperkeratosis of the palms and soles (especially the heels) beginning at
Palmoplantar keratoderma Fig. 11-13 Vohwinkel keratoderma.
Fig. 11-12 Unna–Thost keratoderma.
about the time of the menopause. The discrete, thickened, hyperkeratotic patches are most pronounced at sites of pressure such as around the rim of the sole. Fissuring of the thickened patches may be present. There is a striking resemblance to plantar psoriasis, and indeed, keratoderma climactericum may represent a form of psoriasis. Therapy consists of keratolytics such as 10% salicylic acid ointment, lactic acid creams, or 20–30% urea mixtures. The response to topical corticosteroids is often disappointing. Acitretin is more effective than isotretinoin.
Hereditary palmoplantar keratoderma Hereditary palmoplantar keratoderma (Unna–Thost) is characterized by a dominantly inherited, marked congenital thickening of the epidermal horny layer of the palms and soles, usually symmetrically and affecting all parts equally (Fig. 11-12). At times the thickening extends to the lateral or dorsal surfaces, especially over the knuckles. The arches of the feet are generally spared. The epidermis is thick, yellowish, and horny. The uniform thickening forms a rigid plate, which ends with characteristic abruptness at the periphery of the palm. Hyperhidrosis may cause a sodden appearance. The condition is poorly responsive to therapy. Five percent salicylic acid, 12% ammonium lactate, and 40% urea have been used. Systemic retinoid therapy is impractical because of bone toxicity, and topical retinoids are generally not effective.
Palmoplantar keratodermas and malignancy Howell–Evans reported a diffuse, waxy keratoderma of the palms and soles occurring as an autosomal-dominant trait associated with esophageal carcinoma. Other related features are oral leukoplakia, esophageal strictures, squamous cell carcinoma of tylotic skin, and carcinoma of the larynx and stomach. The tylosis esophageal cancer gene has been localized to chromosome 17q25. Acquired forms of palmoplantar keratodermas have also been associated with cancers of the esophagus, lung, breast, urinary bladder, and stomach.
Mutilating keratoderma of Vohwinkel Vohwinkel described honeycomb palmoplantar hyperkeratosis, associated with starfish-like keratoses on the backs of the hands and feet, linear keratoses of the elbows and knees, and annular constriction (pseudo-ainhum) of the digits (Fig. 11-13), which may progress to autoamputation. Inheritance is mostly autosomal-dominant, although a recessive type exists. The disease is more frequent in women and in whites, with onset in infancy or early childhood. Reported associations include deafness, deaf–mutism, high-tone acoustic impairment, congenital alopecia universalis, pseudopelade-type alopecia, acanthosis nigricans, ichthyosiform dermatoses, spastic paraplegia, myopathy, nail changes, mental retardation, and bullous lesions on the soles. Vohwinkel keratoderma maps to chromosome 1q21 and represents a mutation of loricrin. There have been some reports of a response to acitretin (or etretinate) therapy. Mutations in connexin 26 produce a similar phenotype. Other forms of mutilating keratoderma also occur. They lack the constricting bands, honeycomb palmoplantar hyperkeratosis, and starfish-like keratoses of Vohwinkel syndrome. The affected digits are often shortened, narrow, rigid, and tapered (Fig. 11-14).
Olmsted syndrome Olmsted syndrome is characterized by mutilating palmoplantar keratoderma and periorificial keratotic plaques. The distinctive features of this syndrome include a congenital, sharply marginated palmoplantar keratoderma; constriction of the digits; linear keratotic streaks on the flexural aspects of the wrists; onychodystrophy; and periorificial keratoses. Constriction of digits may result in spontaneous amputations. Extensive grafting has sometimes been necessary. Most cases of Olmsted syndrome are sporadic. Associated abnormalities have included hyperhidrosis of the palms and soles and congenital deafness. Histologically, there is acanthosis, papillomatosis, and orthokeratotic hyperkeratosis. The finding of Ki-67 staining of suprabasal keratinocytes suggests that Olmsted syndrome is a hyperproliferative disorder of the epidermis. 209
The early onset of periodontal disease has been attributed to alterations in polymorphonuclear leukocyte function caused by Actinomyces actinomycetemcomitans, although a variety of other bacteria have also been implicated. Acro-osteolysis and pyogenic liver abscesses may occur. There are asymptomatic ectopic calcifications in the choroid plexus and tentorium. Some patients have responded to acitretin, etretinate, or isotretinoin. The stocking–glove distribution of the hyperkeratosis is similar to that seen in mal de Meleda. Haim–Munk syndrome is autosomal-recessive with periodontal disease, keratoderma, and onychogryphosis, linked to cathepsin C mutations.
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Striate keratodermas
Fig. 11-14 Mutilating keratoderma.
Acrokeratoelastoidosis of Costa This autosomal-dominantly inherited condition is more common in women. Small, round, firm papules occur over the dorsal hands, knuckles, and lateral margins of the palms and soles. The lesions appear in early childhood and progress slowly. They are most often asymptomatic. The characteristic histologic feature is dermal elastorrhexis.
Mal de Meleda Mal de Meleda is a rare, autosomal-recessive form of palmoplantar keratoderma seen in individuals from the island of Meleda. The hyperkeratosis does not remain confined to the palms, and the extensor surfaces of the arms are frequently affected. The disease has been mapped to chromosome 8q, and mutations in the ARS (component B) gene have been identified in families with this disorder. Mutations in the gene encoding secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1) have been found. “Nagashima-type” keratosis is a nonprogressive, autosomalrecessive palmoplantar keratoderma that resembles a mild form of mal de Meleda.
Papillon–Lefèvre syndrome The Papillon–Lefèvre syndrome is inherited in an autosomalrecessive fashion and presents with palmoplantar keratoderma and destructive periodontitis usually beginning in young childhood. Well-demarcated, erythematous, hyperkeratotic lesions on the palms and soles may extend to the dorsal hands and feet. Hyperkeratosis may also be present on the elbows, knees, and Achilles tendon areas. Transverse grooves of the fingernails may occur. Severe gingival inflammation with loss of alveolar bone is typical. Histology reveals a psoriasiform pattern. Mutations in the cathepsin C gene have been detected. The condition usually has an early age of onset, but a late-onset variant has been reported. Some patients with late-onset disease have not shown mutations in the cathepsin C gene. 210
The striate keratodermas are a group of autosomal-dominant palmoplantar keratodermas with streaking hyperkeratosis involving the fingers and extending on to the palm of the hand. In some patients, a heterozygous C to A transversion involving the desmoglein 1 gene has been found. Mutations in the desmoplakin gene have also been described. Brunauer– Fohs–Siemens syndrome is one form with diminished desmosomes, clumping of keratin filaments, and enlarged keratohyalin granules. Mutations in desmoglein 1, desmoplakin, and keratin 1 have been described in these patients. In other patients, desmosome numbers are normal, but their inner plaques are attenuated. Striate keratoderma has also been reported in association with Rubinstein–Taybi syndrome.
Richner–Hanhart syndrome Richner–Hanhart syndrome (tyrosinemia type 2) is characterized by corneal opacities and keratosis palmoplantaris. The skin manifestations usually develop after the first year of life, and relate to defects in tyrosine aminotransferase. Newborn screening can allow early intervention with dietary restriction.
Aquagenic wrinkling of the palms (acquired aquagenic syringeal acrokeratoderma) Patients with this disorder, also called papulotranslucent acrokeratoderma, develop white papules on the palms after water exposure. The lesions are sharply demarcated from the surrounding skin and appear white. There may be a central prominent pore within each white lesion (Fig. 11-15). The lesions appear 3–5 min after exposure to water and resolve within a short time of drying. Sometimes the white skin can be peeled off. It may be a marker for cystic fibrosis and has also been reported in patients taking aspirin or rofecoxib. Autosomal-dominant inheritance has been suggested in some cases, and abnormal aquaporin 5 has been described in sweat glands. Bédard MS, et al: Palmoplantar keratoderma and skin grafting: postsurgical long-term follow-up of two cases with Olmsted syndrome. Pediatr Dermatol 2008 Mar–Apr; 25(2):223–229. Bergman R, et al: Disadhesion of epidermal keratinocytes: a histologic clue to palmoplantarkeratodermas caused by DSG1 mutations. J Am Acad Dermatol 2010; 62(1):107–113. Bowden PE: Mutations in a keratin 6 isomer (K6c) cause a type of focal palmoplantar keratoderma. J Invest Dermatol 2010; 130(2):336–338. Kabashima K, et al: “Nagashima-type” keratosis as a novel entity in the palmoplantar keratoderma category. Arch Dermatol 2008 Mar; 144(3):375–379. Kabashima K, et al: Aberrant aquaporin 5 expression in the sweat gland in aquagenic wrinkling of the palms. J Am Acad Dermatol 2008 Aug; 59(2 Suppl 1):S28–S32.
Exfoliative dermatitis (erythroderma) Fig. 11-15 Acquired aquagenic syringeal acrokeratoderma.
Katz KA, et al: Aquagenic wrinkling of the palms in patients with cystic fibrosis homozygous for the delta F508 CFTR mutation. Arch Dermatol 2005 May; 141(5):621–624. Khandpur S, et al: Chronic arsenic toxicity from Ayurvedic medicines. Int J Dermatol 2008 Jun; 47(6):618–621. Lountzis NI, et al: Sorafenib-induced palmoplantar hyperkeratosis. J Drugs Dermatol 2008 Jun; 7(6):588–589. Meissner T, et al: Richner–Hanhart syndrome detected by expanded newborn screening. Pediatr Dermatol 2008 May–Jun; 25(3):378–380. Nakajima K, et al: Papillon–Lefèvre syndrome and malignant melanoma. A high incidence of melanoma development in Japanese palmoplantar keratoderma patients. Dermatology 2008; 217(1):58–62.
Exfoliative dermatitis (erythroderma) Exfoliative dermatitis is also known as dermatitis exfoliativa, pityriasis rubra (Hebra), and erythroderma (Wilson–Brocq). Patients present with extensive erythema and scaling (Fig. 11-16). Ultimately, the entire body surface is dull scarlet and covered by small, laminated scales that exfoliate profusely. Vesiculation and pustulation are usually absent. An extensive telogen effluvium is often noted. In both PRP and mycosis fungoides, distinctly spared islands of skin are frequently noted. Patients with PRP also commonly have thickened, orange palms and “nutmeg grater” follicular papules on the dorsa of the fingers (see above). Itching of the erythrodermic skin may be severe and the onset is often accompanied by symptoms of general toxicity, including fever and chills. Secondary infections by pyogenic organisms often complicate the course of the disease in the absence of treatment. Severe complications include sepsis, high-output cardiac failure, acute respiratory distress syndrome, and capillary leak syndrome. The mortality rate attributable to the erythroderma approaches 7% in some series.
Etiology Erythroderma is frequently the result of generalization of a pre-existing chronic dermatosis such as psoriasis or atopic dermatitis. Many other cases are related to a medication, and
Fig. 11-16 Erythroderma.
some occur as a manifestation of an internal malignancy, erythrodermic mycosis fungoides, or the Sézary syndrome. In children, immune defects must be considered. Internal malignancies, pemphigus foliaceus, generalized dermatophytosis, and even Norwegian scabies may show the picture of generalized exfoliative dermatitis. There have been reports of inad equate intake of branched-chain amino acids in infants with maple syrup urine disease producing exfoliative erythroderma. However, in a significant number of patients the cause remains idiopathic, even after extensive evaluation. In several reported series the largest group of patients had pre-existing dermatoses, including atopic dermatitis, chronic actinic dermatitis, psoriasis, seborrheic dermatitis, PRP, and allergic contact dermatitis. Drug eruptions are generally the next most common group, followed by idiopathic cases, cutaneous T-cell lymphoma, paraneoplastic erythroderma, and leukemia cutis. Common implicated drugs include allopurinol, sulfa drugs, gold, phenytoin, phenobarbital, isoniazid, carbamazepine, cisplatin, dapsone, mefloquine, tobramycin, minocycline, nifedipine, and iodine. In a study of erythrodermic patients managed in the community, exacerbation of pre-existing dermatoses accounted for 61% as compared to 51% of those evaluated at a university medical; idiopathic cases for 14% and 31%, respectively; and cutaneous T-cell lymphoma for 1% and 6%, respectively. In a study of 51 children with erythroderma, immunodeficiency was diagnosed in 30%, ichthyosis in 24%, Netherton syndrome in 18%, and eczematous or papulosquamous dermatitis in 20%. Five of the 51 patients remained idiopathic. A biopsy established the diagnosis in only 19 (45%) of 42 cases. The mortality rate was 16%, usually related to an immunodeficiency disorder. In a comparison of patients with and without HIV infection, erythroderma in the HIV-positive group was most commonly related to drug reactions (40.6%), with ethambutol accounting for 30.8%. In the non-HIV group, drug reactions accounted for only 22.5%. HIV-positive patients did not have an overall increase in the number of episodes of erythroderma. Mycosis fungoides can be erythrodermic without meeting the criteria for the Sézary syndrome. Sézary syndrome consists 211
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of generalized exfoliative dermatitis with intense pruritus, leonine facies, alopecia, palmoplantar hyperkeratosis, and onychodystrophy. The criteria for a diagnosis of Sézary syndrome include an absolute Sézary cell count of at least 1000 cells/mm3; a CD4/CD8 ratio of 10 or higher by flow cyto metry, caused by an increase in circulating T cells or loss of expression of pan-T-cell markers; increased lymphocyte counts with evidence of a T-cell clone by Southern blot or polymerase chain reaction; or a chromosomally abnormal T-cell clone. Prognosis is poor and similar to that of patients with nodal involvement. Hodgkin disease may show generalized exfoliative dermatitis. Fever, lymphadenopathy, splenomegaly, and hepato megaly are frequently present. The erythrocyte sedimentation rate is elevated in most of these patients.
methotrexate are useful in psoriatic erythroderma. Isotretinoin, acetretin, and methotrexate are useful in erythroderma caused by PRP. Immunosuppressive agents, such as azathioprine and methotrexate, may occasionally be necessary in idiopathic erythroderma not responding to therapy. Kotrulja L, et al: Differential diagnosis of neonatal and infantile erythroderma. Acta Dermatovenerol Croat 2007; 15(3):178–190. Milavec-Puretić V, et al: Exfoliative erythroderma. Acta Dermatovenerol Croat 2007; 15(2):103–107. Okoduwa C, et al: Erythroderma: review of a potentially life-threatening dermatosis. Indian J Dermatol 2009; 54(1):1–6. Sehgal VN, et al: Erythroderma/exfoliative dermatitis: a synopsis. Int J Dermatol 2004 Jan; 43(1):39–47. Sehgal VN, et al: Erythroderma/generalized exfoliative dermatitis in pediatric practice: an overview. Int J Dermatol 2006 Jul; 45(7): 831–839.
Histopathology Exfoliative dermatitis may retain the histologic features of the original disease process. This is particularly true in psoriasis and mycosis fungoides. Often, however, the histology is nonspecific, with hyperkeratosis, mild acanthosis, and focal parakeratosis.
Treatment In drug-induced erythroderma, the offending drug must be stopped. Application of a mid-strength corticosteroid after soaking, and occlusion under a sauna suit are often helpful, regardless of the cause of the erythroderma. Wet pajamas can be added under the sauna suit. Acitretin, cyclosporine, and
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 11-1 Fig. 11-2 Fig. 11-3 Fig. 11-4 pilaris. Fig. 11-5 Fig. 11-6 Fig. 11-7 Fig. 11-8
Pityriasis rubra pilaris. Pityriasis rubra pilaris. (Courtesy of James Fitzpatrick, MD) Palmar hyperkeratosis in pityriasis rubra pilaris. Checkerboard pattern of parakeratosis in pityriasis rubra Keratolysis exfoliativa. Plantar seedlike keratoderma. Acquired aquagenic syringeal acrokeratoderma. Exfoliative dermatitis.
Bonus images for this chapter can be found online at http://www.expertconsult.com
Lichen Planus and Related Conditions
Lichen planus Lichen planus (LP) is a pruritic, inflammatory disease of the skin, mucous membranes, and hair follicles. It occurs through out the world, in all races. It is a common disorder, comprising more than 0.5% of all dermatological visits. It may be familial in 1–2% of cases. The pattern of LP detected and the age dis tribution vary among various genetic and geographic groups. In persons of European descent, it appears largely after the age of 20, and peaks between 40 and 70 years. Very few cases appear after age 80. Childhood LP typically accounts for 5% or less of cases. However, in some regions, childhood cases are responsible for more than 10% of all LP cases. These areas include the Indian subcontinent, Arab countries, and Mexico. Race appears to be the critical factor, since in the UK 80% of childhood LP is seen in Indians. The primary lesions of LP are characteristic, almost patho gnomonic, small, violaceous, flat-topped, polygonal papules (Fig. 12-1). The color of the lesions initially is erythematous. Well-developed lesions are violaceous, and resolving lesions are often hyperpigmented, especially in persons of color. The surface is glistening and dry, with scant, adherent scales. On the surface, gray or white puncta or streaks (Wickham striae) cross the lesions. Dermoscopy may enhance the visualization of this critical diagnostic element. Lesions begin as pinpoint papules and expand to 0.5–1.5 cm plaques. Infrequently, larger lesions are seen. There is a predilection for the flexor wrists, trunk, medial thighs, shins, dorsal hands, and glans penis (Fig. 12-2). The face is only rarely involved, and when it is, lesions are usually confined to the eyelids and/or lips. The palms and soles may be affected with small papules or hyperkeratotic plaques (Fig. 12-3). Certain morphologic patterns favour certain locations, e.g. annular lesions favoring the penis (Fig. 12-4), and keratotic lesions favoring the anterior shins. The Koebner phenomenon occurs in LP. Pruritus is often prominent in LP. The pruritus may precede the appearance of the skin lesions, and, as with scabies, the intensity of the itch may seem out of proportion to the amount of skin disease. It may be almost intolerable in acute cases. Most patients react to the itching of LP by rubbing rather than scratching, and consequently scratch marks are usually not present. The natural history of LP is highly variable and dependent on the site of involvement and the clinical pattern. Two-thirds of patients with skin lesions will have LP for less than 1 year and many patients spontaneously clear in the second year. Mucous membrane disease is much more chronic. Recurrences are common. Nail changes are present in approximately 5–10% of patients. Involvement of the nail can occur as an initial manifestation, especially in children. Longitudinal ridging and splitting are most common. Onycholysis may be present and the lunula may be red. Involvement of the entire matrix may lead to obliteration of the whole nail plate (idiopathic atrophy of the
12
nail). Yellow nail syndrome may be simulated by LP of the nails. Pterygium formation is very characteristic of LP of the nails (Fig. 12-5). The nail matrix is destroyed by the inflamma tion and replaced by fibrosis. The proximal nailfold fuses with the proximal portion of the nailbed. LP may be a cause of some cases of twenty-nail dystrophy of childhood. Twenty-nail dys trophy in the absence of periungual lesions or pterygium
Fig. 12-1 Lichen planus, violaceous, flat-topped papules with minimal scale.
Fig. 12-2 Lichen planus of the penis.
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Fig. 12-3 Lichen planus of the soles.
anus similar lesions are observed; they are generally whitish, owing to maceration. In the vulvovaginal areas, erosive or ulcerative disease is common and may coexist with typical reticulate lesions. Vulval splitting may be caused by LP. Conjunctival involvement is a very rare complication of LP. It occurs in patients with oral and gingival involvement. Cicatrization and subepithelial scarring can occur, as well as keratitis. It may closely simulate mucous membrane pemphi goid. Routine histology and direct immunofluorescence (DIF) may be required to confirm the diagnosis. LP of the esophagus is increasingly being recognized, but still occurs in only 1% of cases of LP. The diagnosis is fre quently delayed. Dysphagia, odynophagia, and weight loss are typical manifestations. The mid-esophagus is primarily affected. Virtually all the patients have coexistent oral disease. Esophageal involvement is much more common in women with vulvovaginal and oral disease, in whom 15% develop esophageal lesions. Stricture formation occurs in 80% of esophageal LP and may require frequent dilatations. Esophageal squamous cell carcinoma may complicate esopha geal LP, suggesting that, once this diagnosis is made, routine gastrointestinal evaluation is required. There are many clinical variants of LP. Whether these rep resent separate diseases or part of the LP spectrum is unknown. They all demonstrate typical LP histologically. They are described separately, since their clinical features are distinct from classic LP. Some patients with these clinical variants may have typical skin lesions of classic LP as well. The more common or better-known variants are described below.
Linear lichen planus
Fig. 12-4 Annular lichen planus of the penis.
Small linear lesions caused by the Koebner phenomenon often occur in classic LP. Limitation of LP to one band or streak has also been described in less than 1% of patients, except in Japan, where up to 10% of reported cases are linear. Although origi nally described as following dermatomes (zosteriform), the lesions actually follow lines of Blaschko. It is more common in children, but also occurs in adults. Papules with varying degrees of overlying hyperkeratosis, or simple hyperpigmen tation may be the presenting manifestations. There are often skip areas of normal skin between the individual lesions.
Annular/annular atrophic lichen planus
Fig. 12-5 Lichen planus, nail involvement with pterygium. (Courtesy of Lawrence Lieblich, MD)
formation usually resolves spontaneously, and frequently in these cases, no other stigmata of cutaneous or mucosal LP are found. Rarely, nailbed LP can result in onychopapilloma, a localized distal subungual hyperkeratosis. Involvement of the genitalia, with or without lesions at other sites, is common. On the glans or shaft of the penis the lesions may consist of flat, polygonal papules, or these may be annular. Erosive LP can occur on the glans. Simultaneous involvement of the gingival and penile mucosa may occur. On the labia and 214
Men represent 90% of patients with annular LP. Lesions with this configuration favour the axilla, penis/scrotum, and groin. LP lesions of the mucosae, scalp, and nails are rare in patients with annular LP. Patients usually have fewer than 10 lesions. Most patients with annular LP are asymptomatic. The ringed lesions are composed of small papules and measure about 1 cm in diameter. Central hyperpigmentation may be the dom inant feature. They may coalesce to form polycyclic figures. Annular lesions may also result from central involution of flat papules or plaques, forming lesions with violaceous, elevated borders and central hyperpigmented macules.
Hypertrophic lichen planus (lichen planus verrucosus) Hypertrophic LP occurs most commonly on the shins, although it may be situated anywhere. The typical lesions are verrucous plaques with variable amounts of scale. At the edges of the plaques, small, flat-topped, polygonal papules may at times be discovered. Superficial inspection of the lesion often suggests psoriasis or a keratinocytic neoplasm rather than LP, but the typical appearance resembling rapidly cooled igneous
Ulcerative/mucosal lichen planus
in these patients. In oral LP the “classic” reticulate lesions are most prominent in 23% of patients. Symptoms are least common in patients with reticulate lesions; 23% are sympto matic and then only when the tongue is involved. All patients with erosive lesions are symptomatic, usually with burning or pain. Patients may simultaneously have several patterns, so patients are characterized by the primary form they exhibit. Lesions appear on any portion of the mouth, and multisite involvement is common. The buccal mucosa is involved in 90%, the gingiva in more than half, and the tongue in about 40%. On the gingiva, LP may produce desquamative gingivitis (Fig. 12-7). Oral LP may involve any portion of the mouth. The buccal mucosa is involved in 90% of cases, and the gingiva in more than 50%. Gingival involvement is particularly hard to diagnose, and often requires biopsy for both histology and DIF to confirm the diagnosis and exclude autoimmune causes of desquamative gingivitis. Gingival involvement is associated with accelerated gingival recession and aggressive manage ment of oral hygiene, and control of candidal overgrowth is critical in the management of oral LP patients. Mechanical injury from dental procedures and poor-fitting appliances, as well as increased plaque from an inability to clean teeth due to pain, may trigger or exacerbate gingival LP. On the tongue and palate, lesions are often mistaken for leukoplakia (Fig. 12-8). The lower lip is involved in 15% of oral LP patients, but
Ulcerative LP is rare on the skin but common on the mucous membranes. Typical skin lesions of LP rarely ulcerate. A rare ulcerative variant of cutaneous LP, or lupus erythematosus/ LP overlap syndrome, affects the feet and toes, causing bullae, ulcerations, and permanent loss of the toenails. These chronic ulcerations on the feet are painful and disabling. Cicatricial alopecia may be present on the scalp and the buccal mucosa may also be affected. Skin grafting of the soles has produced successful results. Oral mucosal LP is the most common form of mucosal LP, and it is usually chronic. Between 10 and 15% of patients with oral LP will also have skin lesions. Women represent 75% of patients with oral LP. Oral LP in women begins 10 years later than in men (57 years vs 47 years). Oral lesions may be reticu late (reticular) (Fig. 12-6), erythematous (atrophic), or ulcera tive (erosive). The most common pattern in oral LP is the ulcerative form (40% of patients). Usually, reticulate and ery thematous lesions are found adjacent to the ulcerative areas. The erythematous pattern is the predominant pattern in 37% of patients, but almost always reticulate lesions are also seen
Fig. 12-7 Desquamative gingivitis secondary to lichen planus.
Fig. 12-6 Lichen planus, reticulate white lesions of the buccal mucosa.
Fig. 12-8 Lichen planus of the tongue.
Lichen planus
rock (igneous rock sign) may be useful in suspecting LP over keratinocytic neoplasms. The lesions are of variable size, but are frequently several centimeters in diameter and larger than the lesions of classic LP. The anterior lower leg below the knee is the sole area of involvement in the majority of patients. Clinical diagnosis may be difficult and biopsy is often required. Histologically, the pseudoepitheliomatous keratinocyte hyper plasia may be marked, leading to the erroneous diagnosis of squamous cell carcinoma. True squamous cell carcinoma may also evolve from longstanding hypertrophic LP, and over 50% of cutaneous squamous cell carcinoma arising in LP occurs below the knee in lesions of hypertrophic LP. In addition, keratoacanthoma-like proliferations may occur in lesions of hypertrophic LP. This has also been called “hypertrophic lichen planus-like reactions combined with infundibulocystic hyperplasia.” Hypertrophic LP is chronic and often refractory to topical therapy. Hypertrophic lupus erythematosus resem bles hypertrophic LP both clinically and histologically. Hypertrophic lupus tends to affect the distal extremities, face, and scalp. The finding of continuous granular immunoglobu lin on DIF strongly suggests a diagnosis of hypertrophic lupus erythematosus rather than LP.
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the upper lip in only 2%. Oral LP is stable but chronic, with less than 3% of patients having a spontaneous remission in an average 5-year follow-up. Aggressive oral hygiene plays an important role in the management of gingival LP. Mercury, gold, cobalt, indium, manganese, chromate, nickel, or palladium sensitivity may be found by patch testing in up to 60–75% of patients with oral LP or oral lichenoid reactions. In patients with positive patch tests to metals, these tests appear relevant in at least 44% of patients, and removal of the offending amalgam leads to improvement of the oral lichenoid process in 60–100% of patch test-positive patients (more than 60% of patients who did not remove their amalgam also improved). Patch testing, however, may not identify all patients whose oral lichenoid lesions improve with removal of the oral metal. Neither can histopathological evaluation iden tify the metal-induced patients. This has made the role of metals in the induction of oral lichenoid lesions and oral LP very controversial. Rarely, patients with metal sensitivity will also have skin and nail lesions that improve with removal of the oral metal. Metal sensitivity as a cause of an oral lichenoid reaction should be considered, especially in those patients whose oral involvement is directly adjacent to amalgam fill ings. If patch testing is positive for amalgam or metals, removal of the amalgam should be considered. Oral lichenoid reactions to cinnamates and spearmint have also been reported. Involvement of the vulva and vagina with LP, along with the gingiva, has been called the vulvovaginal–gingival (VVG) syndrome. Although all three of these mucous membranes may be involved, only one or two sites may be involved at any one time. The prevalence of erosive vulvar LP has been under appreciated until recently, simply because many women with LP will not volunteer their vulvovaginal complaints unless specifically asked. Women affected with vulvar LP have vulvar pain or burning. Vulvar LP produces lesions very similar to oral lichen planus, with erythema, leukokeratosis, and erosion. Surrounding the red or eroded lesions is a narrow rim of white reticulation. This rim is the most fruitful area to biopsy in order to confirm the diagnosis. Scarring (Fig. 12-9) of the vagina and vulva with adhesions, vestibular bands, and atrophy of the labia minora or prepuce occurs, making the morphology similar to vulvar lichen sclerosus. In one-third, typical reticulate buccal LP is seen, and in up to 80% the oral mucosa is also involved. Cutaneous lesions occur in between 20% and 40% of VVG patients. The course of the vulvovaginal syndrome is protracted and patients frequently have sequelae, including chronic pain, dyspareunia, and even scarring of the conjunctiva, urethra, and oral, laryngeal, pharyngeal, and
Fig. 12-9 Scarring and erosions in the vulvovaginal–gingival syndrome.
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esophageal mucosae. Nails are involved in about 15% of patients with VVG (as compared to only 2% of patients with oral LP). The VVG syndrome is now considered to be a sepa rate subgroup of mucosal LP that is particularly disabling, scarring, and refractory to therapy. While the pathogenesis of LP is unknown, there is evidence that erosive LP of the vulva (and lichen sclerosus) may have an autoimmune basis. A personal and family history of auto immune disorders (usually thyroid disease) is present in up to 30% of patients with vulvar LP, and up to 40% have circulating autoantibodies. The prevalence of autoimmune phenomena is NOT increased in patients with classic cutaneous LP. The autoantibodies do not appear to be pathogenic, as the disease seems to be caused by cytotoxic T cells. Erosive LP has signifi cant impact on quality of life, and patients with erosive LP have high levels of depression, anxiety, and stress.
Cancer risk and lichen planus Rare cases of squamous cell carcinoma of the skin occurring on the lower leg in lesions of hypertrophic LP have been reported. There is no statistical increase in cutaneous or vis ceral carcinoma in patients with cutaneous LP, and cutaneous LP alone is not considered to be a condition with increased cancer risk. Oral and vulvovaginal LP does appear, however, to increase the risk of developing squamous cell carcinoma. Between 0.4% and 5% (on average about 1–2%) of patients with oral LP will develop oral squamous cell carcinoma. Squamous cell carcinoma only occurs in patients with ery thematous or ulcerative LP, not in patients with only the retic ulate pattern. Of the oral LP patients who develop oral squamous cell carcinomas, about 45% have only one cancer. The majority develop multiple cancers, and close vigilance is recommended in these patients. LP patients with erosive penile and vaginal disease also have developed squamous cell carcinoma. The number of penile cases is too low to determine the frequency of this consequence, but in the case of vulvar LP, the frequency of development of SCC may be as high as 3%. Clinicians should have a low threshold to biopsy fixed erosive or leukokeratotic lesions in patients with mucosal LP. The use of oral and topical calcineurin inhibitors for LP has been associated with the appearance of squamous cell carci noma on the genitalia. There is no evidence that the medica tions caused the neoplasia, but if these agents are used, regular follow-up and careful examination are required.
Hepatitis-associated lichen planus Three liver conditions have been associated with LP: hepatitis C virus (HCV), HBV immunization, and primary biliary cir rhosis. HCV infection was found in proportionately more patients with LP than in controls in 20 of 25 studies. The preva lence of HCV infection in patients with LP varies from 1.6% to 20%. There is an association with the human leukocyte antigen (HLA)-DR6 allele. The association of HCV infection and LP has been questioned. In a large series of patients with oral LP from the US, none of the 195 patients was infected with HCV, while 29% of patients with oral LP from Italy had HCV. Twenty percent of patients infected with HCV in Scotland had oral LP, as compared to 1% of seronegative patients. Although the data are conflicting, screening for HCV appears appropri ate in persons from a geographic region or population in which HCV infection is commonly associated with LP. The clinical features of LP in patients with hepatitis C infection are identical to classic LP, but LP patients with HCV infection are reported as being more likely to have erosive mucous mem brane disease. The existence of underlying hepatitis cannot be
Bullous lichen planus Two forms of LP may be accompanied by bullae. In classic LP, usually on the lower extremities, individual lesions will vesic ulate centrally (Fig. 12.10). This represents macroscopic exag geration of the subepidermal space formed by the lichenoid interface reaction destroying the basal keratinocytes. These lesions often spontaneously resolve. Lichen planus pemphigoides describes a rare subset of patients who usually have typical LP, then develop blistering on their LP lesions and on normal skin. Less commonly, the blistering antedates the LP. Clinically, they appear to be a combination of LP and bullous pemphigoid. Oral disease may occur and resemble either LP or mucous membrane pemphi goid. Lichen planus pemphigoides has been triggered by
Fig. 12-10 Generalized lichen planus.
medications and PUVA. Pruritus may be severe and lesions may evolve to resemble pemphigoid nodularis. Bullous pem phigoid affects an older age group than lichen planus pemphi goides (typical onset for lichen planus pemphigoides is between age 30 and 50). Histologically, the LP lesions show LP and the bullous lesions show the features of bullous pem phigoid. DIF is positive in a linear pattern, with IgG and C3 along the basement membrane zone, at the roof of saline split skin. The antigen targeted by the autoantibody in lichen planus pemphigoides is located in the same region as the bullous pemphigoid antigen (at the basal hemidesmosome). Antibodies from patients with lichen planus pemphigoides typically bind the 180 kD bullous pemphigoid antigen, but in a different region from bullous pemphigoid sera. Lichen planus pemphi goides tends to follow a benign and chronic course, even when compared to bullous pemphigoid. Treatment is similar to bullous pemphigoid, with potent topical steroids, systemic steroids, tetracycline, nicotinamide, intravenous immunoglob ulin, and immunosuppressives all being variably effective.
Lichen planus
predicted by clinical pattern or the results of liver function tests. Treatment of hepatitis C with interferon-α may be associ ated with the initial appearance of LP or exacerbation of preexisting LP. LP may occur at the sites of interferon injections, and skin testing may reproduce LP-like lesions. LP may improve or not change with interferon and ribavirin treatment for hepatitis C. Improvement is usually seen towards the end of the treatment course. Most patients do not completely clear their LP. The HCV genome is not found in lesions of LP associ ated with HCV infection. HBV immunization may be associated with the appearance of LP in both children and adults. More than 30 cases have been reported. Lesions are typical of LP and the oral mucosa may be affected. Most typically, the first lesions of LP appear about 1 month after the second dose of vaccine. Lesions typi cally resolve after some time. Primary biliary cirrhosis and LP may coexist. Patients with this liver abnormality, in addition, have a marked propensity to develop a lichenoid eruption while on d-penicillamine therapy. Xanthomas in patients with primary biliary cirrhosis may appear initially in lesions of LP, and the infiltrate, while lichenoid, may contain xanthomatous cells. Primary sclerosing cholangitis has been associated with oral LP in at least five patients.
Pathogenesis and histology LP is characterized by an immunologic reaction mediated by T cells. These cells induce keratinocytes to undergo apoptosis by an unknown mechanism. Recently, there have been reports of insulin resistance and frank type 2 diabetes mellitus being increased in patients with LP compared to controls. Lichen planus pemphigoides is hypothesized to result from exposure to the immune system of epitopes in the BP180 antigen as keratinocytes are destroyed by the lichenoid inflam mation. Epitope spreading can occur, and lichen planus pem phigoides patients may also have autoantibodies to the same epitopes as bullous pemphigoid patients. The histologic features of LP are distinctive and vary with the stage of the lesion. In early lesions there is an interface dermatitis along the dermoepidermal junction. As the lesion evolves, the epidermis takes on a characteristic appearance. There is destruction of the basal layer with a “saw-tooth” pattern of epidermal hyperplasia, orthokeratosis, and beaded hypergranulosis. The basal cells are lost, so the basal layer is described as “squamatized.” In the superficial dermis there is a dense, bandlike infiltrate composed of lymphocytes and melanophages. “Civatte bodies” (cytoid bodies, colloid bodies) represent necrotic keratinocytes in the superficial dermis. Hypertrophic LP shows marked epidermal hyperplasia (pseudoepitheliomatous hyperplasia). Old lesions of LP show effacement of the rete ridge pattern, melanophages in the upper dermis, and occasional Civatte bodies. LP rarely dem onstrates parakeratosis or eosinophils. The presence of either of these suggests a different cause of lichenoid tissue reaction, such as lichenoid drug eruption. Lichen planopilaris, frontal fibrosing alopecia, and Graham– Little–Piccardi–Lassueur syndrome show the findings of LP, centered on the superficial follicular epithelium. On DIF, clumps of IgM, and less frequently IgA, IgG, and C3, are com monly present subepidermally, corresponding to the colloid bodies. Dense shaggy staining for fibrinogen along the base ment membrane zone is characteristic of LP. A lichenoid drug eruption may be difficult to differentiate from LP. The pres ence of eosinophils or parakeratosis supports the diagnosis of lichenoid drug eruption. Although LP virtually never has eosi nophils or parakeratosis, they are not universally present in other lichenoid eruptions such as lichenoid drug eruption. Graft versus host disease tends to have a sparser infiltrate. Hypertrophic lupus may be histologically identical to LP, and the diagnosis is best made by clinical correlation and DIF. In most other forms of lupus erythematosus, there is a greater tendency for epidermal atrophy with parakeratosis, dermal 217
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mucin is found, and follicular plugging is more prominent. The infiltrate in lupus tends to surround and involve deep portions of the appendageal structures, such as the follicular isthmus and eccrine coil. Deep nodular perivascular lympho plasmacytic infiltrates and necrosis of the fat lobule with fibrin or hyalin rings are also findings characteristic of lupus erythematosus.
Differential diagnosis Classic LP displays lesions that are so characteristic that clini cal examination is often adequate to lead to suspicion of the diagnosis. Lichenoid drug eruptions may be difficult to distin guish. A lichenoid drug reaction should be suspected if the eruption is photodistributed, scaly but not hypertrophic, and confluent or widespread—clinical features that are unusual for idiopathic LP. The presence of oral mucosa involvement may prompt suspicion of LP, but oral lesions may occasionally occur in lichenoid drug eruptions as well. Pityriasis rosea, guttate psoriasis, the small papular or lichenoid syphilid, and pityriasis lichenoides et varioliformis acuta are dermatoses that may resemble generalized LP. Mucous membrane lesions may be confused with leukoplakia, lupus erythematosus, mucous patches of syphilis, candidiasis, cancer, and the oral lesions of autoimmune bullous diseases, such as pemphigus or cicatricial pemphigoid. On the scalp the atrophic lesions may be mistaken for other cicatricial alopecias, such as lupus erythematosus, folliculitis decalvans, and pseudopelade of Brocq. Hypertrophic LP type may simulate psoriasis and squa mous cell carcinoma in situ. Isolated patches of LP may resem ble lichen simplex chronicus or, if heavily pigmented, may suggest a fixed drug eruption.
Treatment
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Limited lesions may be treated with superpotent topical ster oids or intralesional steroid injections. In patients with wide spread disease, these treatments are usually unsatisfactory. Widespread lesions respond well to systemic corticosteroids but tend to relapse as the dose is reduced. Monthly pulse dosing has been championed by dermatologists in India. Phototherapy may be effective for cutaneous LP, including narrow-band ultraviolet (UV) B, UVA1, and PUVA. Topical cream PUVA has been used effectively in genital LP. Isotretinoin and acitretin, in doses similar to or slightly lower than those used for psoriasis, may also be useful and avoid the long-term complications of systemic steroids. They are espe cially helpful in cases of hypertrophic LP. Retinoid therapy may be combined with phototherapy in refractory cases. Photodynamic therapy with topical 5-aminolevulinic acid can be effective in penile LP. Low molecular weight heparin (enox aparin), 3 mg injected subcutaneously once a week, led to remission of cutaneous and reticulate oral LP in 61% of patients and improvement in 11%. Erosive oral LP responded variably and lichen planopilaris not at all. For erosive skin lesions topical tacrolimus or pimecrolimus can be effective. Oral immunosuppressive agents may be effective for cutaneous LP, but their potential toxicity limits use to the most severe cases. Cyclosporine in typical psoriasis doses is very beneficial. Similarly, mycophenolate mofetil can induce remission in severe cases of cutaneous and oral LP. For oral lesions, superpotent steroids in Orabase or gel form are useful. Vinyl dental trays may be used to apply steroid ointments to the gingiva. Begin with 30 min applications three times a day and reduce to maintenance of 20 min every evening. Addition of nystatin to clobetasol in Orabase may be especially effective. Overall, more than 70% of patients with
vulvar LP have their symptoms relieved with topical clobeta sol. Intralesional injections may be used for focal unresponsive lesions. Topical tacrolimus 0.1% ointment has become stand ard treatment in erosive LP of the oral and genital mucosa. While burning may occur initially, this can be reduced by concomitant use of topical steroids or initial use of a lower strength. Higher concentrations, up to 0.3%, may be used. Most patients have a partial but significant response, with increased ability to eat with much less pain. Blood levels can be detected, independent of area of involvement, but tend to decrease over time as the oral erosions heal. Pimecrolimus can be used successfully in patients intolerant of topical tacrolimus. Sustained remissions are rare, and chronic use is usually required to maintain remission. Topical cyclosporine is ineffective. Topical isotretinoin, in concentrations up to 0.18%, can be effective. PUVA, photodynamic therapy, and 308 nm excimer laser have been effective in oral LP. Hydroxychloroquine, 200–400 mg/day for 6 months, was reported to produce an excellent response in 9 of 10 patients with oral LP. Thalidomide has also proven effective in doses of 50–150 mg/day. The systemic agents recommended above to treat cutaneous LP may also improve oral disease. For VVG syndrome, corticosteroids topically and systemically are beneficial. Topical therapy with corticosteroids may be enhanced by mixing the steroid in vaginal bioadhesive moisturizer (Replens). Iontophoresis may improve delivery. Methotrexate, mycophenolate mofetil, and cyclosporine are usually effective in the most refractory cases. Extracorporeal photochemotherapy (photopheresis) has proven effective in refractory oral LP. Aghahosseini F, et al: Methylene blue mediated photodynamic therapy: a possible alternative treatment for oral lichen planus. Lasers Surg Med 2006; 38:33. Al-Khenaizan S: Lichen planus occurring after hepatitis B vaccination: a new case. J Am Acad Dermatol 2001; 45:614. Al-Khenaizan S, et al: Ulcerative lichen planus of the sole: excellent response to topical tacrolimus. Int J Dermatol 2008; 47:626. Ang P, et al: Pruritic linear eruption on a child. Arch Dermatol 2001; 137:85. Balasubramaniam P, et al: Lichen planus in children: review of 26 cases. Clin Exp Dermatol 2008; 33:457. Bansal R: Segmental lichen planus. Intl J Dermatol 2004; 43:985. Baran R: Lichen planus of the nails mimicking the yellow nail syndrome. Br J Dermatol 2000; 143:1117. Belfiore P, et al: Prevalence of vulval lichen planus in a cohort of women with oral lichen planus: an interdisciplinary study. Br J Dermatol 2006; 155:994. Berk D, et al: Dermatologic disorders associated with chronic hepatitis C: effect of interferon therapy. Clin Gastro and Hepato 2007; 5:142. Bermejo-Fenoll A, et al: Familiar oral lichen planus: presentation of six families. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102:e12. Bezanis G, et al: Verrucous plaques on the leg. Arch Dermatol 2003; 139:933. Camisa C, Popovsky JL: Effective treatment of oral erosive lichen planus with thalidomide. Arch Dermatol 2000; 136:1442. Carbone M, et al: Systemic and topical corticosteroid treatment of oral lichen planus: a comparative study with long-term follow-up. J Oral Pathol Med 2003; 32:323. Chandan V, et al: Esophageal lichen planus. Arch Pathol Lab Med 2008; 132:1026. Chave TA, Graham-Brown RAC: Keratoacanthoma developing in hypertrophic lichen planus. Br J Dermatol 2003; 148:592. Chryssostalis A, et al: Esophageal lichen planus: a series of eight cases including a patient with esophageal verrucous carcinoma. A case series. Endo 2008; 40:764. Chu CY, et al: Lichen planus with xanthomatous change in a patient with primary biliary cirrhosis. Br J Dermatol 2000; 142:377. Cooper S, et al: The association of lichen sclerosus and erosive lichen planus of the vulva with autoimmune disease. Arch Dermatol 2008; 144:1432.
Level NJ: No evidence for therapeutic effect of topical ciclosporin in oral lichen planus. Br J Dermatol 2006; 155:477. Limas C, Limas CJ: Lichen planus in children: a possible complication of hepatitis B vaccines. Pediatr Dermatol 2002; 19:204. Lodi G, et al: Lichen planus and hepatitis C virus: a multicentre study of patients with oral lesions and a systematic review. Br Assoc Dermatol 2004; 151:1172. Lodi G, et al: Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Infections and etiopathogenesis. Oral Surg Oral Med Oral Pathol Oral Endod 2005; 100:40. Lonsdale-Eccles AA, Velangi S: Topical pimecrolimus in the treatment of genital lichen planus: a prospective case series. Br J Dermatol 2005; 153:390. Lozada-Nur F, Sroussi H: Tacrolimus powder in Orabase 0.1% for the treatment of oral lichen planus and oral lichenoid lesions: an open clinical trial. Oral Surg Oral Med Oral Pathol Oral Endod 2006; 102:744. Luis-Montaya P, et al: Lichen planus in 24 children with review of the literature. Ped Dermatol 2005; 22:295. Lundqvist EN, et al: Psychological health in patients with genital and oral erosive lichen planus. Eur Acad Dermatol Venereol 2006; 20:661. Maender J, et al: Complete resolution of generalized lichen planus after treatment with thalidomide. J Drugs Dermatol 2005; 4:86. Malhotra A, et al: Betamethasone oral mini-pulse therapy compared with topical triamcinolone acetonide (0.1%) paste in oral lichen planus: a randomized comparative study. J Am Acad Dermatol 2008; 58:596. Maluf R, et al: Bilateral lower eyelid margin erosion associated with lichen planus. Ophth Plastic Recon Surg 2006; 22:310. Mansura A, et al: Ultraviolet A-1 as a treatment for ulcerative lichen planus of the feet. Photodermatol Photoimmunol Photomed 2006; 22:164. Maticic M, et al: Lichen planus and other cutaneous manifestations in chronic hepatitis C: pre- and post-interferon-based treatment prevalence vary in a cohort of patients from low hepatitis C virus endemic area. Eur Acad Dermatol Venereol 2008; 22:779. Mignogna M, et al: Dysplasia/neoplasia surveillance in oral lichen planus patients: a description of clinical criteria adopted at a single centre and their impact on prognosis. Oral Oncol 2006; 42:819. Mohrenschlager M, et al: Primary manifestation of a zosteriform lichen planus: isotopic response following herpes zoster sine herpete. Br J Dermatol 2008; 158:1145. Morales-Callaghan A Jr, et al: Annular atrophic lichen planus. J Am Acad Dermatol 2005; 52:906. Nagao Y, et al: Exacerbation of oral erosive lichen planus by combination of interferon and ribavirin therapy for chronic hepatitis C. Int J Molecul Med 2005; 15:237. Nagao Y, et al: Insulin resistance and lichen planus in patients with HCV-infectious liver diseases. J Gastroenterol Hepatol 2008; 23:580. Nakova I, et al: Psychological profile in oral lichen planus. J Clin Periodontol 2005; 32:1034. Neville JA, et al: Treatment of severe cutaneous ulcerative lichen planus with low molecular weight heparin in a patient with hepatitis C. Cutis 2007; 79:37. Nousari HC, et al: Successful treatment of resistant hypertrophic and bullous lichen planus with mycophenolate mofetil. Arch Dermatol 1999; 135:1420. Okiyama N, et al: Squamous cell carcinoma arising from lichen planus of nail matrix and nail bed. J Am Acad Dermatol 2005; 53:908. Ortiz-Ruiz A, et al: Oral lichen planus and sensitization to manganese in a dental prosthesis. Contact Dermatitis 2006; 54:214. Pakravan M, et al: Isolated lichen planus of the conjunctiva. Br J Ophthalmol 2006; 90:1325. Parodi A, et al: Prevalence of stratified epithelium-specific antinuclear antibodies in 138 patients with lichen planus. J Am Acad Dermatol 2007; 56:974. Passeron T, et al: Treatment of erosive oral lichen planus by the 308 nm excimer laser. Lasers Surg Med 2004; 34:205. Passeron T, et al: Treatment of oral erosive lichen planus with 1% pimecrolimus cream. Arch Dermatol 2007; 143:472. Perez A, et al: Occupational contact dermatitis from 2,4-dinitrofluorobenzene. Contact Dermatitis 2004; 51:314. Petropoulou H, et al: Effective treatment of erosive lichen planus with thalidomide and topical tacrolimus. Intl J Dermatol 2006; 45:1244. Pigatto P, et al: Oral lichen planus: mercury and its kin. Arch Dermatol 2005; 141:1472.
Lichen planus
Copper S, Wojnarowska F: Influence of treatment of erosive lichen planus of the vulva on its prognosis. Arch Dermatol 2006; 142:289. Cunha K, et al: Prevalence of oral lichen planus in Brazilian patients with HCV infection. Oral Surg Oral Med Oral Pathol Oral Radio Endod 2005; 100:330. Di Fede O, et al: Unexpectedly high frequency of genital involvement in women with clinical and histological features of oral lichen planus. Acta Derm Venereol 2006; 86:433. Ditrichova D, et al: Oral lichenoid lesions and allergy to dental materials. Biomed Pap Med Fac Univ Palacky Olomuc Czech Repub 2007; 151:333. Durrani O, et al: Bicanalicular obstruction in lichen planus. A characteristic pattern of disease. Ophthal 2008; 115:386. Eisen D: The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients. J Am Acad Dermatol 2002; 46:207. Fiveson D, et al: Treatment of generalized lichen planus with alefacept. Arch Dermatol 2006; 142:151. Frieling U, et al: Treatment of severe lichen planus with mycophenolate mofetil. J Am Acad Dermatol 2003; 49:1063. Gonzalez-Moles MA, et al: Treatment of severe erosive gingival lesions by topical application of clobetasol propionate in custom trays. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 95:688. Guiglia R, et al: A combined treatment regimen for desquamative gingivitis in patients with oral lichen planus. J Oral Patholo Med 2007; 36:110. Guyot AD, et al: Treatment of refractory erosive oral lichen planus with extracorporeal photochemotheraphy: 12 cases. Br J Dermatol 2007; 156:553. Hamada T, et al: Lichen planus pemphigoides and multiple keratoacanthomas associated with colon adenocarcinoma. Br J Dermatol 2004; 151:232. Harden D, et al: Lichen planus associated with hepatitis C virus: no viral transcripts are found in the lichen planus, and effective therapy for hepatitis C virus does not clear lichen planus. J Am Acad Dermatol 2003; 49:847. Harting M, Hsu S, et al: Lichen planus pemphigoides: a case report and review of the literature. Dermatol Online J 2006; 12:10. Hopsu E, Pitkaranta A: Idiopathic, inflammatory, medial meatal, fibrotising otitis presenting with lichen planus. J Laryn Oto 2007; 121:796. Hoskyn J, Guin J: Contact allergy to cinnamil in a patient with oral lichen planus. Contact Dermatitis 2005; 52:161. Hoshi A, et al: Penile carcinoma originating from lichen planus on glans penis. J Urology 2008; 71:816. Issa Y, et al: Oral lichenoid lesions related to dental restorative materials. Br Dent J 2005; 198:361. Kaliakatsou F, et al: Management of recalcitrant ulcerative oral lichen planus with topical tacrolimus. J Am Acad Dermatol 2002; 46:35. Kato Y, et al: A case of lichen planus caused by mercury allergy. Br J Dermatol 2003; 148:1268. Kirby B, et al: Treatment of lichen planus of the penis with photodynamic therapy. Br J Dermatol 1999; 141:765. Kirtschig G, et al: Successful treatment of erosive vulvovaginal lichen planus with topical tacrolimus. Br J Dermatol 2002; 147:625. Kollner K, et al: Treatment of oral lichen planus with the 308-nm UVB excimer laser—early preliminary results in eight patients. Lasers Surg Med 2003; 33:158. Kortekangas-Savolainen O, Kiilholma P: Treatment of vulvovaginal erosive and stenosing lichen planus by surgical dilatation and methotrexate. Acta Obstetricia et Gynecol Scandinavica 2007; 86:339. Kossard S, et al: Hypertrophic lichen planus-like reactions combined with infundibulocystic hyperplasia. Arch Dermatol 2004; 140:1262. Krasowska D, et al: Development of squamous cell carcinoma with lesions of cutaneous lichen planus. Eur J Dermatol 2007; 17:447. Kuramoto N, et al: PUVA-induced lichen planus pemphigoides. Br J Dermatol 2000; 142:509. Kyriakis KP, et al: Sex and age distribution of patients with lichen planus. Eur Acad Dermatol Venereol 2006; 18:625. Laeijendecker R, et al: Oral lichen planus and allergy to dental amalgam restorations. Arch Dermatol 2004; 140:1434. Laeijendecker R, et al: Oral lichen planus and hepatitis C virus infection. Arch Dermatol 2005; 141:906. Lener EV, et al: Successful treatment of erosive lichen planus with topical tacrolimus. Arch Dermatol 2001; 137:419.
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Pinto JM, et al: Lichen planus and leukocytoclastic vasculitis induced by interferon alpha-2b in a subject with HCV-related chronic active hepatitis. J Eur Acad Dermatol Venereol 2003; 17:193. Polderman MC, et al: Ultraviolet A1 in the treatment of generalized lichen planus: a report of 4 cases. J Am Acad Dermatol 2004; 50:646. Quispel R, et al: High prevalence of esophageal involvement in lichen planus: a study using magnification chromoendoscopy. Endo 2009; 41:187. Radfar L, et al: A comparative treatment study of topical tacrolimus and clobetasol in oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105:187. Rahman SB, et al: Unilateral blaschkoid lichen planus involving the entire half of the body, a unique presentation. Dermatol Online J 2007; 13:36. Rahnama Z, et al: The relationship between lichen planus and hepatitis C in dermatology outpatients in Kerman, Iran. Int J Dermatol 2005; 44:746. Reich HL, et al: Annular lichen planus: a case series of 20 patients. J Am Acad Dermatol 2004; 50:595. Reichrath J, et al: Treatment of genito-anal lesions in inflammatory skin diseases with PUVA cream photochemotherapy: an open pilot study in 12 patients. Richert B, et al: Nail bed lichen planus associated with onychopapilloma. Br J Dermatol 2007; 156:1071. Rogers RS, Bruce AJ: Lichenoid contact stomatitis. Arch Dermatol 2004; 140:1524. Sakuma-Oyama Y, et al: Lichen planus pemphigoides evolving into pemphigoid nodularis. Clin Exp Dermatol 2003; 28:613. Salem CB, et al: Captopril-induced lichen planus pemphigoides. Pharmacoepidemiol Drug Safety 2008; 17:722. Sanchez-Perez J, et al: Lichen planus with lesions on the palms and/or soles: prevalence and clinicopathological study of 36 patients. Br J Dermatol 2000; 142:310. Saricaoglu H, et al: Narrowband UVB therapy in the treatment of lichen planus. Photodermatol Photoimmunol Photomed 2003; 19:265. Scalf LA, et al: Dental metal allergy in patients with oral cutaneous, and genital lichenoid reactions. Am J Contact Dermatitis 2001; 12:146. Scardina GA, et al: A randomized trial assessing the effectiveness of different concentrations of isotretinoin in the management of lichen planus. Int J Oral Maxillofac Surg 2006; 35:67. Schwartz M, et al: Two siblings with lichen planus and squamous cell carcinoma of the oesophagus. Eur J Gastroenterol Hepatol 2006; 10:1111. Setterfield JF, et al: The vulvovaginal gingival syndrome: a severe subgroup of lichen planus with characteristic clinical features and a novel association with the class II HLA DQb1* 0201 allele. J Am Acad Dermatol 2006; 55:98. Seyhan M, et al: High prevalence of glucose metabolism disturbance in patients with lichen planus. Diabetes Research Clin Practice 2007; 77:198. Shichinohe R, et al: Successful treatment of severe recalcitrant erosive oral lichen planus with topical tacrolimus. Eur Acad Dermatol Venereol 2006; 20:66. Sing SK, et al: Squamous cell carcinoma arising from hypertrophic lichen planus. Eur Acad Dermatol Venereol 2006; 20:745. Singal A: Familial mucosal lichen planus in three successive generations. Int J Dermatol 2005; 44:81. Swift J, et al: The effectiveness of 1% pimecrolimus cream in the treatment of oral erosive lichen planus. J Periodontol 2005; 76:627. Thongprasom K, et al: Clinical evaluation in treatment of oral lichen planus with topical fluocinolone acetonide: a 2-year follow-up. J Oral Pathol Med 2003; 32:315. Thorne JE, et al: Lichen planus and cicatrizing conjunctivitis: characterization of five cases. Am J Ophthalmol 2003; 136:239. Thornhill M, et al: The role of histopathological characteristic in distinguishing amalgam-associated oral lichenoid reactions and oral lichen planus. J Oral Pathol Med 2006; 35:233. Tilly J, et al: Lichenoid eruptions in children. J Am Acad Dermatol 2004; 51:606. Tong DC, Ferguson MM: Concurrent oral lichen planus and primary sclerosing cholangitis. Br J Dermatol 2002; 147:356. Torti D, et al: Oral lichen planus. Arch Dermatol 2007; 143:511. Tosti A, et al: Nail changes in lichen planus may resemble those of yellow nail syndrome. Br J Dermatol 2000; 142:848.
Tosti A, et al: Nail lichen planus in children: clinical features, response to treatment, and long-term follow-up. Arch Dermatol 2001; 137:1027. Vazques-Lopez F, et al: Dermoscopy of active lichen planus. Arch Dermatol 2007; 143:1092. Verma S: Lichen planus affecting eyelid alone: a rare entity. Indian J Dermatol Venereol Leprol 2006; 72:398. Walsh DS, et al: A vaginal prosthetic device as an aid in treating ulcerative lichen planus of the mucous membrane. Arch Dermatol 1995; 131:265. Welsh JP, et al: A novel visual clue for the diagnosis of hypertrophic lichen planus. Arch Dermatol 2006; 142:954 Westbrook R, Stuart R: Esophageal lichen planus: case report and literature review. Dysphagia 2008; 23:331. Wong CS, et al: Isolated vulval splitting—is this normal or pathological? J Obstet Gynaecol 2004; 24:899. Xia J, et al: Short-term clinical evaluation of intralesional triamcinolone acetonide injection for ulcerative oral lichen planus. J Oral Pathol Med 2006; 35:327. Yashar S, et al: Lichen sclerosus–lichen planus overlap in a patient with hepatitis C virus infection. Br J Dermatol 2004; 150:168. Yokozeki H, et al: Twenty-nail dystrophy (trachyonychia) caused by lichen planus in a patient with gold allergy. Br J Dermatol 2005; 152:1089. Zakrzewska JM, et al: A systematic review of placebo-controlled randomized clinical trials of treatments used in oral lichen planus. Br J Dermatol 2005; 153:336. Zillikens D, et al: Autoantibodies in lichen planus pemphigoides react with a novel epitope within the C-terminal NC16A domain of BP180. J Invest Dermatol 1999; 113:117.
Follicular lichen planus (lichen planopilaris) Lichen planopilaris is lichen planus involving the follicular apparatus (Fig. 12-11). Most cases involve the scalp and it is an important cause of cicatricial alopecia (see Chapter 33). Seventy to 80% of affected patients are women, usually around the age of 50. The oral mucosa is involved, with reticulate lichen planus in 7–27% of patients, and between 20% and 40% of patients have cutaneous involvement. Graham–Little– Piccardi–Lassueur syndrome describes patients with lichen planopilaris of the scalp with coexistent keratosis pilaris-like lichen planopilaris lesions and nonscarring alopecia of the eye brows, axillae, and pubic area. Thalidomide and cyclosporine have been reported to be effective. Cooper S, et al: The association of lichen sclerosus and erosive lichen planus of the vulva with autoimmune disease. Arch Dermatol 2008; 144:1432.
Fig. 12-11 Follicular lichen planus surrounding a classic lichen planus papule.
Lichen planus pigmentosus is seen primarily in Central America, the Indian subcontinent, the Middle East, and Japan. It appears to be a form of LP restricted to certain racial groups. The persons from these genetic groups can develop the condi tion when they move to North America and Europe, but Caucasians from Europe and North America do not develop lichen planus pigmentosus when they move to tropical areas where the disease is common. Lichen planus pigmentosus patients are young (between 20 and 45 in most cases), and men and women are equally represented. Men present a decade earlier (mean age 26 vs 34). The face and neck are primarily involved, but the axilla, inframammary region, and groin may also be affected. Lesions may be unilateral. The condition is usually mild (2–3), but recent American College of Obstetricians and Gynecologists (ACOG) guidelines suggest that laboratory and imaging studies are best used to exclude a virilizing tumor. The diag nosis of PCOS is made clinically by the presence of anovulation (fewer than nine periods per year or periods >40 days apart) and signs of hyperandrogenism, such as acne and hirsutism. Acne neonatorum is explained by circulating maternal hor mones, whereas acne extending or developing after the neo natal period may be a form of acne cosmetica, acne venenata, drug-induced acne, or part of an endocrinologic disorder. In the absence of any of these etiologies, qualitative or quantita tive alterations of cutaneous androgen, metabolism, or increased end-organ sensitivity could be postulated as patho genetic mechanisms for preadolescent acne.
Pathology Comedones reveal a thinned epithelium and a dilated follicu lar canal filled with lamellar lipid-impregnated keratinous 230
material. In pustular cases there are folliculocentric abscesses surrounded by a dense inflammatory exudate of lymphocytes and polymorphonuclear leukocytes. In addition to these find ings, indolent nodular lesions frequently show plasma cells, foreign body giant cells, and proliferation of fibroblasts. Epithelial-lined sinus tracts may form.
Treatment General principles It is important to take a complete historical record of prior therapies, including all over-the-counter products. The dose, timing, combinations, side effects, and response to interven tions should be obtained. Corticosteroids, anabolic steroids, neuroleptics, lithium, and cyclosporine may worsen acne. A family history of acne and, if present, its tendency to scarring should be noted. Women should be queried regularly about menstrual irregularities and hair growth in a male pattern, as well as use of cosmetics. Failure of treatment may be because of drug interactions, coexisting conditions, or antibiotic resistance; however, the most common and important cause is lack of adherence to the treatment plan. Utilizing medications that are well tolerated, have convenient dosing regimens, and are cosmeti cally acceptable will help, but thorough patient education is essential. Explaining how lesions form, and the expected response to, and duration and possible side effects of treat ment, and giving clear unambiguous instructions are key. Patients should be aware of the difference between active inflammatory lesions and the purplish-red or hyperpigmented macules of inactive resolved lesions. Topical application to the entire affected area rather than to specific lesions should be emphasized, and the fact that oral and topical medications should be used daily as the treatment is preventative in nature should be discussed. A high glycemic diet may worsen acne, however the strength of its influence is unknown. The authors do not counsel patients to alter their diets. Scrubbing of the face increases irritation and may worsen acne. Use of only the prescribed medications and avoidance of potentially drying over-thecounter products, such as astringents, harsh cleansers, or anti bacterial soaps, should be emphasized. Non-comedogenic cosmetics are recommended, and pressed powders and oilbased products should be avoided.
Medical therapy Systemic and topical retinoids, systemic and topical antimicro bials, and systemic hormonal therapy are the main therapeutic classes of treatment available. Treatment guidelines are out lined in Box 13-1.
Topical treatment As all topical treatments are preventative, use for 6–8 weeks is required to judge their efficacy. The entire acne-affected area is treated, not just the lesions, and long-term usage is the rule. In many patients, topical therapy may be effective as mainte nance therapy after initial control is achieved with a combina tion of oral and topical treatment. Topical retinoids It has long been appreciated that these agents are especially effective in promoting normal desquama tion of the follicular epithelium; thus, they reduce comedones and inhibit the development of new lesions. Additionally, they have a marked anti-inflammatory effect, inhibiting the activity of leukocytes, the release of proinflammatory cytokines and other mediators, and the expression of transcription factors and toll-like receptors involved in immunomodulation. They also help penetration of other active agents. Thus, they should
Mild 1. Comedonal • Topical retinoid ± physical extraction (first line) • Alternate retinoid, salicylic acid, azelaic acid (second line) 2. Papular/pustular • Topical antimicrobial combination + topical retinoid, benzoyl peroxide wash if mild trunkal lesions (first line) • Alternate antimicrobials + alternate topical retinoids, azelaic acid, sodium sulfacetamide–sulfur, salicylic acid (second line)
Moderate 1. Papular/pustular • Oral antibiotic + topical retinoid + benzoyl peroxide (first line) • Alternate antibiotic, alternate topical retinoid, alternate benzoyl peroxide (second line) • In women, spironolactone + oral birth control pill + topical retinoids ± topical antibiotic and/or benzoyl peroxide • Isotretinoin if relapses quickly off oral antibiotics, does not clear, or scars
Severe 1. Nodular/conglobate • Isotretinoin • Oral antibiotic + topical retinoid + benzoyl peroxide • In women, spironolactone + oral birth control pill + topical retinoid ± topical or oral antibiotics and/or benzoyl peroxide
be utilized in nearly every patient with acne and are the pre ferred agents in maintenance therapy. Tretinoin was the first of this group of agents to be used for acne. Popular forms of tretinoin are 0.025% and 0.05% in a cream base because these are less irritating than the gels and liquids. Its incorporation into microspheres and a polyolpre polymer also helps to limit irritation and make the product more stable in the presence of light and oxidizers. Tretinoin treatment may take 8–12 weeks before improvement occurs. When patients are tolerating the medication and are slow to respond, retinoic acid gel or solution may be utilized. Tretinoin should be applied at night and is in pregnancy category C. Adapalene is a well-tolerated retinoid-like compound, which has efficacy equivalent to the lower concentrations of tretinoin. As it is light-stable, it may be applied in either the morning or the evening. It is in pregnancy category C. Tazarotene is comparatively strong in its action, but also rela tively irritating. It should be applied once at night or every other night, and as it is in pregnancy category X, contraceptive counseling should be provided. Initially utilizing retinoids on an every-other-night basis, or using a moisturizer with them, may lessen their irritancy. They are also particularly useful in patients with skin of color as they may lighten postinflammatory hyperpigmentation. Benzoyl peroxide Benzoyl peroxide has a potent antibacte rial effect. P. acnes resistance does not develop during use. Its concomitant use during treatment with antibiotics will limit the development of resistance, even if only given for short 2- to 7-day pulses. While it is most effective in inflammatory acne, some studies have shown it to be comedolytic also. The wash formulations may be utilized for mild trunkal acne when sys temic therapies are not required. Treatment is usually once or twice a day. Benzoyl peroxide may irritate the skin and produce peeling. Water-based for mulations of lowest strength are least irritating. Application
lessened to once a day or every other day will also help limit this. Allergic contact dermatitis will rarely develop, suggested by the complaint of itch rather than stinging or burning. It is in pregnancy category C. Topical antibacterials Topical clindamycin and erythro mycin are available in a number of formulations. In general, they are well tolerated and are effective in mild to moderate inflammatory acne. These topical products are in pregnancy category B. Use of these topical antibiotics alone, however, is not recommended because of increasing antibiotic resistance. As mentioned above, concurrent therapy with benzoyl per oxide will limit this problem. Concomitant use with a topical retinoid will hasten the response and allow for more rapid discontinuance of the antibiotic. Dapsone is available topically in a gel formulation. Hemolytic anemia may occur and a discoloration of the skin is not uncommon when benzoyl peroxide is applied after topical dapsone. Additionally, concomitant oral use of trimethoprim/sulfamethoxazole will increase the systemic absorption of topical dapsone. It is in pregnancy category C. Sulfur, sodium sulfacetamide, resorcin, and salicylic acid Although benzoyl peroxide, retinoids, and topical antibiotics have largely supplanted these older medications, sulfur, resorcin, and salicylic acid preparations are still useful and moderately helpful if the newer medications are not tolerated. They are frequently found in over-the-counter preparations. Sulfacetamide–sulfur combination products are mildly effec tive in both acne and rosacea. The latter should be avoided in patients with known hypersensitivity to sulfonamides. Azelaic acid This dicarboxylic acid is remarkably free from adverse actions and has mild efficacy in both inflammatory and comedonal acne. It may help to lighten postinflammatory hyperpigmentation and is in pregnancy category B. Combination topical therapy Several products are available which combine antibiotics such as clindamycin and benzoyl peroxide, or retinoids and either antibiotics or benzoyl perox ide. In general these medications increase adherence, as they require less frequent application of medication, and they may also limit irritation compared with the cumulative topical application of each product separately. However, they limit flexibility and may cause more irritation than a single product used alone.
Acne vulgaris
Box 13-1 Acne treatment
Oral antibiotics These agents are indicated for moderate to severe acne, in patients with inflammatory disease in whom topical combina tions have failed or are not tolerated, for the treatment of chest, back, or shoulder acne, or in patients in whom absolute control is deemed essential, such as those who scar with each lesion or develop inflammatory hyperpigmentation. It generally takes 6–8 weeks to judge efficacy. Starting at a high dose and reducing it after control is preferred. Working to maintain control eventually with topical retinoids or retinoid–benzoyl peroxide combination therapy is ideal; however, keeping patients free of disease for 1–2 months before each decrease in dosage is best to prevent flaring. Most courses of oral therapy are of at least 3–6 months’ duration. There is concern that oral antibiotics may reduce the effec tiveness of oral birth control pills. It is appropriate for this as yet unproved (except with rifampin, which is not used for acne) association to be discussed with patients and a second form of birth control offered. Tetracycline Tetracycline is the safest and cheapest choice, and will give a positive response in many patients. It is usually given at an initial dose of 250–500 mg 1–4 times a day, with gradual reduction of the dose, depending on clinical response. It is best taken on an empty stomach, at least 30 min before meals and 2 h afterwards, which often limits dosage to twice 231
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a day. Calcium or iron in food supplements combines with tetracycline, reducing absorption by as much as half. Vaginitis or perianal itching may result from tetracycline therapy in about 5% of patients, with Candida albicans usually present in the involved site. The only other common side effects are gastrointestinal symptoms such as nausea. To reduce the incidence of esophagitis, tetracyclines should not be taken at bedtime. Staining of growing teeth occurs, preclud ing its use in pregnant women and in children under the age of 9 or 10. Tetracycline should also be avoided when renal function is impaired. Doxycycline The usual dose is 50–100 mg once or twice a day, depending on the disease severity. Photosensitivity reac tions are not uncommon with this form of tetracycline and can be dramatic. Subantimicrobial-dose doxycycline, doxycycline hyclate 20 mg, may be given twice daily. The advantage of this is that the anti-inflammatory activity is being utilized but no antibiotic resistance results because of the low dose. A sustained-release 40 mg formulation is also available. These low-dose preparations appear to be of low efficacy, however. Minocycline Minocycline is the most effective oral antibiotic in treating acne vulgaris. In patients whose P. acnes develops tetracycline resistance, minocycline is an alternative. The usual dose is 50–100 mg once or twice a day, depending on the severity of disease. Its absorption is less affected by milk and food than is that of tetracycline. Vertigo may occur and begin ning therapy with a single dose in the evening may be prudent. An extended-release preparation is also available, which limits the vestibular side effects. Pigmentation in areas of inflamma tion, of oral tissues, in postacne osteoma or scars, in a photo distributed pattern, on the shins, in the sclera, nailbed, ear cartilage, teeth, or in a generalized pattern may also be seen (Fig. 13-9). Additionally, lupus-like syndromes, a hyper sensitivity syndrome (consisting of fever, hepatitis, and eosinophilia), serum sickness, pneumonitis, and hepatitis are uncommon but potentially serious adverse effects of minocycline. Erythromycin For those who cannot take tetracyclines because of side effects or in pregnant women requiring oral antibiotic therapy, erythromycin may be considered. The effi cacy is low. Side effects are mostly gastrointestinal upset; vaginal itching is a rare occurrence. The initial dose is 250– 500 mg 2–4 times a day, reduced gradually after control is achieved. Erythromycin may increase blood levels of other drugs metabolized by the cytochrome P450 system. Clindamycin Past experience has shown clindamycin to give an excellent response in the treatment of acne; however, the potential for the development of pseudomembranous colitis and the availability of retinoids has limited its use. The initial dose is 150 mg three times a day, reduced gradually as control is achieved.
Fig. 13-9 Minocycline-induced blue pigmentation of the teeth and nails.
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Other antibiotics Sulfonamides are occasionally prescribed; however, the potential for severe drug eruptions limits their use. Trimethoprim–sulfamethoxazole (Bactrim, Septra), in double-strength doses twice a day initially, is effective in many cases unresponsive to other antibiotics. Trimethoprim alone, 300 mg twice a day, is also useful. Amoxicillin, in doses from 250 mg twice daily to 500 mg three times a day, is also an alternative and may be useful in pregnancy as it falls into pregnancy category B. Dapsone has been used in severe acne conglobata, but is rarely used today. Isotretinoin is favored. Bacterial resistance P. acnes antimicrobial resistance has become a clinically relevant problem. Erythromycin and clin damycin resistance is widespread and usually presents simul taneously. Once P. acnes becomes resistant to tetracycline, it is also resistant to doxycycline, so if lack of efficacy due to pro longed oral therapy with one of them is suspected, a switch to minocycline is necessary. While concomitant use of benzoyl peroxide will help limit cutaneous drug resistance problems, it is now appreciated that Staphylococcus aureus in the nares, streptococci in the oral cavity, and enterobacteria in the gut may also become resistant, and close contacts, including treat ing dermatologists, may harbor such drug-resistant bacteria. Strategies to prevent antibiotic resistance include limiting the duration of treatment, stressing the importance of adherence to the treatment plan, restricting the use of antibiotics to inflammatory acne, encouraging retreatment with the same antibiotic unless it has lost its efficacy, avoiding the use of dissimilar oral and topical antibiotics at the same time, and using isotretinoin if unable to maintain clearance without oral antibacterial treatment.
Hormonal therapy Hormonal interventions in women may be beneficial in the absence of abnormal laboratory tests. The work-up for the woman with signs of hyperandrogenism, such as acne, men strual irregularities, hirsutism, or androgenetic alopecia, is presented above. Women with normal laboratory values often respond to hormonal therapy. Results take longer to be seen with these agents, with first evidence of improvement often not apparent for 3 months and continued improved response seen for at least 6 months. Particularly good candidates for hormonal treatment include women with PCOS, late-onset adrenal hyperplasia, or another identifiable endocrinologic condition; and women with late-onset acne, severe acne, acne that has not responded to other oral and topical therapies, or acne that has relapsed quickly after isotretinoin treatment. Women with acne primarily located on the lower face and neck, and deep-seated nodules that are painful and longlasting, are often quite responsive to hormonal intervention (Fig. 13-10).
Fig. 13-10 Typical jawline lesions in an adult woman.
Oral retinoid therapy Isotretinoin This drug is approved only for severe cystic acne: however, it is useful in less severe forms of acne so as to prevent the need for continuous treatment and the repeated office visits that many patients require. It was a consensus of experts that oral isotretinoin treatment is warranted for severe acne, poorly responsive acne that improves by less than 50% after 6 months of therapy with combined oral and topical antibiotics, acne that relapses off oral treatment, scars, or acne that induces psychological distress. Additionally, other agreed indications were Gram-negative folliculitis, inflammatory rosacea, pyoderma faciale, acne fulminans, and hidradenitis suppurativa. This retinoid is a reliable remedy in nearly all acne patients (Fig. 13-11). The dose is 0.5–1 mg/kg/day in one or two daily doses. For severe trunkal acne in patients who tolerate higher doses, treatment may be given in doses up to 2 mg/kg/day. In practice, most patients are started at a 20–40 mg dose so as to avoid an early flare, and then increased to 40–80 mg/day so as to limit side effects, which generally are dose-related. Doses as low as 0.1 mg/kg/day are very nearly as effective as the higher doses in clearing acne; the disadvantage is that they are less likely to produce a prolonged remission even after 20 weeks of treatment. To obtain the greatest chance of a pro longed remission, patients should receive 120–150 mg/kg over the treatment course. An easy way to calculate the total dose needed is to multiply the weight in kilograms by 3. The product is the total number of 40 mg capsules needed to reach the low end of the dosage spectrum. The major advantage of isotretinoin is that it is the only acne therapy that is not open-ended (i.e. that leads to a remission, which may last many months or years). Approximately 40– 60% of patients remain acne-free after a single course of isotretinoin. Approximately one-third of the relapsing patients will need only topical therapy, the others oral treatments. Many patients in the latter category prefer to be retreated with isotretinoin due to its reliable efficacy and ability to predict side effects, as they will be similar to those experienced in the first course. In Azoulay et al’s study, fully 26% of isotretinointreated patients received a second course within a 2-year period. Some subsets of patients tend to relapse more often. In patients under 16, 40% need a second course of isotretinoin
Acne vulgaris
Oral contraceptives These agents block both adrenal and ovarian androgens. Ortho Tri-Cyclen, Estrostep, Alesse, Yasmin, and Yaz are examples of birth control pills that have beneficial effects on acne. Both the physician and the patient should be familiar with the adverse reactions associ ated with oral contraceptives, such as nausea, vomiting, abnormal menses, melasma, weight gain, breast tenderness, and rarely thrombophlebitis, pulmonary embolism, and hypertension. Spironolactone As pregnancy while on antiandrogen treat ment will result in feminization of a male fetus, spironolac tone is usually prescribed in combination with oral contraceptives. It may be effective in doses from 25–200 mg/ day. Most women will tolerate a starting dose of 50–100 mg/ day. Most also tolerate 150 mg per day but many will have side effects at 200 mg per day. Side effects are dose-dependent and include breast tenderness, headache, dizziness, lighthead edness, fatigue, irregular menstrual periods, and diuresis. In a study by Shaw in patients treated with 50–100 mg/day, hyperkalemia was measurable, but in the absence of renal or cardiac disease was clinically insignificant. In his series, a third of patients cleared, a third had marked improvement, a quarter showed partial improvement, and 7% had no response. Spironolactone is often used with other topical or oral acne therapy. Several months of treatment are usually required to see benefit. Dexamethasone Dexamethasone, in doses from 0.125 to 0.5 mg given once at night, reduces androgen excess and may alleviate cystic acne. Corticosteroids are effective in the treat ment of adult-onset adrenal hyperplasia, but antiandrogens are also used increasingly in this setting. Prednisone Although steroids may produce steroid acne, they are also effective anti-inflammatory agents in severe and intractable acne vulgaris. In severe cystic acne and acne con globata, corticosteroid treatment is effective; however, side effects restrict its use. It is generally only given to patients with severe inflammatory acne during the first few weeks of treat ment with isotretinoin, for initial reduction of inflammation, and to reduce isotretinoin-induced flares. Other hormonal agents Finasteride, flutamide, estrogen, gonadotropin-releasing agonists, and metformin (by decreas ing testosterone levels) have all been shown to have a benefi cial effect on acne but due to side effects, expense, or other considerations are not commonly used.
Fig. 13-11 A, Severe back acne before isotretinoin. B, Response to treatment.
A
B
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within 1 year and 73% within 2 years. Adult women and patients with mild acne tend to relapse more often and more quickly than severely affected 17- to 22-year-olds. While patients’ tolerance and response to repeated courses are similar to their experience with the first course, adult women who relapse may be better managed with hormonal therapies, and mild acne treated with standard therapy. In adult acne patients, who frequently tolerate the side effects of isotretinoin less well, lower doses and/or intermit tent therapy is possible. Goulden et al studied 80 adult acne patients whom they treated with 0.5 mg/kg/day for 1 week in every 4 over a period of 6 months. Acne resolved in 88% and 39% relapsed after 1 year. Seukeran and Cunliffe treated nine patients aged 56–75 years with 0.25 mg/kg/day for 6 months. All patients cleared and all but one remained clear 36 months later. Patient education is critical in isotretinoin therapy. Its most serious adverse effect is the risk of severe damage to the fetus if it is given during pregnancy. Retinoid embryopathy is a well-defined syndrome characterized by craniofacial, cardio vascular, central nervous system, and thymus abnormalities. It is of the utmost importance that a woman of child-bearing potential follows closely the recommendations clearly out lined in extensive material provided by the manufacturer. The use of consent forms, contraception education, and unequivo cal documentation of the absence of pregnancy through monthly laboratory testing are important components of a Food and Drug Administration (FDA)-mandated verification program designed to prevent pregnancy during treatment. Women should not become pregnant until off medication for at least 1 month. The drug is not mutagenic and there is no risk to a fetus conceived while the male partner is taking the drug. Another major area of educational emphasis concerns the psychological effects of the medication. Reports of depression, psychosis, suicidal ideation, suicide, and attempted suicide have prompted numerous studies of the mental health of patients taking isotretinoin. While the usual outcome is an improvement of mood because of the clearance of the disease, and only one of the many large-scale population-based studies has found evidence of an elevated incidence of depression, there are a small number of patients who have developed depression and have positive dechallenge and rechallenge tests. Close monitoring for depression, fully educating the patient, and enlisting the help of a roommate or family member to look for changes in mood are all methods used to assess the psychological status of the patient on isotretinoin. Inflammatory bowel disease (IBD) is a third concern. Patients with this condition have been successfully treated with isotretinoin without flaring, new onset of IBD in patients exposed to isotretinoin is of concern. The age of onset of IBD overlaps with the age at which acne will frequently be treated with isotretinoin and antibiotics. A review of Medwatch cases revealed 85 cases with new-onset IBD in isotretinoin users. Three cases improved off isotretinoin and then relapsed on re-exposure. Most did not improve or resolve with discontinu ation of the medicine, with seven requiring surgery. Studies investigating a possible association of IBD and isotretinoin or tetracycline class antibiotics are ongoing. Some have reported significant associations, but results are either contradictory or are unverified. Other side effects of isotretinoin are dose-dependent and generally not serious. Dry lips, skin, eyes, and oral and nasal mucosa occur in up to 90% of patients. These can be treated with moisturization. Dryness of the nasal mucosa leads to colonization by S. aureus in 80–90% of treated subjects. Skin abscesses, staphylococcal conjunctivitis, impetigo, facial cel lulitis, and folliculitis may result. Such colonization may be
avoided by the use of bacitracin ointment applied to the ante rior nares twice a day during isotretinoin therapy. Arthralgias may occur but, like other side effects, do not require interrup tion of therapy unless severe. Monitoring of serum lipids is carried out, as some patients will develop hypertriglyceri demia. This may be controlled by avoidance of smoking and alcohol, and by following a diet that is low in fat. It should be realized that patients who develop this complication, and their families, are at risk for the development of the metabolic syndrome. Liver function tests should be checked at regular intervals, depending on patient risk factors and the dose utilized.
Intralesional corticosteroids Intralesional corticosteroids are especially effective in reduc ing inflammatory nodules. Kenalog-10 (triamcinolone aceto nide 10 mg/mL) is best diluted with sterile normal saline solution to 2.5 mg/mL. Injecting less than 0.1 mL directly into the center of the nodule will help safeguard against atrophy and hypopigmentation.
Physical modalities Local surgical treatment is helpful in bringing about quick resolution of the comedones, although many clinicians wait until after 2 or more months of topical retinoids to extract those that remain. The edge of the follicle is nicked with a No 11 scalpel blade and the contents of the comedo are expressed with a comedo extractor. Scarring is not produced by this procedure. Light electrode desiccation is an alternative. In isotretinoin-treated patients, macrocomedones present at weeks 10–15 may be expressed, since they tend to persist throughout therapy. The use of photodynamic therapy and various forms of light, laser, or radiofrequency energy is under investigation. It is clear that there is an ability to destroy sebaceous glands or kill P. acnes with such interventions; however, the methods to deliver such treatments in an efficient, cost-effective, safe, rela tively painfree, and practical manner are evolving. These treat ments will be a welcome addition as they have the potential to provide care without the concerns associated with systemic drugs. More studies of larger patient populations with appro priate controls are needed to evaluate their place in the spec trum of acne treatments.
Complications Even with the excellent treatment options available, scarring may occur. This may be quite prominent and often results from the cystic type of acne, although smaller lesions may produce scarring in some individuals. Pitted scars, widemouthed depressions, and keloids, primarily seen along the jawline and chest, are common types of scarring (Fig. 13-12). These may improve spontaneously over the course of a year or more. Many treatment options are available. Chemical peeling, ablative, nonablative, and vascular laser treatments, skin needling or rolling, dermabrasion, scar excision, subci sion, punch grafts alone or followed by dermabrasion or laser smoothing, intralesional corticosteroids or fluorouracil, frac tionated laser resurfacing, fat transfer, and the use of filler substances are among the procedures reported to be effective in improving the appearance. Other complications from acne are prominent residual hyperpigmentation, especially in darker-skinned patients; pyogenic granuloma formation, which is more common in acne fulminans and in patients treated with high-dose isotretin oin; osteoma cutis, which consists of small, firm papules resulting from long-standing acne vulgaris; and solid facial
Fig. 13-12 Keloid of the chest secondary to acne.
edema. The latter is a persistent, firm facial swelling that is an uncommon, though distressing, result of acne vulgaris or acne rosacea. Both corticosteroids and isotretinoin have been reported to be effective treatments. Arowojolu AO, et al: Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev 2007; 1:CD004425. Autoniou C, et al: Clinical and therapeutic approach to childhood acne. Pediatr Dermatol 2009; 26:373. Azoulay L, et al: Isotretinoin therapy and the incidence of acne relapse. Br J Dermatol 2007; 157:1240. Azoulay L, et al: Isotretinoin and the risk of depression in patients with acne vulgaris. J Clin Psychiatry 2008; 69:S26. Berard A, et al: Isotretinoin, pregnancies, abortions and birth defects. Br J Clin Pharmacol 2007; 63:196. Bowe WP, et al: Diet and acne. J Am Acad Dermatol 2010; 63:124. Bremmer JD, et al: Functional brain imaging alterations in acne patients treated with isotretinoin. Am J Psych 2005; 162:983. Brown RJ, et al: Minocycline-induced drug hypersensitivity syndrome followed by multiple autoimmune sequelae. Arch Dermatol 2009; 145:63. Chia CY, et al: Isotretinoin therapy and mood changes in adolescents with moderate to severe acne. Arch Dermatol 2005; 141:557. Costello M, et al: Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database Syst Rev 2007; 1:CD005552. Cunliffe WJ, Gollnick H: A clinical and therapeutic study of 29 patients with infantile acne. Br J Dermatol 2001; 145:463. Ehrmann DA: Polycystic ovary syndrome. New Engl J Med 2005; 352:1223. Frangos JE, et al: Acne and oral contraceptives. J Am Acad Dermatol 2008; 58:781. Goldsmith LA, et al: American Academy of Dermatology Consensus Conference on the safe and optimal use of isotretinoin. J Am Acad Dermatol 2004; 50:900. Gollnick H, et al: Management of acne. J Am Acad Dermatol 2003; 49:S1. Goodman GJ, et al: The management of postacne scarring. Dermatol Surg 2007; 33:1175. Goulden V, et al: Treatment of acne with intermittent isotretinoin. Br J Dermatol 1997; 137:106. Hahm BJ, et al: Changes of psychiatric parameters and their relationships by oral isotretinoin in acne patients. J Dermatol 2009; 36:255. Haider A, et al: Treatment of acne vulgaris. JAMA 2004; 292:726. Hu S, et al: Fractional resurfacing for the treatment of atopic facial acne scars in Asian skin. Dermatol Surg 2009; 35:826. Jacobs DG, et al: Suicide, depression, and isotretinoin. J Am Acad Dermatol 2001; 45:S168. James WD: Clinical practice: acne. New Engl J Med 2005; 352:1463. Katsambas A, et al: New and emerging treatments in dermatology: acne. Dermatol Ther 2008; 21:86. Kim J, et al: Activation of Toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 2002; 169:1535.
Acne conglobata
Lee AT, et al: Dermatologic manifestations of polycystic ovary syndrome. Am J Clin Dermatol 2007; 8:201. Lee DH, et al: Comparison of a 585-nm pulsed dye laser and a 1064-nm Nd:YAG laser for the treatment of acne scars. J Am Acad Dermatol 2009; 60:801. Levy R, et al: Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol 2003; 139:467. Manolache L, et al: A case of solid facial oedema successfully treated with isotretinoin. J Eur Acad Dermatol Venereol 2009; 23:965. Margolis D, et al: Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. Am J Gastroenterol 2010; (epub). Norman RJ, et al: Polycystic ovary syndrome. Lancet 2007; 370:685. Plewig G, Kligman AM: Acne and Rosacea, 3rd edn. New York: Springer, 2000. Purdy S, et al: Acne. BMJ 2006; 333:949. Railan D, et al: Laser treatment of acne, psoriasis, leukoderma and scars. Semin Cutan Med Surg 2009; 27:285. Reddy D, et al: Possible association between isotretinoin and inflammatory bowel disease. Am J Gastroenterol 2006; 101:1569. Rodonodi N, et al: High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne. Ann Intern Med 2002; 136:582. Ross JI, et al: Antibiotic-resistant acne. Br J Dermatol 2003; 148:467. Sakamoto FH, et al: Photodynamic therapy for acne vulgaris. J Am Acad Dermatol 2010; 63:195. Seti TL, et al: Polycystic ovary syndrome. Am J Med 2007; 120:128. Seukeran DC, Cunliffe WJ: Acne in the elderly. Br J Dermatol 1998; 139:99. Shaw JC: Low-dose adjunctive spironolactone in the treatment of acne in a retrospective analysis of 85 consecutively treated patients. J Am Acad Dermatol 2000; 43:498. Shaw JC, et al: Long-term safety of spironolactone in acne. J Cutan Med Surg 2002; 6:541. Skidmore RA, et al: Effects of a subantimicrobial dose of doxycycline in the treatment of moderate acne. Arch Dermatol 2003; 139:459. Strahan JE, et al: Cyclosporine-induced infantile nodulocystic acne. Arch Dermatol 2009; 145:797. Strauss JS, et al: Guidelines of care for acne vulgaris management. J Am Acad Dermatol 2007; 56:651. Taub AF: Procedural treatments for acne vulgaris. Dermatol Surg 2007; 33:1005. Thiboutot D: Hormones and acne. Semin Cutan Med Surg 2001; 20:144. Thiboutot D, et al: New insights into the management of acne. J Am Acad Dermatol 2009; 60:S1. Torrelo A, et al: Severe acne infantum successfully treated with isotretinoin. Pediatr Dermatol 2005; 22:357. Wysowaski DK, et al: An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001; 45:515. Zaenglein AL, et al: Expert committee recommendations for acne management. Pediatrics 2006; 118:1188.
Acne conglobata Cystic acne is the mildest form of acne conglobata (con globate means shaped in a rounded mass or ball), an un usually severe type of acne. This form is characterized by numerous comedones (many of which are double or triple) and large abscesses with interconnecting sinuses, cysts, and grouped inflammatory nodules (Fig. 13-13). Suppuration is characteristic of acne conglobata. Pronounced scars remain after healing. The cysts occur on the back, buttocks, chest, forehead, cheeks, anterior neck, and shoulders (Fig. 13-14). They contain a thick, yellowish, viscid, stringy, blood-tinged fluid. After incision and drainage of the cyst there is frequently a prompt refilling with the same type of material. These cysts are sug gestive of the type found in hidradenitis suppurativa. Hidradenitis suppurativa and dissecting cellulitis of the scalp may be seen with acne conglobata, an association known as the follicular occlusion triad. 235
Acne fulminans
13 Acne
This rare form of extremely severe cystic acne occurs primarily in teenage boys. It is characterized by highly inflammatory nodules and plaques that undergo swift suppurative degen eration, leaving ragged ulcerations, mostly on the chest and back. The face is usually less severely involved. Fever and leukocytosis are common. Polyarthralgia and polymyalgia, destructive arthritis, and myopathy have been reported in association with it. Focal lytic bone lesions may be seen. Prednisone, 40–60 mg, is necessary during the initial 4–6 weeks to calm the dramatic inflammatory response. After 4 weeks 10–20 mg of isotretinoin is added. This should be slowly increased to standard doses and continued for a full 120–150 mg/kg cumulative course. Large cysts may be opened and the contents expressed. Intralesional corticosteroids will aid their resolution. Infliximab may also be useful.
Fig. 13-13 Acne conglobata with fistula formation.
Iqbal M, et al: Acne fulminans with SAPHO syndrome treated with infliximab. J Am Acad Dermatol 2005; 52:S118. Neely GM, et al: Acne fulminans. S D Med 2006; 59:387. Seukeran DC, et al: The treatment of acne fulminans: a review of 25 cases. Br J Dermatol 1999; 141:307.
SAPHO syndrome
Fig. 13-14 Acne conglobata of the back.
This severe and painful disease occurs most frequently in young men around 16 years; it may extend and persist into adulthood and even into the fifth decade of life, especially over the posterior neck and back. Women are less frequently affected. Athletes and bodybuilders should be questioned about the use of anabolic steroids, which may induce such aggressive acne. The therapy of choice in all but the earliest lesions is isotretin oin, 0.5–1 mg/kg/day to a total dose of 150 mg/kg, with a second course if resolution does not occur after a rest period of 2 months. Pretreatment with prednisone and low initial doses of isotretinoin, as described for acne fulminans, are rec ommended to avoid flaring of disease. CO2 laser to open the sinus tracts and fractional laser to the scars is another method of therapy. Infliximab added to isotretinoin was a useful adjunct in one reported patient. Gerber PA, et al: The dire consequences of doping. Lancet 2008; 372:656. Hasegawa T, et al: Acne conglobata successfully treated by fractional laser after CO laser abrasion of cysts combined with topical tretinoin. J Dermatol 2009; 36:118. Melnik B, et al: Abuse of anabolic-androgenic steroids and bodybuilding acne. J Dtsch Dermatol Ges 2007; 5:110. Shirakawa M, et al: Treatment of acne conglobata with infliximab. J Am Acad Dermatol 2006; 55:344.
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SAPHO syndrome is characterized by synovitis, acne, pustu losis, hyperostosis, and osteitis. Skin findings may include acne fulminans, acne conglobata, pustular psoriasis, hidrad enitis suppurativa, dissecting cellulitis of the scalp, Sweet syn drome, Sneddon–Wilkinson disease, and palmoplantar pustulosis. The chest wall and mandible are the most common sites for musculoskeletal complaints. Bone changes of the ante rior chest wall on nuclear scans are the most specific diagnostic findings. Acquired hyperostosis syndrome (AHYS) and, in a familial setting of a dominantly inherited disorder, pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA syndrome) both present with similar clinical scenerios. The latter is due to mutations in the CD2-binding protein on chro mosome 15q. Systemic retinoids and infliximab have been suc cessful in treating these patients. If isotretinoin is used, it should be initiated at a low dosage, such as 10 mg per day, in combination with prednisone for the first month to prevent flaring of the disease. Methotrexate, sulfasalazine, tumor necrosis factor (TNF) antagonists, and cyclosporine are other likely effective choices. Pamidronate is effective in treating the osteo-articular manifestations. Colina M, et al: Sustained remission of SAPHO syndrome with pamidronate. Clin Exp Rheumatol 2009; 27:112. Colina M, et al: Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome. Arthritis Rheum 2009; 61:813. Galadari H, et al: Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome treated with a combination of isotretinoin and pamidronate. J Am Acad Dermatol 2009; 61:123. Poindexter G, et al: Synovitis-acne-pustulosis-hyperostosis-osteitis syndrome. J Am Acad Dermatol 2008; 59(2Suppl 1):S53. Sabugo F, et al: Infliximab can induce a prolonged clinical remission and a decrease in thyroid hormonal requirements in a patient with SAPHO syndrome and hypothyroidism. Clin Rhematol 2008; 27:533. Tallon B, et al: Peculiarities of PAPA syndrome. Rheumatology (Oxford) 2006; 45:1140.
Other acne variants Tropical acne Tropical acne is unusually severe acne occurring in the tropics during the seasons when the weather is hot and humid.
Acneiform eruptions
Fig. 13-15 Tropical acne.
Nodular, cystic, and pustular lesions occur chiefly on the back, buttocks, and thighs (Fig. 13-15). Characteristically, the face is spared. Conglobate abscesses occur often, especially on the back. Comedones are sparse. Acne tropicalis usually occurs in young adults who may have had acne vulgaris at an earlier age. This is especially true of those in the armed forces sta tioned in the tropics and carrying backpacks. Treatment is that for cystic acne, but acne tropicalis may persist until the patient moves to a cooler and less humid climate.
Acne aestivalis Also known as Mallorca acne, this rare form of acne starts in the spring, progresses during the summer, and resolves com pletely in the fall. It affects almost exclusively women between the ages of 25 and 40. Dull red, dome-shaped, hard, small papules, usually not larger than 3–4 mm, develop on the cheeks and commonly extend on to the sides of the neck, chest, shoulders, and characteristically the upper arms. Comedones and pustules are notably absent or sparse. Acne aestivalis does not respond to antibiotics but benefits from application of retinoic acid.
Excoriated acne Also known as picker’s acne and acne excoriée des jeunes filles, excoriated acne is seen primarily in young women with a superficial type of acne in which the primary lesions are trivial or even nonexistent, but in which the compulsive neu rotic habit of picking the face and squeezing minute come dones produces secondary lesions that crust and may leave scars. Often the lesion that is excoriated is minute, seen only in a magnifying mirror. This condition may be a sign of depression or anxiety. It is an obsessive–compulsive symptom. If the patient admits to picking but being unable to stop this habit, improvement may follow support and acne therapy. However, most patients will require interventions with selective serotonin reuptake inhibitors, such as fluoxetine, paroxetine, or sertraline, behavior modification, or psychotherapy. Other pharmaco logic treatments that have been successful in case reports include doxepin, clomipramine, naltrexone, pimozide, and olanzapine. Arnold LM, et al: Psychogenic excoriation. CNS Drugs 2001; 15:351. Brabek E, et al: Herpetic folliculitis and syringitis simulating acne excoriée. Arch Dermatol 2001; 37:97.
Acneiform eruptions are follicular eruptions characterized by papules and pustules resembling acne. Breaks in the epithe lium and spillage of follicular contents into the dermis lead to the lesions. They are not necessarily confined to the usual sites of acne vulgaris, often have a sudden onset, are monomor phous, and usually appear in a patient well past adolescence. If secondary to a drug, an eruption begins within days of ini tiation of the medication, may be accompanied by fever and malaise, and resolves when the drug is stopped. Acneiform eruptions may originate from skin exposure to various industrial chemicals, such as fumes generated in the manufacture of chlorine and its byproducts. These chlorinated hydrocarbons may cause chloracne, consisting of cysts, pus tules, folliculitis, and comedones. The most potent acneiforminducing agents are the polyhalogenated hydrocarbons, notably dioxin (2,3,7,8 tetrachlorobenzodioxin). Cutting and lubricating oils, crude coal tar applied to the skin for medicinal purposes, heavy tar distillates, coal tar pitch, and asbestos are known to cause acneiform eruptions. Acne venenata is another term applied to this process. Acneiform eruptions are induced by medications such as iodides from radiopaque contrast media or potassium iodide, bromides in drugs such as propantheline bromide, testoster one, cyclosporine, antiepileptic medications, lithium, and systemic corticosteroids. When medium or high doses of corticosteroids are taken for as short a time as 3–5 days, a distinctive eruption may occur, known as steroid acne. It is a sudden outcropping of inflamed papules, most numerous on the upper trunk and arms (Fig. 13-16), but also seen on the face. The lesions typically present as papules rather than come dones; however, a histologic study confirmed they begin fol licularly with microcomedone formation. Tretinoin (Retin-A), 0.05% cream applied once or twice a day, may clear the lesions within 1–3 months despite the continuation of high doses of corticosteroid. Oral antibiotics and other typical acne medica tions are also effective. Topical steroids, especially the fluori nated types or when applied under occlusion, may also induce an acneiform eruption. Topical tacrolimus and pimecrolimus may both induce a papulopustular eruption. Epidermal growth factor inhibitors, including monoclonal antibodies and tyro sine kinase inhibitors used in cancer therapy, produce a folliculitis in the majority of treated patients. Often oral mino cycline and topical benzoyl peroxide are given prophylacti cally at the outset of the cancer therapy to prevent what may be a dose-limiting reaction. Finally, radiation therapy for malignancy can induce acne in the radiation port.
Acneiform eruptions
Hjorth N, et al: Acne aestivalis: Mallorca acne. Acta Dermatol Venereol 1972; 2:61. Wells JM: Tropical acne—one hundred cases. J R Army Med Corps 1981; 127:55.
Agero AL, et al: Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006; 55:657. Antille C, et al: Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. Arch Dermatol 2004; 140:457. El Sayed F, et al: Rosaceiform eruption to pimecrolimus. J Am Acad Dermatol 2006; 54:548. Hengge UR, et al: Adverse effects of topical glucocorticoids. J Am Acad Dermatol 2006; 54:1. Hu JC, et al: Cutaneous side effects of epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2007; 56:317. Li T, et al: Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol 2009; 4:107. Melnik B, et al: Abuse of anabolic-androgenic steroids and bodybuilding acne. J Dtsch Dermatol Ges 2007; 5:110.
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Fig. 13-16 A and B, Steroid acne. (Courtesy of Curt Samlaska, MD)
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A
B
Fig. 13-17 Gram-negative folliculitis.
Pelclova D, et al: Adverse health effects in humans exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Rev Environ Health 2006; 21:119. Plewig G, et al: Acneiform dermatoses. Dermatology 1998; 196:102.
Gram-negative folliculitis Gram-negative folliculitis occurs in patients who have had moderately inflammatory acne for long periods and have been treated with long-term antibiotics, mainly tetracyclines. While on antibiotic treatment, patients develop either superficial pustules 3–6 mm in diameter flaring out from the anterior nares, or fluctuant, deep-seated nodules (Fig. 13-17). Culture of these lesions usually reveals a species of Klebsiella, Escherichia coli, Enterobacter, or, from the deep cystic lesions, Proteus. With long-term, broad-spectrum antibiotic therapy the ante rior nares may become colonized with these Gram-negative organisms. As the use of long-term antibiotic therapy declines, this disease has become less common. Isotretinoin is very effective and is the treatment of choice in this disease. James and Leyden have shown that this treat ment not only clears the acne component of the disease but also eliminates the colonization of the anterior nares with 238
Fig. 13-18 Acne keloidalis nuchae.
Gram-negative organisms. If isotretinoin cannot be tolerated or is contraindicated, amoxicillin or trimethoprim– sulfamethoxazole may be effective in suppressing the disease. Boni R, et al: Treatment of Gram-negative folliculitis in patients with acne. Am J Clin Dermatol 2003; 4:273. Neubert U, et al: Bacteriologic and immunologic aspects of Gramnegative folliculitis: a study of 46 patients. Int J Dermatol 1999; 38:270.
Acne keloidalis Acne keloidalis is most frequently encountered in young adult Black, Hispanic, or Asian men who otherwise are in excellent health. It is not associated with acne vulgaris and is a primary cicatricial alopecia variant. It is a persistent folliculitis and perifolliculitis of the back of the neck that presents as inflam matory papules and pustules. Over time fibrosis ensues with coalescence of firm papules into keloidal plaques (Fig. 13-18). At times, sinus tract formation results. Histologically, acne keloidalis is characterized by perifol licular, chronic (lymphocytic and plasmacytic) inflammation, most intense at the level of the isthmus and lower infundibu lum of terminal hairs. There is lamellar fibroplasia, most marked at the level of the isthmus and, eventually, in the
Adegbidi H, et al: Keloid acne of the neck. Int J Dermatol 2005; 44(Suppl 1):49. Bajaj V, et al: Surgical excision of acne keloidalis nuchae with secondary intention healing. Clin Exp Dermatol 2008; 33:53. Ogunbiyi A, et al: Acne keloidalis in females. J Natl Med Assoc 2005; 97:1178. Sperling LC, et al: Acne keloidalis is a form of primary scarring alopecia. Arch Dermatol 2000; 136:479.
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keloidal masses, the connective tissue becomes sclerotic, forming hypertrophic scars or keloids. Persistent free hairs in the dermis may be responsible for the prolonged inflammation and eventual scarring. Topical therapy with potent steroid ointments or foams alone, or following tretinoin gel, twice a day is useful for the follicular papules. Oral antibiotics of the tetracycline group may be added and are helpful in suppressing the inflamma tory response. Triamcinolone acetonide by intralesional injec tion, using Kenalog-10, into the inflammatory follicular lesions, and Kenalog-40 into the hypertrophic scars and keloids, is useful in reducing inflammation and fibrosis. Smaller lesions may be excised to a level below the hair follicle and closed. This may be followed by Kenalog-40 every 3 weeks. For larger lesions, deep excision or CO2 laser ablation left to heal by primary intention may be necessary. Laser hair removal with the Nd:YAG laser may be utilized as a preventative measure.
Fig. 13-19 Hidradentitis of the axilla.
Hidradenitis suppurativa Clinical features Hidradenitis suppurativa is a chronic disease characterized by recurrent abscess formation, primarily within the folded areas of skin that contain both terminal hairs and apocrine glands. The primary site of inflammation is not the gland but the ter minal hair. Dissecting terminal folliculitis is a term Plewig uses to unify diseases primarily affecting the terminal hair follicle such as hidradenitis suppurativa, acne keloidalis nuchae, pilonidal sinus, and dissecting cellulitis of the scalp. The axilla is the most commonly affected site. Among other areas, the inguinal and submammary areas are favored in women (Figs 13-19 and 13-20), with the buttock, perianal, and atypical areas (such as retroauricular and trunk) more often affected in men, although any and all areas may be affected in either sex. It is a postpubertal process that affects women approximately four times more often than men. The disease is characterized by the development of tender, red nodules, which at first are firm but soon become fluctuant and painful. Rupture of the lesion, suppuration, formation of sinus tracts, and extensive scarring are distinctive. As one area heals, recurrent lesions form, so that the course of the disease is protracted. It may eventually lead to the formation of honey combed, fistulous tracts with chronic infection. The individual lesions contain a thick, viscous, mucoid, suppurative material. When a probe is used to explore the suppurating nodule, a burrowing sinus tract is usually detected that may extend for many centimeters, running horizontally just underneath the skin surface. Disease severity varies and may be quantified by the Sartorius scale. This takes into account the number, type, and sites of lesions. Also to be considered is the impact on the quality of life that this chronic, recurrent, painful, odiferous, messy condition has. The majority of the approximately 1% of the population affected by this disease are mildly affected; however, severe debilitating disease is commonly observed. In this affected group, men outnumber women. Men more often have a history of acne and pilonidal cysts than women. Squamous cell carcinoma (after an average of 19 years of active disease), interstitial keratitis, spondyloarthropathy, urethral
Fig. 13-20 Hidradentitis of the groin.
vesical and rectal fistulas, anemia, hypoproteinemia, and amy loidosis have been reported to complicate hidradenitis sup purativa, but are rare. Significant lymphedema of the penis and groin, along with alteration of the anatomy because of surgical intervention, often makes physical examination of these sites difficult. The risk of squamous cell carcinoma occur ring as an ulceration or thickening in a skin crease, which can metastasize and cause death, requires attention to detail in this regard.
Etiology Detailed histologic studies of hidradenitis suppurativa reveal that terminal follicle hyperkeratosis is followed by rupture of the follicular epithelium, and release of keratin, sebum, bacteria, and hairs into the dermis. The resulting inflammatory process engulfs the apocrine gland, and leads to rupture of the overlying skin, fibrosis, and sinus tract formation. Secondary bacterial infection with Staphylococcus aureus, Streptococcus pyogenes, and various Gram-negative organisms may occur. The initiating event is unknown. Associated findings of obesity, mechanical friction, smoking, immunologic dysfunction, and endocrinologic abnormalities such as diabetes and hyper androgenism are seen in varying frequencies in different studies. Mechanical friction, often worsened by obesity, is an exacerbating factor, as is bacterial infection. There is an autosomal-dominantly inherited form of this disease. One study revealed that those with a positive family history tended to have less severe disease. 239
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Differential diagnosis Hidradenitis is to be differentiated from common furuncles, which are typically unilateral. Hidradenitis must also be dif ferentiated from Bartholin abscess, scrofuloderma, actino mycosis, granuloma inguinale, and lymphogranuloma venereum.
Treatment Despite the numerous forms of treatment available, a perma nent cure is uncommon. The earliest lesions often heal quickly with intralesional steroid therapy, and this should be tried initially in combination with topical cleocin or oral tetracycline or minocycline. Topical daily cleansing with an antibacterial soap, chlorhexidine solution, or benzoyl peroxide wash is an important preventative measure. Additionally, laser hair removal, if performed, should be done in unaffected sites as a preventative therapy. Reduction of friction by wearing loosefitting clothing and weight loss if needed, and avoidance of excessive sweating through the use of topical aluminum chlo ride or botulinum toxin A injections and heat avoidance may help. In cases with draining sinuses, culture of the pus may reveal S. aureus or Gram-negative organisms. The latter are usually cultured in chronic cases. Antibiotics should be selected based on sensitivities of the cultured organism. Useful systemic antibiotics include the tetracyclines, amoxicillin, sulfamethoxazole/trimethoprim DS, dapsone, clindamycin or antibiotic plus rifampin combination. Incision and drainage is strongly discouraged. Isotretinoin is effective in some cases, but a remission seldom follows its use. In the largest study to date, Boer et al treated 68 patients with a mean dose of 0.56 mg/kg of isotretinoin for 4–6 months. Clearing was obtained in 23.5% and long-term remission was seen in 16.2%. Secondary infection with S. aureus often occurs. Infliximab, etanercept, and adalimumab may clear the condition during their use; however, response is variable. In women, spironolactone and oral birth control pills are often an excellent choice, and finasteride in men or postmenopausal women may also be a helpful adjuvant. Cyclosporine may work well in selected cases. Photodynamic therapy and lasers have also been investi gated to various degrees in hidradenitis. Methylaminolaevulinate or 5-aminolevulinic acid prior to blue or red light activation (photodynamic therapy) has had reports of success in some cases, but also anecdotal reports of lack of efficacy. It is inconvenient, costly, and often painful, and does not produce remission, so further studies are required before such treatment can be recommended. Neodymium-doped yttrium aluminum garnet laser treatment has been reported to be quite effective in a prospective, randomized controlled trial of 22 severely affected individuals. After a series of three monthly sessions resulted in significant improvement, Nd:YAG laser treatment holds real promise in the therapy of hidradenitis. Chances of permanent cure are best when excision of the affected areas is done. Wide surgical excision, using intra operative color-marking of sinus tracts, is most effective at limiting recurrence; however, it has moderate morbidity, espe cially in the groin and perianal areas. The recurrence rate is low in the axillary and perianal areas; however, the inguinal folds and especially the submammary sites more often recur so that excision of the latter site is uncommonly recommended. CO2 laser may also destroy lesions and sinus tracts. The open areas may be closed or left to heal secondarily. Alikhan A, et al: Hidradenitis suppurativa. J Am Acad Dermatol 2009; 60:539.
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Blanco R, et al: Long-term successful adalimumab therapy in severe hidradenitis suppurativa. Arch Dermatol 2009; 145:580. Boer J, et al: Long-term results of isotretinoin in the treatment of 68 patients with hidradenitis suppurativa. J Am Acad Dermatol 1999; 40:73. Buimer MG, et al: Hidradenitis suppurativa. Br J Surg 2009; 96:350. Canoui-Poitrine F, et al: Clinical characteristics of a series of 302 French patients with hidradenitis suppurativa, with an analysis of factors associated with disease severity. J Am Acad Dermatol 2009; 61:51. Chandramohan K, et al: Squamous cell carcinoma arising from perianal lesion in a familial case of hidradenitis suppurativa. Int Wound J 2009; 6:141. Joseph MA, et al: Hidradenitis suppurativa treated with finasteride. J Dermatolog Treat 2005; 18:75. Kaur MR, et al: Hidradenitis suppurativa treated with dapsone. J Dermatolog Treat 2006; 17:211. Kraft JN, et al: Hidradenitis suppurativa in 64 female patients: retrospective study comparing oral antibiotics and antiandrogen therapy. J Cutan Med Surg 2007; 11:125. Lam J, et al: Hidradenitis suppurativa. Pediatr Dermatol 2007; 24:465. Lee RA, et al: Hidradenitis suppurativa. Adv Dermatol 2007; 23:289. Lee RA, et al: A prospective clinical trial of open-label etanercept for the treatment of hidradenitis suppurativa. J Am Acad Dermatol 2009; 60:565. Madan V, et al: Outcomes of treatment of nine cases of recalcitrant severe hidradenitis suppurativa with carbon dioxide laser. Br J Dermatol 2008; 159:1309. Mandal A, et al: Experience with different treatment modules in hidradenitis suppurativa. Surgeon 2005; 3:23. Matusiak L, et al: Hidradenitis suppurativa and associated factors: still unsolved problems. J Am Acad Dermatol 2009; 61:362. Mendoca CO, et al: Clindamycin and rifampicin combination therapy for hidradenitis suppurativa. Br J Dermatol 2006; 154:977. Montes-Romero JA, et al: Amyloidosis secondary to hidradenitis suppurativa. Eur J Intern Med 2008; 19:e32. Revuz JE, et al: Prevalence and factors associated with hidradenitis suppurativa: results from two case-control studies. J Am Acad Dermatol 2008; 59:596. Rubin RJ, et al: Perianal hidradenitis suppurativa. Surg Clin North Am 1994; 74:1317. Saraceno R, et al: Methyl aminolaevulinate photodynamic therapy for the treatment of hidradenitis suppurativa and pilonidal cysts. Photodermatol Photoimmunol Photomed 2009; 25:164. Tierney E, et al: Randomized control trial for the treatment of hidradenitis suppurativa with a neodymium-doped yttrium aluminium garnet laser. Dermatol Surg 2009; 35:1. Wolkenstein P, et al: Quality of life impairment in hidradenitis suppurativa. J Am Acad Dermatol 2007; 56:621.
Dissecting cellulitis of the scalp Also known as perifolliculitis capitis abscedens et suffodiens, this is an uncommon chronic suppurative disease of the scalp characterized by numerous follicular and perifollicular inflam matory nodules. These nodules suppurate and undermine to form intercommunicating sinuses as long as 5 cm (Fig. 13-21). Scarring and alopecia ensue, although seropurulent drainage may last indefinitely. Adult black men are most commonly affected, and the vertex and occiput of the scalp are the sites of predilection. The primary lesions are follicular and perifollicular ery thematous papules which progress to abscesses. This disease is a variant of dissecting terminal hair folliculitis, along with hid radenitis suppurativa, acne keloidalis nuchae, and pilonidal sinus. Coagulase-positive S. aureus may be found in the lesions. Treatment is generally unsuccessful unless the most vigor ous procedures are followed. The combination of intralesional steroid injections and isotretinoin at a dose of 0.5–1.5 mg/kg/ day for 6–12 months may be successful. Starting at a lower dose such as 10 mg per day for the first month or two may prevent a flare of the condition. The length of remission with isotretinoin is variable, but treatment may be repeated with similar results expected. Oral antibiotics such as the
Rosacea Fig. 13-22 Erythrotelangiectatic rosacea.
Fig. 13-21 Dissecting folliculitis. (Courtesy of Curt Samlaska, MD)
tetracyclines, trimethoprim–sulfamethoxazole, or the quinolo nes may produce good results. If S. aureus is cultured, the combination of oral rifampin and clindamycin has produced excellent results. A surgical approach is at times necessary. Marsupialization or excision of sinus tracks may help limit inflammation. The Nd:YAG laser used with the intent to remove hair has led to long-term improvement. Georgala S, et al: Dissecting cellulitis of the scalp treated with rifampicin and isotretinoin. Cutis 2008; 82:195. Greenblatt DT, et al: Dissecting cellulitis of the scalp responding to oral quinolones. Clin Exp Dermatol 2008; 33:99. Krasner BD, et al: Dissecting cellulitis treated with the long-pulsed Nd:YAG laser. Dermatol Surg 2006; 32:1039. Sukhatme SV, et al: Refractory dissecting cellulitis of the scalp treated with adalimumab. J Drugs Dermatol 2008; 7:981.
Acne miliaris necrotica (acne varioliformis) Acne miliaris necrotica consists of follicular vesicopustules, sometimes occurring as solitary lesions that are usually very itchy. They appear anywhere in the scalp or adjacent areas, rupture early, and dry up after a few days. In some patients, especially those who manipulate the lesions, S. aureus may be cultured. If they leave large scars, the term acne varioliformis is used; they are probably not separate diseases. Treatment is with culture-directed antibiotics, or if the culture is negative, oral tetracycline or minocycline. Doxepin is helpful if patients manipulate their lesions. Fisher DA: Acne necroticans and Staphylococcus aureus. J Am Acad Dermatol 1988; 18:1136. Kossard S, et al: Necrotizing lymphocytic folliculitis: the early lesion of acne necrotica. J Am Acad Dermatol 1987; 16:1007. Zirn JR, et al: Chronic acneiform eruption with crateriform scars. Arch Dermatol 1996; 132:1365.
Rosacea Clinical features Rosacea is characterized by a persistent erythema of the convex surfaces of the face, with the cheeks and nose most frequently
Fig. 13-23 Papulopustular rosacea. (Courtesy of Curt Samlaska, MD)
affected, followed by involvement of the brow and chin. There is a tendency to spare the periocular skin. Rosacea occurs most often in light-skinned women between the ages of 30 and 50; however, the severe type with phymatous changes occurs almost exclusively in men. Additional features commonly manifested include telangiectasia, flushing, erythematous papules and pustules. These tend to cluster in patterns, allow ing for the identification of several subsets of patients, the importance of their recognition being that the therapeutic implications differ. The erythrotelangiectatic type (Fig. 13-22) is characterized by a prominent history of a prolonged (over 10 min) flushing reaction to various stimuli, such as emotional stress, hot drinks, alcohol, spicy foods, exercise, cold or hot weather, or hot baths and showers. Often a burning or stinging sensation accompanies the flush, but sweating, lightheadedness, and palpitations do not. The skin is of fine texture, may have a roughness and scaling of the affected central facial sites, and is easily irritated. Over time a purplish suffusion and promi nent telangiectasia may result. The papulopustular subset of patients manifests a strikingly red central face accompanied by erythematous papules often surmounted by a pinpoint pustule (Fig. 13-23). The history of flushing is also present in most patients, but usually symp toms of irritancy are not prominent. The skin is of normal or 241
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at times slightly sebaceous quality and edema of the affected sites may be present. Such edema may dominate the clinical presentation, with the forehead, eyelids, and cheeks variably affected. This has been termed Morbihan’s disease and is most likely to complicate the papulopustular and glandular types. In the glandular type of rosacea, men with thick sebaceous skin predominate. The papules are edematous, the pustules are often 0.5–1.0 cm in size, and nodulocystic lesions may be present (Fig. 13-24). They tend to cluster in the central face, but in affected women the chin is favored. There is frequently a history of adolescent acne and typical scars may be seen. Flushing is less common, as is telangiectasia, but persistent edema may be problematic. It is in this subtype that rhino phyma (Fig. 13-25) most commonly occurs. Hypertrophic, hyperemic, large nodular masses are centered over the distal half of the nose. Rarely, such soft tissue overgrowth can affect the chin, ears, or forehead. Hugely dilated follicles contain long vermicular plugs of sebum and keratin. The histologic features are pilosebaceous gland hyperplasia with fibrosis, inflammation, and telangiectasia.
Etiology The cause of rosacea remains unknown. Most patients have an abnormal vasomotor response to thermal and other stimuli, as described above. Additionally, chronic solar damage is an important contributor in producing damage to the dermal matrix and ground substance, especially in the erythro telangiectatic subtype. Chronic vasodilatation, edema, and compromise of lymphatic drainage occur and lead to tel angiectasia and fibrosis. Pilosebaceous unit abnormalities are not commonly felt to be part of the pathogenesis of this condi tion; however, some evidence points to abnormalities being present, especially in the glandular type of patient. It is to be expected that the pathogenic factors will vary among the subsets of patients. Demodex and Helicobacter pylori have been extensively investigated and do not appear to be central to the etiology of rosacea.
Other clinical considerations Ocular findings Blepharitis, recurrent chalazion, and conjunctivitis may be seen in all subsets of rosacea (Fig. 13-26). The eye itself may be affected, with keratitis, iritis, and episcleritis. An abnormal Schirmer test occurs in 40% of rosacea patients. Complaints are often of a gritty, stinging, itchy, or burning sensation in the eye. Light sensitivity and a foreign body sensation are also present at times. Ocular rosacea occurs equally in men and women. Such eye findings may occur before the skin disease. Since these findings have therapeutic implications and patients will not always complain of them to their dermatologist, these signs and symptoms should be actively sought when evaluat ing rosacea patients.
Extrafacial lesions Flushing may involve the ears, lateral facial contours, neck, upper chest, and scalp. Papules and pustules may be present in persistent erythema of the scalp or the earlobes.
Topical steroid use
Fig. 13-24 Glandular rosacea.
Fig. 13-25 Rhinophyma.
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Long-term use of topical steroids on the face may result in persistent erythema, papules, and pustules. The sites involved correspond to the areas of application and are not necessarily limited to the central convexities. Treatment is discontinuance of the offending drug and institution of topical tacrolimus in combination with short-term minocycline. Topical tacrolimus itself has paradoxically been reported to induce a rosacea-like reaction, so coverage with minocycline while discontinuing topical steroids is necessary. Additionally, drinking alcohol after application of tacrolimus or pimecrolimus may induce
Fig. 13-26 Ocular rosacea.
Perioral dermatitis While this condition has been classified within the umbrella of rosacea variants, its distribution, signs, and symptoms vary such that it is included separately in this chapter.
Granulomatous lesions Some patients with persistent facial erythema of the convexi ties will have, on biopsy of an erythematous papule, a granu lomatous response closely resembling sarcoidosis or a necrotizing granuloma. Many experienced clinicians will accu rately predict such findings from the clinical examination. Here the most important consideration is the fact that the response to treatment may be slower. When involvement of granulomatous facial papules includes the eyelids and upper lip, and is not associated with vascular manifestations, such as flushing, erythema, or telangiectasia, the term granulomatous facial dermatitis is preferred. This condition is discussed separately.
Differential diagnosis The persistent erythema of the central face should be differen tiated from that seen in polycythemia vera, carcinoid, masto cytosis, and connective tissue disease (lupus erythematosus, dermatomyositis, and mixed connective tissue disease). These conditions do not have associated papules and pustules, will manifest a variety of systemic symptoms and extrafacial signs, and specific laboratory markers are available to confirm clini cal suspicions. Haber syndrome is a genodermatosis character ized by a rosacea-like facial dermatosis and multiple verrucous lesions on non-sun-exposed skin. Onset of the facial lesions is in the first two decades of life, in contrast to the later onset of rosacea. While rosacea may occur in human immunodefi ciency virus (HIV) disease, a papulonodular eruption of the face that may simulate acne rosacea also occurs in patients with acquired immunodeficiency syndrome (AIDS). On expressing the contents of hair follicles with a comedo extrac tor, numerous Demodex mites are seen. In such cases, success with permethrin cream and lindane has been reported, and also lotions containing 5% benzoyl peroxide and 5% precipi tated sulfur (Sulfoxyl) are helpful.
Treatment Treatments are directed at specific findings manifested by rosacea patients. Since erythema, telangiectases, papules and pustules, phymas, flushing, ocular symptoms, and skin sensi tivity are variably present in the three subsets of disease, the specific approach utilized will differ according to the factors present. Other treatments are useful in all patients.
General nonpharmacologic and nonsurgical interventions Sunscreens are an important component of therapy for all patients. They should be applied each morning. Those contain ing physical blockers in a dimethicone or cyclomethicone vehicle are in general better tolerated, especially by the erythro telangiectatic patients, than those with chemical agents. General avoidance of irritants such as astringents, peeling or acidic agents, and abrasive or exfoliant preparations is recom mended. Cosmetic coverage of the erythema and telangiectases is best with a light green or yellow-tinted foundation set with powder.
If flushing is induced by specific trigger factors, their avoid ance as much as possible is best. Soybe hypothesized that the central face is predisposed to rosacea as the edema and lack of movement of tissues with muscular movement may lead to lymphedema and inflammation. Circular massage for several minutes a day led to impressive improvement. This benign intervention may be considered and ought to be studied. Artificial tears and cleansing the lids with warm water two times daily will help ocular symptoms.
Rosacea
flushing, which may be confused with new-onset flushing related to rosacea.
Topical therapy Metronidazole, sodium sulfacetamide, sulfur cleansers and creams, and azelaic acid are approved for use in rosacea. They are the most commonly prescribed medications and are espe cially useful for the papulopustular patients and some patients with the erythrotelangiectatic type. Benzoyl peroxide and topical clindamycin, alone or in combination, are often quite beneficial and well tolerated by the glandular subset of patients. If oral antibiotics are needed, the topical products may be used to maintain remission after discontinuance of oral preparations. Pimecrolimus or tacrolimus may also improve selected patients’ erythema, especially those with an accompanying roughness or scaling of the skin surface. They help the irritated erythrotelangiectatic and at times the papulopustular patients, but are not effective in the glandular type, and tacrolimus in its ointment base may exacerbate the inflammatory compo nent in these patients. They calm inflammation and abate symptoms, but require brief (no longer than 1 week) pretreat ment with a potent topical steroid to be tolerated initially. The role of topical retinoids requires study. Many rosacea patients may tolerate a night-time application of tretinoin if cetaphil lotion is used immediately prior to use. Retinoids may help repair sun-damaged skin and normalize some of the abnor malities present. Topical application of a selective α1adrenergic receptor agonist, oxymetazoline, helped one patient’s flushing and redness, but this treatment requires more data before it can be recommended since rebound ery thema is a concern.
Oral therapy Oral antibiotics, particularly tetracycline 250–500 mg each morning, doxycycline 50–100 mg once or twice daily, or mino cycline 50–100 mg once or twice a day, control more aggres sive papular and pustular lesions, and aid in the treatment of ocular lesions. Subantimicrobial doxycycline is also available in a 40 mg extended-release formulation. It is only occasion ally useful in the author’s experience. Oral antibiotics should be discontinued once clearance of the inflammatory lesions is obtained; usually 2 or 3 months is necessary. The topical approved preparations above should be used as long-term maintenance after clearance with the oral medications, as disease will recur in most patients if all therapy is stopped. If significant ocular symptoms are present, oral antibiotics are an effective and convenient method of relieving both the skin and eye concerns. Isotretinoin given in lower doses than in acne vulgaris, and at times as a long-term suppressant, may be necessary for management of more resistant disease. It pro duces dramatic improvement even in cases resistant to other forms of therapy, but relapse often occurs in a few weeks or months. The authors rarely use oral metronidazole (side effects) or the macrolides (lack of efficacy) despite their reported utility in this condition. Oral medications for reduction of flushing are uncommonly helpful. Occasionally an escalating dose of propranolol or clonidine is helpful in reducing symptomatic flushing, but most affected patients find the side effects occur before the 243
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beneficial effects are evident. One method is to start pro pranolol at 10 mg three times daily, and if no response is seen in 2 weeks, to increase the dose by 10 mg at one dose, then again every 2 weeks until either side effects require discon tinuation or response occurs. Responses are mostly seen at a dose of 20–40 mg three times daily.
Surgical intervention Surgical approaches to the reshaping of rhinophyma have included the use of a heated scalpel, electrocautery, dermabra sion, laser ablation, tangential excision combined with scissor sculpting, and radiofrequency electrosurgery. Often a combi nation of these approaches is used to obtain the best esthetic result. Lasers and light devices are useful for treating the ery thema and telangiectases, but the cost is not covered by insur ance and this limits their availability. In a comparative study the pulsed dye laser and intense pulse light device both significantly reduced erythema, telangiectasia, and patientreported symptoms, and performed similarly well. Some vascular and CO2 fractionated lasers may also help in dermal collagen remodeling and nonablative rejuvenation, such that the dermal matrix may be strengthened. For the patient inca pacitated by flushing, burning, and stinging, endoscopic trans thoracic sympathectomy may be considered, but this extreme measure should only rarely be considered, as serious compli cations may result. An advocacy group that supports research and education in rosacea, the National Rosacea Society, is an excellent resource for patients. Aloi F, et al: The clinicopathologic spectrum of rhinophyma. J Am Acad Dermatol 2000; 42:468. Altinyazar HC, et al: Adapalene vs metronidazole gel for the treatment of rosacea. Int J Dermatol 2005; 44:252. Antille C, et al: Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. Arch Dermatol 2004; 140:457. Craige H, et al: Symptomatic treatment of idiopathic and rosaceaassociated cutaneous flushing with propranolol. J Am Acad Dermatol 2005; 53:881. Crawford GH, et al: Rosacea I. J Am Acad Dermatol 2004; 5:327. Crawford KM, et al: Pimecrolimus for treatment of acne rosacea. Skin Med 2005; 4:147. Elewski BE, et al: Rosacea. J Eur Acad Dermatol Venereol 2010; epub. El Sayed F, et al: Rosaceiform eruption to pimecrolimus. J Am Acad Dermatol 2006; 54:548.
Garg G, et al: Clinical efficacy of tacrolimus in rosacea. J Eur Acad Dermatol Venereol 2009; 23:239. Izikson L, et al: The flushing patient. J Am Acad Dermatol 2006; 55:193. Karabulut AA, et al: A randomized, single-blind, placebo-controlled, split-face study with pimecrolimus cream 1% for papulopustular rosacea. J Eur Acad Dermatol Venereol 2008; 22:729. Kilty S, et al: Surgical treatment of rhinophyma. J Otolaryngol Head Neck Surg 2008; 37:269. Kroshinshky D, et al: Pediatric rosacea. Dermatol Ther 2006; 19:196. Lee DH, et al: Pimecrolimus 1% cream for the treatment of steroidinduced rosacea. Br J Dermatol 2008; 158:1069. Liu RH, et al: Azelaic acid in the treatment of papulopustular rosacea. Arch Dermatol 2006; 142:1047. Neuhaus IM, et al: Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Dermatol Surg 2009; 35:920. Ogunleye T, et al: Ethanol-induced flushing with topical pimecrolimus use. Dermatitis 2008; 19:E1. Pelle MT, et al: Rosacea II. Therapy. J Am Acad Dermatol 2004; 51:499. Powell FC: Clinical practice: rosacea. N Engl J Med 2005; 352:793. Shanler SD, et al: Successful treatment of the erythema and flushing of rosacea using a topically applied selective alpha 1-adrenergic receptor agonist, oxymetazoline. Arch Dermatol 2007; 143:1369. Stone DU, et al: Ocular rosacea. Curr Opin Ophthalmol 2004; 15:499. van Zuuren E, et al: Interventions for rosacea. Cochrane Database Syst Rev 2005; 20:CD003262. Van Zuuren EJ, et al: Systematic review of rosacea treatments. J Am Acad Dermatol 2007; 56:107. Wilkin J, et al: Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 2002; 46:584. Yoon TY, et al: Pimecrolimus-induced rosacea-like demodicidosis. Int J Dermatol 2007; 46:1103. Zhao YE, et al: Retrospective analysis of the association between Demodex infestation and rosacea. Arch Dermatol 2010; 146:896.
Pyoderma faciale This uncommon eruptive facial disorder consists of a dramati cally fulminant onset of superficial and deep abscesses, cystic lesions (Fig. 13-27), and sometimes sinus tracts. Edema and at times an intense reddish or cyanotic erythema accompany this pustular process. The lesions often contain greenish or yellow ish purulent material. Older cysts contain an oily substance. The condition occurs mostly in postadolescent women. It is distinguished from acne by the absence of comedones, rapid onset, fulminating course, and absence of acne on the back and Fig. 13-27 A and B, Pyoderma faciale. (Courtesy of Curt Samlaska, MD)
A
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B
Akhyani M, et al: The association of pyoderma faciale and erythema nodosum. Clin Exp Dermatol 2007; 32:275. Crawford GH, et al: Pyoderma faciale. J Am Acad Dermatol 2005; 53:1106. Fender AB, et al: Pyoderma faciale. Cutis 2008; 81:488. Plewig G, et al: Pyoderma faciale. Arch Dermatol 1992; 128:1611.
Perioral dermatitis This common perioral eruption consists of discrete papules and pustules on an erythematous and at times scaling base. It is a distinctive dermatitis confined symmetrically around the mouth, with a clear zone of some 5 mm between the vermilion border and the affected skin (Fig. 13-28). There is no itching; however, an uncomfortable burning sensation may be present. It occurs almost exclusively in women between the ages of 20 and 35. The use of fluorinated topical steroids is the most frequently identified cause. Exposure may be in the form of creams, ointments, or inhalers. Treatment includes discontinuing topical steroids or pro tecting the skin from the inhaled product. Additionally, tetra cycline, 250–500 mg once a day, or minocycline, 100 mg once or twice a day, will lead to control. Tacrolimus ointment 0.1% or pimecrolimus cream will prevent flaring after stopping steroid use. In those patients without steroid exposure, oral or topical antibiotics, and topical adapalene, azelaic acid, and metronidazole have been successful in clearing the eruption.
Periorbital dermatitis Periorbital (periocular) dermatitis is a variant of perioral der matitis occurring on the lower eyelids and skin adjacent to the upper and lower eyelids. Fluorinated topical steroids have been implicated as the cause. If intranasal inhaled steroids are
Fig. 13-28 Perioral dermatitis.
used, a perinasal distribution may be seen. Prompt response to the same treatment employed in the perioral site is expected. Chen AY, et al: Steroid-induced rosacealike dermatitis. Cutis 2009; 83:198. Nguyen V, et al: Periorificial dermatitis in children and adolescents. J Am Acad Dermatol 2006; 55:781. Poulos GA, et al: Perioral dermatitis associated with an inhaled corticosteroid. Arch Dermatol 2007; 142:1460. Schwarz T, et al: A randomized, double-blind, vehicle-controlled study of 1% pimecrolimus cream in adult patients with perioral dermatitis. J Am Acad Dermatol 2008; 59:34. Weber K, et al: Critical appraisal of reports on the treatment of perioral dermatitis. Dermatology 2005; 210:300.
Granulomatous facial dermatitis Several dermatoses of the face characterized by granulomas are included in this category. Patients with persistent facial erythema involving one or more convex surfaces of the face will have lesions that show a granulomatous reaction histo logically, and are included within rosacea. Some patients have no other stigmata of rosacea and their nosology is unclear. These other entities, which meet no other criteria for rosacea other than having pink papules on the face, are included here. Skowron et al have proposed the term FIGURE (facial idio pathic granulomas with regressive evolution).
Granulomatous facial dermatitis
chest. Pyoderma faciale is differentiated from rosacea by the inconsistent history of flushing, the absence of pre-existing erythema or telangiectases of the convex portions of the face, and by the large abscesses and nodules. Treatment is similar to that of acne fulminans. Oral steroids are given for several weeks followed by the addition of isotretinoin, 10–20 mg, increasing to 0.5–1 mg/kg only after the acute inflammatory component is well under control. Steroids may usually be discontinued after several weeks of isotretinoin, but the latter should be given for a full 120– 150 mg/kg total dose. As patients are predominately women of child-bearing age, pregnancy issues require full discussion. Indeed, four of Plewig et al’s patients were pregnant and thus could not use isotretinoin.
Lupus miliaris disseminatus faciei Firm, yellowish-brown or red, 1–3 mm, monomorphous, smooth-surfaced papules are present not only on the butterfly areas but also on the lateral areas, below the mandible, and periorificially (Fig. 13-29). The eyelid skin is characteristically involved. The discrete papules appear as yellowish-brown lesions on diascopy and as caseating epithelioid cell granulo mas histologically. Patients usually lack a history of flushing, do not have persistent erythema or telangiectasia, have involvement of the eyelids, and heal with scarring, as opposed to rosacea patients. Long-term therapy with minocycline or isotretinoin may be used, often with gratifying results. Eventually, self-involution is expected but may take several years to occur.
Granulomatous perioral dermatitis in children In otherwise healthy prepubertal children a profusion of grouped papules may develop on the perioral, periocular, and perinasal areas (Fig. 13-30). Eight of the initial 59 reported
Fig. 13-29 Lupus miliaris.
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Choi YL, et al: Case of childhood granulomatous periorificial dermatitis in a Korean boy treated by oral erythromycin. J Dermatol 2006; 33:806. Lucas CR, et al: Granulomatous periorificial dermatitis. J Cutan Med Surg 2009; 13:115. Misago N, et al: Childhood granulomatous periorificial dermatitis. J Eur Acad Dermatol 2005; 19:470. Skowron F, et al: F.I.G.U.R.E.: facial idiopathic granulomas with regressive evolution. Dermatology 2000; 201:289. Tarm K, et al: Granulomatous periorificial dermatitis. Cutis 2004; 73:399. Urbatsch AJ, et al: Extrafacial and generalized granulomatous periorificial dermatitis. Arch Dermatol 2002; 138:1354. Van de Scheur MR, et al: Lupus miliaris disseminatus faciei. Dermatology 2003; 206:120.
Fig. 13-30 Childhood granulomatous facial dermatitis.
cases have also had generalized lesions. Besides extremity and trunkal lesions, several of the girls have had dramatic lesions of the labia majora. Both sexes are affected equally. Children with skin of color (Afro-Caribbean, African American, and Asian) dominate the reports but white patients are also sus ceptible. Because the histologic appearance is granulomatous, sarcoidosis is often considered. Topical steroids, however, may worsen the condition and systemic involvement is not present. Topical metronidazole, erythromycin, sulfacetamide– sulfur combinations, and oral macrolide and tetracycline are usually effective.
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Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 13-1 Minocycline-induced pigmentation at sites of inflammation in a patient with acne. Fig. 13-2 Staphylococcal infection while on Accutane. (Courtesy of Curt Samlaska, MD) Fig. 13-3 Acne conglobata. Fig. 13-4 Rosacea. Fig. 13-5 Steroid rosacea.
Bonus images for this chapter can be found online at http://www.expertconsult.com
Bacterial Infections
Bacterial infections in the skin often have distinct morphologic characteristics that should alert the clinician to the fact that a potentially treatable and reversible condition exists. These cutaneous signs may be an indication of a generalized sys temic process or simply an isolated superficial event. Immunodeficiencies with low immunoglobulins, neutro penia, reduced neutrophil migration or killing, and disease caused by the human immunodeficiency virus (HIV) may be associated with severe or refractory pyogenic infections. Atopic dermatitis and syndromes with atopic-like dermatitis are also predisposed to bacterial infections. The categorization of these infections will be first those dis eases caused by Gram-positive bacteria, then those caused by Gram-negative bacteria, and finally several miscellaneous dis eases caused by the rickettsiae, mycoplasmas, chlamydiae, and spirochetes. Center for Communicable Diseases (CDC): STD treatment guidelines 2006. MMWR 2006; 55:1. Fernandez-Obregon AC, et al: Current use of anti-infectives in dermatology. Expert Rev Anti Infect Ther 2005; 3:557. Grice EA, et al: Topographical and temporal diversity of the human skin microbiome. Science 2009; 324:1190. Hogan MT: Cutaneous infections associated with HIV/AIDS. Dermatol Clin 2006; 24:473. Lupi O, et al: Tropical dermatology: bacterial tropical diseases. J Am Acad Dermatol 2006; 54:559. May AK: Skin and soft tissue infections. Surg Clin North Am 2009; 89:403. Nathwani D: New antibiotics for the management of complicated skin and soft tissue infections. Int J Antimicrob Agents 2009; 34(Suppl 1):S24. Schauber J, et al: Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol 2008; 122:261. Schweiger ES, et al: Novel antibacterial agents for skin and skin structure infections. J Am Acad Dermatol 2004; 50:331. Wu JJ, et al: Vaccines and immunotherapies for the prevention of infectious diseases having cutaneous manifestations. J Am Acad Dermatol 2004; 50:495.
INFECTIONS CAUSED BY GRAM-POSITIVE ORGANISMS Staphylococcal infections The skin lesions induced by this Gram-positive coccus appear usually as pustules, furuncles, or erosions with honey-colored crusts; however, bullae, widespread erythema and desquama tion, or vegetating pyodermas may also be indicators of Staphylococcus aureus infection. Purulent purpura may indicate bacteremia or endocarditis caused by S. aureus, or, in immuno compromised patients, S. epidermidis. Two distinctive cutane ous lesions that occur with endocarditis are the Osler node and Janeway lesion or spot. The former is a painful, erythematous nodule with a pale center located on the fingertips. The latter
14
is a nontender, angular hemorrhagic lesion of the palms (Fig. 14-1) and soles. These lesions are likely to be due to septic emboli. S. aureus is a normal inhabitant of the anterior nares in 20– 40% of adults, and also resides on the hands and perineum in smaller numbers of individuals. Nasal carriers are particularly prone to infections with this bacterium because of its continu ous presence on the skin and nasal mucosa. Spread of infection in the hospital setting is frequently traced to the hands of a healthcare worker. Proper handwashing technique is essential in limiting this nosocomial complication. HIV-infected patients are at least twice as commonly nasal carriers, and they tend to harbor S. aureus in higher frequency and density at other sites of the body, thus predisposing them to skin and systemic infection. Antibiotic resistance has become a clinically important con sideration in many infections, but meticillin-resistant S. aureus (MRSA), which has been a nosocomial problem for years, is now a common community-acquired skin infection. MRSA infection may be suspected from a knowledge of local patterns of resistance, lack of response to initial meticillin-sensitive S. aureus (MSSA)-directed therapy, such as cefalexin, and factors predisposing to colonization and infection with this organism. Predisposing factors include age (older than 65), exposure to others with MRSA infection, prior antibiotic therapy, and recent hospitalization or chronic illness. In patients with risk factors, multiple drug resistance is likely and treatment with intravenous vancomycin or linezolid may be necessary. In community-acquired infection in patients without risk factors, clindamycin, trimethoprim–sulfamethoxazole (alone or com bined with rifampin), minocycline, or oral linezolid will often be effective. Definitive antibiotic therapy may be tailored to the antibiotic susceptibility of the cultured organism.
Superficial pustular folliculitis (impetigo of Bockhart) Bockhart impetigo is a superficial folliculitis with thin-walled pustules at the follicle orifices. Favorite locations are the extremities and scalp, although it is also seen on the face, especially periorally. These fragile, yellowish-white, domed pustules develop in crops and heal in a few days. S. aureus is the most frequent cause. The infection may secondarily arise in scratches, insect bites, or other skin injuries.
Sycosis vulgaris (sycosis barbae) Sycosis vulgaris, formerly known as barber’s itch, is a perifol licular, chronic, pustular staphylococcal infection of the bearded region (Fig. 14-2), characterized by the presence of inflammatory papules and pustules, and a tendency to recur rence. The disease begins with erythema and burning or itching, usually on the upper lip near the nose. In a day or two one or more pinhead-sized pustules, pierced by hairs, develop.
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Fig. 14-1 Janeway lesion in subacute bacterial endocarditis.
Fig. 14-3 Staphylococcal folliculitis.
Fig. 14-2 Sycosis barbae.
Fig. 14-4 Staphylococcal abscess.
These rupture after shaving or washing and leave an ery thematous spot, which is later the site of a fresh crop of pus tules. In this manner the infection persists and gradually spreads. At times the infection may extend deep into the fol licles. A hairless, atrophic scar bordered by pustules and crusts may result. Marginal blepharitis with conjunctivitis is usually present in severe cases of sycosis. Sycosis vulgaris is to be distinguished from tinea, acne vul garis, pseudofolliculitis barbae, and herpetic sycosis. Tinea barbae rarely affects the upper lip, which is a common location for sycosis. In tinea barbae the involvement is usually in the submaxillary region or on the chin, and spores and hyphae are found in the hairs. Pseudofolliculitis barbae manifests torpid papules at the sites of ingrowing beard hairs in black men. In herpes simplex the duration is usually only a few days and even in persistent cases there are vesicles, which help to dif ferentiate the disease from sycosis vulgaris.
Treatment
Folliculitis Staphylococcal folliculitis may affect other areas, such as the eyelashes, axillae, pubis, and thighs (Fig. 14-3). On the pubis it may be transmitted among sexual partners, and miniepidemics of folliculitis and furunculosis of the genital and gluteal areas may be considered a sexually transmitted disease (STD). Staphylococcal folliculitis has also been reported fre quently among patients with acquired immunodeficiency syn drome (AIDS) and may be a cause of pruritus. An atypical, plaque-like form has been reported. 248
Deep lesions of folliculitis represent small follicular abscesses and must be drained. Superficial pustules will rupture and drain spontaneously. Many patients will heal with drainage and topical therapy. Bactroban or retapamulin ointment and topical cleocin solution are effective topical agents. Skin surface staphylococcal carriage in abrasions and eczematous areas may be addressed with topical antibiotics as above, topical chlorhexidine, or bleach baths. The latter can be pre pared by adding one half-cup of Clorox bleach to a tub of bathwater. If drainage and topical therapy fail or if there is accompanying soft-tissue infection, a first-generation cephalo sporin, or a penicillinase-resistant penicillin such as dicloxacil lin, is indicated, unless MRSA is suspected (see above). When the inflammation is acute, hot, wet soaks with Burow solution diluted 1 : 20 (Domeboro) are beneficial. An anhydrous formu lation of aluminum chloride (Drysol, Xerac-AC) is effective when used once a night for chronic folliculitis, especially of the buttocks. Antibiotic ophthalmic ointments are used for blepharitis.
Furunculosis A furuncle, or boil, is an acute, round, tender, circumscribed, perifollicular staphylococcal abscess that generally ends in central suppuration (Fig. 14-4). A carbuncle is merely two or more confluent furuncles, with separate heads. The lesions begin in hair follicles, and often continue for a prolonged period by autoinoculation. Some lesions disappear
Chronic furunculosis
Fig. 14-5 Staphylococcal abscess in a diabetic patient.
before rupture, but most undergo central necrosis and rupture through the skin, discharging purulent, necrotic debris. Sites of predilection are the nape, axillae, and buttocks, but boils may occur anywhere. The integrity of the skin surface may be impaired by irrita tion, pressure, friction, hyperhidrosis, dermatitis, dermato phytosis, or shaving, among other factors. Local barrier compromise predisposes to infection by providing a portal of entry for the ubiquitous S. aureus. The proximate cause is either contagion or autoinoculation from a carrier focus, usually in the nose or groin. Certain systemic disorders may predispose to furunculosis: alcoholism; malnutrition; blood dyscrasias; disorders of neu trophil function; iatrogenic or other immunosuppression, including AIDS; and diabetes (Fig. 14-5). Patients with several of these diseases, as well as those receiving renal dialysis or under treatment with isotretinoin or acitretin, are often nasal carriers of S. aureus. Additionally, atopic dermatitis also pre disposes to the S. aureus carrier state. This fact helps explain the observed increases in the incidence of infections in these diseases.
Hospital furunculosis Epidemics of staphylococcal infections occur in hospitals. Marked resistance to antibacterial agents in these cases is com monplace. Attempts to control these outbreaks center on meticulous handwashing. In nurseries, a fall in neonatal colo nization and infections with S. aureus and non-group A strep tococci may be achieved by using a 4% solution of chlorhexidine for skin and umbilical cord care.
Treatment Warm compresses and antibiotics taken internally may arrest early furuncles. A penicillinase-resistant penicillin or a firstgeneration cephalosporin should be given orally in a dose of 1–2 g/day according to the severity of the case. Meticillinresistant and even vancomycin-resistant strains occur, as described above. In cases of staphylococcal infections that are unresponsive to these usual measures, antibiotic-resistant strains should be suspected and sensitivities checked. Bactroban applied to the anterior nares daily for 5 days and bleach baths may help prevent recurrence. When the lesions are incipient and acutely inflamed, incision should be strictly avoided and moist heat employed. When the furuncle has become localized and shows definite fluctuation, incision with drainage is indicated. The cavity should be packed with iodoform or vaseline gauze. In these cases, oral antibiotics are not usually necessary. In boils of the external auditory canal, upper lip, and nose, incision and drainage is generally only performed if antibiotic
Despite treatment, recurrences of some boils may be antici pated. Usually no underlying disease is present to predispose to this; rather, autoinoculation and intrafamilial spread among colonized individuals are responsible. One of the most important factors in prevention is to avoid autoinoculation. It is important to emphasize that the nasal carrier state predisposes to chronic furunculosis. The skin surface in the region of the furuncles may be a source of colo nization, especially if there are cuts, excoriation, or eczematous changes. In addition, the hazard of contamination from the perianal and intertriginous areas is to be considered. In general, indications for elimination of the carriage state are recurrent infection, evidence of spread to others, or high-risk individuals in the household. Routine precautions to be taken in attempting to break the cycle of recurrent furunculosis should be the daily use of a chlorhexidine wash, with special attention to the axillae, groin, and perianal area; laundering of bedding and clothing on a daily basis initially; the use of bleach baths; and frequent hand washing. Additionally, the application of Bactroban ointment twice a day to the nares of patients and family members every fourth week has been found to be effective. Rifampin, 600 mg/ day, combined with dicloxacillin for MSSA or trimethoprim– sulfamethoxazole for MRSA, for 10 days, or low-dose (150 mg/ day) clindamycin for 3 months are other options that are effec tive in eradicating the nasal carriage state. The use of baci tracin ointment inside the nares twice a day throughout the course of isotretinoin therapy eliminates, or markedly reduces, the risk of inducing nasal carriage of S. aureus, and hence sta phylococcal infections.
Staphylococcal infections
therapy fails. In these latter circumstances, antibiotic ointment (Bactroban) should be applied, and antibiotics given inter nally. Warm saline-solution compresses should be applied liberally.
Pyogenic paronychia Paronychia is an inflammatory reaction involving the folds of the skin surrounding the fingernail. It is characterized by acute or chronic purulent, tender, and painful swellings of the tissues around the nail, caused by an abscess in the nailfold. When the infection becomes chronic, horizontal ridges appear at the base of the nail. With recurrent bouts new ridges appear. The primary predisposing factor that is identifiable is sepa ration of the eponychium from the nail plate. The separation is usually caused by trauma as a result of moisture-induced maceration of the nailfolds from frequent wetting of the hands. The relationship is close enough to justify treating chronic paronychia as work-related in bartenders, food servers, nurses, and others who often wet their hands. The moist grooves of the nail and nailfold become secondarily invaded by pyogenic cocci and yeasts. The causative bacteria are usually S. aureus, Streptococcus pyogenes, Pseudomonas species, Proteus species, or anaerobes. The pathogenic yeast is most frequently Candida albicans. The bacteria usually cause acute abscess formation (Staphylococcus) (Fig. 14-6) or erythema and swelling (Streptococcus) (Fig. 14-7), and C. albicans most frequently causes a chronic swelling. If an abscess is suspected, applying light pressure with the index finger against the distal volar aspect of the affected digit will better demonstrate the extent of the collected pus by inducing a well-demarcated blanching. Smears of purulent material will help confirm the clinical impression. Myremecial warts may at times mimic 249
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Fig. 14-6 Staphylococcal paronychia.
Fig. 14-8 Botryomycosis.
will improve cure rates. Rarely, long-term antibiotic therapy may be required. While Candida is the most frequently recovered organism in chronic paronychia, topical or oral antifungals lead to cure in only about 50% of cases. If topical steroids are used to decrease inflammation and allow for tissue repair, cure results more reliably (nearly 80% in one study). Often an antifungal liquid such as miconazole is combined with a topical corticosteroid cream or ointment.
Botryomycosis
Fig. 14-7 Streptococcal paronychia and impetigo.
paronychia. Subungual black macules followed by edema, pain, and swelling have been reported to be a sign of osteo myelitis caused by S. aureus or Streptococcus viridans, in chil dren with atopic dermatitis. Treatment of pyogenic paronychia consists mostly of protec tion against trauma and concentrated efforts to keep the affected fingernails meticulously dry. Rubber or plastic gloves over cotton gloves should be used whenever the hand must be placed in water. Acutely inflamed pyogenic abscesses should be incised and drained. The abscess may often be opened by pushing the nailfold away from the nail plate. In acute suppurative paronychia, especially if stains show pyo genic cocci, a semisynthetic penicillin or a cephalosporin with excellent staphylococcal activity should be given orally. If these are ineffective, MRSA or a mixed anaerobic bacteria infection should be suspected. Augmentin for the latter or treatment dictated by the sensitivities of the cultured organism 250
Botryomycosis is an uncommon, chronic, indolent disorder characterized by nodular, crusted, purulent lesions (Fig. 14-8). Sinuses that discharge sulfur granules are present. These heal with atrophic scars. The granules most commonly yield S. aureus on culture, although cases caused by Pseudomonas aeruginosa, Escherichia coli, Proteus, Bacteroides, and Streptococcus have been reported. Botryomycosis occurs frequently in patients with altered immune function, such as those with neutrophilic defects. Other predisposing factors include diabetes, HIV infection, alcoholism, and Job syndrome. Appropriate antibiotics, surgical drainage, and surgical exci sion are methods used to treat botryomycosis.
Blastomycosis-like pyoderma Large verrucous plaques with elevated borders and multiple pustules occur. Most patients have some underlying systemic or local host compromise. Bacteria such as S. aureus, P. aeruginosa, Proteus, E. coli, or streptococci may be isolated. Antibiotics appropriate for the organism isolated are curative; however, response may be delayed and prolonged therapy required. Acitretin may also be useful.
S. aureus abscess formation within the deep, large, striated muscles usually presents with fever and muscle pain. It is more common in the tropics, where it may affect adults but most commonly occurs in children. In temperate climates it occurs in children and patients with AIDS. The most frequent site in tropical disease is the thigh, while in HIV-infected patients the deltoid muscle is most often involved, followed closely by the quadriceps. Swelling and, occasionally, ery thema or yellow or purplish discoloration are visible signs of pyomyositis, but these are late findings. Magnetic resonance imaging (MRI) with gadolinium injection will help delineate the extent of disease. Drainage of the abscess and appropriate systemic antibiotics are the recommended treatment.
Impetigo contagiosa Impetigo contagiosa is a staphylococcal, streptococcal, or com bined infection characterized by discrete, thin-walled vesicles that rapidly become pustular and then rupture. Impetigo occurs most frequently on the exposed parts of the body: the face (Fig. 14-9), hands, neck, and extremities. Impetigo on the scalp is a frequent complication of pediculosis capitis. The disease begins with 2 mm erythematous macules, which may shortly develop into vesicles or bullae. As soon as these lesions rupture, a thin, straw-colored, seropurulent discharge is noted. The exudate dries to form loosely stratified goldenyellow crusts, which accumulate layer upon layer until they are thick and friable. The crusts can usually be removed readily, leaving a smooth, red, moist surface that soon collects droplets of fresh exudate again; these are spread to other parts of the body by fingers or towels. As the lesions spread peripherally and the skin clears centrally, large circles are formed by fusion of the spreading lesions to produce gyrate patterns. In streptococcal-induced impetigo, regional lymphadenopathy is common, but not serious. Most studies find 50–70% of cases are due to S. aureus, with the remainder being due to either S. pyogenes or a combination of these two organisms. Streptococci may represent an early pathogen in the pathogenesis of impetigo, with staphylococci replacing streptococci as the lesion matures. Group B strepto cocci are associated with newborn impetigo and groups C and G are rarely isolated from impetigo, as opposed to the usual group A. Impetigo occurs most frequently in early childhood (Fig. 14-10), although all ages may be affected. It occurs in the tem perate zone, mostly during the summer in hot, humid weather. Common sources of infection for children are pets, dirty fin gernails, and other children in schools, daycare centers, or crowded housing areas; for adults, common sources include infected children and self-inoculation from nasal or perineal carriage. Impetigo often complicates pediculosis capitis, scabies, herpes simplex, insect bites, poison ivy, eczema, and other exudative, pustular, or itching skin diseases. Group A β-hemolytic streptococcal skin infections are sometimes followed by acute glomerulonephritis (AGN). Nephritogenic streptococci are generally associated with impetigo rather than with upper respiratory infections. There is no evidence that AGN occurs with staphylococcal impetigo. The important factor predisposing to AGN is the serotype of the streptococcus producing the impetigo. Type 49, 55, 57, and 60 strains and strain M-type 2 are related to nephritis. The incidence of AGN with impetigo varies from about 2% to 5% (10–15% with nephritogenic strains of streptococcus) and occurs most frequently in childhood, generally under the age of 6. The prognosis in children is mostly excellent; however,
Staphylococcal infections
Pyomyositis
Fig. 14-9 Impetigo.
Fig. 14-10 Impetigo.
in adults the prognosis is not as good. Treatment, however early and however appropriate, is not believed to reduce the risk of occurrence of AGN. The histopathology is that of an extremely superficial inflam mation about the funnel-shaped upper portion of the pilo sebaceous follicles. A subcorneal vesicopustule is formed, containing a few scattered cocci, together with debris of poly morphonuclear leukocytes and epidermal cells. In the dermis there is a mild inflammatory reaction—vascular dilation, edema, and infiltration of polymorphonuclear leukocytes. Impetigo may simulate several diseases. The circinate patches are frequently mistaken for ringworm, but clinically are quite different. Impetigo is characterized by superficial, very weepy lesions covered by thick, bright yellow or orange crusts with loose edges, which do not resemble the scaling patches with peripheral erythema seen in tinea. Impetigo may be mistaken for Toxicodendron dermatitis, but it is more crusted and pustular, and more liable to involve the nostrils, corners of the mouth, and ears; it is not associated with the puffing of the eyelids, the linear lesions, or the itchiness that are so often present in dermatitis caused by poison ivy or oak. In varicella the lesions are small, widely distributed, discrete, umbilicated vesicles that are usually also present in the mouth, a site not involved by impetigo. In ecthyma the lesions are crusted ulcers, not erosions.
Treatment Systemic antibiotics combined with topical therapy are advised. Because most cases are caused by Staphylococcus, a semisynthetic penicillin or a first-generation cephalosporin is 251
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recommended, unless MRSA is suspected, as detailed above. All treatment should be given for 7 days. It is necessary to soak off the crusts frequently, after which an antibacterial ointment should be applied. If the lesions are localized, especially if facial, and are present in an otherwise healthy child, topical therapy may be effective as the sole treatment. Applying antibiotic ointment as a prophylactic to sites of skin trauma will prevent impetigo in high-risk children attend ing daycare centers. In one study infections were reduced by 47% with antibiotic ointment compared with 15% with a placebo. Additionally, if recurrent staphylococcal impetigo develops, a culture of the anterior nares may yield this organ ism. Such carrier states may be treated by application of mupi rocin ointment to the anterior nares twice a day or a 10-day course of rifampin, 600 mg/day combined with dicloxacillin (for MSSA) or trimethoprim–sulfamethoxazole (for MRSA).
This variety of impetigo occurs characteristically in newborn infants, though it may occur at any age. The neonatal type is highly contagious and is a threat in nurseries. In most cases the disease begins between the fourth and tenth days of life with the appearance of bullae, which may appear on any part of the body. Common early sites are the face and hands. Constitutional symptoms are at first absent, but later weakness and fever or a subnormal temperature may be present. Diarrhea with green stools frequently occurs. Bacteremia, pneumonia, or meningitis may develop rapidly, with fatal termination. In warm climates particularly, adults may have bullous impetigo (Fig. 14-11), most often in the axillae or groins, or on the hands. Usually no scalp lesions are present. The lesions are strikingly large, fragile bullae, suggestive of pemphigus. When these rupture they leave circinate, weepy, or crusted lesions, and in this stage it may be called impetigo circinata. Children with bullous impetigo may give a history of an insect bite at the site of onset of lesions. The majority are caused by phage types 71 or 55 coagulase-positive S. aureus or a related group 2 phage type. Bullous impetigo may be an early manifestation of HIV infection.
Staphylococcal scalded skin syndrome (SSSS) is a generalized, confluent, superficially exfoliative disease, occurring most commonly in neonates and young children. It was known in the past as Ritter’s disease or dermatitis exfoliativa neonato rum. It has been reported to occur rarely in adults. When it does occur in an adult, usually either renal compromise or immunosuppression is a predisposing factor. SSSS is a febrile, rapidly evolving, generalized, desquama tive infectious disease, in which the skin exfoliates in sheets. It does not separate at the dermoepidermal junction, as in toxic (drug-induced) epidermal necrolysis (TEN), but within the granular layer. The lesions are thus much more superficial and less severe than in TEN, and healing is much more rapid. They also extend far beyond areas of actual staphylococcal infection, by action of the exfoliative exotoxins types A and B elaborated by the staphylococcus in remote sites. Usually the staphylo cocci are present at a distant focus, such as the pharynx, nose, ear, or conjunctiva. Septicemia or a cutaneous infection may also be the causative focus. Its clinical manifestations begin abruptly with fever, skin tenderness, and erythema involving the neck, groins, and axillae (Fig. 14-12). There is sparing of the palms, soles, and mucous membranes. Nikolsky sign is positive. Generalized exfoliation follows within the next hours to days, with large sheets of epidermis separating. Group 2 S. aureus, most commonly phage types 71 or 55, is the causative agent in most cases. If cultures are taken, they should be obtained from the mucous membranes because the skin erythema and desquamation are due to the distant effects of the exfoliative toxins, unlike the situation in bullous impetigo, where S. aureus is present in the lesions. Rapid diagnosis can be made by examining frozen sections of a blister roof and observing that the full thickness of the epidermis is not necrotic as in TEN but rather is cleaved below the granular layer. The exfoliative toxins A, B, and D specifi cally cleave desmoglein 1, the antigenic target of autoantibod ies in pemphigus foliaceus, thus accounting for the clinical and histologic similarity to pemphigus observed in SSSS and
Fig. 14-11 Bullous impetigo.
Fig. 14-12 Staphylococcal scalded skin syndrome.
Bullous impetigo
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Staphylococcal scalded skin syndrome
Staphylococcal infections
bullous impetigo. Treatment of choice is a penicillinaseresistant penicillin such as dicloxacillin combined with fluid therapy and general supportive measures. If MRSA is cul tured, and response is sluggish, antibiotics directed according to the susceptibilities of the recovered organism are needed. The prognosis is good in children; however, the mortality rate in adults can reach 60%.
Gram-positive toxic shock syndromes Toxic shock syndrome (TSS) is an acute, febrile, multisystem illness, having as one of its major diagnostic criteria a wide spread macular erythematous eruption. It is usually caused by toxin-producing strains of S. aureus, most of which were ini tially isolated from the cervical mucosa in menstruating young women. Now cases are most often due to infections in wounds, catheters, contraceptive diaphragms, or nasal packing. The mortality of these nonmenstrual cases is higher (up to 20%) compared with menstrual-related cases (under 5%), probably as a result of delayed diagnoses. Additionally, a very similar syndrome has been defined in which the cause is group A, or rarely group B, streptococci. This latter multiorgan disease has systemic components similar to classic staphylococcal TSS; however, the infection is usually a rapidly progressive, destructive soft-tissue infection such as necrotizing fasciitis. Those with an underlying chronic illness, recently recovered from varicella, or using nonsteroidal anti-inflammatory agents are predisposed. It has a case fatality rate of 30%. The strepto cocci are usually of M-types 1 and 3, with 80% of the isolates producing pyrogenic exotoxin A. The Center for Communicable Diseases (CDC) case defini tion of staphylococcal TSS includes the following: a tempera ture of 38.9°C or higher, an erythematous eruption, desquamation of the palms and soles 1–2 weeks after onset (Fig. 14-13), hypotension, and involvement of three or more other systems—gastrointestinal (vomiting, diarrhea), muscu lar (myalgias, increased creatinine phosphokinase level), mucous membrane (hyperemia), renal (pyuria without infec tion or raised creatinine or blood urea nitrogen levels), hepatic (increased bilirubin, SGOT, or SGPT), hematologic (platelets 1000 mg/dL. When the diabetes is brought under control, the triglyceride levels are lowered and prompt involution of the lesions is seen. Weight reduction and carbohydrate intake restriction are also helpful. Identical phenomena may occur in von Gierke’s disease, a form of glycogen storage disease in which there is a lack of hepatic glucose-6phosphatase.
Chronic renal failure If plasma protein levels are reduced by urinary loss in the nephrotic syndrome (or by plasmapheresis or repeated bleeding), a compensatory increase of lipoproteins may occur, with hyperlipidemia and various kinds of xanthoma. HLP 4 and V profiles are most commonly seen. Renal failure with or without dialysis may cause hypertriglyceridemia.
Myxedema Lipoprotein lipase needs thyroid hormone to work, and its failure may lead to HLP 1, 4, 5 disease. Thyroid hormone deficiency may lead to hypercholesterolemia because thyroid hormone is needed in the oxidation of hepatic cholesterol to bile salts. Xanthelasma and xanthomas are common in myxedema.
Pancreatitis Hyperlipidemia in the hyperchylomicronemic syndromes (types I and V) may cause pancreatitis; it may be recurrent, and pancreatic necrosis and death may occur. Alternatively, pancreatitis (perhaps initiated by ethanol) may cause type I or V hyperlipoproteinemia by inducing insulin deficiency and a relative lack of lipoprotein lipase activity. A triglyceride level of 1000 mg/dL is required for pancreatitis to occur in the setting of hypertriglyceridemia. The amylase may be normal, but the lipase will be elevated.
Medication-induced hyperlipoproteinemia Estrogens, by decreasing lipoprotein lipase activity and increasing VLDL synthesis, may cause HLP 1 or 5 patterns. Eruptive xanthomas may occur. Oral prednisone may induce insulin deficiency and cause HLP 4 or 5 patterns to develop. Oral retinoids, indomethacin, protease inhibitors for HIV, and olanzapine may also cause eruptive xanthomas via hypertriglyceridemia.
Cerebrotendinous xanthomatosis is an autosomal-recessive disease caused by an accumulation of cholestanol in plasma lipoproteins and xanthomatous tissue. The underlying abnormality is a mutation in the sterol 27-hydroxylase gene (CYP27A) in the mitochondria, leading to incomplete oxidation of cholesterol to bile acids. Cholestanol, an intermediate, accumulates as a result in tendons, brain, heart, lungs, and the lens of the eye. The disorder is characterized by prominent tendinous xanthomas, especially of the Achilles tendons (not present in all cases), macroglossia, and progressive neurologic dysfunction in many forms, as well as cataracts, atherosclerotic coronary disease, and endocrine abnormalities. Plasma cholestanol is elevated and can exceed more than ten times normal levels. The condition is treated with chenodeoxycholic acid, and early treatment can prevent the progressive neurological impairment.
Phytosterolemia (sitosterolemia) In phytosterolemia, a rare autosomal-recessive disorder, plant sterols (β-sitosterol, stigmasterol, and campesterol) and shellfish sterols (lathosterol and desmosterol) are found in excessive amounts in all tissues except the brain. This disorder is caused by mutations in the genes encoding the ABCG5 and ABCG8 transporters, which are needed to pump sterols out to intestinal cells back into the lumen of the gut, and used to pump plant sterols into the bile. Patients develop tendinous xanthomas, xanthelasma, and tuberous, palmar, and plantar xanthomas. In most patients there is also type IIa hyperlipoproteinemia and accelerated atherosclerosis. Other features are arthritis, splenomegaly, and hematologic disorders. Ezetimibe (an inhibitor of NPC1L1 [Niemann–Pick C1-like 1]), chenodeoxycholic acid, and cholestyramine can be effective in lowering the cholesterol and plant sterols.
Verruciform xanthoma Verruciform xanthoma (VX) is an uncommon lesion that occurs as a reddish-orange or paler hyperkeratotic plaque or papillomatous growth with a pebbly or verrucous surface. The most common site is the oral mucosa. It has also been reported on other mucosal surfaces, genitalia, lower extremities (Fig. 26-24), and elsewhere. Epidermal nevus-like lesions in CHILD syndrome have characteristics of VX. Recessive dystrophic epidermolysis bullosa, lymphedema, and graft vs host disease have been associated with VX. Additionally, VX has been reported in psoriatic lesions undergoing PUVA therapy and in psoriasiform skin lesions in an HIV-positive patient. Histologically, there is acanthosis without atypia, parakerato-
Fig. 26-24 Verruciform xanthoma.
sis, and xanthoma cells in the papillary dermis. In a small percentage of VX, a mutation in the NSDHL gene (3β-hydroxysteroid dehydrogenase) has been found. This gene is also mutated in CHILD syndrome, explaining why the latter and VX share the same histology.
Familial α-lipoprotein deficiency (hypoalphalipoproteinemia, Tangier disease) Tangier disease is caused by mutations in the cell-membrane protein ABCA1, which mediates the secretion of excess cholesterol from cells into the HDL metabolic pathway. This results in a profound deficiency of HDL, and accumulation of cholesterol in tissue macrophages. The characteristic clinical finding is yellow, enlarged tonsils from accumulation of lipid in this localized area. Xanthomas do not occur; however, there is diffuse accumulation of cholesterol esters in the skin, as well as the intestines, thymus, bone marrow, lymph nodes, and spleen. Peripheral neuropathy, splenomegaly (with thrombocytopenia) and premature coronary artery disease are other features of Tangier disease. ABC (ATP-binding cassette) transporters generally have transmembrane domains that move substrates across cell membranes. Defects in 14 of the over 50 known ABC transporters cause 13 genetic diseases, including cystic fibrosis, age-related macular degeneration, phytosterol emia, and adrenoleukodystrophy.
Secondary hyperlipoproteinemia
Cerebrotendinous xanthomatosis
Alam M, et al: Tuberous xanthomas in sitosterolemia. Pediatr Dermatol 2000; 17:447. Bel S, et al: Cerebrotendinous xanthomatosis. J Am Acad Dermatol 2001; 45:292. Broeshart JH, et al: Normolipemic plane xanthoma associated with adenocarcinoma and severe itch. J Am Acad Dermatol 2003; 49:119. Brown CA, et al: Tuberous and tendinous xanthomata secondary to ritonavir-associated hyperlipidemia. J Am Acad Dermatol 2005; 52:S86. Brunzell JD: Clinical practice. Hypertriglyceridemia. N Engl J Med 2007; 357:1009. Burnside NJ, et al: Type III hyperlipoproteinemia with xanthomas and multiple myeloma. J Am Acad Dermatol 2005; 53:S281. Chan CC, et al: Xanthelasma is not associated with increased risk of carotid atherosclerosis in normolipidaemia. Int J Clin Pract 2008; 62:221. Chang HY, et al: Eruptive xanthomas associated with olanzapine use. Arch Dermatol 2003; 139:617. Chung HG, et al: CD 30 (Ki-1)-positive large-cell cutaneous T-cell lymphoma with secondary xanthomatous changes after radiation therapy. J Am Acad Dermatol 2003; 48:S28. Connolly SB, et al: Management of cutaneous verruciform xanthoma. J Am Acad Dermatol 2000; 42:343. Crook M: Xanthelasma and cardiovascular risk. Int J Clin Pract 2008; 62:178. Dotsch J, et al: Unmasking of childhood hypothyroidism by disseminated xanthomas. Pediatrics 2001; 108:E96. Garcia MA, et al: Alagille syndrome: cutaneous manifestations in 38 children. Pediatr Dermatol 2005; 22:11. Garg A, Simha V: Update on dyslipidemia. J Clin Endocrinol Metab 2007; 92:1581. Geyer AS, et al: Eruptive xanthomas associated with protease inhibitor therapy. Arch Dermatol 2004; 140:617. Girish MP, Gupta MD: Xanthomatous pseudospectacles in familial hypercholesterolemia. N Engl J Med 2005; 352:2424. Hegele RA: Plasma lipoproteins: genetic influences and clinical implications. Nat Rev Genet 2009; 10:109. Horne MK 3rd, et al: In vitro characterization of a monoclonal IgG(kappa) from a patient with planar xanthomatosis. Eur J Haematol 2008; 80:495. Huang HY, et al: Normolipemic papuloeruptive xanthomatosis in a child. Pediatr Dermatol 2009; 26:360. Li SG: Images in clinical medicine. Familial hypercholesterolemia. N Engl J Med 2009; 360:1885.
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Lorenz S, et al: Treatment of diffuse plane xanthoma of the face with the erbium:YAG laser. Arch Dermatol 2001; 137:1413. Malbran A, et al: Case report: diffuse plane xanthoma with low C4 and systemic inflammatory symptoms. Dermatol Online J 2009; 15:5. Mehra S, et al: A novel somatic mutation of the 3beta-hydroxysteroid dehydrogenase gene in sporadic cutaneous verruciform xanthoma. Arch Dermatol 2005; 141:1263. Mehta BP, Shmerling RH: Teaching neuroimage: cerebrotendinous xanthomatosis. Neurology 2008; 71:e4. Nayak KR, et al: Eruptive xanthomas associated with hypertriglyceridemia and new-onset diabetes mellitus. N Engl J Med 2004; 350:1235. Noel B: Premature atherosclerosis in patients with xanthelasma. J Eur Acad Dermatol Venereol 2007; 21:1244. Ozdöl S, et al: Xanthelasma palpebrarum and its relation to atherosclerotic risk factors and lipoprotein (a). Int J Dermatol 2008; 47:785. Pilo de la Fuente B, et al: Cerebrotendinous xanthomatosis: neuropathological findings. J Neurol 2008; 255:839. Rhyne J, et al: Multiple splice defects in ABCA1 cause low HDL-C in a family with hypoalphalipoproteinemia and premature coronary disease. BMC Med Genet 2009; 10:1. Shirdel A, et al: Diffuse normolipaemic plane xanthomatosis associated with adult T-cell lymphoma/leukaemia. J Eur Acad Dermatol Venereol 2008; 22:1252. Siddi GM, et al: Multiple tuberous xanthomas as the first manifestation of autosomal recessive hypercholesterolemia. J Eur Acad Dermatol Venereol 2006; 20:1376. Sinnott BP, Mazzone T: Tuberous xanthomas associated with olanzapine therapy and hypertriglyceridemia in the setting of a rare apolipoprotein E mutation. Endocr Prac 2006; 12:183. Sopena J, et al: Disseminated verruciform xanthoma. Br J Dermatol 2004; 151:717. Stalenhoef AF: Phytosterolemia and xanthomatosis. N Engl J Med 2003; 349:51. Togo M, et al: Identification of a novel mutation for phytosterolemia. Genetic analyses of 2 cases. Clin Chim Acta 2009; 401:165. Tsuang W: Hypertriglyceridemic pancreatitis: presentation and management. Am J Gastroenterol 2009; 104:984. Uehara Y, et al: POPC/apoA-I discs as a potent lipoprotein modulator in Tangier disease. Atherosclerosis 2008; 197:283. von Bergmann K, et al: Cholesterol and plant sterol absorption: recent insights. Am J Cardiol 2005; 96:10D. Zarubica A, et al: ABCA1, from pathology to membrane function. Pflugers Arch 2007; 453:569.
Niemann–Pick disease This rare autosomal-recessive condition has three recognized subtypes. The disorder was originally described in Ashkenazi Jews. Type A and type B disease are both caused by mutations in the acid sphingomyelinase gene (SMPD1). Type A disease is more severe, presents in infancy with neurovisceral disease, and is often fatal. Type B disease is purely visceral (nonneurologic) and survival into adulthood is characteristic. Skin lesions in type A and B patients include xanthomas (skincolored to tan papules) and yellow-brown induration of the skin. Histologically, foamy histiocytes are found, which on electron microscopy have characteristic cytoplasmic inclusions. Type C disease (and the former type D disease of Nova Scotia) are due to mutations in the NPC1 and NPC2 genes. NPC1 and 2 are involved in endosomal-lysosomal cholesterol trafficking. Niemann–Pick type C is a neurovisceral disease with a variable age of onset and neurodegenerative course. Patients may present from the perinatal period to adulthood. Cholestatic jaundice is characteristic. Early-onset disease is often associated with severe neurologic disease and death before age 5. Late infantile and juvenile forms have neurologic disease. The adult form may demonstrate visceral involvement and psychiatric and cognitive disorders. Death occurs before age 50. One patient with Niemann–Pick type C developed idiopathic nodular panniculitis. 526
Bukhari I: Idiopathic nodular panniculitis in Niemann–Pick disease. J Eur Acad Dermatol Venereol 2005; 19:600. Fancello T, et al: Molecular analysis of NPC1 and NPC2 gene in 34 Niemann–Pick C Italian patients: identification and structural modeling of novel mutations. Neurogenetics 2009; 10:229. Rodriguez-Pascau L, et al: Identification and characterization of SMPD1 mutations causing Niemann–Pick types A and B in Spanish patients. Hum Mutat 2009; 30:1117. Sturley SL, et al: Unraveling the sterol-trafficking defect in Niemann– Pick C disease. Proc Natl Acad Sci USA 2009; 106:2093. Toussaint M, et al: Specific skin lesions in a patient with Niemann–Pick disease. Br J Dermatol 1994; 131:895.
Gaucher’s disease Gaucher’s disease is a rare autosomal-recessive disorder caused by insufficient activity of the lysosomal enzyme acid-β glucosidase (glucocerebrosidase, GBA). The disease occurs most frequently among Ashkenazi Jews. Approximately 1 in 20 carry the defective gene. Lysosomal accumulation of glucosylceramide, the substrate of GBA in macrophages, causes the disease manifestations. In rare cases, Gaucher’s disease is caused by mutations in the prosaposin gene, which encodes the saposin C activator protein that is necessary for optimal activity of β-glucosidase. Gaucher cells are identified histologically—large macrophages, 20–100 µm in diameter, with one nucleus or a few small nuclei, and pale cytoplasm that stains faintly for fat but is PAS-positive. The disease occurs at any age but three types are recognized: type 1 (adult type), without neurologic involvement; type 2, the infantile form, with acute early neurologic manifestations; and type 3, the juvenile chronic neuropathic type. Some type 2 patients have congenital ichthyosis that precedes neurologic manifestations, and some are born with a collodian membrane. Epidermal ultrastructural and biochemical abnormalities occur in all type 2 patients. Hepatosplenomegaly, osteopenia/osteoporosis of the long bones, pingueculae of the sclera, and a distinctive bronze coloration of the skin from melanin characterize the adult type. A deeper pigmentation may extend from the knees to the feet (Fig. 26-25). This is often caused by hemosiderin and may be accompanied by thrombocytopenia and splenomegaly. The diagnosis is confirmed by DNA testing for the affected gene. Therapy now consists of enzyme replacement therapy with intravenous mannose-terminated glucocerebrosidase, but this is very expensive. Bone marrow transplantation performed before neurologic deficits occur has a high mortality rate (20–50%), but when successful has halted neurologic progression. Enzyme therapy is successful in treating some of the
Fig. 26-25 Gaucher pigmentation of the lower leg.
Grabowski GA: Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet 2008; 372:1263. Grosbois B, et al: Gaucher disease and monoclonal gammopathy: a report of 17 cases and impact of therapy. Blood Cells Mol Dis 2009; 43:138. Hughes DA: Enzyme, substrate, and myeloma in Gaucher disease. Am J Hematol 2009; 84:199. Mitsui J, et al: Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol 2009; 66:571. Tajima A, et al: Clinical and genetic study of Japanese patients with type 3 Gaucher disease. Mol Genet Metab 2009; 97:272. Tylki-Szymanska A, et al: Non-neuronopathic Gaucher disease due to saposin C deficiency. Clin Genet 2007; 72:538.
Lipoid proteinosis
scars, especially on the face (Fig. 26-27). Scalp involvement may lead to mild loss of hair. Neurological sequelae include epilepsy, dystonia, and cognitive impairments. Distinctive histologic features include extreme dilation of the blood vessels, thickening of their walls, progressive hyalinization of sweat glands, and infiltration of the dermis and subcutaneous tissue with extracellular hyaline deposits. Normal skin and mucous membranes also show changes of endothelial proliferation of the subpapillary vessels and a homogeneous thickening of the walls of the deeper vessels. Type IV collagen and laminin are increased around vessels. The disease is caused by mutations in the extracellular matrix protein 1. Differentiation from erythropoietic protoporphyria may be difficult, especially histologically. Topical steroids, surgical removal of selected deposits, and occasional reports of improvement with systemic retinoids are treatments of limited benefit. While occasional patients die of respiratory obstruction in infancy, the disease is otherwise compatible with a normal lifespan.
Angiokeratoma corporis diffusum
manifestations of the adult form, but it is limited by cost. Substrate reduction therapy using the glycolipid synthesis inhibitor N-butyldeoxynojirimycin (miglustat) is also available. The intense study of Gaucher’s disease has led to two interesting findings. More than 15% of adult patients with Gaucher’s disease have monoclonal gammopathy, and in about 20% of these patients there is an associated myelodysplasia (myeloma or lymphoma). More than 7% of adult Gaucher’s disease patients will develop myeloma. Heterozygous carriers of GBA mutations are frequently found in patients with Parkinson disease. Parkinson disease is associated with certain “pathogenic” variant GBA mutations.
Chan I, et al: The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1. Exp Dermatol 2007; 16:881. Desmet S, et al: Clinical and molecular abnormalities in lipoid proteinosis. Eur J Dermatol 2005; 15:344. Rao R, et al: Vesiculobullous lesions in lipoid proteinosis: a case report. Dermatol Online J 2008; 14:16. Toosi S, Ehsani AH: Treatment of lipoid proteinosis with acitretin: a case report. J Eur Acad Dermatol Venereol 2009; 23:482.
Angiokeratoma corporis diffusum (Fabry disease)
Also known as Urbach–Wiethe disease and hyalinosis cutis et mucosae, this rare autosomal-recessive condition usually presents in infancy with a hoarse cry or voice. Mucosal lesions include yellowish-white infiltrative deposits on the inner surfaces of the lips, undersurface of the tongue, fauces, and uvula. Inability to protrude the “woody” tongue fully is characteristic. Xerostomia may occur. In childhood, beaded eyelid papules occur. Uveitis and hyaline deposits on and in the eye may develop. Waxy, yellow papules and nodules with generalized skin thickening occur (Fig. 26-26). Mechanical friction leads to hyperkeratosis of the hands, elbows, knees, buttocks, and axillae, becoming almost verrucous in some patients. Minor trauma leads to bullae that heal with pock-like or acne-like
Fabry disease is a rare X-linked lysosomal storage disease. It is caused by mutations in the alphagalactosidase A gene (GLA), leading to a deficiency in alphagalactosidase A. This results in the inability to catabolize glycosphingolipids, and globotriaosylceramide accumulates in lysosomes in many tissues, including endothelial cells, erector pili muscles, and visceral organs. Although males are affected more severely and earlier, female carriers can have all the stigmata of the full-blown disease. Skin lesions are common, and in about one-quarter of male patients, a dermatologist makes the diagnosis. The most characteristic skin lesions are widespread punctate telangiectatic
Fig. 26-26 Papules of the eyelid in lipoid proteinosis. (Courtesy of Eric Krause, MD)
Fig. 26-27 Acneiform scarring in lipoid proteinosis.
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Fig. 26-28 Fabry disease.
vascular papules that on first inspection suggest purpura, but are actually angiokeratomas. Some show hyperkeratotic tops, but these are less prominent than in other forms of angio keratoma. Angiokeratomas occur in 66% of males and 36% of females with Fabry disease. The average age of onset in males is about age 20; in females it is about 10 years later. Lesions can be present as early as age 1. Lesions tend to occur in the “bathing trunk” area, from the umbilicus to the genitalia (in which areas they may be present in large numbers). Smaller “macular angiomas” are seen, especially on the pro ximal limbs, palms, and soles, around the nail folds of the digits, and on the vermilion border of the lips (Fig. 26-28). Telangiectasias occur in about 25% of male patients presenting around age 25 and in women around age 40. The vascular lesions can be treated with intense pulse light or various vascular lasers. Other skin manifestations include lower limb edema and lymphedema. Leg ulceration can occur. Hair growth is scanty. Hypohidrosis is reported by 50% or more of males and more than a quarter of female patients, starting in their twenties. Anhidrosis occurs in 25% of male patients. Heat intolerance can occur. About 13% of females and 6% of males complain of hyperhidrosis. Visceral disease is common, especially of the kidneys, cardiovascular system, and gastrointestinal tract. Only one organ may be involved. Proteinuria followed by renal failure may begin as early as the second decade and typically presents around age 40. Cardiovascular events (myocardial infarction, arrhythmia, angina, and congestive heart failure) typically appear at around age 40, contributing to premature mortality. About 5% of men and women suffer strokes at around age 40. Abdominal pain, nausea, vomiting and diarrhea can all occur. Neuropathic pain is the most common initial presentation, affecting around two-thirds of patients. It may begin in childhood, but its nonspecific nature and the lack of physical findings delay the diagnosis, usually by more than a decade, until other stigmata appear. The acroparesthesia or burning pain affects primarily the longest nerves and is most severe on the hands and feet. It may be transient or last for hours. There is a loss of Adelta-fibers. Treatment is as for neuropathy, with tricyclics, gabapentin, capsaicin, and anticonvulsants. Around 25% of Fabry patients develop carpal tunnel syndrome. Cramps and fasciculation may be the presenting neurological symptoms. 528
Distinctive whorl-like opacities of the cornea occur in 90% of patients, and 50% develop characteristic spokelike cataracts in the posterior capsular location. Telangiectasias may be present on the conjunctiva and in the eye. The diagnosis may be confirmed by finding diminished levels of α-galactosidase A in leukocytes, serum, fibroblasts, or amniotic fluid cells. Less than 10% enzyme activity is usually detected in affected males. In females the diagnosis requires the identification of a genetic mutation in the GLA gene. This can be quite difficult if an affected male relative is not identified, since more than 300 mutations in the GLA gene have so far been described that cause Fabry disease. Histologically, there is dilation of capillaries in the papillary dermis, resulting in endothelium-lined lacunae filled with blood and surrounded by acanthotic and hyperkeratotic epidermis. Electron microscopy reveals characteristic electrondense bodies in endothelial cells, pericytes, erector pili muscles, and fibroblasts. They are also present in normal skin of affected adults and children. Enzyme replacement therapy (ERT) is safe and can reverse substrate storage in the lysozyme. ERT leads to a reduction in neuropathic pain, relief of gastrointestinal symptoms, and stabilization of renal function and cardiomyopathy. In patients with a glomerular filtration rate (GFR) below 60 mL/min, renal function may, however, continue to deteriorate. Left ventricular mass decreases, but the vascular coronary disease may not be reversed. Although widespread angiokeratomas are typical of Fabry disease, patients with other rare autosomal-recessive lysosomal storage diseases, such as galactosialidosis, aspartyl glycosaminuria, GM1 gangliosidosis (β-galactosidase deficiency, which may also manifest extensive dermal melanocytosis), and α-N-acetylgalactosaminidase deficiency (Kanzaki disease), have been reported to have Fabry-like angiokeratomas. Finally, several patients without any detectable enzyme deficiency have been reported. Among them was a family with autosomal-dominantly inherited Fabry-like angiokeratomas associated with arteriovenous malformations. It should be emphasized that there are many normal patients who have widespread small petechia-like lesions that erupt in adulthood. This is a variant of cherry angiomas.
Fucosidosis Angiokeratomas identical to those of Fabry disease occur in types II and III forms of this rare lysosomal storage disease. Fucosidosis can be distinguished clinically by the frequent presence of facial dysmorphism, severe mental retardation, weakness, spasticity, and seizures. The most severely affected die in childhood (type I), without the development of typical angiokeratomas. In type II disease, severe spondyloepiphyseal dysplasia and normal intelligence are found. The adolescent type III type can also have angiokeratomas. The condition is autosomal-recessive and is caused by a deficiency in α-Lfucosidase, usually detected in leukocytes.
Sialidosis Sialidosis (mucolipidosis type I) is an autosomal-recessive lysosomal storage disease caused by mutations in the sialidase gene, NEU1. Two types are described, the most severe of which is the infantile form (type II), in which the children die within the first two years of life. Type I disease is less severe and is characterized by mental retardation, myoclonus, cerebellar ataxia, hypotonia, skeletal abnormalities, and facial dysmorphism. Angiokeratoma can occur.
This is a rare autosomal-recessive lysosomal storage disease of glycoprotein metabolism. It is due to a deficiency of β-mannosidase that results in the accumulation of a characteristic disaccharide in the lysosomes, which may also be found in the urine. In addition to the Fabry-like angiokeratomas, mental retardation, hearing loss, aggressive behavior, peripheral neuropathy, recurrent infections, epilepsy, coarse facies, and skeletal abnormalities are often present. Bodensteiner D, et al: Successful reinstitution of agalsidase beta therapy in Fabry disease patients with previous IgE-antibody or skin-test reactivity to the recombinant enzyme. Genet Med 2008; 10:353. Calzavara-Pinton PG, et al: Angiokeratoma corporis diffusum and arteriovenous fistulas with dominant transmission in the absence of metabolic disorders. Arch Dermatol 1995; 131:57. Clarke JT: Narrative review: Fabry disease. Ann Intern Med 2007; 146:425. Eng CM, et al: Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 2007; 30:184. Hanson M, et al: Association of dermal melanocytosis with lysosomal storage disease. Arch Dermatol 2003; 139:916. Heroman JW, et al: Cherry red spot in sialidosis (mucolipidosis type I). Arch Ophthalmol 2008; 126:270. Kanitakis J, et al: Fucosidosis with angiokeratoma: immuno histochemical and electron microscopic study of a new case and literature review. J Cutan Pathol 2005; 32:506. Karen JK, et al: Angiokeratoma corporis diffusum (Fabry disease). Dermatol Online J 2005; 11:8. Laaksonen SM, et al: Neuropathic symptoms and findings in women with Fabry disease. Clin Neurophysiol 2008; 119:1365. Molho-Pessach V, et al: Angiokeratoma corporis diffusum in human beta-mannosidosis: report of a new case and a novel mutation. J Am Acad Dermatol 2007; 57:407. Morais P, et al: Angiokeratomas of Fabry successfully treated with intense pulsed light. J Cosmet Laser Ther 2008; 10:218. Nakai K, et al: Multiple leg ulcers in a patient with Fabry disease. J Eur Acad Dermatol Venereol 2008; 22:382. Nance CS, et al: Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome. Arch Neurol 2006; 63:453. Orteu CH, et al: Fabry disease and the skin: data from FOS, the Fabry outcome survey. Br J Dermatol 2007; 157:331. Pintos-Morell G, Beck M: Fabry disease in children and the effects of enzyme replacement treatment. Eur J Pediatr 2009; 168:1355. Tsukadaira A, et al: Diagnosis of fucosidosis through a skin rash. Intern Med 2005; 44:907.
ics, but 22 years, on average, in insulin-dependent patients, and 49 years in non–insulin-dependent patients. While it is reported to affect only 0.3% of patients with diabetes, the prevalence is much higher (over 2%) in series of patients with type I diabetes. Sixty percent of patients with NL have diabetes mellitus; another 20% will have glucose intolerance or a family history of diabetes. In 15%, NL precedes the onset of frank diabetes by an average of 2 years. Control of the diabetes does not influence the course of the NL. The earliest changes are sharply bordered, elevated, small red papules; these may be capped by a slight scale and do not disappear under diascopic pressure. Later, the lesions develop into irregularly round or oval lesions with well-defined borders and a smooth, glistening (glazed) surface. The center becomes depressed and sulfur-yellow, so that a firm yellowish lesion forms, surrounded by a broad violet–red or pink border. In the yellow portion, numerous telangiectases and ectatic veins are evident. Ulceration occurs in one-third of NLD cases. In an unusual case, the plaques were studded with exophytic nodules resembling tuberous xanthomas. This patient had marked hyperlipidemia, perhaps contributing to the morphology. Rarely, squamous cell carcinoma may occur in chronic ulcers. The most common location of the lesions is the shins (Fig. 26-29); about 85% occur on the legs. A much less common site is the forearms, and lesions have been reported on the trunk, face, scalp, palms, and soles. Only rarely are sites other than the legs present. Histologically, well-developed lesions of NL demonstrate a superficial, deep, and interstitial inflammatory process that involves the whole reticular dermis and often the panniculus. Because the dermis is firm, punch biopsy specimens appear rectangular rather than tapered. The inflammatory cells include lymphocytes, histiocytes, multinucleate giant cells, and plasma cells. At low magnification there are layered palisaded granulomas with pale pink degenerated collagen alternating with ampophilic-staining histiocytes. In contradistinction to granuloma annulare, mucin is not increased in the centers of the granulomas, and there is no normal dermis in NL lesions. Between granulomas in granuloma annulare, the
Necrobiosis lipoidica
Beta-mannosidase deficiency
SKIN DISORDERS IN DIABETES MELLITUS Skin lesions are common in diabetic patients, with up to twothirds having at least one skin finding. Xerosis appears to be particularly common, afflicting 50% of those with type I diabetes. Keratosis pilaris is also common, affecting more than 10% of diabetic patients. Other specific cutaneous findings of diabetes are discussed below.
Necrobiosis lipoidica/necrobiosis lipoidica diabeticorum Necrobiosis lipoidica (NL) is characterized by wellcircumscribed, firm, depressed, waxy, yellow–brown plaques, usually of the anterior shin. Although NL can occur in persons without diabetes mellitus, two-thirds are insulin-dependent diabetics. If it occurs in diabetes, it is called necrobiosis lipoidica diabeticorum (NLD). Women are three times more commonly affected than men; the condition usually appears between the ages of 20 and 40, but may occur in children or the elderly. The average age of onset is 34 years for all diabet-
Fig. 26-29 Necrobiosis lipoidica diabeticorum.
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collagen pattern is relatively normal, although inflammatory cells may be present. The overlying epidermis tends to be thinned, with loss of the normal rete ridge pattern. Treatment, after control of the diabetes is achieved, is not completely satisfactory, but NLD has improved in one patient treated with a thiazolidinedione, pioglitazone. Initial therapy is superpotent topical steroids with occlusion. Topical calcineurin inhibitors can also be effective. Intralesional injections of triamcinolone suspension into the inflammatory papules and active advancing edges can be quite effective. Injection into the yellow center is of little benefit and may result in ulceration. It had been proposed that NLD is due to the microangiopathy of diabetes. For this reason, agents designed to improve circulation have been used, at times with success. These include low-dose aspirin, nicotinamide, pentoxifylline, and dipyridamole. The blood flow in lesions of NLD is normal, however, suggesting that this is better considered as an inflammatory dermatosis. Phototherapy, including PUVA and UVA-1, has been effective in selected patients. Oral immunomodulatory therapy should be considered in those patients failing topical treatment. Antimalarial treatment and thalidomide are non-immunosuppressive options that would not alter blood sugar control. Systemic anti-inflammatories reported to be effective in selected cases include systemic steroids, mycophenolate mofetil, and cyclosporine A; TNF inhibitors can be effective in refractory cases. Hyperbaric oxygen may be used for cases with chronic ulceration. In severe cases with persistent ulceration, excision and skin grafting have been effective, although the NLD may recur in or at the edges of the grafts. Despite initial reports of success, photodynamic therapy only improves about one-third of treated patients. Pancreas-kidney transplantation led to resolution in one case, but the patient also received mycophenolate mofetil, prednisone, and tacrolimus orally. Ahmed I, Goldstein B: Diabetes mellitus. Clin Dermatol 2006; 24:237. Beattie PE, et al: UVA1 phototherapy for treatment of necrobiosis lipoidica. Clin Exp Dermatol 2006; 31:235. Berking C, et al: Photodynamic therapy of necrobiosis lipoidica: a multicenter study of 18 patients. Dermatology 2009; 218:136. Boyd AS: Treatment of necrobiosis lipoidica with pioglitazone. J Am Acad Dermatol 2007; 57:S120. Clayton TH, et al: Successful treatment of chronic ulcerated necrobiosis lipoidica with 0.1% tacrolimus ointment. Br J Dermatol 2005; 152:581. Cummins DL, et al: Generalized necrobiosis lipoidica treated with a combination of split-thickness autografting and immunomodulatory therapy. Int J Dermatol 2004; 43:852. Durupt F, et al: Successful treatment of necrobiosis lipoidica with antimalarial agents. Arch Dermatol 2008; 144:118. Elmholdt TR, et al: A severe case of ulcerating necrobiosis lipoidica. Acta Derm Venereol 2008; 88:177. Ferringer T, et al: Cutaneous manifestations of diabetes mellitus. Dermatol Clin 2002; 20:483. Gullo D, et al: Healing of chronic necrobiosis lipoidica lesions in a type 1 diabetic patient after pancreas-kidney transplantation: a case report. J Endocrinol Invest 2007; 30:259. Hammami H, et al: Perforating necrobiosis lipoidica in a girl with type 1 diabetes mellitus: a new case reported. Dermatol Online J 2008; 14:11. Hu SW, et al: Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with infliximab: report of a case. Arch Dermatol 2009; 145:437. Kukreja T, Peterson J: Thalidomide for the treatment of refractory necrobiosis lipoidica. Arch Dermatol 2006; 142:20. Lim C, et al: Squamous cell carcinoma arising in an area of longstanding necrobiosis lipoidica. J Cutan Pathol 2006; 33:581. Michaels BD, et al: Tuberous necrobiosis lipoidica. Arch Dermatol 2007; 143:546. Narbutt J, et al: Long-term results of topical PUVA in necrobiosis lipoidica. Clin Exp Dermatol 2006; 31:65. Ngo B, et al: Skin blood flow in necrobiosis lipoidica diabeticorum. Int J Dermatol 2008; 47:354.
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Pavolic MD, et al: The prevalence of cutaneous manifestations in young patients with type 1 diabetes. Diabetes Care 2007; 30:1964. Peyri J, et al: Necrobiosis lipoidica. Semin Cutan Med Surg 2007; 26:87. Tan E, et al: Systemic corticosteroids for the outpatient treatment of necrobiosis lipoidica in a diabetic patient. J Dermatolog Treat 2007; 18:246. Vanhooteghem O, et al: Epidermoid carcinoma and perforating necrobiosis lipoidica: a rare association. J Eur Acad Dermatol Venereol 2005; 19:756. Wee SA, Possick P: Necrobiosis lipoidica. Dermatol Online J 2004; 10:18. West EA, et al: A case of recalcitrant necrobiosis lipoidica responding to combined immunosuppression therapy. J Eur Acad Dermatol Venereol 2007; 21:830. Zeichner JA, et al: Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept. J Am Acad Dermatol 2006; 54:S120.
Other diabetic dermadromes In addition to necrobiosis lipoidica, there are many cutaneous signs in this common endocrinopathy.
Diabetic dermopathy (shin spots) Dull-red papules that progress to well-circumscribed, small, round, atrophic, hyperpigmented lesions on the shins are a common cutaneous sign of diabetes, occurring in up to 40% of diabetic patients. They are twice as frequent in men. Lesions begin on the lower extremities as crops of four or five dull red macules 0.5–1 cm in diameter. As the lesions resolve, they become shallow, depressed, and hyperpigmented scars. Although they occur individually in people who do not have diabetes, if four or more are present the specificity is high for diabetes.
Diabetic bullae Noninflammatory, spontaneous, painless blistering, most often in acral locations, is characteristic (Fig. 26-30). Lesions tend to involve the lower legs and be 10 cm or more in
Fig. 26-30 Bullous eruption of diabetes.
Fig. 26-31 Carotenemia, yellow palm shown next to normal palm.
diameter. The incidence is 0.16% per year. In one series of 5000 persons with diabetes, 25 patients (0.5%) developed diabetic bullae over a 3-year period. In many cases lesions heal spontaneously in 4–5 weeks, usually without scarring. However, lesions may be complicated by chronic ulceration at times. Aggressive and cautious management with dressings and diabetic foot care is required. Minor amputations may be needed. Lesions appear following periods of relative hypoglycemia, perhaps explaining the clinical resemblance of diabetic bullae to pressure bullae. Both subepidermal and intraepidermal locations have been reported as the site of blister formation, but in the authors’ experience lesions are subepidermal. Electron microscopic studies show separation at the lamina lucida level. DIF is negative. There is a reduced threshold to suction-induced blistering in insulin-dependent diabetics.
Carotenosis Carotenosis is a yellowish discoloration of the skin, especially of the palms and soles (Fig. 26-31), which is sometimes seen in diabetic patients.
Limited joint mobility and waxy skin Limited joint mobility and waxy skin are important not only because of the 30–50% prevalence of these conditions in diabetic patients with long-standing disease, but also because they are associated with microvascular complications, such as nephropathy and retinopathy. Joint symptoms begin with limitation of joint mobility in the fifth finger at the metacarpo phalangeal and proximal joints and progress radially to the other fingers. The condition is bilateral, symmetrical, and painless. Dupuytren’s contractures and palmar fibrosis may be associated. Involvement of the feet also occurs and is thought to contribute to the development of chronic ulcerations. Such open sores on the neuropathic, microvascularly compromised, infection-prone diabetic foot pose a constant threat to life and limb.
Other associated conditions in patients with diabetes Various abnormalities associated with diabetes are erysipelaslike erythema of the legs or feet; sweating disturbances; paresthesias of the legs; mal perforans ulcerations; a predisposition to certain infections such as mucormycosis, group B strepto-
Anand KP, Kashyap AS: Bullosis diabeticorum. Postgrad Med J 2004; 80:354. Arkkila PE, et al: Dupuytren’s disease in type 1 diabetic patients. Clin Exp Rheumatol 1996; 14:59. Aye M, et al: Dermatological care of the diabetic foot. Am J Clin Dermatol 2002; 3:463. Boulton AJM, et al: Neuropathic diabetic foot ulcers. N Engl J Med 2004; 351:48. Huntley AC: Finger pebbles: a common finding in diabetes mellitus. J Am Acad Dermatol 1986; 14:612. Jabbour SA: Cutaneous manifestations of endocrine disorders. Am J Clin Dermatol 2003; 4:315. Kakourou T, et al: Limited joint mobility and lipodystrophy in children and adolescents with insulin-dependent diabetes mellitus. Pediatr Dermatol 1994; 11:310. Larsen K, et al: Incidence of bullosis diabeticorum: a controversial cause of chronic foot ulceration. Int Wounds J 2008; 5:591. Lopez PR, et al: Bullosis diabeticorum associated with a prediabetic state. South Med J 2009 May 7 (Epub ahead of print).
Hartnup disease
coccal infections, nonclostridial gas gangrene, and malignant external otitis resulting from Pseudomonas; disseminated granuloma annulare; eruptive xanthomas; clear cell syringomas; rubeosis of the face; lipoatrophy or lipohypertrophy at sites of insulin injection; acquired perforating disorders; acanthosis nigricans; skin tags; and finger-pebbling.
OTHER METABOLIC DISORDERS Citrullinemia Citrullinemia occurs in two forms. Type I is caused by a deficiency of the enzyme argininosuccinic acid synthetase (ASS1) gene. This enzyme converts citrulline and aspartic acid to argininosuccinic acid, as a part of the urea cycle. Low plasma arginine levels result, and the hypothesis is that, since keratin is 16% arginine, dermatitis may occur. Neonates who present with severe deficiencies and hyperammonemic crises may develop erosive, erythematous, scaling patches and plaques prominent in the perioral, lower abdominal, diaper, and buttock regions. This eruption clears with arginine supplementation. Short, sparse hair may also be present. Citrullinemia type II is due to a defect in the SCL25A13 gene and is seen primarily in East Asia. The deficient enzyme is a liver-type mitochondrial aspartate-glutamate carrier. It presents between adolescence and adulthood. In carbamyl phosphate synthetase deficiency, low plasma arginine levels may also occur, and similar cutaneous findings have been reported in this second metabolic defect of the urea cycle. Diets high in arginine will heal the skin lesions. Engel K, et al: Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene. Hum Mutat 2009; 30:300. Fiermonte G, et al: An adult with type 2 citrullinemia presenting in Europe. N Engl J Med 2008; 358:1408. Goldblum OM, et al: Neonatal citrullinemia associated with cutaneous manifestations and arginine deficiency. J Am Acad Dermatol 1986; 14:321. Takeoka M, et al: Carbamyl phosphate synthetase 1 deficiency. Pediatr Neurol 2001; 24:193.
Hartnup disease Hartnup disease is an inborn error of tryptophan excretion; it was named after the Hartnup family, in which it was first noted. It is the second most common inherited aminoaciduria after phenylketonuria. The characteristic findings are a pellagra-like dermatitis following exposure to sunlight, intermittent cerebellar ataxia, psychosis, and constant aminoaciduria. 531
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The dermatitis occurs on exposed parts of the skin, chiefly the face, neck, hands, and legs. The erythematous scaly patches flare up into a hot, red, exudative state after exposure to sunlight, followed by hyperpigmentation. Stomatitis and vulvitis also occur. The disease becomes milder with increasing age. Rarely, an acrodermatitis enteropathica-like eruption with normal zinc levels may occur in patients with Hartnup disease. Hartnup disease is an autosomal-recessive trait. Large amounts of neutral amino acids including tryptophan are present in the urine, establishing the diagnosis. Hartnup disease is caused by mutations in the SLC6A19 gene. SLC6A19 transports neutral amino acids across the apical membrane of epithelial cells in the gut and kidneys. The skin lesions respond to niacinamide, but the neurologic disease may not improve. Azmanov DN, et al: Persistence of the common Hartnup disease D173N allele in populations of European origin. Ann Hum Genet 2007; 71:755. Azmanov DN, et al: Further evidence for allelic heterogeneity in Hartnup disorder. Hum Mutat 2008; 29:1217. Sander CS, et al: Severe exfoliative erythema of malnutrition in a child with coexisting coeliac and Hartnup’s disease. Clin Exp Dermatol 2009; 34:178. Seyhan ME, et al: Acrodermatitis enteropathica-like eruptions in a child with Hartnup disease. Pediatr Dermatol 2006; 23:262. Zheng Y, et al: A novel missense mutation in the SLC6A19 gene in a Chinese family with Hartnup disorder. Int J Dermatol 2009; 48:388.
Prolidase deficiency Prolidase deficiency is an autosomal-recessive inherited inborn error of metabolism. Prolidase cleaves dipeptides containing C-terminal proline or hydroxyproline. When this enzyme is deficient, the normal recycling of proline residues obtained from collagen degradation is impaired. A build-up of iminodipeptides results, with disturbances in connective tissue metabolism and excretion of large amounts of iminodipeptides in the urine. Also, the absence of prolidase activity causes increased keratinocyte apoptosis, which may be in part responsible for the skin lesions. Clinically, 85% of patients have some dermatologic manifestations. The most important cutaneous signs, which almost always appear before the affected person is 12 years old, are skin fragility; ulceration and scarring of the lower extremities; photosensitivity and telangiectasia; poliosis; scaly, erythematous, maculopapular, and purpuric lesions; and thickening of the skin with lymphedema of the legs. Systemic signs and symptoms include mental deficiency, splenomegaly, and recurrent infections. An unusual facial appearance is noted at times, with low hairline, frontal bossing, and saddle nose. The nasal septum may be perforated. Some patients with prolidase deficiency meet American Rheumatology Association (ARA) criteria for the diagnosis of SLE, but worsen if immunosuppressive treatment is given. Antinuclear antibodies (ANA) and anti ds-DNA may be positive. Prolidase measurement may be determined in erythrocytes, leukocytes, or fibroblasts. Many therapeutic options have been described, such as oral supplements of manganese and ascorbic acid, both modulators of prolidase activity; however, results of treatment are highly variable. Topical proline 5% in ointment helped heal chronic leg ulcers in one patient, although it did not prevent the appearance of new ulcerations. Apheresis exchange repeated monthly may improve the leg ulcers. In long-standing ulcerations squamous cell carcinomas may occur. Bissonnette R, et al: Prolidase deficiency. J Am Acad Dermatol 1993; 29:818. Di Rocco M, et al: Systemic lupus erythematosus-like disease in a 6-year-old boy with prolidase deficiency. J Inherit Metab Dis 2007; 30:814.
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Dunn R, Dolianitis C: Prolidase deficiency: the use of topical proline for treatment of leg ulcers. Australas J Dermatol 2008; 49:237. Fimiani M, et al: Squamous cell carcinoma of the leg in a patient with prolidase deficiency. Br J Dermatol 1999; 140:362. Isik D, et al: Nasal reconstruction in a patient with prolidase deficiency syndrome. J Plast Reconstr Aesthet Surg 2008; 61:1256. Lupi A, et al: Therapeutic apheresis exchange in two patients with prolidase deficiency. Br J Dermatol 2002; 147:1237. Shrinath M, et al: Prolidase deficiency and systemic lupus erythematosus. Arch Dis Child 1997; 76:441.
Phenylketonuria Phenylketonuria (PKU) is an autosomal-recessive disorder of phenylalanine metabolism due to a deficiency in the enzyme phenylalanine hydroxylase. Phenylalanine is not metabolized to tyrosine. PKU is the most common form of inherited amino aciduria, affecting 1 in 15 000 live births in the USA. It is characterized by mental deficiency; epileptic seizures; pigmentary dilution of skin, hair, and eyes; pseudoscleroderma; and dermatitis (Fig. 26-32). It is most common in white persons. Affected children are blue-eyed, with blond hair and fair skin. They are usually extremely sensitive to light, and about 50% have an eczematous dermatitis. It is clinically similar to atopic dermatitis, with a predilection for the flexures. It is worst in the youngest patients, may improve with dietary treatment, and has been exacerbated by phenylalanine challenge in a carrier of the recessive gene. Skin lesions may be sclerodermatous in nature. Indurations of the thighs and buttocks are present early in infancy and increase with time. After many years the lesions soften and become atrophic. Blood levels of phenylalanine are high. The presence of phenylpyruvic acid in the urine is demonstrated by a characteristic deep-green color when a few drops of ferric chloride solution are added to it. Green diapers occur in histidinemia, as well as in PKU. In developed countries universal screening is practiced, so dietary therapy with phenylalanine restriction, combined with supplementation of tyrosine and other amino acids, is instituted. This prevents the manifestations of the disease. If compliance is poor, the manifestations, including eczema, may develop at any age, followed by improvement of the skin with reinstitution of the diet. Al-Mayouf SM, Al-Owain MA: Progressive sclerodermatous skin changes in a child with phenylketonuria. Pediatr Dermatol 2006; 23:136. Belloso LM, et al: Cutaneous findings in a 51-year-old man with phenylketonuria. J Am Acad Dermatol 2003; 49:S190.
Fig. 26-32 Light-skinned, light-haired phenylketonuria patient with dermatitis. (Courtesy of Jeff Miller, MD)
Alkaptonuria and ochronosis Fig. 26-33 Ochronotic pigmentation of ear cartilage.
Fig. 26-34 Exogenous ochronosis.
Alkaptonuria and ochronosis Alkaptonuria, inherited as an autosomal-recessive trait, is caused by the lack of renal and hepatic homogentisic acid oxidase, the enzyme necessary for the catabolism of homo gentisic acid, a product of tyrosine and phenylalanine metabolism. Excess homogentisic acid is excreted in the urine and deposited in connective tissues throughout the body, especially the cartilage. The urine is dark and becomes black on standing. For many years the dark urine may be the only indication of the presence of alkaptonuria. In the mean time, large amounts of homogentisic acid are accumulated in the body tissues. By the third decade of life the deposition of pigment becomes apparent. The early sign is the pigmentation of the sclera (Osler’s sign) and the cartilage of the ears (Fig. 26-33). Later the cartilage of the nose and tendons, especially those on the hands, becomes discolored. Blue or mottled brown macules appear on the skin. The bluish macules have a predilection for the fingers, ears, nose, genital regions, apices of the axillae, and buccal and vaginal mucosa. Palmoplantar pigmentation may occur. The sweat glands are rich in ochronotic pigment granules, and the intradermal injection of epinephrine into the skin of the axillary vault will yield brown–black sweat droplets in the follicular orifices. The cerumen is often black. Internally, the larynx, great vessels, valves of the heart, kidneys, esophagus, tonsils, and dura mater may be involved. Histologically, there are large, irregular ochre bodies within the reticular dermis. They represent degenerated elastic fibers with deposition of ochronotic pigment, and stain black with crystal violet or methylene blue. Ochronotic arthropathy involves the axial spine joints first. Next affected are the knees, shoulders, and hips. Radiographic films show a characteristic appearance of early calcification of the intervertebral disk and later narrowing of the intervertebral spaces with eventual disk collapse. There is no effective treatment. Dietary restriction of tyrosine and phenylalanine is recommended, but may not prevent progression of disease. Joint and cardiac valve replacement may be necessary.
Exogenous ochronosis Topically applied phenolic intermediates, such as hydroquinone, carbolic acid (phenol), picric acid, and resorcinol, may produce exogenous ochronosis (Fig. 26-34). Even 2% over-thecounter hydroquinone can produce ochronosis if used regu-
Fig. 26-35 Large ochre bodies in the dermis in exogenous ochronosis.
larly for a long period. Hydroquinone specifically inhibits the enzyme homogentisic acid oxidase locally, resulting in accumulation of this substance on the collagen fibers in tissues where it is applied. Most patients affected have high Fitzpatrick phototype (IV–VI). Since most patients use the hydroquinone to treat melasma, findings of melasma may overlay the skin findings of exogenous ochronosis. The typical findings are gray–brown or blue–black macules, usually over the zygomatic regions. Caviar-like hyperchromic pinpoint papules may occur, which on dermoscopy can be seen associated with follicular openings. Confetti-like depigmentation (from the hydroquinone) may be admixed with the hyperpigmentation. Histologically, exogenous ochronosis and alkaptonuria have identical changes on skin biopsy (Fig. 26-35). Treatment is less than satisfactory. Stopping the application of hydroquinone may lead to improvement. Bellew SG, et al: Treatment of exogenous ochronosis with a Q-switched alexandrite (755 mm) laser. Dermatol Surg 2004; 30:555. Bongiomo MR, et al: Exogenous ochronosis and striae atrophicae following the use of bleaching creams. Int J Dermatol 2005; 44:112. Butany JW, et al: Ochronosis and aortic valve stenosis. J Card Surg 2006; 21:182. Charlin R, et al: Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy. Int J Dermatol 2008; 47:19. Lubics A, et al: Extensive bluish gray skin pigmentation and severe arthropathy. Arch Dermatol 2000; 36:548. Phornphutkul C, et al: Natural history of alkaptonuria. N Engl J Med 2002; 347:2111. Tan SK, et al: Hydroquinone-induced exogenous ochronosis in Chinese: two case reports and a review. Int J Dermatol 2008; 47:639.
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Wilson’s disease (hepatolenticular degeneration) Wilson’s disease is an autosomal-recessive derangement of copper transport. The disease is due to a dysfunction of a copper-transporting enzyme, P-type ATPase (ATP7B), which is required to excrete copper into the bile. This leads to accumulation of copper in the liver, brain, cornea, and kidney. Affected persons develop hepatomegaly, splenomegaly, and neuropsychiatric changes. Slurred speech, a squeaky voice, salivation, dysphagia, tremors, incoordination, and spasticity may all occur. There is progressive, fatal hepatic and central nervous system degeneration. Azure lunulae (sky-blue moons) of the nails occur in 10% of patients, and the smoky, greenish-brown Kayser–Fleischer rings develop at the edges of the corneas. Hyperpigmentation develops on the lower extremities in most patients. A vague greenish discoloration of the skin on the face, neck, and genitalia may also be present. An idiopathic blistering eruption that ceased with treatment of Wilson’s disease has been reported. Skin changes of cirrhosis (vascular spiders and palmar erythema) may occur. Low ceruloplasmin level in the serum leads to suspicion of the diagnosis, along with elevated 24-hour urinary copper excretion and elevated free serum copper. Ten percent of carriers for Wilson’s disease have a low ceruloplasmin, so additional tests should be performed to confirm the diagnosis. The treatment is a low copper diet, often with agents that bind copper and enhance its excretion from the body. D-penicillamine removes copper by chelating it. The dose is 1 or 2 g/day orally. Potential side effects include pemphigus, cutis laxa, and elastosis perforans serpiginosa, which has been reported repeatedly in Wilson patients on penicillamine. Trientine, another copper chelator, enhances copper excretion. It has less toxicity, but is somewhat less effective than D-penicillamine. Zinc supplementation leads to increased metallothionein in the gut and liver. This leads to more copper excretion in the stool and the formation of non-toxic copper complexes in the liver. Zinc cannot be given at the same time as a chelator. Treatment must be continued for life. Mak CM, Lam CW: Diagnosis of Wilson’s disease: a comprehensive review. Crit Rev Clin Lab Sci 2008; 45:263. Medici V, et al: Wilson disease: a practical approach to diagnosis, treatment and follow-up. Dig Liver Dis 2007; 39:601. Pfeiffer RF: Wilson’s disease. Semin Neurol 2007; 27:123.
Tyrosinemia II (Richner–Hanhart syndrome) Tyrosinemia is an autosomal-recessive syndrome resulting from a deficiency of hepatic tyrosine aminotransferase, an important enzyme in the degradation of tyrosine and phenyl alanine. It is caused by mutations in the TAT gene. The diagnosis is confirmed by identifying elevated levels of serum tyrosine. Clinical features are mild to severe keratitis, and hyperkeratotic and erosive lesions of palms and soles, often with mild mental retardation. Photophobia and tearing commonly occur as the keratitis begins, and ultimately neovascularization is seen. Painful palmar and plantar hyperkeratosis may be the only manifestation. The fingertips, and hypothenar and thenar eminences are primarily affected on the palms. Initially, only the soles may be affected, with hyperkeratosis primarily over the tips of the digits and on weight-bearing surfaces. In any child presenting with palmoplantar keratoderma, this diagnosis must be considered. A low-tyrosine, low-phenylalanine diet may improve or prevent the eye and skin lesions, but may or may not benefit established mental retardation. 534
Meissner T, et al: Richner–Hanhart syndrome detected by expanded newborn screening. Pediatr Dermatol 2008; 25:378. Pasternack SM, et al: Identification of two new mutations in the TAT gene in a Danish family with tyrosinaemia type II. Br J Dermatol 2009; 160:704. Tallab TM: Richner–Hanhart syndrome. J Am Acad Dermatol 1996; 35:857.
Hurler syndrome (mucopolysaccharidosis I) Hurler syndrome, or gargoylism, is an autosomal-recessive lysosomal storage disease of mucopolysaccharide metabolism. A deficiency of α-L-iduronidase is the causative defect. This enzyme is responsible for the breakdown of heparan sulfate and dermatan sulfate. All patients have undetectable enzyme activity by current assays, yet there is significant polymorphism in the severity and age of onset. In general, cases are divided into severe mucopolysaccharidosis (MPS I) (Hurler syndrome) and attenuated MPS I (Hurler–Scheie/Scheie syndrome). Hurler syndrome is characterized by mental retardation, hepatosplenomegaly, umbilical and inguinal hernia, genital infantilism, corneal opacities, and skin abnormalities. Patients with Hurler syndrome have facial dysmorphism, with a broad saddle nose, thick lips, and a large tongue. The skin is thickened, with ridges and grooves, especially on the upper half of the body. Fine lanugo hair is profusely distributed all over the body. Large, coarse hair is prominent, especially on the extremities. Dermal melanocytosis, characterized by extensive, blue pigmentation with both a dorsal and a ventral distribution, indistinct borders, and a persistent and/or progressive course, occurs in some patients with lysosomal storage disease, including patients with Hurler syndrome, Hunter syndrome, and GM1-gangliosidosis type 1. The skeletal system is deformed, with hydrocephalus, kyphosis, and gibbus (cat-back shape). The hands are broad and have clawlike fingers. The joints are distorted. The diagnosis of MPS I is made by demonstrating elevated urinary glycosaminoglycan levels, and deficient enzyme activity in fibroblasts, leukocytes, serum, or blood spots. Prenatal diagnosis is possible. Hematopoietic stem cell transplantation (HSCT) is the most effective treatment for Hurler syndrome. It can prevent mental deterioration if performed early enough (before age 2 and before developmental quotients fall below 70). Cardiac and joint complications are not prevented by HSCT. ERT with recombinant human α-L-iduronidase is an option in patients who are not candidates for HSCT. Hanson M, et al: Association of dermal melanocytosis with lysosomal storage disease. Arch Dermatol 2003; 139:916. Muenzer J, et al: Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics 2009; 123:19.
Hunter syndrome (mucopolysaccharidosis II) Hunter syndrome is X-linked recessive lysosomal storage disease. It is due to a deficiency of the enzyme iduronate-2sulfatase. The pebbly lesions of MPS II in the skin of the upper back, neck, chest, proximal arms, or thighs represent the only diagnostic skin changes of the mucopolysaccharidoses. The lesions are firm, flesh-colored to white papules and nodules, which coalesce into a cobblestone or reticular pattern (Fig. 26-36). They generally occur at about age 10. Histologically, they demonstrate increased dermal mucin and metachromatic granules in the cytoplasm of dermal fibroblasts and at times in eccrine sweat glands and epidermal keratinocytes. Additionally, the dermal melanocytosis described above for Hurler syndrome may occur in Hunter syndrome.
CADASIL syndrome Fig. 26-36 Hunter syndrome papules.
Dermatan sulfate and heparan sulfate are excreted in the urine in large amounts, and the diagnosis can be confirmed by absent iduronate-2-sulphatase in leukocytes. HSCT and ERT can be useful in appropriately evaluated patients. Guffon N, et al: Bone marrow transplantation in children with Hunter syndrome: outcome after 7 to 17 years. J Pediatr 2009; 154:733. Ito K, et al: The effect of haematopoietic stem cell transplant on papules with “pebbly” appearance in Hunter’s syndrome. Br J Dermatol 2004; 151:207. Jones SA, et al: Mortality and cause of death in mucopolysaccharidosis type II: a historical review based on data from the Hunter Outcome Survey (HOS). J Inherit Metab Dis 2009; 32:534. Ochiai T, et al: Significance of extensive Mongolian spots in Hunter’s syndrome. Br J Dermatol 2003; 148:1173. Sakata S, et al: Skin rash with the histological absence of meta chromatic granules as the presenting feature of Hunter syndrome in a 6-year-old boy. Br J Dermatol 2008; 159:249.
Morquio’s disease (mucopolysaccharidosis IV) This autosomal-recessive disorder is characterized by dwarfism, prognathism, corneal opacities, deafness, progressive kyphoscoliosis, flat feet, and knock-knees. The standing position is a crouch. Sacral dimpling may be present at birth. There is increased excretion of keratan sulfate. The enzyme deficiencies are galactosamine-6-sulfate sulfatase in Morquio A and β-galactosidase in Morquio B. Ohashi A, et al: Sacral dimple: incidental findings from newborn evaluation. Mucopolysaccharidosis IVa disease. Acta Paediatr 2009; 98:768.
Hyaluronidase deficiency (mucopolysaccharidosis IX) A deficiency of hyaluronidase, caused by mutations in HYAL1, leads to short stature, erosions of the acetabula, and multiple periauricular soft-tissue masses. There is no neurologic or visceral involvement. Hyaluronan is an extracellular matrix component important for cell migration, proliferation, and differentiation, and is a structural component of connective tissue. Turnover of this glycosaminoglycan is dependent upon hyaluronidases, each of which has different tissue expression patterns, likely explaining the mild phenotype of this newly described condition. Trigs-Raine B, et al: Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX. Proc Natl Acad Sci USA 1999; 96:6296.
Fig. 26-37 PAS-stained inclusions in Lafora’s disease.
Lafora’s disease Lafora’s disease is an autosomal-recessive form of progressive myoclonic and tonic-clonic epilepsy beginning at puberty. It is characterized by myoclonic jerks followed by progressive ataxia, dysphagia, dysarthria, dementia, and death in early adulthood. Diagnosis is established in the proper clinical setting by demonstration of characteristic PAS-positive cytoplasmic inclusion bodies in the eccrine ducts, axillary apocrine myoepithelial cells (Fig. 26-37), and peripheral nerves. The best site to biopsy is the axilla. Other conditions in which similar polyglucosan inclusions can be seen include normal aging (amyloid bodies), double athetosis syndrome, amyotrophic lateral sclerosis, and glycogen storage disease type IV. Cutaneous manifestations are rare. Papulonodular lesions on the ears and indurated, thickened plaques on the arms have been reported. Large amounts of acid mucopolysaccharides were demonstrated histologically in these lesions. The syndrome is caused by mutations of either the EPM2A gene (80% of cases) or NHLRC1, which encodes ubiquitin ligase. The products of these two genes form a complex critical to the regulation of neuronal function. This explains how mutations in either gene lead to the same phenotype. Karimipour D, et al: Lafora’s disease. J Am Acad Dermatol 1999; 41:790. Singh S, Ganesh S: Lafora progressive myoclonus epilepsy: a metaanalysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes. Hum Mutat 2009; 30:715.
CADASIL syndrome Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurovascular disease of young and middle-aged people. It is the most common heritable cause of stroke and vascular dementia in adults. It is caused by mutations in NOTCH3, a transmembrane protein. Children have cognitive impairment, young adults have depression and migraine with aura, and those in their forties and fifties experience apathy, mood disturbances, 535
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and motor disability. Executive dysfunction in the late thirties to fifties is followed by dementia in the sixties and seventies. One patient developed generalized hemorrhagic macules and papules. There is deposition of a granular eosinophilic ma terial, NOTCH 3, in the media of arterial walls due to mutations in the NOTCH intercellular signaling pathways. This may be demonstrated on skin biopsy by electron microscopy or by a specific immunostain. However, the recommended diagnostic procedure is genetic testing, screening all 23 exons. Ultrastructural examination of skin biopsy is restricted to patients with negative genetic screening and features highly suggestive of CADASIL. Chabriat H, et al: CADASIL. Lancet Neurol 2009; 8:643. Lee YC, et al: The remarkably variable expressivity of CADASIL: report of a minimally symptomatic man at an advanced age. J Neurol 2009; 256:1026. Ratzinger G, et al: CADASIL: an unusual manifestation with prominent cutaneous involvement. Br J Dermatol 2005; 152:246. Rumbaugh JA, et al: CADASIL. J Am Acad Dermatol 2000; 43:1128. Walsh JS, et al: CADASIL. J Am Acad Dermatol 2000; 43:1125.
Farber disease Also known as fibrocytic dysmucopolysaccharidosis and lipogranulomatosis, Farber disease is characterized by periarticular swellings; a weak, hoarse cry; pulmonary failure; painful joint deformities; and motor and mental retardation. The onset is during the first months of life; death can be expected before the age of 2. The rubbery subcutaneous nodules have a distinct yellowish hue and are 1–2 cm in diameter. They are usually located over the joints, lumbar spine, scalp, and weight-bearing areas. Histologically, they are granulomas. Diagnosis can be aided by finding Farber bodies (curvilinear bodies) within the cytoplasm or phagosomes of fibroblasts, histiocytes, or endothelial cells, banana-shaped bodies within Schwann cells, and zebra bodies within endothelial cells and neurons. There is an accumulation of ceramide and its degradation products in foam cells due to a specific deficiency of lysosomal ceramidase.
Gout Classic gout presents as an acute monoarthritis, usually of the great toe or knee, in a middle-aged to elderly man with hyper uricemia. In such patients with chronic disease, usually present for more than 10 years, monosodium urate monohydrate may be deposited in the subcutaneous tissues, forming nodules called tophi. These vary from pinhead- to pea-sized or, rarely, even baseball-sized. They are commonly found on the rims of the ears and over the distal interphalangeal articulations (Fig. 26-38). Tophi are of a yellow or cream color. In the course of time they tend to break down and discharge sodium urate crystals, afterward healing and perhaps breaking down again. The diagnosis is verified histologically by finding the characteristic long, needle-shaped crystals of monosodium urate. Because routine processing dissolves these deposits, fixation in absolute ethanol or freezing is optimal for their demonstration, but is rarely done since most specimens are submitted in formalin. Rather 10 micron unstained sections from formalin fixed specimens can demonstrate characteristic crystals under polarized light. Atypical gout occurs as a polyarticular chronic arthritis, often of the hands. It occurs equally in women and men, and there may be tophi, frequently overlying Heberden nodes, at presentation. Another risk group is organ transplant patients, of whom 10% develop gout. Acute arthritis is treated with NSAIDs, prednisone or colchicines, while long-term management is with uricosuric agents or xanthine oxidase inhibitors.
Lesch–Nyhan syndrome Also known as juvenile gout, Lesch–Nyhan syndrome is a rare, X-linked, recessively inherited disorder characterized by childhood hyperuricemia, gout, tophi (Fig. 26-39),
Levade T, et al: Neurodegenerative course in ceramidase deficiency (Farber disease) correlates with the residual lysosomal ceramide turnover in cultured living patient cells. J Neurol Sci 1995; 134:108. Rauch HJ, et al: Banana bodies in disseminated lipogranulomatosis (Farber disease). Am J Dermatopathol 1983; 5:263.
Adrenoleukodystrophy (Schilder’s disease) Adrenoleukodystrophy (X-ALD) is an X-linked disorder in which cerebral white matter becomes progressively demyelin ated and serious adrenocortical insufficiency usually occurs. X-ALD is caused by mutations in the ALD gene, which codes for a protein named adrenoleukodystrophy protein (ALDP). The protein defect results in impaired degradation of very long chain fatty acids (>22 carbons). Skin hyperpigmentation often calls attention to the adrenal disease, and mental deterioration indicates the even graver diagnosis of ALD. A mild ichthyotic appearance to the skin of the trunk and legs, and sparse hair with trichorrhexis nodosa-like features may occur. Skin biopsies may show characteristic vacuolization of eccrine secretory coils (duct cells being spared), and biopsies of the skin and conjunctiva may show diagnostic clefts in Schwann cells surrounding myelinated axons. Bone marrow transplantation may benefit a small subset of patients. Crum BA, et al: 26-year-old man with hyperpigmentation of skin and lower extremity spasticity. Mayo Clin Proc 1997; 72:479. Unterberger U, et al: Diagnosis of X-linked adrenoleukodystrophy in blood leukocytes. Clin Biochem 2007; 40:1037.
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Fig. 26-38 Gouty tophus.
Fig. 26-39 Lesch–Nyhan syndrome.
Chopra KF, et al: Finger pad tophi. Cutis 1999; 64:233. Puig JG, et al: The spectrum of HPRT deficiency. Medicine (Baltimore) 2001; 80:102. Rott KT, et al: Gout. JAMA 2003; 289:2857. Terkeltaub RA, et al: Gout. N Engl J Med 2003; 349:1647.
Weaver J, et al: Simple non-staining method to demonstrate urate crystals in formalin-fixed, paraffin-embedded skin biopsies. J Cutan Pathol 2009; 36:560.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 26-1 Tuberous xanthomas. Fig. 26-2 Tendinous xanthomas. Fig. 26-3 Eruptive xanthomas. Fig. 26-4 Interdigital xanthomas in homozygous familial hypercholesterolemia. Fig. 26-5 Zebra bodies in Fabry disease. Fig. 26-6 Large ochre bodies in the dermis in exogenous ochronosis.
Lesch–Nyhan syndrome
choreoathetosis, progressive mental retardation, and selfmutilation. The cutaneous lesions are distinctive. Massive self-mutilation of lips with the teeth occurs. The fingers are also badly chewed. The ears and nose are occasionally mutilated. An early diagnostic clue is orange crystals in the diaper. The blood uric acid is increased and allopurinol, 200–400 mg/ day, is given. There is a marked deficiency in an enzyme of purine metabolism, hypoxanthine guanine phosphoribosyltransferase (HGPRT).
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Genodermatoses and Congenital Anomalies
Genetic disorders are often grouped into three categories: chromosomal, single gene, and polygenetic. Chromosomal disorders can be numerical, such as trisomy and monosomy, or structural, resulting from translocations or deletions. Most genodermatoses show single-gene or mendelian inheritance (autosomal-dominant, autosomal-recessive, or X-linked recessive genes). Polygenetic syndromes often involve complex interactions of genes. Autosomal-dominant conditions require only a single gene to produce a given phenotype. Usually the patient has one affected parent or is affected by a new mutation. The disease is transmitted from generation to generation. Autosomalrecessive traits require a homozygous state to produce the abnormality. The pedigree will often reveal parental consanguinity. Parents will be clinically unaffected but often have affected relatives. X-linked conditions occur when the mutant gene is carried on the X chromosome. If a disease is X-linked recessive, the loss is evident in males (XY), who do not have a second X chromosome to express the normal allele. Therefore, X-linked recessive traits occur almost exclusively in males. They cannot transmit the disease to sons (who inherit their Y chromosome), but all their daughters will be carriers. Carrier females who are heterozygous (having one normal and one abnormal X chromosome) occasionally show some subtle evidence of the disease. This occurs as a result of Lyonization (the physiologic segmental inactivation of one of the X-chromosomes). X-linked dominant disease states are commonly lethal in males. Survival is possible in females who retain a normal allele. As the mutation is lethal in many affected cell lines, females commonly demonstrate loss of normal tissue in the affected segments (loss of digits, microph thalmia, loss of teeth). X-linked dominant traits result in pedigrees in which more than one female is affected but no males express the disease. Rarely, males may survive, especially if they have Klinefelter syndrome (XXY). Mosaicism is the presence of two or more genetically distinct cell lines in a single individual. It may occur as a result of physiologic inactivation of one X chromosome (Lyonization) or as the result of postzygotic somatic mutation. Mosaicism often presents in a linear and whorled pattern along the lines of Blaschko. In mosaic states, genes that are detrimental to a cell population during fetal development (such as incontinentia pigmenti) typically result in thin segments, as they are overgrown by the adjacent normal tissue. Conversely, genes that confer a growth advantage during fetal development (e.g. a mutated tumor suppressor gene in segmental neurofibromatosis) may result in broad plaque-type lesions that have grown beyond the boundaries of a typical Blaschko segment. In autosomal-dominant conditions, a normal allele remains, but is not enough to prevent disease. Loss of heterozygosity (LOH) is the segmental loss of this remaining normal allele. LOH may give rise to segments of the body with an exaggerated presentation of the syndrome. The affected area corresponds to a Blaschko segment or plaque. The forehead plaque
of tuberous sclerosis is related to a mutation in a tumor suppressor gene. The loss of the tumor suppressor gene imparts a growth advantage and loss of heterozygosity leaves no suppressor gene product in the segment. As a result, the affected segment grows beyond its Blaschko boundaries, forming a broad plaque. When a patient presents with segmental distribution of a disorder, it is critical to determine if the disorder is a result of mosaicism or LOH. In the latter case, the abnormal allele is present throughout the body, including gonadal tissue. In a patient who presents with segmental neurofibromatosis but has Lisch nodules or axillary freckling, LOH rather than mosaicism is likely to account for the segmental presentation. The risk of passing the gene to a child is roughly 50 : 50. A geneticist should be involved during discussions of risk of transmission, as the mechanisms may be complex. Patients with mosaicism based on postzygotic somatic gene mutation may have gonadal mosaicism and be capable of passing on the gene. Gonadal mosaicism is more likely when more than one segment is present on different regions of the body. Prior to gastrulation (when a cavity forms in the embryo), every cell is pluripotent and can give rise to an entire organism, or contribute to multiple sites of the body. At the time of gastrulation, cells become dedicated to produce specific segments of the body. Blaschko segments in different regions suggest a mutation that occurred prior to gastrulation when the involved cell lines could contribute to different parts of the body, including the gonads. Polygenetic disorders, such as psoriasis, may also present with limited and linear forms that may relate to segmental LOH. Happle R: Superimposed segmental manifestation of polygenic skin disorders. J Am Acad Dermatol 2007 Oct; 57(4):690–699. Irvine AD, et al: The molecular genetics of the genodermatoses: progress to date and future directions. Br J Dermatol 2003; 148:1. Luu M, et al: Prenatal diagnosis of genodermatoses: current scope and future capabilities. Int J Dermatol 2010 Apr; 49(4):353–361.
X-LINKED, MOSAIC, AND RELATED DISORDERS Incontinentia pigmenti Also known as Bloch–Sulzberger disease, incontinentia pigmenti is an X-linked dominant condition characterized by spattered pigmentation on the trunk, preceded by vesicular and verrucous changes. It appears in girls during the first weeks after birth (Fig. 27-1). Most lesions are evident by the time the infant is 4–6 weeks old. A vesicular phase is present in 87% of cases. This first stage begins in most individuals before 6 weeks of age and is replaced by verrucous lesions after several weeks to months in two-thirds of patients. Although these usually resolve by 1 year of age, lesions may persist for many years. In the third, or pigmentary, phase, pigmented macules in streaks, sprays, splatters, and whorls follow the lines of Blaschko. The pigmentary stage may last
Naegeli–Franceschetti–Jadassohn syndrome
Fig. 27-1 Early incontinentia pigmenti.
for many years and then fade away, leaving no sequelae. A fourth stage may be seen in some adult women, manifesting subtle, faint, hypochromic or atrophic linear lesions, most commonly on the extremities. Histologically, the vesicular stage is characterized by spongiosis with eosinophils. As the lesions mature, clusters of dyskeratotic cells appear within the epidermis. Dyskeratotic cells predominate in the verrucous stage, and pigmented incontinence (dermal melanophages) predominates in hyperpigmented lesions. Other cutaneous changes include patchy alopecia at the vertex of the scalp, atrophic changes simulating acrodermatitis chronica atrophicans on the hands, onychodystrophy, sub ungual tumors with underlying lytic bone lesions, and palmoplantar hyperhidrosis. Extracutaneous manifestations occur in 70–90% of patients. Most commonly involved are the teeth (up to 90%), bones (40%), central nervous system (CNS) (33%), and eyes (35%). Immune dysfunction with defective neutrophil chemotaxis and elevated IgE has been reported. Eosinophilia is common. Incontinentia pigmenti is an important cause of neonatal seizures and encephalopathy. Dental abnormalities usually manifest by the time the individual is 2 years old. Dental defects include delayed eruption, partial anodontia (43%), microdontia, and cone- or peg-shaped teeth (30%). The most common CNS findings are seizures (13%), mental retardation (12%), spastic paralysis (11%), microcephaly, destructive encephalopathy, and motor retar dation. The eye changes include strabismus, cataracts, retinal detachments, optic atrophy, blue sclerae, and exudative chorio retinitis. Skeletal abnormalities include syndactyly, skull deformities, dwarfism, spina bifida, club foot, supernumerary ribs, hemiatrophy, and shortening of the legs and arms. Incontinentia pigmenti is caused by a mutation in the NEMO gene on the X chromosome, localized to Xq28. The gene is generally lethal in male fetuses, although males with Klinefelter syndrome (47,XXY) may survive. Mosaicism may also account for some cases in males. NEMO mutations also cause X-linked ectodermal dysplasia with immunodeficiency, characterized by alopecia, hypohidrosis, dental anomalies, and defects in humoral immunity. Incontinentia pigmenti achromians differs in that it is a negative image, with hypopigmentation (see below). It has autosomal-dominant inheritance, no vesicular or verrucous stages, and a higher incidence of CNS abnormalities. Patients with linear and whorled nevoid hypermelanosis lack the vesicular and verrucous phases. There is no treatment for incontinentia pigmenti. Use of ruby lasers to treat pigmented lesions in infants and young children is not necessary and may worsen the condition.
Also known as the chromatophore nevus of Naegeli, Naegeli– Franceschetti–Jadassohn syndrome differs from incontinentia pigmenti in that the pigmentation is reticular and there are no preceding inflammatory changes, vesiculation, or verrucous lesions. Vasomotor changes and hypohidrosis are present. There is reticulate pigmentation involving the neck, flexural skin, and perioral and periorbital areas. Diffuse keratoderma and punctiform accentuation of the palms and soles may occur. Dermatoglyphics are abnormal, producing atrophic or absent ridges on fingerprints. Congenital malalignment of the great toenails may be found. Dental abnormalities are common and many patients are edentulous. Both sexes are equally affected, and the syndrome appears to be transmitted as an autosomal-dominant trait related to mutations in keratin 14, causing increased susceptibility to tumor necrosis factor (TNF)-α-induced apoptosis. The syndrome is allelic to dermatopathia pigmentosa reticularis.
Incontinentia pigmenti achromians
Usually, the end stage of streaks of incontinentia pigmenti starts to fade at age 2, and by adulthood there may be little residual pigmentation.
Chang TT, et al: A male infant with anhidrotic ectodermal dysplasia/ immunodeficiency accompanied by incontinentia pigmenti and a mutation in the NEMO pathway. J Am Acad Dermatol 2008 Feb; 58(2):316–320. Ehrenreich M, et al: Incontinentia pigmenti (Bloch–Sulzberger syndrome): a systemic disorder. Cutis 2007 May; 79(5):355–362. Fusco F, et al: Clinical diagnosis of incontinentia pigmenti in a cohort of male patients. J Am Acad Dermatol 2007 Feb; 56(2):264–267. Lee JH, et al: Serial changes in white matter lesions in a neonate with incontinentia pigmenti. Childs Nerv Syst 2008 Apr; 24(4):525–528. Loh NR, et al: A genetic cause for neonatal encephalopathy: incontinentia pigmenti with NEMO mutation. Acta Paediatr 2008 Mar; 97(3):379–381. Lugassy J, et al: KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli–Franceschetti–Jadassohn syndrome. J Invest Dermatol 2008 Jun; 128(6):1517–1524. Mancini AJ, et al: X-linked ectodermal dysplasia with immunodeficiency caused by NEMO mutation: early recognition and diagnosis. Arch Dermatol 2008 Mar; 144(3):342–346. Pacheco TR, et al: Incontinentia pigmenti in male patients. J Am Acad Dermatol 2006 Aug; 55(2):251–255.
Incontinentia pigmenti achromians (hypomelanosis of Ito) Incontinentia pigmenti achromians (IPA) is characterized by various patterns of bilateral or unilateral hypopigmentation following the lines of Blaschko (Fig. 27-2). The lesions suggest the “negative image” of incontinentia pigmenti and usually develop by the first year of life. The female to male ratio is about 2.5:1. Three-quarters of affected individuals have associated anomalies of the CNS, eyes, hair, teeth, skin, nails, mus culoskeletal system, or internal organs, including polycystic kidney disease. Patients may manifest psychomotor or mental retardation, autism, microcephaly, coarse facies, and dysmorphic ears. Some patients have had associated Sturge–Weber syndrome-like leptomeningeal angiomatosis. More than half of these patients have chromosomal abnormalities, with most demonstrating mosaicism for aneuploidy or unbalanced translocations. Several patients have demonstrated trisomy 13 mosaicism. No inflammatory changes or vesiculation are found before the development of the hypo pigmentation. There is no treatment, but eventual repigmentation is the rule. 539
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Fig. 27-2 Incontinentia pigmenti achromians.
Vergine G, et al: Glomerulocystic kidney disease in hypomelanosis of Ito. Pediatr Nephrol 2008 Jul; 23(7):1183–1187.
Linear and whorled nevoid hypermelanosis This disorder of pigmentation develops within a few weeks of birth and progresses for 1–2 years before stabilizing. There is linear and whorled hyperpigmentation following the lines of Blaschko without preceding bullae or verrucous lesions. Sparing of mucous membranes, eyes, palms, and soles is noted. Congenital anomalies, such as mental retardation, cerebral palsy, atrial septal defects, dextrocardia, auricular atresia, and patent ductus arteriosus may be present. Bilateral giant cerebral aneurysms have been reported. There is no sexual predilection. Biopsy of pigmented areas demonstrates increased pigmentation of the basal layer and prominence of melanocytes without incontinence of pigment. Most cases appear to be sporadic, although familial cases have been reported. Sporadic forms have been attributed to mosaicism. Because of confusion with other pigmented disorders, such as incontinentia pigmenti, early linear epidermal nevi, hypomelanosis of Ito, and nevus depigmentosus, it is likely that linear and whorled nevoid hypermelanosis may be more common than previously appreciated. Di Lernia V: Linear and whorled hypermelanosis. Pediatr Dermatol 2007 May–Jun; 24(3):205–210. Lu Y, et al: Linear and whorled nevoid hypermelanosis complicated with inflammatory linear verrucous epidermal nevus and ichthyosis vulgaris. J Dermatol 2007 Nov; 34(11):765–768. Yuksek J, et al: Linear and whorled nevoid hypermelanosis. Dermatol Online J 2007 Jul 13; 13(3):23.
Chondrodysplasia punctata A variant of the original Conradi–Hünermann syndrome or chondrodystrophia calcificans congenita, chondrodysplasia punctata is characterized by ichthyosis of the skin similar to that of the collodion baby, followed by hyperkeratotic “whirl and swirl” patterns on erythematous skin. In addition to reddening, the waxy, shiny skin (Fig. 27-3) has hyperkeratotic 540
Fig. 27-3 Chondrodysplasia punctata.
scales of a peculiar crushed eggshell configuration. As the child grows, follicular atrophoderma and pseudopelade develop. Usually, the ichthyosis clears within the first year of life but may leave behind hyperpigmentation similar to that seen in incontinentia pigmenti. An additional feature is minor nail defects, such as platonychia and onychoschizia. There are four forms of chondrodysplasia punctata, which are classified by their inheritance patterns. The Conradi– Hünermann type is associated with autosomal-dominant inheritance, facial dysmorphia with a low nasal bridge, short stature, mild disease, cataracts, and few skin lesions. The rhizomelic form has autosomal-recessive inheritance, marked shortening of the extremities, cataracts, ichthyosis, and nasal hypoplasia; the patient dies in infancy. The X-linked recessive type has been described as part of contiguous gene deletion syndromes, with short stature, telebrachydactyly, and nasal hypoplasia. The X-linked dominant form (Happle syndrome, Conradi–Hünermann–Happle syndrome, or CDPX2) is lethal in males. Happle syndrome (X-linked dominant chondrodysplasia punctata) has ichthyosiform erythroderma along the lines of Blaschko, cataracts, asymmetrical limb shortening, and calcified stippling of the epiphyses of long bones. Follicular atrophoderma replaces the erythroderma after the first year. The skeletal defects revealed on radiographic evaluation include irregular calcified stippling of the cartilaginous epiphyses in the long bones, costal cartilages, and vertebral diaphysis. The stippling occurs in the fetus and persists until age 3 or 4. The humeri and femurs may be shortened and there may be joint dysplasia. Histologic evaluation of the ichthyotic lesions reveals a thinned, granular cell layer, calcification of keratotic follicular plugs, and focal hyperpigmentation of basal keratinocytes. The keratotic follicular plugs and calcium deposits are characteristic of this disease and very helpful in establishing the diagnosis in newborns. Various types are related to defects in peroxisomal metabolism, plasmalogen, and cholesterol biosynthesis. X-linked recessive chondrodysplasia punctata (CDPX1) is due to a defect in arylsulfatase E, located on Xp22.3. There may be an association between the rhizomelic variety and maternal autoimmunity and connective tissue disease.
Klinefelter syndrome Klinefelter syndrome, the most common sex chromosome disorder, consists of hypogonadism, gynecomastia, eunuch oidism, small or absent testicles, and elevated gonadotropins. There may be a low frontal hairline, sparse body hair with only a few hairs in the axillary and pubic areas, scanty or absent facial hair in men, and shortening of the fifth digit of both hands. Thrombophlebitis and recurrent or chronic leg ulcerations may be a presenting manifestation; these may be more common than previously reported. The cause of the hyper coagulable state is believed to be an increase in plasminogen activator inhibitor-1 levels. Patients are at an increased risk of a variety of cancers, especially male breast cancer, hematologic malignancies, and sarcomas (retinoblastoma and rhabdomyosarcoma). Many of these patients are tall; some are obese. Dull mentality or misbehavior is frequent, and psychiatric disorders occur in about one-third of these patients. Klinefelter syndrome is most frequently associated with an XXY sex chromosome pattern, although other variations occur as the number of X chromosomes increases. Marked improvement in appearance has been achieved by the injection of testosterone.
XXYY genotype The XXYY genotype is considered to be a variant of Klinefelter syndrome. In addition to the changes seen in Klinefelter, there are vascular changes, such as cutaneous angiomas, acrocyanosis, and peripheral vascular disease leading to stasis dermatitis. Hypertelorism, clinodactyly, pes planus, and dental abnormalities are common. Systemic manifestations include asthma, cardiac defects, radioulnar synostosis, inguinal hernia, cryptorchidism, CNS defects, attention deficit disorder, autism, and seizures. Paduch DA, et al: New concepts in Klinefelter syndrome. Curr Opin Urol 2008 Nov; 18(6):621–627. Tartaglia N, et al: A new look at XXYY syndrome: medical and psychological features. Am J Med Genet A 2008 Jun 15; 146A(12):1509–1522.
Turner syndrome Turner syndrome, also known as gonadal dysgenesis, is characterized by a webbed neck, low posterior hairline margin, increased carrying angle at the elbow (cubitus valgus), congenital lymphedema, and a triangular mouth. Patients may demonstrate alopecia of the frontal area on the scalp, koilonychia, cutis laxa, cutis hyperelastica, mental retardation, short stature, infantilism, retarded sexual development, primary amenorrhea, numerous melanocytic nevi, and an increased risk of melanoma, pilomatricoma, and thyroid disease. Coarctation of the aorta is frequently found. There may be an increased incidence of alopecia areata and halo nevi in these patients.
Patients with Turner syndrome have only 45 chromosomes rather than the normal 46. An X chromosome is missing, resulting in an XO genotype. Mosaicism, structural abnormalities of the X chromosome, or a partial deficiency of one sex chromosome may account for a number of the variations in gonadal dysgenesis. Several genetic loci have been implicated, including the short stature homeobox gene. Loss of long-arm material (Xq) can result in short stature and ovarian failure, but deletions distal to Xq21 do not appear to affect stature. Loss of the short arm (Xp) produces the full phenotype. Very distal Xp deletions usually have normal ovarian function. No specific treatment is available. Growth hormone (hGH) has been used to treat the short stature. A review of the Cochrane Central Register of Controlled Trials determined that hGH increases short-term growth, but there are few data regarding its effects on final height. Loscalzo ML: Turner syndrome. Pediatr Rev 2008 Jul; 29(7):219–227. Wood S, et al: Pilomatricomas in Turner syndrome. Pediatr Dermatol 2008 Jul–Aug; 25(4):449–451.
Multiple lentigines (LEOPARD) syndrome
Ausavarat S, et al: Two novel EBP mutations in Conradi–Hünermann– Happle syndrome. Eur J Dermatol 2008 Jul–Aug; 18(4):391–393. Nino M, et al: Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata. Am J Med Genet A 2008 Apr 15; 146A(8):997–1008. Pazzaglia UE, et al: The nature of cartilage stippling in chondrodysplasia punctata: histopathological study of Conradi-Hünermann syndrome. Fetal Pediatr Pathol 2008 Aug; 27(2):71–81. Shanske AL, et al: Chondrodysplasia punctata and maternal autoimmune disease: a new case and review of the literature. Pediatrics 2007 Aug; 120(2):e436–441.
Noonan syndrome Noonan syndrome is an autosomal-dominant disease with a webbed neck that mimics Turner syndrome. Males and females are equally affected, and the chromosome number is normal. The major features are a characteristic facies with hyper telorism, prominent ears, webbed neck, short stature, un descended testicles, low posterior neck hairline, cardiovascular abnormalities (pulmonary stenosis and hypertrophic cardiomyopathy), and cubitus valgus. Some 25–40% of patients have dermatologic findings: lymphedema; short, curly hair; dystrophic nails; a tendency toward keloid formation; soft, elastic skin; keratosis pilaris atrophicans (ulerythema of the eyebrows); and abnormal dermatoglyphics. The Noonan syndrome gene, PTPN11, encodes the nonreceptor protein tyrosine phosphatase SHP-2 involved in the RasMAPK (Ras-mitogenactivated protein kinase) pathway. Growth hormone can help patients achieve more normal stature.
Multiple lentigines (LEOPARD) syndrome The LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is also known as the multiple lentigines syndrome, Gorlin syndrome II, cardio-cutaneous syndrome, lentiginosis profusa syndrome, or progressive cardiomyopathic lentiginosis. The lentigines are small, dark brown, polygonal, and irregularly shaped macules, usually measuring 2–5 mm in diameter. Individual lesions may be larger, even up to 1–1.5 cm. Melanoma has been described in these patients, so atypical lesions should be biopsied. LEOPARD syndrome shares many clinical features with Noonan syndrome. They are allelic disorders, as patients with both syndromes demonstrate mutations in the Noonan syndrome gene, PTPN11. Although the “R” in LEOPARD stands for growth retardation, some individuals with the syndrome also exhibit mild mental retardation or speech difficulties. Many cases appear sporadically; however, inheritance as an autosomal-dominant genetic trait has also been reported. Allanson JE: Noonan syndrome. Am J Med Genet C Semin Med Genet 2007 Aug 15; 145C(3):274–279. Aoki Y, et al: The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat 2008 Aug; 29(8):992–1006. Noordam K: Expanding the genetic spectrum of Noonan syndrome. Horm Res 2007; 68(Suppl 5):24–27.
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Sarkozy A, et al: LEOPARD syndrome. Orphanet J Rare Dis 2008 May 27; 3:13. Seishima M, et al: Malignant melanoma in a woman with LEOPARD syndrome: identification of a germline PTPN11 mutation and a somatic BRAF mutation. Br J Dermatol 2007 Dec; 157(6):1297–1299.
Cardio-facio-cutaneous syndrome Cardio-facio-cutaneous syndrome is a congenital condition manifested by numerous anomalies. Typical features include a characteristic craniofacial appearance, psychomotor and growth retardation, congenital cardiac defects, and skin and hair abnormalities. The most frequent dermatologic findings involve the hair, which may be sparse, curly, fine or thick, woolly or brittle. In more than half of the reported cases, the patient has dry, scaly, or “hyperkeratotic,” ichthyotic skin. Other cutaneous findings include sparse or absent eyebrows and eyelashes, low posterior hairline, patchy alopecia, scant body hair, follicular hyperkeratosis, keratosis pilaris, keratosis pilaris atrophicans faciei, palmoplantar keratoderma, seborrheic dermatitis, eczema, lymphedema, hemangiomas, caféau-lait spots, pigmented nevi, hyperpigmented macules or stripes, cutis marmorata, and sacral dimples. Nail dystrophy, koilonychia, and dysplastic teeth have also been reported. The syndrome is associated with KRAS, BRAF and MAP2K1/2 mutations. The differential diagnosis includes Noonan syndrome, Turner syndrome, Pallister–Killian mosaic aneuploid syndrome (mosaic tetrasomy 12p/trisomy 12p), and Costello syndrome. The difficulty often arises in assessing the facial features, which are similar in all of these syndromes. Exclusion of PTPN11 mutations in cardio-facio-cutaneous syndrome and Costello syndrome confirms distinct genetic etiologies. Deletion of the long arm of chromosome 12, del(12)(q21.2q22), has been associated with cardio-facio-cutaneous syndrome. Rodriguez-Viciana P, et al: Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. Methods Enzymol 2008; 438:277–289.
Fig. 27-4 Angiofibromas (adenoma sebaceum).
Fig. 27-5 Oral papillomas in tuberous sclerosis.
PHAKOMATOSES The phakomatoses are the various inherited disorders of the CNS that have congenital retinal tumors and cutaneous involvement. They include tuberous sclerosis, von Recklinghausen’s disease (neurofibromatosis), von Hippel– Lindau disease (angiomatosis retinae), ataxia-telangiectasia, nevoid basal cell carcinoma syndrome, nevus sebaceus, and Sturge–Weber syndrome.
Tuberous sclerosis (epiloia, Bourneville disease) Tuberous sclerosis, described by Desiree-Magloire Bourneville in 1880, is also called epiloia (epi = epilepsy, loi = low intelligence, a = adenoma sebaceum). This classic triad of adenoma sebaceum (Fig. 27-4), mental deficiency, and epilepsy, however, is present in only a minority of patients. Other associated features include periungual fibromas, shagreen plaques (collagenoma), oral papillomatosis (Fig. 27-5), gingival hyperplasia, ash-leaf hypomelanotic macules (Fig. 27-6), skin fibromas, and café-au-lait spots. Adenoma sebaceum (angiofibromas) are 1–3 mm, yellowishred, translucent, discrete, waxy papules that are distributed symmetrically, principally over the cheeks, nose, and forehead. They have also been reported in patients with multiple endocrine neoplasia (MEN) 1 and the Birt–Hogg–Dube syndrome. These lesions are present in 90% of patients older than 4 years of age, persist indefinitely, and may increase in number. 542
Fig. 27-6 Ash-leaf macules.
Shagreen plaque is named after a type of leather tanned to produce knobs on the surface, resembling shark skin. Patches of this type of “knobby” skin, varying from 1 to 8 cm in diameter, are found on the trunk, most commonly on the lumbosacral area. They are connective tissue nevi composed almost exclusively of collagen, occur in 40% of patients, and develop in the first decade of life.
Fig. 27-7 Periungual fibromas.
Koenen tumors (periungual angiofibromas) (Fig. 27-7) occur in 50% of patients. The tumors are small, digitate, protruding, asymptomatic, and periungual and/or subungual. They have their onset at puberty. Similar lesions may occur on the gingiva. Nails may also demonstrate longitudinal groves, long leukonychia and short red streaks. Congenital white leaf-shaped macules, called hypomelanotic macules, are found in 85% of patients with tuberous sclerosis, their number ranging from 1 to 100. Occasional patients may not develop them until they are 6–8 years of age. They may be shaped like an ash leaf, but linear and confetti-type white macules may also be present. Wood’s light examination should be performed when evaluating a patient for tuberous sclerosis. Focal poliosis (localized tufts of white hair) may be present at birth. Solitary ash-leaf macules are not uncommon in the general population and may be confused with other hypopigmented macules, such as nevus depigmentosus. Mental deficiency, usually appreciated early in life, is present in 40–60% of patients, varying widely in its manifestations. Epilepsy also occurs, is variable in its severity, and usually also presents early in life. Between 80 and 90% of patients have seizures or nonspecific electroencephalographic abnormalities. Hamartomatous proliferations of glial and neuronal tissue produce potato-like nodules in the cortex. X-ray evaluation will reveal these once they are calcified, but computed tomographic (CT) scans, cranial ultrasonography, and magnetic resonance imaging (MRI) may define these lesions as early as 6 weeks of age, and thus are useful in making an early diagnosis. These brain tumors may progress to gliomas. Subependymal nodules (candle drippings) are similar lesions in the ventricular walls. Astrocytomas may also occur. Forehead plaques may be a marker for more serious intra cranial involvement. Retinal tumors (phakomas) occur, which are optic nerve or retinal nerve hamartomas. Various ophthalmologic findings, such as pigmentary changes, nystagmus, and angioid streaks, occur in 50% of patients. Renal hamartomas (angiomyolipomas [45%], cystic disease [18%], fibroadenomas, or mixed tumors) and cardiac tumors (rhabdomyomas [43%]) may also occur. In the familial variety of tuberous sclerosis, 80% of patients have angiomyolipomas, which are often bilateral and frequently cause renal failure. Women of childbearing age
Tuberous sclerosis
may present with pulmonary lymphangioleiomyomatosis with progressive respiratory failure or spontaneous pneumo thorax. The condition is characterized by diffuse proliferation of smooth muscle cells and cystic degeneration of the pulmonary parenchyma, and relates to the perivascular epithelioid cells (“PEC” cells) implicated in various PEComas. Nearly half of patients with epiloia have bony abnormalities such as bone cysts and sclerosis, which can be seen on x-ray evaluation. Five or more pits in the enamel of permanent teeth are a marker for this disease. Tuberous sclerosis is a common inherited autosomaldominant disease with highly variable penetrance. Prevalence estimates range from 1 in 5800 to 1 in 15 000. Up to 50% of cases may occur as a result of spontaneous mutations. There are two genes, the mutations of which produce indistinguishable phenotypes—9q34 (TSC1) and 16p13.3 (TSC2). TSC1 and TSC2 are tumor suppressor genes. TSC2 encodes for tuberin, a putative GTPase-activating protein for rap1 and rab5. TSC1 encodes for hamartin, a novel protein with no significant homology to tuberin or any other vertebrate protein. Hamartin and tuberin associate physically in vivo, suggesting that they function in the same complex rather than in separate pathways. This interaction of tuberin and hamartin explains the indistinguishable phenotypes caused by mutations in either gene. Hamartomas frequently demonstrate loss of the remaining normal allele (loss of heterozygosity).
Diagnosis The ash-leaf macules are usually present at birth and are most easily seen with a Wood’s light. If x-ray examination fails to show calcified intracranial nodules, ultrasonography, a CT scan, or MRI should be performed. Fundoscopic examination, hand and foot x-ray evaluation, and renal ultrasonography are often rewarding in a patient with few clinical findings, as up to 31% of asymptomatic parents have been identified using these tests. Multiple periungual fibromas are highly correlated with the syndrome, but solitary fibromas may occur in unaffected individuals. Molecular analysis for TSC1 and TSC2 may be the only way to identify “mildly affected” individuals.
Treatment Adenoma sebaceum can be treated by shaving, dermabrasion, or laser therapy. Lesions are likely to recur, requiring repeat treatment. Cranial irradiation of astrocytomas should be avoided because this may result in the subsequent development of glioblastomas. Topical and systemic rapamycin shows some promise for prevention of tumor growth, and is effective in models of the disease. Aldrich SL, et al: Acral lesions in tuberous sclerosis complex: insights into pathogenesis. J Am Acad Dermatol 2010; 63:244–251. Curatolo P, et al: Tuberous sclerosis. Lancet 2008 Aug 23; 372(9639):657–668. Datta AN, et al: Clinical presentation and diagnosis of tuberous sclerosis complex in infancy. J Child Neurol 2008 Mar; 23(3): 268–273. Korol UB, et al: Gingival enlargement as a manifestation of tuberous sclerosis: case report and periodontal management. J Periodontol 2008 Apr; 79(4):759–763. Rama Rao GR, et al: Forehead plaque: a cutaneous marker of CNS involvement in tuberous sclerosis. Indian J Dermatol Venereol Leprol 2008 Jan–Feb; 74(1):28–31. Rauktys A, et al: Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model. BMC Dermatol 2008 Jan 28; 8:1.
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Neurofibromatosis (von Recklinghausen’s disease) Neurofibromatosis is an autosomal-dominantly inherited syndrome manifested by developmental changes in the nervous system, bones, and skin. In type 1 neurofibromatosis (NF-1, von Recklinghausen’s disease), which includes more than 85% of cases, patients have many neurofibromas (Fig. 27-8), caféau-lait spots, axillary freckles (Fig. 27-9), giant pigmented hairy nevi, sacral hypertrichosis, cutis verticis gyrata, and macroglossia. Neurofibromas of the areolae occur in more than 90% of women with this disease. Lisch nodules are found
in the irides of about one-quarter of patients under 6 years of age and in 94% of adult patients. Type 2 neurofibromatosis, central or acoustic neurofibromatosis, is distinguished by bilateral acoustic neuromas, usually in the absence of cutaneous lesions, although neurofibromas and schwannomas may occur. Type 3 (mixed) and 4 (variant) forms resemble type 2 but have cutaneous neurofibromas. Patients with these types are at greater risk for developing optic gliomas, neurilemmomas, and meningiomas. These forms are inherited as autosomal-dominant traits. Segmental neurofibromatosis (Fig. 27-10) may arise from postzygotic somatic mutation or LOH. Neurofibromas are soft tumors that can be pushed down into the panniculus by light pressure with the finger (“buttonholing”) and spring back when released. Histologically, they are well circumscribed, but rarely encapsulated, spindle cell proliferations with a mucinous background and many mast cells. The spindle cells have a wavy appearance. Neurofibromas occur as a result of proliferation of all supporting elements of the nerve fibers. The proliferation is composed of Schwann cells, perineurial cells, endoneurial cells, mast cells, and blood vessels. Axon stains demonstrate individual axons spread randomly throughout the tumor. Subcutaneous plexiform neurofibromas are virtually patho gnomonic of NF-1 and may be a manifestation of LOH. They occur as large nodules containing multiple encapsulated neurofibromas. The overlying skin is usually hyperpigmented (Fig. 27-11). On palpation, they resemble a “bag of worms.”
Fig. 27-8 Neurofibromatosis type 1.
A
B
Fig. 27-9 Axillary freckling.
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Fig. 27-10 A and B, Segmental neurofibromatosis.
Diagnosis The diagnosis of NF-1 requires two or more of the following criteria to be fulfilled: 1. six or more café-au-lait macules with a greatest diameter of more than 5 mm in prepubertal individuals, and a greatest diameter of more than 15 mm in postpubertal individuals 2. two or more neurofibromas of any type or one plexiform neurofibroma 3. freckling in the axillary or inguinal regions 4. optic gliomas 5. two or more Lisch nodules 6. a distinctive osseous lesion, such as a sphenoid dysplasia or thinning of the long bone cortex with or without pseudarthrosis 7. a first-degree relative (parent, sibling, or offspring) with the disease. Fig. 27-11 Segmental neurofibromatosis.
Histologically, they demonstrate numerous elongated encapsulated neurofibromas, often embedded in diffuse neuro fibroma that involves the dermis and subcutaneous fat. The café-au-lait macule is a uniformly pigmented, smoothedged, light brown macule. Most often, these macules are present at birth and almost always present by the time the patient is 1 year of age. The finding of six or more of these lesions measuring at least 1.5 cm in diameter is diagnostic, usually indicating NF-1. In children, the minimum diameter for a significant lesion is 0.5 cm. Histologically, basilar hyperpigmentation is noted and giant melanosomes may be seen. Axillary freckling (Crowe’s sign) may occur, extending to the neck and involving the inguinal, genital, and perineal areas. Many organ systems may be involved. Acromegaly, cretinism, hyperparathyroidism, myxedema, pheochromocytoma (G PAHX gene transition. Neurol Sci 2008 Jun; 29(3):173–175. Straube R, et al: Membrane differential filtration is safe and effective for the long-term treatment of Refsum syndrome—an update of treatment modalities and pathophysiological cognition. Transfus Apheresis Sci 2003; 29:85.
Rud syndrome Rud syndrome is characterized by ichthyosis, hypogonadism, small stature, mental retardation, acanthosis nigricans, epilepsy, macrocytic anemia, and, rarely, retinitis pigmentosa. Most kindreds have shown autosomal-recessive inheritance and may be atypical variants of well-described disorders, such as Sjögren–Larsson syndrome or Refsum syndrome, rather than representing a distinct inherited disorder. Some patients have X-linked steroid sulfatase deficiency. Rajagopalan B: Non-bullous ichthyosiform erythroderma associated with retinitis pigmentosa. Am J Med Genet 2001; 99:181. Stoll C, et al: A syndrome of congenital ichthyosis, hypogonadism, small stature, facial dysmorphism, scoliosis and myogenic dystrophy. Ann Genet 1999; 42:45.
De Raeve L, et al: Trichothiodystrophy-like hair abnormalities in a child with keratitis ichthyosis deafness syndrome. Pediatr Dermatol 2008 Jul–Aug; 25(4):466–469. Mazereeuw-Hautier J, et al: Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients. Br J Dermatol 2007 May; 156(5):1015–1019. Nemoto-Hasebe I, et al: Keratitis-ichthyosis-deafness syndrome lacking subjective hearing impairment. Acta Derm Venereol 2008; 88(4):406–408.
Congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome
The keratitis-ichthyosis-deafness (KID or Senter) syndrome is characterized by vascularization of the cornea, an extensive congenital ichthyosiform eruption, neurosensory deafness, reticulated hyperkeratosis of the palms and soles, hypotrichosis, partial anhidrosis, nail dystrophy, and tight heel cords. Distinctive leathery, verrucoid plaques involve the central portion of the face and ears. These changes, with absent eyebrows and eyelashes (Fig. 27-25), and furrows about the mouth and chin, give the children a unique facies. Occasionally, hairs may demonstrate bright and dark bands with polarized microscopy, as seen in trichothiodystrophy. Some kindreds lack deafness. The disorder is related to missense mutations in the GJB2 gene that encodes connexin-26 (Cx26). Most cases are sporadic.
Present at birth, congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome is characterized by unilateral inflammatory epidermal nevi and ipsilateral limb hypoplasia or limb defects (Fig. 27-26). Features may vary widely, from complete absence of an extremity to defects of internal organs involving the musculoskeletal, cardiovascular, or central nervous systems. Biopsy may demonstrate abnormal lamellar granules in the upper stratum spinosum. The condition is believed to be X-linked dominant and lethal in hemizygous males. Survival in males has been reported as a result of mosaicism. In females, Lyonization may produce cutaneous patterns following the lines of Blaschko, similar to incontinentia pigmenti or X-linked dominant chondrodysplasia. The pathogenesis is related to mutations in the NSDHL gene that is localized at Xq28 and involved in cholesterol metabolism. When unilateral epidermal nevi show features of verruciform xanthoma, CHILD syndrome should be suspected. The CHILD nevus is distinguished by ptychotropism (flexural involvement), waxy yellowish scaling, lateralization showing both diffuse and linear involvement, and the presence of foamy macrophages in the dermal papillae.
Fig. 27-25 KID syndrome.
Fig. 27-26 CHILD syndrome, left hand has a bony defect.
Keratitis-ichthyosis-deafness syndrome
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Isotretinoin treatment may exacerbate and promote corneal vascularization. Treatment with acitretin has been reported to clear the hyperkeratotic ichthyotic lesions with little effect on the cornea or hearing. Cyclosporine A eye drops have been used to treat corneal neovascularization.
Erythrokeratodermia variabilis Erythrokeratodermia variabilis, also called erythrokeratodermia figurata variabilis, and Mendes da Costa-type erythrokeratodermia, is a rare autosomal-dominant disorder characterized by erythematous patches and hyperkeratotic plaques of sparse but generalized distribution. The erythematous patches may assume bizarre geographic configurations that are sharply demarcated (Fig. 27-27). Over time, they change their shape or size, or involute completely. The keratotic plaques are reddishbrown, often polycyclic, and fixed in location. The extensor surfaces of the limbs, buttocks, axillae, groins, and face are most often involved. Approximately 50% of patients display a palmoplantar keratoderma associated with peeling. Hair, nails, and mucous membranes are spared. The onset of the condition is shortly after birth or, rarely, at birth, or in early adult life. There may be some improvement with age, particularly after menopause. Exacerbations have been seen during pregnancy. The figurate erythematous component may be accentuated by exposure to heat, cold, or wind. Emotional upsets may also be a factor. The gene has been mapped to 1p34–p35, the gene GJB3 coding for a gap junction protein α-4 (connexin 31). Histo logically, there is hyperkeratosis and parakeratosis, and a diminished granular layer. Acanthosis may occur. Ultra structurally, epidermal keratinosomes are diminished. Systemic retinoids such as acitretin or isotretinoin can restore the deficient keratinosomes and partially clear the hyperkeratotic plaques. The disease often relapses when therapy is discontinued. Urea, salicylic acid, and lactic acid have proved useful for the hyperkeratotic plaques. Schnichels M, et al: The connexin31 F137L mutant mouse as a model for the human skin disease erythrokeratodermia variabilis (EKV). Hum Mol Genet 2007 May 15; 16(10):1216–1224.
Sta˘nescu L, et al: Erythrokeratodermia variabilis variant with circumscribed variable erythema and periorificial fixed Bazex Dupré erythema. Rom J Morphol Embryol 2007; 48(4):443–447.
Progressive symmetric erythrokeratodermia Progressive symmetric erythrokeratodermia (erythrokeratodermia progressiva symmetrica) is a rare, autosomaldominantly inherited disorder that manifests soon after birth with erythematous, hyperkeratotic plaques that are symmetrically distributed on the extremities, buttocks, and face, sparing the trunk. Palmoplantar keratoderma may be present. The lesions may regress at puberty. Occipital alopecia, oligodontia, and severe caries have been reported. The cause in one kindred was related to an insertion mutation in the loricrin gene. A novel locus has been identified—21q11.2–21q21.2 Topical treatments, including keratolytics, corticosteroids, and retinoids, have had variable success.
Pityriasis rotunda
Ishibashi M, et al: Abnormal lamellar granules in a case of CHILD syndrome. J Cutan Pathol 2006 Jun; 33(6):447–453. Kim CA, et al: CHILD syndrome caused by a deletion of exons 6–8 of the NSDHL gene. Dermatology 2005; 211(2):155–158.
Bongiorno MR, et al: Progressive symmetric erythrokeratodermia associated with oligodontia, severe caries, disturbed hair growth and ectopic nail: a new syndrome? Dermatology 2008 Sep 18; 217(4):347–350. Cui Y, et al: Identification of a novel locus for progressive symmetric erythrokeratodermia to a 19.02-cM interval at 21q11.2–21q21.2. J Invest Dermatol 2006 Sep; 126(9):2136–2139 (Epub 2006).
Acquired ichthyosis Ichthyosis clinically similar to ichthyosis vulgaris may develop in patients with several systemic diseases. Acquired ichthyosis has been reported with Hodgkin disease, and may be a presenting symptom. It has also occurred in non-Hodgkin lymphoma, mycosis fungoides, multiple myeloma, and carcinomatosis. In hypothyroidism, patients may develop fine scaling of the trunk and extremities, as well as carotenemia and diffuse alopecia. Characteristic ichthyosiform lesions may develop in patients with sarcoidosis, particularly over the lower extremities. Biopsy of the lesion will often show granulomas. Ichthyosiform changes have also been reported in patients with Hansen’s disease, nutritional deficiency, acquired immune deficiency syndrome (AIDS), human T-cell lymphotropic virus infection, lupus erythematosus, and dermato myositis. Drug-induced ichthyosis may occur with nicotinic acid, statins, triparanol, and butyrophenones. Sparsa A, et al: Acquired ichthyosis with pravastatin. J Eur Acad Dermatol Venereol 2007 Apr; 21(4):549–550.
Pityriasis rotunda
Fig. 27-27 Erythrokeratoderma variabilis.
Pityriasis rotunda (pityriasis circinata) manifests as perfectly circular scaly patches on the torso and proximal portions of the extremities (Fig. 27-28). The scale is adherent and resembles that of icthyosis vulgaris. There is a strong ethnic predisposition, with a preponderance of reports in black persons, Japanese, Koreans, and Italians. Some cases are associated with systemic illnesses, especially in darker-skinned patients. Associated illnesses include tuberculosis, other pulmonary disorders, liver disease, malnutrition, leukemia, lymphoma, and carcinoma of the esophagus or stomach. Familial cases with autosomal-dominant transmission have also been described. Two forms of the disease occur. Type I is found in black or Asian persons, usually has fewer than 30 hyperpigmented lesions, is nonfamilial, and may be associated with systemic disease. Type II disease occurs in white persons, has larger numbers of hypopigmented lesions, is often familial, and usually is not associated with internal disease. 557
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Fig. 27-28 Pityriasis rotunda.
Immunosuppression, ultraviolet exposure, and radiation therapy may exacerbate porokeratosis and promote the development of skin cancers within the lesions. The linear type has the greatest risk of malignant transformation. Segmental forms have been reported in a blaschkoid distribution and following radiation therapy. Topical 5-fluorouracil (5-FU) is generally effective in destroying individual lesions. It may have to be applied under occlusion but may result in scarring. In disseminated superficial actinic porokeratosis (DSAP), where the risk of malignant transformation is very low, the risks of treatment with 5-FU must be weighed against the generally indolent course of the lesions. Sun protection, emollients, and observation for signs of malignant degeneration may be the most suitable course of action for many patients with DSAP. Other agents that have been shown to be effective for some patients with DSAP include topical vitamin D3 analogs, diclofenac gel, and topical retinoids, including tazarotene. Salicylic acid and α-hydroxyl acids may make the lesions less noticeable. Topical imiquimod has been used for porokeratosis, including porokeratosis of Mibelli. Oral retinoids have shown efficacy, but the lesions commonly recur after treatment, and long-term treatment with these agents is impractical. Combinations of oral retinoids and topical 5-FU have been effective for refractory DSAP and porokeratosis plantaris, palmaris, et disseminata, but the side effects of treatment may be considerable. Destructive modalities must extend into the dermis and produce scarring. More superficial treatment is commonly followed by recurrence. Other effective modalities include photodynamic therapy, cryotherapy, electrodesiccation and curettage, CO2 laser ablation, Q-switched ruby laser, fractional photothermolysis, flashlamp-pumped pulsed dye laser, frequency-doubled Nd:YAG laser, dermabrasion, and Grenz ray.
Plaque-type porokeratosis (Mibelli)
Fig. 27-29 Porokeratosis with keratotic ridge. (Courtesy of Curt Samlaska, MD)
The differential diagnosis includes tinea versicolor, tinea corporis, erythrasma, Hansen’s disease, fixed drug eruptions, and pityriasis alba. Some patients note a seasonal improvement during the summer, and some respond to emollients during the winter months. Low levels of steroid sulfatase have been identified in some patients and familial cases have been observed. Topical and systemic retinoids have been used successfully, but often the condition is unresponsive unless there is an underlying systemic illness that can be treated. Friedmann AC, et al: Familial pityriasis rotunda in black-skinned patients; a first report. Br J Dermatol 2007 Jun; 156(6):1365–1367. Yoshida Y, et al: Pityriasis rotunda with low levels of steroid sulfatase. Eur J Dermatol 2007 May–Jun; 17(3):248.
Porokeratosis Porokeratosis comprises a heterogeneous group of disorders that are inherited in an autosomal-dominant fashion. Except for the punctate type, they are characterized by distinct clinical findings of a keratotic ridge with a central groove that corresponds to the cornoid lamella on histology (Fig. 27-29). The groove may be accentuated by the application of gentian violet followed by removal with alcohol. The dye remains in the groove. Povidone iodine has been used in a similar fashion. 558
Plaque-type porokeratosis is a chronic, progressive disease characterized by the formation of slightly atrophic patches surrounded by an elevated, warty border. The lesion begins as a small keratotic papule, which spreads peripherally and becomes depressed centrally. Eventually, it becomes a circinate or serpiginous, well-defined plaque surrounded by a keratotic wall or collar. This wall is grayish or brownish, and frequently is surmounted by a tiny groove or linear ridge running along its summit. The enclosed central portion of the plaque consists of dry, smooth, atrophic skin, the lanugo hairs generally being absent when the patches occur in hairy areas. Linear or zosteriform distribution of the lesions may also occur. If the nail matrix is involved, nail dystrophy may develop. Lesions may appear during chemotherapy for malignancy, after renal transplantation, while on PUVA treatment, and in areas of chronic sun damage or chemical exposure, such as benzylhydrochlorothiazide. Sites of predilection are the surfaces of the hands and fingers, and the feet and ankles. The disease also occurs on the face and scalp (where it produces bald patches), on the buccal mucosa (where the ridge becomes macerated by moisture and appears as a milky white, raised cord), and on the glans penis (where it causes erosive balanitis). Histologically, the principal diagnostic changes are in the area of the cornoid lamella. This area demonstrates a column of parakeratotic keratin extending at about a 45° angle from a focus of dyskeratotic cells in the malpighian layer. The column trails behind the focus of dyskeratosis as the focus expands peripherally. The granular cell layer is absent beneath the parakeratotic column. The central portion of the lesion may demonstrate atrophy with loss of the rete ridge pattern, lichenoid dermatitis, or psoriasiform hyperplasia.
Porokeratosis Fig. 27-30 Disseminated superficial actinic porokeratosis.
Disseminated superficial actinic porokeratosis Disseminated superficial actinic porokeratosis (DSAP) is characterized by numerous superficial, circinate, keratotic, brownish-red macules found on sun-exposed skin (Fig. 27-30). It is more common in women. The keratotic ridge is thin and thread-like, but may be accentuated by application of gentian violet followed by removal with alcohol. A surgical skinmarking pen or cotton-tipped applicator works equally well for dye application. The distribution of the lesions on the sun-exposed areas indicates that actinic radiation is an important factor in the pathogenesis, and new lesions have been induced by exposure at commercial tanning salons. Exacerbations occur in up to two-thirds of patients during summer. Immunosuppression is also well documented as exacerbating the disease. It has been seen in patients with AIDS, cirrhosis, and Crohn’s disease. Organ transplant patients may develop DSAP. Improvement of the immunosuppression may lead to resolution of the lesions. Gene loci for DSAP have been localized to chromosomes 12q23.2–24.1 and 15q25.1–26.1, suggesting that DSAP is a genetically heterogeneous disorder.
Fig. 27-31 Linear porokeratosis with squamous cell carcinoma.
Fig. 27-32 Porokeratotic eccrine ostial and dermal duct nevus.
Linear porokeratosis Linear porokeratosis may be segmental or generalized. It may be identified during the newborn period, and when found in the segmental pattern, may follow the lines of Blaschko. Ulcerations and erosions involving the face or extremities may delay the correct diagnosis, and linear porokeratosis should be included in the differential diagnosis of ulcerative lesions in the neonatal period. This form of porokeratosis has the highest risk of developing cutaneous malignancies, including squamous cell carcinoma (Fig. 27-31), Bowen’s disease, and basal cell carcinoma.
Porokeratosis palmaris, plantaris, et disseminata In this distinctive form of porokeratosis, lesions first appear on the palms or soles, or more often both. Onset is frequently noted when patients are in their twenties. Slowly, the lesions may extend over the entire body. In porokeratotic eccrine ostial and dermal duct nevus, the presentation clinically appears like a nevus comedonicus of the palm or sole (Fig. 27-32), but histologic analysis reveals multiple coronoid, lamella-like, parakeratotic columns. In porokeratosis punctata, palmaris, et plantaris or punctate porokeratosis, lesions are limited to the hands and feet.
Porokeratotic eccrine ostial and dermal duct nevus This is a related condition that affects the eccrine ostia and typically presents with volar keratoses. Ahn SJ, et al: Case of linear porokeratosis: successful treatment with topical 5% imiquimod cream. J Dermatol 2007 Feb; 34(2):146–147. Chrastil B, et al: Fractional photothermolysis: a novel treatment for disseminated superficial actinic porokeratosis. Arch Dermatol 2007 Nov; 143(11):1450–1452. Itoh M, et al: Successful treatment of disseminated superficial actinic porokeratosis with Q-switched ruby laser. J Dermatol 2007 Dec; 34(12):816–820. James AJ, et al: Segmental porokeratosis after radiation therapy for follicular lymphoma. J Am Acad Dermatol 2008 Feb; 58(2 Suppl): S49–50. Kluger N, et al: Genital porokeratosis: treatment with diclofenac topical gel. J Dermatolog Treat 2007; 18(3):188–190. Lorenz GE, et al: Linear porokeratosis: a case report and review of the literature. Cutis 2008 Jun; 81(6):479–483. Montes de Oca-Sánchez G, et al: Porokeratosis of Mibelli of the axillae: treatment with topical imiquimod. J Dermatolog Treat 2006; 17(5):319–320. Suárez-Amor O, et al: Coexistence of linear porokeratosis and disseminated superficial actinic porokeratosis: a type 2 segmental manifestation. Acta Derm Venereol 2007; 87(4):363–364.
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Darier’s disease (keratosis follicularis, Darier–White disease) Darier’s disease is an autosomal-dominantly inherited skin disorder characterized by brown keratotic papules that tend to coalesce into patches in a seborrheic distribution. Early lesions are small, firm papules, almost the color of normal skin. Each papule becomes covered with a greasy, gray–brown crust that fits into a small concavity in the summit of the papule. As the lesions grow older, their color darkens. Over the course of years, the papules grow and may fuse to form malodorous, papillomatous, vegetating growths. The neck, shoulders, face, extremities, front of the chest, and midline of the back are sites of predilection for the disease. A frequent site for the earliest lesions is behind the ears. As the eruption spreads, the entire trunk, buttocks, genitals, and other parts of the skin may be involved. Usually, the eruption is symmetrical and widespread, but striking unilateral or segmental involvement may also occur. Cases with segmental distribution probably represent postzygotic mutations. Vegetations appear chiefly in the axillae, gluteal crease, and groin, and behind the ears. The scalp is generally covered with greasy crusts. Lesions on the face are often prominent about the nose. The lips may be crusted, fissured, swollen, and superficially ulcerated, and there may be a patchy keratosis with superficial erosions on the dorsum of the tongue. Small white papules or pebbling may be present on the gingiva and palate. Involvement of the oropharynx, esophagus, hypopharynx, larynx, and anorectal mucosa has been reported. Punctate keratoses are frequently noted on the palms and soles. A general horny thickening of the palms and soles may be present because of innumerable, closely set, small papules. On the dorsa of the hands and on the shins the flat verrucous papules may resemble verrucae planae. The nails show subungual hyperkeratosis, fragility, and splintering, with longitudinal alternating white and red streaks, and triangular nicking of the free edges (Fig. 27-33). Esophageal involvement has been described.
Darier’s disease is usually worse in the summer. It may begin after severe sunburn, and in some patients the lesions may be reproduced with suberythema doses of UVB. Lithium carbonate has been shown to induce Darier’s disease in some individuals. Disseminated cutaneous herpes simplex may be a complication of the disease. Abnormal dissolution of desmosomal plaque proteins is seen, specifically desmoplakin I and II, plakoglobin, and desmoglein. Acantholysis occurs as a result of deficiency in the tonofilament/desmosome attachment. Ca2+-dependent cell– cell adhesion molecules (epithelial cadherins) are markedly reduced on the acantholytic cells of patients with Darier’s disease. The Darier gene (ATP2A2) has been localized to 12q23–24.1 and codes for the second isoform of a calcium ATPase of the sarco-/endoplasmic reticulum (SERCA2) pump, which transports Ca2+ from the cytosol into the endoplasmic reticulum. Inhibition of SERCA impairs trafficking of desmoplakin to the cell surface, contributing to acantholysis.
Histology Darier’s disease is characterized by acantholytic dyskeratosis with overlying hyperkeratosis. Abnormally keratinizing cells appear as round eosinophilic or basophilic cells (corps ronds), which often demonstrate a pale halo surrounding the nucleus. Grains are flat, deeply basophilic, dyskeratotic cells, seen most frequently in the stratum granulosum and stratum corneum. Both grains and corps ronds are separated from the surrounding cells as a result of acantholysis. Formation of a suprabasal cleft (lacuna) is noted, and may involve hair follicles as well as the surface epidermis. Dermal papillae covered by a single layer of basal cells project as villi into the acantholytic space.
Treatment During flares, topical antibacterial agents, oral antibiotics, and short-term application of a corticosteroid may be of benefit. For localized disease, topical retinoids may be effective, but papules often occur at the periphery of the treated region. Oral retinoids are the drugs of choice for most severe cases. Cyclosporine may control severe flares, and topical sunscreens and ascorbic acid can prevent disease flares in some patients. For hypertrophic lesions, dermabrasion, laser vaporization, or excision and grafting can be considered. Photodynamic therapy using topical 5-aminolaevulinic acid produces an initial inflammatory response that lasts 2–3 weeks. In some patients, this is followed by sustained improvement. Because of the initial inflammatory response, it is only appropriate for patients who have failed most other options. Pani B, et al: Darier’s disease: a calcium-signaling perspective. Cell Mol Life Sci 2008 Jan; 65(2):205–211. Sanderson EA, et al: Localized Darier’s disease in a Blaschkoid distribution: two cases of phenotypic mosaicism and a review of mosaic Darier’s disease. J Dermatol 2007 Nov; 34(11):761–764. Stewart LC, et al: Vulval Darier’s disease treated successfully with ciclosporin. J Obstet Gynaecol 2008 Jan; 28(1):108–109. Vieites B, et al: Darier’s disease with esophageal involvement. Scand J Gastroenterol 2008 Apr; 2:1–2.
Acrokeratosis verruciformis
Fig. 27-33 Darier nail.
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This rare autosomal-dominant genodermatosis is characterized by numerous flat verrucous papules occurring on the backs of the hands, insteps, knees, and elbows. The papules are closely grouped and resemble warts, except that they are flatter and more localized. The verrucous lesions are identical to those in Darier’s disease, and some, but not all, cases of
Serarslan G, et al: Acitretin treatment in acrokeratosis verruciformis of Hopf. J Dermatolog Treat 2007; 18(2):123–125. Wang PG, et al: Genetic heterogeneity in acrokeratosis verruciformis of Hopf. Clin Exp Dermatol 2006 Jul; 31(4):558–563.
Pachyonychia congenita In 1906, Jadassohn and Lewandowsky described a rare, often familial, anomaly of the nails, to which they gave the name pachyonychia congenita. It is characterized by thickened nailbeds of all fingers and toes, palmar and plantar hyperkeratosis, blistering under the callosities, palmar and plantar hyperhidrosis, spiny follicular keratoses, and benign leuko keratosis of the mucous membranes. The nail plates are extremely hard and are firmly attached to the nailbeds. The nailbed is filled with yellow, horny, keratotic debris, which may cause the nail to project upward at the free edge (Fig. 27-34). Paronychial inflammation is frequently present. Delayed onset of pachyonychia in young adulthood has been described, as has acro-osteolysis. On the extensor surfaces of the extremities, buttocks, and lumbar regions spine-like follicular keratotic papules are found. Removal of these central cores leaves a slightly bleeding cavity. The eruption on the outer aspects of the upper and lower extremities is also follicular, resembling keratosis pilaris. This latter condition is not constant and disappears at times. Painful friction blisters may develop on the plantar aspects of the toes or heels, or along the edges of the feet, and cases have been misdiagnosed as epidermolysis bullosa. Leukokeratosis of the tongue and oral mucosa, as well as occasional laryngeal involvement with hoarseness, may occur. This oral leukokeratosis resembles an oral white sponge nevus histologically and is not predisposed to the development of malignancy. Pachyonychia congenita is divided into four types. Type I (Jadassohn–Lewandowsky syndrome) is the most common and is described above. Type II (Jackson–Sertoli syndrome)
Fig. 27-34 Pachyonychia congenita.
has the same features as type I, with the additional features of natal teeth and steatocystoma multiplex. Patients with type II syndrome typically have less severe palmoplantar keratoderma, and oral lesions may be absent. Type III (Schafter– Branauer syndrome) is like type I, with the addition of leukokeratosis of the corneas. Pachyonychia congenita tarda was suggested as the name for late-onset disease (type IV). Type IV disease has been described with hyperpigmentation around the neck, waist, axillae, thighs, flexures of the knees, buttocks, and abdomen. Pigmentary incontinence and amyloid deposition are seen in biopsy specimens. Pachyonychia congenita is usually inherited as an autosomaldominant trait, although recessive forms have been reported. There is a genetic mutation of keratin 6a or 16 in type I disease, and of keratin 6b or 17 in type II disease. Mutant-specific small inhibitory RNAs (siRNAs) and hedgehog signaling may be important in disease expression. Avulsion of the nails brings about only temporary relief. Vigorous curettage of the matrix and nailbed is the simplest and most effective therapy. Destruction of the nail matrix with phenol may be partially effective, but recurrence of nailbed hyperkeratosis is common. The keratoderma is difficult to treat, but topical lactic acid, ammonium lactate, salicylic acid, or urea may be of some benefit. Isotretinoin has been reported to clear the keratotic papules and the oral leukokeratosis, but not the palms or soles. Acitretin has been shown to be effective in treating the late-onset form.
Dyskeratosis congenita (Zinsser–Cole–Engman syndrome)
acrokeratosis verruciformis of Hopf are caused by mutations in the ATP2A2 gene. Histologically, hyperkeratosis, thickening of the granular layer, acanthosis, and church spire papillomatosis characterize the disease. Available treatments are liquid nitrogen therapy, shave excision, and CO2 laser ablation. Recurrence is common. Acitretin has been used successfully.
Gu LH, et al: Hedgehog signaling, keratin 6 induction, and sebaceous gland morphogenesis: implications for pachyonychia congenita and related conditions. Am J Pathol 2008 Sep; 173(3):752–761. Leachman SA, et al: Therapeutic siRNAs for dominant genetic skin disorders including pachyonychia congenita. J Dermatol Sci 2008 Sep; 51(3):151–157. Murugesh SB, et al: Acro-osteolysis: a complication of Jadassohn– Lewandowsky syndrome. Int J Dermatol 2007 Feb; 46(2):202–205. Zamiri M, et al: Pachyonychia congenita type 2: abnormal dentition extending into adulthood. Br J Dermatol 2008 Aug; 159(2):500–501.
Dyskeratosis congenita (Zinsser–Cole–Engman syndrome) Dyskeratosis congenita is a rare congenital syndrome characterized by cutaneous poikiloderma, nail dystrophy, and premalignant leukoplakia. Atrophy and telangiectasia are accompanied by tan–gray, mottled, hyper- and hypopigmented macules or reticulated patches (Fig. 27-35). These lesions are located typically on the upper torso, neck, and face, although the extremities may also be involved. The nails may be thin and dystrophic, although only ridging and longitudinal fissuring may be seen in mild cases. This is the first component of the syndrome to appear, becoming apparent between the ages of 5 and 15. The other cutaneous lesions generally follow within 3–5 years. Leukoplakia occurs mostly on the buccal mucosa, where extensive involvement with verrucous thickening may be present. The anus, vagina, conjunctiva, and urethral meatus can be involved. Malignant neoplasms of the skin, mouth, nasopharynx, esophagus, rectum, and cervix may occur in sites of leukoplakia. Other manifestations of dyskeratosis congenita include hyperhidrosis of the palms and soles, bullous conjunctivitis, gingival disorders, dental caries, hypodontia, thin tooth enamel, periodontitis, dysphagia resulting from esophageal strictures and diverticula, skeletal abnormalities, aplastic anemia, mental deficiency, and hypersplenism. In many cases, a Fanconi type of anemia develops, beginning with leukopenia and thrombocytopenia, and progressing to severe pancytopenia. Pulmonary complications include interstitial fibrosis and Pneumocystis jirovecii (formerly carinii) pneumonia. 561
tion, and café-au-lait macules), absence of the thumbs, aplasia of the radius, severe hypoplastic anemia, thrombocytopenia, retinal hemorrhage, strabismus, generalized hyperreflexia, and testicular hypoplasia. The syndrome is associated with increased risk of myelomonocytic leukemia, squamous cell carcinoma, and hepatic tumors. No hypersensitivity to UV light, x-rays, or chemical agents is present. Human papillomavirus DNA is often found in the squamous cell carcinomas. Both cutaneous and pulmonary manifestations of associated Sweet’s syndrome have been reported. Some patients manifest short stature, failure to thrive, absent thumbs, short palpebral fissures, and typical skin abnormalities, but no hematologic abnormalities. The syndrome is inherited in an autosomal-recessive fashion. Complementation analysis has shown five complementation groups (FA-A, FA-B, FA-C, FA-D, and FA-E) and therefore five associated genes. The genes play an important role in hematopoiesis, and abnormal gene expression has been shown to increase apoptosis. FA-A has been localized to 16q24.3, and FA-D to 3p22.26. Chromosome patterns are frequently abnormal.
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Fig. 27-35 Dyskeratosis congenita. (Courtesy of Lawrence Lieblich, MD)
Chatham-Stephens K, et al: Metachronous manifestations of Sweet’s syndrome in a neutropenic patient with Fanconi anemia. Pediatr Blood Cancer 2008 Jul; 51(1):128–130. Dokal I, et al: Inherited aplastic anaemias/bone marrow failure syndromes. Blood Rev 2008 May; 22(3):141–153.
Ectodermal dysplasia Patients with the disorder have short telomeres, related to mutations in genes that encode components of the telomerase complex. These include dyskerin, TERC, TERT, NHP2, and NOP10. The genetic defect for the X-linked form is located on Xq28 and associated with the DKC1 gene for dyskerin, a protein implicated in both telomerase function and ribosomal RNA processing. Autosomal-dominant inheritance is often associated with mutations in hTR (hTERC), involved in the RNA component of telomerase. Some autosomal-dominant cases have anemia and reticulated pigmentation following the lines of Blaschko. Of interest, some patients with idiopathic aplastic anemia or myelodysplastic syndrome without skin findings demonstrate hTERC mutations. Autosomalrecessive inheritance of dyskeratosis congenita has also been reported. Granulocyte colony-stimulating factor and erythropoietin may provide short-term benefits in treating bone marrow failure. Bone marrow transplantation or hematopoietic stemcell transplantation with nonmyeloablative conditioning affords the best outcomes. Hoyeraal–Hreidarsson syndrome is characterized by intra uterine growth retardation, cerebellar hypoplasia, mental retardation, microcephaly, progressive combined immune deficiency, and aplastic anemia. The syndrome is genetically heterogeneous. Some patients demonstrate DKC1 gene mutations and are therefore allelic to dyskeratosis congenita. Atkinson JC, et al: Oral and dental phenotype of dyskeratosis congenita. Oral Dis 2008 Jul; 14(5):419–427. Röth A, et al: Dyskeratosis congenita. Br J Haematol 2008 May; 141(4):412. Vulliamy T, et al: Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci U S A 2008 Jun 10; 105(23):8073–8078.
Fanconi syndrome Also known as familial pancytopenia or familial panmyelo phthisis, Fanconi syndrome may be associated with diffuse pigmentation of the skin (hypopigmentation, hyperpigmenta562
The ectodermal dysplasias are a clinically and genetically heterogenous group of genodermatoses in which the cardinal features are the abnormal, absent, incomplete, or delayed development during embryogenesis of one or more of the epidermal or mucosal appendages (hair, sebaceous glands, nails, teeth, or mucosal glands). Some patients with ectodermal dysplasia also have features of mucous membrane pemphigoid with mucosal anti-basement membrane zone BP-180 autoantibodies and severe bilateral cicatrizing conjunctivitis with blindness. Craniofacial reconstruction and dental implants can improve quality of life for patients with ectodermal dysplasia, but the failure rate of dental implants is high in this population.
Hypohidrotic ectodermal dysplasia (anhidrotic ectodermal dysplasia, Christ–Siemens–Touraine syndrome) The classic triad of this disorder consists of hypotrichosis, anodontia, and hypohidrosis or anhidrosis. Febrile seizures may occur in childhood. Biopsy confirms that eccrine glands are absent or rudimentary. Prenatal skin biopsy may be diagnostic. Patients with the disorder have facies suggestive of congenital syphilis. The cheekbones are high and wide, whereas the lower half of the face is narrow. The supraorbital ridges are prominent and the nasal bridge is depressed, forming a saddle nose. The tip of the nose is small and upturned, and the nostrils are large and conspicuous. The eyebrows are scanty and the eyes slant upward. The lips are thickened, with the upper lip particularly protrusive. At the buccal commissures there may be radiating furrows (pseudorhagades), and on the cheeks there may be telangiectases. Sebaceous gland hyperplasia may be noted on the cheeks and forehead. Absence of mammary glands and nipples has been reported. Generalized hypotrichosis is present with thin, sparse hair on the scalp. The skin is soft, thin, dry, and smooth. There is
Ectodermal dysplasia Fig. 27-36 Hidrotic ectodermal dysplasia.
Fig. 27-37 AEC syndrome with scalp dermatitis.
partial or total anodontia, and nails may be thinned, brittle, and ridged. The teeth may be conical in shape. Mental retardation has been reported but may be a consequence of hyperthermic episodes in childhood. The inheritance pattern is almost always X-linked recessive. Three genes, ectodysplasin (EDA1), EDA-receptor (EDAR), and EDAR-associated death domain (EDARADD), have been described. They are all involved in nuclear factor (NF)-κB activation. Female carriers may have segmental expression that can be demonstrated with a starch iodide test for sweating. Both autosomal-recessive and dominant modes of inheritance have been described. The gene for autosomal-dominant hypohidrotic ectodermal dysplasia has been mapped to 2q11–q13. X-linked anhidrotic ectodermal dysplasia with immuno deficiency is caused by mutations in the gene encoding NF-κB modulator, NEMO, or inhibitor of κB kinase (IKK-γ ). Stop codon mutations are associated with a severe phenotype with associated osteopetrosis and lymphedema.
Hidrotic ectodermal dysplasia The hidrotic type of congenital ectodermal dysplasia is often referred to as Clouston syndrome. Inheritance is autosomaldominant. Eccrine sweat glands function normally and facial features are normal. Alopecia, nail dystrophy, palmoplantar hyperkeratosis (Fig. 27-36), and eye changes, such as cataracts and strabismus, are seen. Some patients have features resembling pachyonychia congenita. Widespread poromas and palmoplantar syringofibroadenomas have been described. The defective gene has been identified as GJB6, encoding the gap junction protein connexin 30 on the pericentromeric region of chromosome 13q (13q11–q12.1).
AEC syndrome (Hay–Wells syndrome) Ankyloblepharon (fusion or partial fusion of the lids), ectodermal defects, and cleft lip and/or palate constitute the AEC syndrome. It has an autosomal-dominant pattern of inheritance. Ankyloblepharon may be present at birth. Sparse hair, dental defects, cleft palate and lip, dystrophic nails, hypospadias, syndactyly, absent lacrimal puncta, stenotic auditory canals, and short stature may be present. An erosive scalp dermatitis is more likely to be observed in AEC than in other ectodermal disorders and occurs at an early age. The scalp dermatitis is often extensive (Fig. 27-37) and difficult to treat, and persists or recurs. Low-frequency ultrasound has been successful in treating scalp wounds unresponsive to other
Fig. 27-38 Ectrodactyly in EEC syndrome.
measures. The syndrome is associated with mutations in the p63 gene.
EEC syndrome Ectodermal dysplasia, ectrodactyly, and cleft lip/palate are defining features of EEC syndrome. EEC lacks scalp dermatitis, has mild hypohidrosis, and ectrodactyly (congenital absence of all or part of a digit) (Fig. 27-38) is a prominent feature. Folliculitis with scarring may be noted during puberty. Like the AEC syndrome, EEC syndrome is associated with mutations in the p63 gene.
Rapp–Hodgkin ectodermal dysplasia syndrome Characteristic features of Rapp–Hodgkin ectodermal dysplasia syndrome include anomalies of hair (pili torti, pili canaliculi, alopecia, erosive folliculitis, thinning of eyebrows/ lashes), cleft lip/palate, onychodysplasia, dental caries, hypodontia, craniofacial abnormality (Fig. 27-39), hypohidrosis, otitis media (hearing deficits), and hypospadias. It is usually inherited in an autosomal-dominant manner. The syndrome is 563
symphalangism, syndactyly, brachydactyly, mental retardation, enamel hypoplasia, and hypertelorism.
27 Genodermatoses and Congenital Anomalies
CHIME syndrome The CHIME syndrome, a rare neuroectodermal disorder, comprises colobomas of the eye, heart defects, ichthyosiform dermatosis, mental retardation, and ear defects. Other features may include facial anomalies, epidermal nevi, developmental delay, infantile macrostomia, recurrent infections, acute lymphoblastic leukemia, and duplicated renal collecting system. The inheritance is believed to be autosomal-recessive.
Lelis syndrome The Lelis syndrome is a form of ectodermal dysplasia with acanthosis nigricans, palmoplantar hyperkeratosis, hypotrichosis, hypohidrosis, nail dystrophy, early loss of adult teeth, and mental retardation.
Fig. 27-39 Rapp–Hodgkin syndrome.
allelic to AEC and EEC, and mutations in the p63 gene have been demonstrated in all three.
Ectodermal dysplasia with corkscrew hairs Abramovits–Ackerman et al described this disorder in 27 patients from seven families who live on Margarita Island, northeast of Venezuela. Salient features include corkscrew hairs (exaggerated pili torti), scalp keloids, follicular plugging, keratosis pilaris, xerosis, eczema, palmoplantar keratodermia, syndactyly, onychodysplasia, and conjunctival neovascularization. Typical facies, anteverted pinnae, malar hypoplasia, cleft lip and palate, and dental abnormalities may also be found. Inheritance is autosomal-recessive. Anhidrosis and hypohidrosis are not features.
Odonto-tricho-ungual-digital-palmar syndrome First described by Mendoza et al, the salient clinical features are natal teeth, trichodystrophy, prominent interdigital folds, simian-like hands with transverse palmar creases, and ungual digital dystrophy, inherited as an autosomal-dominant trait. Hypoplasia of the first metacarpal and metatarsal bones and distal phalanges of the toes may also occur.
Costello syndrome Costello syndrome is characterized by growth retardation, failure to thrive in infancy, coarse facies, redundant skin on the neck, palms, soles, and fingers, acanthosis nigricans, and nasal papillomata. Ventricular dilation is observed in more than 40% of cases. Hydrocephalus, brain atrophy, Chiari malformation, and syringomyelia may occur. Mild to moderate mental deficiency is frequently discovered, and most patients exhibit a characteristic sociable and friendly personality.
Lenz–Majewski syndrome Lenz–Majewski syndrome is characterized by hyperostosis, craniodiaphyseal dysplasia, dwarfism, cutis laxa, proximal 564
Acarturk TO, et al: Correction of saddle nose deformity in ectodermal dysplasia. J Craniofac Surg 2007 Sep; 18(5):1179–1182. Baujat G, et al: Ellis–van Creveld syndrome. Orphanet J Rare Dis 2007 Jun 4; 2:27. Bergendal B, et al: Implant failure in young children with ectodermal dysplasia: a retrospective evaluation of use and outcome of dental implant treatment in children in Sweden. Int J Oral Maxillofac Implants 2008 May–Jun; 23(3):520–524. Birgfeld CB, et al: Midface growth in patients with ectrodactylyectodermal dysplasia-clefting syndrome. Plast Reconstr Surg 2007 Jul; 120(1):144–150. Cabiling DS, et al: Cleft lip and palate repair in Hay–Wells/ ankyloblepharon-ectodermal dysplasia-clefting syndrome. Cleft Palate Craniofac J 2007 May; 44(3):335–339. Caswell D, et al: Low-frequency, therapeutic ultrasound treatment for congenital ectodermal dysplasia in toddlers. Ostomy Wound Manage 2008 Oct; 54(10):58–61. Saw VP, et al: Cicatrising conjunctivitis with anti-basement membrane autoantibodies in ectodermal dysplasia. Br J Ophthalmol 2008 Oct; 92(10):1403–1410. Stanford CM, et al: Perceptions of outcomes of implant therapy in patients with ectodermal dysplasia syndromes. Int J Prosthodont 2008 May–Jun; 21(3):195–200.
Pachydermoperiostosis (idiopathic hypertrophic osteoarthropathy, Touraine–Solente–Gole syndrome) Pachydermoperiostosis is characterized by thickening of the skin in folds and accentuation of creases on the face and scalp, clubbing of the fingers, and periostosis of the long bones. The changes are especially prominent on the forehead, where the horizontal lines are deepened and the skin becomes shiny (Fig. 27-40). The eyelids, particularly the upper ones, are thickened. Likewise, there is thickening of the ears and lips, and the tongue is enlarged. The scalp may be thickened and show cutis verticis gyrata (pachydermie vorticelle). The extremities, especially the elbows, knees, and hands, are enlarged and spadeshaped. The fingers become club-shaped. The palms are rough, and the thenar and hypothenar eminences are enlarged. Hyperhidrosis is common. Hyperkeratotic linear lesions of the palms and soles may be present. These lines are rippled, resembling sand of the “wind-blown desert.” Movements of the muscles may be painful. An association with gynecomastia and osteoporosis has been described. There are inherited and acquired forms. The acquired form may occur with chronic pulmonary, mediastinal, and cardiac diseases that are associated with chronic hypoxia in peripheral tissues. Some cases have been associated with bronchogenic
Fig. 27-40 Pachydermoperiostosis.
carcinoma. When such an association occurs, enlargement of the forehead, hands, and fingers may antedate the recognition of the tumor or may develop after the tumor is known to be present. Bronchogenic carcinoma-associated pachydermoperiostosis occurs almost exclusively in men over the age of 40, whereas inherited Touraine–Solente–Gole syndrome usually occurs as an autosomal-dominant disorder with onset in late adolescence. It is not associated with malignant disease. More prominent signs are seen in males. Autosomal-recessive inheritance with cleft palate and congenital heart defects has been described. Frontal rhytidectomy has been used to treat associated leonine facies, and bone manifestations have shown some response to oral bisphosphonate therapy and arthroscopic synovectomy.
Cutis verticis gyrata Cutis verticis gyrata is characterized by folds and furrows on the scalp, usually in an anteroposterior direction. Most frequently the vertex is involved, but other areas may have the distinctive furrowing. There may be 2–20 folds. The hair itself is normal. Cutis verticis gyrata has been reported primarily in males, with a male to female ratio of 6 : 1. Onset is usually at puberty, with more than 90% of patients developing it before age 30. The condition may be familial when it occurs as a component of pachydermoperiostosis. It has been reported to be the result of developmental anomalies, inflammation, trauma, tumors, nevi, amyloidosis, syphilis, myxedema, Ehlers–Danlos syndrome, Turner syndrome, Klinefelter syndrome, fragile X syndrome, and the insulin resistance syndrome. Biopsy findings can be normal or show thick collagen bundles and hypertrophy of adnexal structures. Cutis verticis gyrata is frequently found in patients with mental retardation, seizures, and schizophrenia. Rarely, a cerebriform intradermal nevus may be mistaken for this disorder. In severely involved cases, excision with grafting or scalp reduction may be indicated. Surgical excision has been used successfully to improve facial involvement. Beier JP, et al: Surgical treatment of facial cutis verticis gyrata with direct excision. J Cutan Med Surg 2007 Jan–Feb; 11(1):4–8. George L, et al: Frontal rhytidectomy as surgical treatment for pachydermoperiostosis: a case report. J Dermatolog Treat 2008; 19(1):61–63. Jojima H, et al: A case of pachydermoperiostosis treated by oral administration of a bisphosphonate and arthroscopic synovectomy. Mod Rheumatol 2007; 17(4):330–332. Ukinc K, et al: Pachydermoperiostosis with gynecomastia and osteoporosis: a rare case with a rare presentation. Int J Clin Pract 2007 Nov; 61(11):1939–1940.
Aplasia cutis congenita has a predilection for the midline of the vertex of the scalp. It presents with localized absence of skin and is rarely associated with full-thickness defects of the cranium. An association with thyroid disease and thyroid medications has been noted. Rarely, multiple symmetrical defects may occur in the skin of the lower extremities. Distal radial epiphyseal dysplasia has been associated with localized aplasia cutis congenita. The “hair collar sign” refers to a ring of long, dark hair encircling the lesion. It is commonly seen with membranous aplasia cutis, which may represent a forme fruste of a neural tube defect. Bullous aplasia cutis congenita demonstrates a fibrovascular or edematous stroma similar to that seen in encephaloceles and meningoceles, suggesting it may also be related to a neural tube defect. Focal preauricular dermal dysplasia is a form of aplasia cutis congenita not typically associated with any extracutaneous anomalies. The SCALP syndrome is a nevus sebaceus syndrome with CNS malformations, aplasia cutis congenita, limbal dermoid, and a giant congenital pigmented melanocytic nevus with neurocutaneous melanosis.
Focal dermal hypoplasia
Aplasia cutis congenita
Krathen MS, et al: Focal preauricular dermal dysplasia: report of two cases and a review of literature. Pediatr Dermatol 2008 May–Jun; 25(3):344–348. Lam J, et al: SCALP syndrome: sebaceous nevus syndrome, CNS malformations, aplasia cutis congenita, limbal dermoid, and pigmented nevus (giant congenital melanocytic nevus) with neurocutaneous melanosis: a distinct syndromic entity. J Am Acad Dermatol 2008 May; 58(5):884–888.
Adams–Oliver syndrome Features of Adams–Oliver syndrome include severe aplasia cutis congenita of the scalp, which may involve both skin and skull ossification defects, limb defects (brachydactyly, syndactyly of toes two and three, and hypoplastic toenails), extensive cutis marmorata telangiectatica congenita, cryptorchidism, and cardiac abnormalities. Other associations include hem angiomas, retro- and micrognathia, strabismus, and atrial septal defect. It is a rare autosomal-dominantly inherited neuroectodermal syndrome. Narang T, et al: Adams–Oliver syndrome: a sporadic occurrence with minimal disease expression. Pediatr Dermatol 2008 Jan–Feb; 25(1):115–116.
Focal dermal hypoplasia (Goltz syndrome) Goltz syndrome is characterized by multiple abnormalities of mesodermal and ectodermal tissues. Reddish-tan, atrophic, often linear or cribriform patches are commonly present on the buttocks, axillae, and thighs (Fig. 27-41). Later, lipocytes accumulate in the lesions in a nevoid fashion, resulting in yellowish-brown nodules. The lesions are strikingly linear and often serpiginous, following lines of Blaschko. They are often narrower than typical Blaschko segments, suggesting that the genetic defect is lethal in many of the affected cells during development. Telangiectases are commonly present. Papillomas may occur around the orifices of the mouth, anus, and vulva. They may be misdiagnosed as condyloma acuminata. An early inflammatory vesicular stage has been described along with cleft lip and palate. Eighty percent of patients have skeletal defects. Bone changes most commonly involve the extremities, where there may be syndactyly, oligodactyly, and adactyly (Fig. 27-42). Scoliosis, spina bifida, and hypoplasia of the clavicle have also been reported. Forty to 50% of patients 565
Petrides G, et al: Caudal appendage in focal dermal hypoplasia (Goltz syndrome). Clin Dysmorphol 2008 Apr; 17(2):129–131.
27 Genodermatoses and Congenital Anomalies
Werner syndrome (adult progeria)
Fig. 27-41 Goltz syndrome.
Fig. 27-42 Goltz syndrome.
have ocular or dental abnormalities, with coloboma being the most common ocular defect. Van Allen–Myhre syndrome appears to represent a severe form of Goltz syndrome with split foot and split hand anomalies. MIDAS syndrome (micr ophthalmia, dermal aplasia, and sclerocornea) is also an X-linked phenotype, but distinct from Goltz syndrome. It has been mapped to Xp22.3. Patients have bilateral microphthalmia with blepharophimosis and linear dermal aplasia often involving the face. Goltz syndrome is related to defects in PORCN, a regulator of Wnt signaling. The large majority of patients with Goltz syndrome have been female. X-linked dominant inheritance, with lethality in males, is likely. Females are protected by X-chromosome mosaicism, identical to the situation in incontinentia pigmenti. Treatment of atrophic erythematous patches has been successful using a flashlamp-pumped pulsed dye laser. Grzeschik KH, et al: Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia. Nat Genet 2007 Jul; 39(7):833–835. Maymí MA, et al: Focal dermal hypoplasia with unusual cutaneous features. Pediatr Dermatol 2007 Jul–Aug; 24(4):387–390. Paller AS: Wnt signaling in focal dermal hypoplasia. Nat Genet 2007 Jul; 39(7):820–821.
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Werner syndrome is a premature aging syndrome characterized by many metabolic and structural abnormalities involving the skin, hair, eyes, muscles, fatty tissues, bones, blood vessels, and carbohydrate metabolism. Cells demonstrate genomic instability. Because most of these signs are not fully manifested before the age of 30, the diagnosis is usually made in middle age. These patients usually die before the age of 50 from malignant disease or vascular accidents. The most characteristic findings are premature aging and arrest of growth at puberty, senile cataracts developing in the late twenties and thirties, premature balding and graying, and scleroderma-like lesions of the skin. A characteristic change is the loss of subcutaneous tissue and wasting of muscles, especially the extremities, so that the legs become spindly and the trunk becomes stocky. Osteoporosis and aseptic necrosis are frequent in the small bones of the hands. The skin changes include poikiloderma, scleroderma, atrophy, hyperkeratoses, and leg ulcers. The skin has a dark gray or blackish diffuse pigmentation. A high-pitched voice and hypogonadism in both sexes are distinctive in this syndrome. Painful callosities with ulcerations may occur around the malleoli, Achilles tendons, heels, and toes. The hair thins on the eyebrows, axillae, and pubis. The skin over the cheekbones becomes taut, producing proptosis and beaking of the nose. Cataracts develop early, and the vocal cords become thickened so that a weak, high-pitched voice ensues. Premature arteriosclerosis and sexual impotence are frequently observed. Diabetes is frequent, and areas of calcinosis circumscripta occur. Gene expression mimics normal aging. A high rate of malignancy is associated with Werner syndrome. Uterine sarcoma, hepatoma, carcinoma of the breast, fibrosarcoma, and thyroid adenocarcinoma have occurred. Histologic changes in the skin may include atrophy of the epidermis and fibrosis of the dermis. Consanguinity and familial incidence are encountered, suggesting a mendelian recessive mode of transmission. Werner syndrome is molecularly heterogeneous. The Werner protein confers adhesive properties to macromolecular proteins and is required for genomic stability. It belongs to the RecQ family of DNA helicases and appears to play a role in telomere maintenance, homologous recombination, and DNA repair. Mutant LMNA encoding nuclear lamin A/C is associated with atypical Werner syndrome with a more severe phenotype. Mutations in LMNA also cause Hutchinson–Gilford progeria, Emery– Dreifuss muscular dystrophy, and dilated cardiomyopathy.
Progeria (Hutchinson–Gilford syndrome) Progeria, or Hutchinson–Gilford syndrome, is characterized by accelerated aging, dwarfism, alopecia, generalized atrophy of the skin and muscles, enlarged head with prominent scalp veins, and a high incidence of generalized atherosclerosis, usually fatal by the second decade. The large bald head and lack of eyebrows and eyelashes are distinctive (Fig. 27-43). The skin is wrinkled, pigmented, and atrophic. The nails are thin and atrophic. Most patients lack subcutaneous fat, which produces the appearance of premature senility. There are usually sclerodermatous plaques on the extremities. The intelligence remains intact. Arteriosclerosis, anginal attacks, and hemi plegia may occur, followed by death from coronary heart disease at an early age. Mutations in LMNA and mosaicism have been identified. Treatment is symptomatic: chiefly, control of diabetes mellitus and treatment of leg ulcerations.
Cockayne syndrome Fig. 27-43 Progeria.
Davis T, et al: The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging. Ann N Y Acad Sci 2007 Apr; 1100:455–469. Kudlow BA, et al: Werner and Hutchinson–Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol 2007 May; 8(5):394–404. Makrantonaki E, et al: Molecular mechanisms of skin aging: state of the art. Ann N Y Acad Sci 2007 Nov; 1119:40–50. Opresko PL: Telomere ResQue and preservation—roles for the Werner syndrome protein and other RecQ helicases. Mech Ageing Dev 2008 Jan–Feb; 129(1-2):79–90. Sidorova JM: Roles of the Werner syndrome RecQ helicase in DNA replication. DNA Repair 2008 Nov 1; 7(11):1776–1786.
Xeroderma pigmentosum Xeroderma pigmentosum is an autosomal-recessive disorder characterized by defective DNA thymidine dimer excision repair, extreme sun sensitivity, freckling, and skin cancer. Sun sensitivity and lentigines (Fig. 27-44) are early skin findings, with the median onset before the age of 2. Skin cancers often appear before 10 years of age, and an increase in internal cancer has been noted as well. In a study of 830 patients, 45% had basal cell carcinoma or squamous cell carcinoma, and melanoma was noted in 5%. Most of the tumors occur on the head and neck. Ocular abnormalities were found in 40% and included ectropion, corneal opacity, and neoplasms. Progressive neurologic degeneration is seen in about 20% of patients. Xeroderma pigmentosum patients in com plementation group C remain free of neurologic problems. Complementation groups are defined by correction of excision repair when fibroblasts from patients in different groups are fused. A variant type with normal excision repair has also been described. Retinoids can prevent the appearance of new cancers, but side effects are significant, and a rebound in the number of cancers occurs when the drug is stopped, suggesting that the tumors are merely suppressed. Photoprotection remains essential for management. Individual tumors may be excised or destroyed with cryotherapy. Some may be treated with topical imiquimod or 5-FU. Topical application of recombinant liposomal encapsulated T4 endonuclease V repairs UV-induced cyclobutane–pyrimidine dimers and is a promising form of therapy. Gene therapy is also being pursued. Guidelines for evaluation and management from the XP Society can be found at www.xps.org. A publication from the National Institutes of Health (NIH) can be found at
Fig. 27-44 Xeroderma pigmentosum. (Courtesy of Ken Kraemer, MD)
www.cc.nih.gov/ccc/patient_education/pepubs/xeroderma. pdf. Xeroderma pigmentosum, Cockayne syndrome, and tricho thiodystrophy are all associated with defects in nucleotide excision repair (NER). Global genome NER repairs DNA lesions throughout the genome, preventing the accumulation of mutations. Transcription-coupled NER prevents cell death caused by stalled transcription by rapidly identifying and repairing defects in the transcribed strand of DNA. Skin tumors in xeroderma pigmentosum patients have sunlightinduced mutations in ras, p53, and ptch genes. Mutations in the XPG gene give rise to the complementation group G form of xeroderma pigmentosum, as well as early-onset Cockayne syndrome. Prenatal diagnosis is possible via cultured chorionic villus cells or amniocytes. The De Sanctis–Cacchione syndrome consists of xeroderma pigmentosum with mental deficiency, dwarfism, and gonadal hypoplasia. It occurs most often in patients in complementation group D. Mutations in the ERCC6 gene, which also cause Cockayne syndrome type B, have been demonstrated as well.
Cockayne syndrome Cockayne syndrome is an autosomal-recessive syndrome with sun sensitivity and neurologic degeneration. It differs from xeroderma pigmentosum in the lack of freckling and skin cancer, and in the presence of dwarfism, beaked nose, loss of subcutaneous tissue, deafness, basal ganglia calcification, failure of brain growth, and retinopathy. Cockayne described the syndrome as dwarfism with retinal atrophy and deafness. Dermatologic features include photodermatitis with telangiectasia, atrophy, and scarring. The hands and feet are large and cyanotic. Microcephaly, sunken eyes, severe flexion contractures, dorsal kyphosis, crypt orchidism, cataracts, growth retardation, mental retardation, hypothalamic and cerebellar dysfunction, and retinitis pigmentosa with optic atrophy may be seen. There is progressive neurologic disturbance with a shortened lifespan. Dermal fibroblasts and lymphoblastoid cell lines, as well as cultured amniotic fluid cells from an affected fetus, demonstrate impaired colony-forming ability, and decreased DNA and RNA synthesis after UV light exposure (254 nm). DNA helicases unwind DNA and are important in DNA replication, DNA repair, and RNA transcription. Mutations in XPB or XPD DNA helicase can result in xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy. The 567
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Cockayne syndrome complementation group A (CSA) and CSB genes responsible for Cockayne syndrome are associated with RNA polymerase. CSB protein plays a role in transcription as well as global nucleotide excision repair. Cockayne syndrome has also been associated with mutations in XPG.
Xeroderma pigmentosum/Cockayne syndrome complex Some patients have skin features of xeroderma pigmentosum and neurologic features of Cockayne syndrome. Patients in complementation groups B, D, and G have presented with the complex. Mutations in the associated genes may give rise to clinical manifestations of xeroderma pigmentosum, Cockayne syndrome, or the xeroderma pigmentosum/Cockayne syndrome complex.
Trichothiodystrophy Trichothiodystrophy is an autosomal-recessive disorder characterized by photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature (PIBIDS). A review of 112 patients noted a wide spectrum of clinical features that varied from patients with only hair involvement to those with profound developmental defects. Common features included intellectual impairment (86%), short stature (73%), ichthyosis (65%), ocular abnormalities (51%), infections (46%), and photosensitivity (42%). More than half of the patients had abnormal characteristics at birth and 19 patients died before the age of 10. Tay syndrome is similar but lacks photosensitivity. Abnormalities in nucleotide excision repair of UV-damaged DNA are present in about 50% of those with the disorder. The UV sensitivity and defective excision repair are similar to those of xeroderma pigmentosum patients, but these patients do not experience an increased incidence of skin cancer. Two of the three described complementation groups match xeroderma pigmentosum groups B and D, with the XPD gene accounting for most photosensitive trichothiodystrophy. A combined xeroderma pigmentosum/trichothiodystrophy complex has been described. Patients with trichothiodystrophy without xeroderma pigmentosum do not have an increase in skin cancer formation. The hair, with sulfur reduced to 50% of the normal value, has distinctive features under polarizing, light, and scanning electron microscopy. With polarizing microscopy, the hair shows alternating bright and dark regions that give a striking striped, or tiger tail, appearance, but the pattern may not be evident at birth. A similar pattern of bright and dark bands has been described in the keratitis ichthyosis deafness syndrome. With light microscopy, hairs from patients with tricho thiodystrophy demonstrate trichoschisis (clean fractures). Trichorrhexis nodosa-like fractures may also be seen. In addition, the hair is markedly flattened and folds over itself like a thick ribbon. The hair shaft outline is irregular and slightly undulating, and the melanin granules are distributed in a wavy pattern. With scanning electron microscopy, the surface shows marked ridging and fluting, and the cuticle scales may be absent or greatly reduced. Bath-Hextall F, et al: Interventions for preventing non-melanoma skin cancers in high-risk groups. Cochrane Database Syst Rev 2007 Oct 17; (4):CD005414. Charles CA, et al: A rare presentation of squamous cell carcinoma in a patient with PIBIDS-type trichothiodystrophy. Pediatr Dermatol 2008 Mar–Apr; 25(2):264–267. Cleaver JE, et al: Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions
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responsible for cancer, neurodegeneration and aging. Mech Ageing Dev 2008 Jul–Aug; 129(7–8):492–497. De Raeve L, et al: Trichothiodystrophy-like hair abnormalities in a child with keratitis ichthyosis deafness syndrome. Pediatr Dermatol 2008 Jul–Aug; 25(4):466–469. Faghri S, et al: Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations. J Med Genet 2008 Oct; 45(10):609–621. Horkay I, et al: Photosensitivity skin disorders in childhood. Photodermatol Photoimmunol Photomed 2008 Apr; 24(2):56–60. Kleijer WJ, et al: Prenatal diagnosis of xeroderma pigmentosum and trichothiodystrophy in 76 pregnancies at risk. Prenat Diagn 2007 Dec; 27(12):1133–1137. Kraemer KH, et al: Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience 2007 Apr 14; 145(4):1388–1396. Malhotra AK, et al: Multiple basal cell carcinomas in xeroderma pigmentosum treated with imiquimod 5% cream. Pediatr Dermatol 2008 Jul–Aug; 25(4):488–491. Niedernhofer LJ: Tissue-specific accelerated aging in nucleotide excision repair deficiency. Mech Ageing Dev 2008 Jul–Aug; 129(7–8):408–415. Rapin I, et al: Cockayne syndrome in adults: review with clinical and pathologic study of a new case. J Child Neurol 2006 Nov; 21(11):991–1006. Stevnsner T, et al: The role of Cockayne syndrome group B (CSB) protein in base excision repair and aging. Mech Ageing Dev 2008 Jul–Aug; 129(7–8):441–448. Wang F, et al: DNA repair gene XPD polymorphisms and cancer risk: a meta-analysis based on 56 case-control studies. Cancer Epidemiol Biomarkers Prev 2008 Mar; 17(3):507–517. Webb S: Xeroderma pigmentosum. BMJ 2008 Feb 23; 336(7641):444–446.
Bloom syndrome (Bloom–Torre–Machacek syndrome) Bloom syndrome is transmitted as an autosomal-recessive trait, chiefly among Jewish persons of Eastern European origin. It is characterized by photosensitive telangiectatic erythema in the butterfly area of the face and dwarfism. Telangiectatic erythematous patches resembling lupus erythematosus develop in the first 2 years of life (Fig. 27-45). Bullous, crusted lesions may be present on the lips. Exacerbation of skin lesions occurs during the summer. Other changes that may be noted are café-au-lait spots, ichthyosis, acanthosis nigricans, syndactyly, irregular dentition, lens opacities, prominent ears, hypospadias, and cryptorchidism. The stunted growth is
Fig. 27-45 Bloom syndrome.
Cefle K, et al: Lens opacities in Bloom syndrome: case report and review of the literature. Ophthalmic Genet 2007 Sep; 28(3):175–178. Holman JD, et al: Genodermatoses with malignant potential. Curr Opin Pediatr 2007 Aug; 19(4):446–454. Thomas ER, et al: Surveillance and treatment of malignancy in Bloom syndrome. Clin Oncol (R Coll Radiol) 2008 Jun; 20(5):375–379.
Rothmund–Thomson syndrome (poikiloderma congenitale) Rothmund–Thomson syndrome is a rare autosomal-recessive disorder. Poikiloderma begins at 3–6 months of age, with tense, pink, edematous patches on the cheeks, hands, feet, and buttocks, sparing the chest, back, and abdomen (acute phase). Sensitivity to sunlight may be manifested by the development of bullae or intense erythema after brief sun exposure. There follows fine reticulated or punctate atrophy associated with telangiectasia and reticulated pigmentation (chronic phase) (Fig. 27-46). Characteristically, the arms and legs are affected, with sparing of the antecubital and popliteal fossae. The skin lesions are characteristic. Otherwise, patients with Rothmund– Thomson syndrome may have a broad range of noncutaneous
lesions. Short stature (two-thirds of patients), small hands with radial ray defects, saddle nose, absence or sparseness of eyebrows and eyelashes (73%), alopecia of the scalp (50%), and numerous bone defects (75%) are frequently observed. Hypogonadism, dystrophic nails, and defective dentition are seen in a significant proportion of patients (25–60%). Cataracts occur in a small percentage of patients in childhood or young adult life. Associated cutaneous neoplasms include squamous cell carcinoma, Bowen’s disease, basal cell carcinoma, and melanoma, but it is the risk for osteosarcoma of bone that is particularly high (>30%). Several patients with compound heterozygous mutations in RECQL4, a human helicase gene, have been reported. Thus, at least a subset of patients with Rothmund–Thomson syndrome has abnormal DNA helicase activity, as do patients with Werner and Bloom syndromes. Cabral RE, et al: Identification of new RECQL4 mutations in Caucasian Rothmund–Thomson patients and analysis of sensitivity to a wide range of genotoxic agents. Mutat Res 2008 Aug 25; 643(1–2):41–47. Howell SM, et al: Amelanotic melanoma in a patient with Rothmund– Thomson syndrome. Arch Dermatol 2008 Mar; 144(3):416–417. Stinco G, et al: Multiple cutaneous neoplasms in a patient with Rothmund–Thomson syndrome: case report and published work review. J Dermatol 2008 Mar; 35(3):154–161.
Scleroatrophic syndrome of Huriez
characterized by normal body proportions, no endocrine abnormalities (except diabetes mellitus), and low birth weight at full term. Dolichocephaly and narrow, delicate facies are present. Immune functions are abnormal, and gastrointestinal and respiratory infections occur frequently. Cancer of all cell types and sites is increased in frequency. Leukemia, lymphoma, adenocarcinoma of the sigmoid colon, and oral and esophageal squamous cell carcinoma, as well as other malignancies, have been associated with Bloom syndrome. About one-quarter of patients under the age of 20 develop a neoplasm. Regular use of a broad-spectrum sunscreen, as well as photoprotection, is recommended. The gene mutated in Bloom syndrome, BLM, codes for a RecQ DNA-helicase. BLM is localized to the nuclear bodies and the nucleolus and is critical for genomic stability. BLM interacts with WRN, the DNA helicase mutated in Werner syndrome, and is part of a large BRCA-1-containing complex containing DNA repair factors. BLM expression is highest during the S and G2 phases of the cell cycle. BLM associates with telomeres and ribosomal DNA. BLM interacts directly with ATM (the protein product of the gene mutated in ataxia-telangiectasia) and together they recognize abnormal DNA structures.
Hereditary sclerosing poikiloderma and mandibuloacral dysplasia Hereditary sclerosing poikiloderma is an autosomal-dominant condition. The skin changes consist of generalized poikiloderma appearing in childhood (but not at birth), with hyperkeratotic and sclerotic cutaneous bands extending across the antecubital spaces, axillary vaults, and popliteal fossae. In addition, the palms and soles may show sclerosis resembling shiny scotch-grain leather. Aortic stenosis, clubbing of the fingers, and localized calcinosis of the skin have also been noted. There is no treatment. The cases described by Weary were subsequently reported later in life as mandibuloacral dysplasia, a rare autosomal-recessive syndrome characterized by mandibular hypoplasia, delayed cranial suture closure, dysplastic clavicles, abbreviated, club-shaped terminal phalanges, myopathy, lipodystrophy, acro-osteolysis, atrophy of the skin of the hands and feet, and typical facial changes. Mandibuloacral dysplasia must be distinguished from pro geria and Werner syndrome. A distinct subtype has been described in two generations of a South African family. The characteristics included poikiloderma, tendon contracture, and pulmonary fibrosis, with apparent autosomal-dominant inheritance. Sparse fine hairs are present on the scalp, face, and body. Khumalo NP, et al: Poikiloderma, tendon contracture and pulmonary fibrosis: a new autosomal dominant syndrome? Br J Dermatol 2006 Nov; 155(5):1057–1061. Lombardi F, et al: Compound heterozygosity for mutations in LMNA in a patient with a myopathic and lipodystrophic mandibuloacral dysplasia type A phenotype. J Clin Endocrinol Metab 2007 Nov; 92(11):4467–4471.
Scleroatrophic syndrome of Huriez Huriez syndrome, a very rare autosomal-dominant disorder, is characterized by: 1. scleroatrophy of the hands, with sclerodactyly 2. ridging, clubbing, or hypoplasia of the nails 3. lamellar keratoderma of the hands and, to a lesser extent, the soles.
Fig. 27-46 Rothmund–Thomson syndrome.
Patients with Huriez syndrome may also have multiple telangiectasias of the lips and face, and flexion contractures of the little finger. Aggressive squamous cell carcinomas occur in 569
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the scleroatrophic skin, including that of the palms and soles (13% lifetime risk, 5% mortality in affected persons). Affected patients have reduced Langerhans cells in affected skin, but normal dermal dendritic cells.
Franceschetti–Klein syndrome (mandibulofacial dysostosis) This syndrome includes palpebral antimongoloid fissures, hypoplasia of the facial bones, macrostomia, vaulted palate, malformations of both the external and internal ear, buccal– auricular fistula, abnormal development of the neck with stretching of the cheeks, accessory facial fissures, and skeletal deformities. Patients who have the complete syndrome usually die in infancy, but patients with the abortive type may live to an old age. The syndrome is allelic to the Treacher Collins syndrome and caused by the Treacher Collins–Franceschetti (TCOF1) gene.
Treacher Collins syndrome This syndrome includes midface hypoplasia with micro gnathia, microtia, conductive hearing loss, and cleft palate. It is inherited as an autosomal-dominant trait and caused by mutations in the TCOF1 gene, which encodes a protein called treacle.
Oculoauriculofrontonasal syndrome This syndrome is sporadic in nature, although autosomalrecessive inheritance has been suggested by some authors. Features include hemifacial microsomia, microtia, ocular hypertelorism, upper palpebral colobomata, preauricular tags, lateral face clefting, and nasal clefting.
Popliteal pterygium syndrome Pterygia or skinfolds may extend from the thigh down to the heel and thus prevent extension or rotation of the legs. Crural pterygia, cryptorchidism, bifid scrotum, agenesis of the labia majora, cleft lip and palate, adhesions between the eyelids, syndactyly, and talipes equinovarus may be present. Autosomal-dominant inheritance has been described, and the syndrome is allelic to the van der Woude syndrome.
Van der Woude syndrome The syndrome is an autosomal-dominant craniofacial disorder characterized by hypodontia, pits of the lower lip, and cleft palate. It is associated with mutations in the IRF6 gene. Other reported associations include natal teeth, ankyloglossia, syndactyly, equinovarus foot deformity, and congenital heart disease. Lower lip pits may be found in other congenital disorders, such as popliteal pterygium syndrome, and occasionally in orofaciodigital syndrome type I (oral frenula and clefts, hypoplasia of alae nasi, and digital asymmetry). Surgical correction is the treatment of choice.
Apert syndrome (acrocephalosyndactyly) Apert syndrome is autosomal-dominantly inherited and is characterized by craniosynostosis and fusion of the digits (syndactyly). Patients present with synostosis of the feet, hands, carpi, tarsi, cervical vertebrae, and skull. The facial features are distorted and the second, third, and fourth fingers are fused into a bony mass with a single nail. Neurologic defects may be due in part to brain compression by the abnormal skull. 570
Oculocutaneous albinism and severe acne vulgaris have been reported with Apert syndrome, although some of the acneiform lesions actually represent follicular hamartomas. Mutations in the fibroblast growth factor receptor (FGFR2) gene are responsible for Apert syndrome, Crouzon syndrome, and Pfeiffer syndrome.
Pfeiffer syndrome The syndrome is autosomal-dominantly inherited and consists of osteochondrodysplasia and craniosynostosis. Type 1 has normal intelligence and generally good outcome. Types 2 and 3 have severe neurologic compromise, a poor prognosis, and sporadic occurrence. Respiratory compromise may occur as a result of tracheal stenosis and fibrous cartilaginous rings.
Crouzon syndrome The syndrome includes craniosynostosis and acanthosis nigricans. It is associated with mutations in the FGFR2 gene. The crouzonodermoskeletal syndrome with choanal atresia and hydrocephalus is caused by mutations in FGFR3, a gene associated with achondroplastic dwarfism.
Carpenter syndrome Carpenter syndrome is an acrocephalopolysyndactyly syndrome with an autosomal-recessive pattern of inheritance. Patients present with craniosynostosis and acral deformities that include syndactyly.
Whistling face syndrome In this rare disorder, also known as craniocarpotarsal syndrome, Freeman–Sheldon syndrome, Windmill–Vane–Hand syndrome, and distal arthrogryposis type 2, the child appears to be whistling all the time. This configuration is the result of microstomia, deep-set eyes, flattened midface, coloboma, contracted joint muscles of the fingers and hands, and alterations of the nostrils. Ulnar deviation of the fingers, kyphoscoliosis, and talipes equinovarus may be present. Brain anomalies have also been reported. Autosomal-dominant, autosomal-recessive, and sporadic variants have been reported. Prenatal diagnosis can be made on ultrasound. Surgical intervention may be required for some patients. Chen CP, et al: Craniosynostosis and congenital tracheal anomalies in an infant with Pfeiffer syndrome carrying the W290C FGFR2 mutation. Genet Couns 2008; 19(2):165–172. Gabbett MT, et al: Characterizing the oculoauriculofrontonasal syndrome. Clin Dysmorphol 2008 Apr; 17(2):79–85. Horbelt CV: Physical and oral characteristics of Crouzon syndrome, Apert syndrome, and Pierre Robin sequence. Gen Dent 2008 Mar–Apr; 56(2):132–134. Perlyn CA, et al: Craniofacial dysmorphology of Carpenter syndrome: lessons from three affected siblings. Plast Reconstr Surg 2008 Mar; 121(3):971–981. Rice DP: Clinical features of syndromic craniosynostosis. Front Oral Biol 2008; 12:91–106. Saadeh PB, et al: Microsurgical correction of facial contour deformities in patients with craniofacial malformations: a 15-year experience. Plast Reconstr Surg 2008 Jun; 121(6):368e–378e.
Syndromes that include abnormalities of the hair Hallerman–Streiff syndrome This syndrome includes characteristic “bird facies,” con genital cataracts, microphthalmia, mandibular hypoplasia,
Polyostotic fibrous dysplasia (Albright’s disease) This may present as slowly progressive lifelong unilateral hair loss: scalp, pubic, axillary, and palpebral. Sickle-cell disease is often characterized by scantiness of body and facial hair.
Cronkhite–Canada syndrome The Cronkhite–Canada syndrome is characterized by alopecia, skin pigmentation, onychodystrophy, malabsorption, and generalized gastrointestinal polyposis.
Marinesco–Sjögren syndrome
Fig. 27-47 Non-infectious granuloma in cartilage–hair hypoplasia. (Courtesy of J. Treat, MD and A Yan, MD)
Most patients are anergic to skin-test panels and have increased numbers of natural killer (NK) cells. The major mutation involves the RMRP gene, which encodes a component of mitochondrial RNA-processing endoribonuclease.
Trichorhinophalangeal syndrome
This syndrome consists of cerebellar ataxia, mental retardation, congenital cataracts, inability to chew food, thin brittle fingernails, and sparse hair. The dystrophic hairs do not have the normal layers (cortex, cuticle, and medulla), and 30% of the hair shafts show narrow bands of abnormal incomplete keratinization. There is an autosomal-recessive type of inheritance in this syndrome and the gene has been mapped to chromosome 5q31.
This is a genetic disorder consisting of fine and sparse scalp hair, thin nails, pear-shaped broad nose, and cone-shaped epiphyses of the middle phalanges of some fingers and toes. Supernumerary teeth have been reported. There is an autosomal-dominant and also a recessive inheritance type. The syndrome can result from either single base-pair mutations or deletion of the TRPS1 gene, which encodes a GATA zinc-finger transcription factor located on chromosomal band 8q24.1.
Trichothiodystrophy
Papillon–Lefèvre syndrome
This is discussed above with xeroderma pigmentosum.
This is characterized by hyperkeratosis palmaris et plantaris, periodontosis, and sparsity of the hair. Hyperhidrosis and other signs and symptoms begin early in life. Inheritance of this disease is of an autosomal-recessive type.
Generalized trichoepitheliomas Generalized trichoepitheliomas, alopecia, and myasthenia gravis may be a variant of the generalized hair follicle hamartoma syndrome. There is a report of a localized variant of this syndrome. Histologically, there is replacement of the hair follicles by trichoepithelioma-like epithelial proliferations associated with hyperplastic sebaceous glands.
Crow–Fukase (POEMS) syndrome This acquired syndrome is characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes such as diffuse hyperpigmentation, dependent edema, skin thickening, hyperhidrosis, and hypertrichosis.
Cartilage–hair hypoplasia (McKusick-type metaphyseal chondrodysplasia) This encompasses short-limbed dwarfism and abnormally fine and sparse hair in children. These children are especially susceptible to viral infections and recurrent respiratory infections. A high incidence of non-Hodgkin lymphoma, leukemia, squamous cell carcinoma, and basal cell carcinoma has been reported. A functional defect of small lymphocytes, with impaired cell-mediated immunity, may occur (Fig. 27-47).
Syndromes that include abnormalities of the hair
hypotrichosis, and dental abnormalities. The nose is thin, sharp, and hooked, and the chin is absent. The hair is diffusely sparse and brittle. Baldness may occur frontally or at the scalp margins, but sutural alopecia—hair loss following the lines of the cranial sutures—is characteristic of this syndrome. The small face is in sharp contrast with a disproportionately large-appearing head. The lips are thin; some of the teeth may be absent while others are dystrophic, resulting in malocclusion. Nystagmus, strabismus, and other ocular abnormalities are present. Cleft palate and syndactyly may be present, representing overlap with oculodentodigital dysplasia associated with GJA1 gene mutation.
Klippel–Feil syndrome This syndrome consists of a low posterior scalp hairline extending on to the shoulders, with a short neck, limiting movement of the neck and suggestive of webbing. The cervical vertebrae are fused. This syndrome is caused by faulty segmentation of the mesodermal somites between the third and seventh weeks in utero. Strabismus, nystagmus, cleft palate, bifid uvula, and high palate are other features. Ear abnormalities include microtia, external ear canal stenosis, and chronic ear inflammation. This syndrome occurs mostly in girls.
McKusick syndrome Features of this syndrome include short-limbed dwarfism and fine, sparse, hypoplastic, and dysmorphic hair.
Atrichia with papules This is a rare disorder characterized by loss of hair beginning shortly after birth and the development of cutaneous cystic papules. Mutations in the hairless gene have been identified in both humans and mice, but a similar phenotype has also 571
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been reported with a normal hairless gene but with vitamin D-resistant rickets type IIA and mutations in the vitamin D receptor gene. The cyst epithelium demonstrates keratin-15 and 17, suggesting derivation from the follicular bulge and the presence of stem cells. Both the hairless gene and the vitamin D receptor gene produce zinc-finger proteins and may have overlapping functions. Kantaputra P, et al: Tricho-rhino-phalangeal syndrome with supernumerary teeth. J Dent Res 2008 Nov; 87(11):1027–1031. Matesic D, et al: Cartilage-hair hypoplasia. Mayo Clin Proc 2007 Jun; 82(6):655. Taskinen M, et al: Extended follow-up of the Finnish cartilage-hair hypoplasia cohort confirms high incidence of non-Hodgkin lymphoma and basal cell carcinoma. Am J Med Genet A 2008 Sep 15; 146A(18):2370–2375. Yildirim N, et al: Klippel–Feil syndrome and associated ear anomalies. Am J Otolaryngol 2008 Sep–Oct; 29(5):319–325.
Keratosis pilaris Keratosis pilaris may be limited in mild cases to the posterior upper arms, and manifests as a horny plug in each hair follicle. The thighs are the next most common site, but lesions may occur on the face, forearms, buttocks, trunk, and legs. Facial involvement may be mistaken for acne vulgaris and may leave small, pitted scars, even when the condition does not scar elsewhere. Variants of keratosis pilaris with more prominent scarring are included under the heading of keratosis pilaris atrophicans. The individual lesions are small, acuminate, follicular papules. They may or may not be erythematous. Sometimes the keratotic plugs are the most prominent feature of the eruption, whereas at other times most of the lesions are punctate erythematous papules. Occasionally, inflammatory acneiform pustules and papules may appear. Forcible removal of one of the plugs leaves a minute cupshaped depression at the apex of the papule, which is soon filled by new keratotic material. The lesions tend to be arranged in poorly defined groups, dotting the otherwise normal skin in a fairly regular pattern. They are prone to appear in xerotic or atopic subjects. Autosomal-dominant inheritance has been described. Other conditions associated with keratosis pilaris are ichthyosis follicularis, atrichia with papular lesions, mucoepidermal dysplasia, cardiofacio-cutaneous syndrome (keratosis pilaris, curly hair, sparse hair with pulmonary valve stenosis, hypertrophic cardiomyopathy, or atrial septal defect), ectodermal dysplasia with corkscrew hairs, and KID syndrome. Keratosis pilaris rubra has prominent erythema and widespread areas of skin involvement, but no atrophy or hyperpigmentation. Treatment is difficult, but some patients respond to topical retinoids. Twelve percent ammonium lactate can produce some smoothing of the lesions but seldom results in improvement of the erythema. Topical calcipotriene is effective in some patients.
found. It has been described repeatedly in association with other genetically determined abnormalities, including X-linked dominant chondrodysplasia punctata, Bazex syndrome (follicular atrophoderma type), and keratosis palmoplantaris disseminata. Bazex (Bazex–Dupré–Christol) syndrome is characterized by congenital hypotrichosis, follicular atropho derma, multiple milia, hypohidrosis, and basal cell carcinomas. Both trichorrhexis nodosa and pili bifurcati have been described in patients with the syndrome.
Keratosis pilaris atrophicans Keratosis pilaris atrophicans is seen in three syndromes: keratosis pilaris atrophicans faciei, atrophodermia vermiculata, and keratosis pilaris follicularis spinulosa decalvans. Keratosis pilaris atrophicans has been reported as being associated with woolly hair and Noonan syndrome. Overlap between the three entities may occur. Response to therapy is often limited, but some success has been noted with keratolytics and retinoids. Pulsed dye laser has led to improvement in erythema, but not skin roughness.
Keratosis pilaris atrophicans faciei and ulerythema ophryogenes Keratosis pilaris atrophicans faciei is characterized by persistent erythema and small, horny, follicular papules with onset during childhood. On involution these leave pitted scars and atrophy, with resulting alopecia. The disorder involves the eyebrows, from which it may rarely spread to the neighboring skin and even to the scalp. The term ulerythema ophryogenes is used to describe cases with involvement limited to the lateral third of the eyebrows. Lesions may also begin on the cheeks or temples, rather than the eyebrows. The follicles become reddened (Fig. 27-48), then develop papules, and finally, follicular atrophy. In keratosis pilaris atrophicans faciei the follicular involvement extends to the cheeks and forehead. Histologically, follicular hyperkeratosis of the upper third of the hair follicle is seen. A small depressed scar forms when the lesion heals. It may occur with atopy or woolly hair, and may be seen in Noonan syndrome and the cardio-facio-cutaneous syndrome. Transmission is autosomal-dominant.
Erythromelanosis follicularis faciei et colli Patients with the condition present with well-demarcated erythema, follicular papules, and hyperpigmentation. Itching and photosensitivity may be prominent.
Follicular atrophoderma Follicular atrophoderma consists of follicular indentations without hairs, notably occurring on extensor surfaces of the hands, legs, and arms. Scrotal (fissured) tongue may also be 572
Fig. 27-48 Ulerythema ophryogenes.
Atrophodermia vermiculata is also known as atrophoderma vermiculata, atrophodermia ulerythematosa, folliculitis ulerythematosa reticulata, and honeycomb atrophy. It is characterized by symmetrical involvement of the face by numerous, closely crowded, small areas of atrophy separated by narrow ridges, producing a cribriform or honeycomb surface. This worm-eaten (vermiculate) appearance results from atrophy of the follicles and surrounding skin. Each atrophic area is an abrupt, pitlike depression 1–3 mm in diameter. Among the ridges a few milia may be seen. The skin covering the ridges is even with the normal skin but is contrasted with it by being somewhat waxy, firmer, and apparently stretched. The cause of the disease is undetermined but familial occurrence has been noted, and it may be associated with other diseases, such as congenital heart block, other cardiac anomalies, neurofibromatosis, oligophrenia, or Down syndrome. Histologically, the epidermis is slightly atrophic, with diminution in size of the interpapillary projections. In the dermis the capillaries are dilated and the vessels have a moderate lymphocytic perivascular infiltration. Follicles may be enlarged, tortuous, dilated, and hyperkeratotic.
Rombo syndrome Rombo syndrome is a rare disorder characterized by atrophodermia vermiculata, cyanosis of the hands and feet, milia, telangiectases, hypotrichosis, multiple basal cell carcinomas, and trichoepitheliomas. The associated vermicular atropho derma produces a coarse, grainy skin texture. The syndrome is inherited in an autosomal-dominant fashion. It must be distinguished from Bazex syndrome, Rasmussen syndrome (milia, trichoepithelioma, and cylindroma), and multiple trichoepitheliomas.
Keratosis follicularis spinulosa decalvans (Siemens-1 syndrome) In keratosis follicularis spinulosa decalvans, keratosis pilaris begins on the face and progresses to involve the scalp, limbs, and trunk. There is hyperkeratosis of the palms and soles. Cicatricial alopecia of the scalp and eyebrows is characteristic. Atopy, photophobia, and corneal abnormalities are commonly
associated. Deafness, physical and mental retardation, recurrent infections, nail abnormalities, acne keloidalis nuchae, tufted hair folliculitis and aminoaciduria have also been purported associations. The disorder is genetically heterogeneous. Although inheritance in large kindreds has been X-linked recessive, X-linked dominant and autosomal-dominant inheritance have also been suggested. In one X-linked form, the defective genetic site is on Xp22.13–p22.2 in the region of the gene for spermidine/spermine N(1)-acetyltransferase.
H syndrome
Atrophodermia vermiculata
Armour CM, et al: Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations. J Med Genet 2008 Apr; 45(4):249–254. Barcelos AC, et al: Bazex-Dupré-Christol syndrome in a 1-year-old boy and his mother. Pediatr Dermatol 2008 Jan–Feb; 25(1):112–113. Bellet JS, et al: Keratosis follicularis spinulosa decalvans in a family. J Am Acad Dermatol 2008 Mar; 58(3):499–502. Chien AJ, et al: Hereditary woolly hair and keratosis pilaris. J Am Acad Dermatol 2006 Feb; 54(2 Suppl):S35–39. Di Lernia V, et al: Folliculitis spinulosa decalvans: an uncommon entity within the keratosis pilaris atrophicans spectrum. Pediatr Dermatol 2006 May–Jun; 23(3):255–258. Hwang S, et al: Keratosis pilaris: a common follicular hyperkeratosis. Cutis 2008 Sep; 82(3):177–180. Janjua SA, et al: Keratosis follicularis spinulosa decalvans associated with acne keloidalis nuchae and tufted hair folliculitis. Am J Clin Dermatol 2008; 9(2):137–140. Marqueling AL, et al: Keratosis pilaris rubra: a common but underrecognized condition. Arch Dermatol 2006 Dec; 142(12):1611–1616. Sardana K, et al: An observational analysis of erythromelanosis follicularis faciei et colli. Clin Exp Dermatol 2008 May; 33(3):333–336.
H syndrome The “H syndrome” is an inherited syndrome characterized by hyperpigmentation, hypertrichosis, and indurated patches of skin involving the lower two-thirds of the body, with hearing loss, hypogonadism, hepatosplenomegaly, short stature, cardiac anomalies, and scrotal masses. The patients exhibit growth hormone deficiency and hypergonadotropic hypo gonadism with azoospermia. Biopsies of involved skin demonstrate acanthosis with dermal and subcutaneous infiltration by histiocytes, plasma cells, and mast cells. Molho-Pessach V, et al: The H syndrome: a genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin with systemic manifestations. J Am Acad Dermatol 2008 Jul; 59(1):79–85.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 27-1 Late pigmentary incontinentia pigmenti. Fig. 27-2 Café-au-lait macules. Fig. 27-3 Proteus syndrome. Fig. 27-4 Ataxia-telangiectasia. Fig. 27-5 Epidermolysis bullosa simplex. Fig. 27-6 Epidermolysis bullosa, dominant dystrophic. Fig. 27-7 Benign familial pemphigus. Fig. 27-8 X-linked ichthyosis. Fig. 27-9 Porokeratosis.
Fig. 27-10 Darier’s disease. (Courtesy of Lawrence Lieblich, MD) Fig. 27-11 Pachyonychia congenita. Fig. 27-12 Pachyonychia congenita. Fig. 27-13 Pachyonychia congenita. Fig. 27-14 Hypohidrotic ectodermal dysplasia. (Courtesy of James Fitzpatrick, MD) Fig. 27-15 Cutis verticis gyrata. Fig. 27-16 Goltz syndrome. Fig. 27-17 Sclerodermatous legs in progeria. Fig. 27-18 Ocular squamous cell carcinoma in xeroderma pigmentosum.
Fig. 27-19 Periungual fibromas (Koenen tumors). (Courtesy of Brooke Army Medical Center Teaching File) Fig. 27-20 Lisch nodules. (Courtesy of Brooke Army Medical Center Teaching File) Fig. 27-21 Segmental neurofibromatosis. Fig. 27-22 Epidermolysis bullosa, dominant dystrophic. Fig. 27-23 Pachyonychia congenita. Fig. 27-24 Rothmund–Thomson syndrome.
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Dermal and Subcutaneous Tumors
The dermis and subcutaneous tissue contain many cellular elements, all capable of both reactive and neoplastic proliferation. In this chapter, proliferations derived from vascular endothelial cells, fibroblasts, myofibroblasts, smooth muscle cells, Schwann cells, and lipocytes are reviewed. Also discussed are several neoplasms of cells invading or aberrantly present in the dermis, such as metastatic cancer, endometriosis, and meningioma.
Cutaneous vascular anomalies Clear differentiation between infantile hemangiomas and vascular malformations is helpful when planning therapy, as infantile hemangiomas involute spontaneously while vascular malformations are persistent. The biology of vascular lesions remains a fertile area for research. Blie et al reported six kindreds in which infantile hemangiomas and/or vascular malformations occurred in various family members in an autosomal-dominant fashion. This unexpected finding clinically links malformations and hemangiomas. The nature of underlying angiogenic etiologic factors awaits elucidation. PHACE syndrome is another instance where hemangiomas and vascular malformations segregate together. Pediatric patients with vascular abnormalities benefit from multidisciplinary evaluation by experts, as the diagnosis and management may be difficult. Garzon MC, et al: Vascular malformations. Part I. J Am Acad Dermatol 2007 Mar; 56(3):353–370. Garzon MC, et al: Vascular malformations. Part II: associated syndromes. J Am Acad Dermatol 2007 Apr; 56(4):541–564. Goh SG, et al: Cutaneous vascular tumours: an update. Histopathology 2008 May; 52(6):661–673.
Hamartomas Hamartomas are characterized by an abnormal arrangement of tissues normally present in a given site. This is in contrast to a nevus, which has an increase in tissue normally present at a given site, but in an orderly “normal” arrangement.
Phakomatosis pigmentovascularis Patients with a combination of vascular malformations and melanocytic or epidermal nevi are grouped into this disorder, and are manifestations of genetic twin spotting. In the traditional classification, types I–IV have nevus flammeus. Those with a coexisting epidermal nevus have type I; if aberrant Mongolian spots are present, it is classified as type II; if a nevus spilus is seen, it is classified as type III; and when both ectopic Mongolian spots and nevus spilus are present, it is classified as type IV. The last three categories may have associated nevus anemicus. The association of extensive cutis marmorata telangiectatica congenita and aberrant Mongolian spots has been classified as type V. If only cutaneous disease
is present, the patient’s condition is designated subtype a; if there is associated systemic disease, subtype b is appended. A revised classification includes only three types: phakomatosis cesioflammea (blue spots and nevus flammeus), phakomatosis spilorosa (nevus spilus and a pale pink spot), and phakomatosis cesiomarmorata (blue spots and cutis marmorata telangiectatica congenita). Associated systemic findings may include intracranial and visceral vascular anomalies, ocular abnormalities, choroidal melanoma, and hemihypertrophy of the limbs. Type II is the most common (85%). Half of patients with this type have serious manifestations, such as Klippel– Trenaunay–Parkes–Weber syndrome or Sturge–Weber syndrome. Bilateral deafness and malignant hypertension have also been described. Some authors have suggested that particularly extensive and aberrant Mongolian spots may be a marker for more severe systemic involvement. Type III has been associated with multiple granular cell tumors. Most patients are Asian. Phacomatosis pigmentokeratotica may be associated with linear connective tissue nevus and pinheadsized angioma-like lesions superimposed on a speckled lentiginous nevus. Boente Mdel C, et al: Phacomatosis pigmentokeratotica: a follow-up report documenting additional cutaneous and extracutaneous anomalies. Pediatr Dermatol 2008 Jan–Feb; 25(1):76–80. Fernández-Guarino M, et al: Phakomatosis pigmentovascularis: clinical findings in 15 patients and review of the literature. J Am Acad Dermatol 2008 Jan; 58(1):88–93. Hall BD, et al: Phakomatosis pigmentovascularis: implications for severity with special reference to Mongolian spots associated with Sturge–Weber and Klippel–Trenaunay syndromes. Am J Med Genet A 2007 Dec 15; 143A(24):3047–3053.
Eccrine angiomatous hamartoma Eccrine angiomatous hamartoma usually appears as a solitary nodular lesion on the acral areas of the extremities, particularly the palms and soles, but identical lesions also occur on areas of the body that normally have few eccrine glands. This lesion appears at birth or in early childhood, and is often associated with pain and hyperhidrosis. The lesion is a domeshaped, tender, bluish nodule. Hypertrichosis may be present. When it is stroked or pinched, drops or beaded rings of perspiration may be seen. Histologically, there is a combination of lobules of mature eccrine glands and ducts with thin-walled blood vessels. Excessive mucin, fat, smooth muscle, and terminal hairs may be present. The lesion has been associated with spindle cell hemangioma, arteriovenous malformation, and verrucous hemangioma. Excision may be necessary because of pain. Galan A, et al: Eccrine angiomatous hamartoma with features resembling verrucous hemangioma. J Cutan Pathol 2007 Dec; 34 Suppl 1:68–70. Toll A, et al: Multifocal segmental hyperthermic and hyperhidrotic naevus flammeus: a peculiar variant of eccrine angiomatous hamartoma? Clin Exp Dermatol 2007 Nov; 32(6):696–698.
These are abnormal structures that result from an aberration in embryonic development or trauma. The abnormality may stem from an anatomic malformation or from functional alteration (as in nevus anemicus). The former are subdivided according to the type of vessel involved: capillary, venous, arterial, lymphatic, or combined. The term “capillary malformation” is sometimes used as a synonym for nevus flammeus, but is best used as a term encompassing a variety of other entities, such as nevus anemicus and cutis marmorata telangiectatica congenita. Happle R: What is a capillary malformation? J Am Acad Dermatol 2008 Dec; 59(6):1077–1079.
Nevus anemicus Nevus anemicus is a congenital disorder characterized by macules of varying size and shape that are paler than the surrounding skin and cannot be made red by trauma, cold, or heat. The nevus resembles vitiligo, but there is a normal amount of melanin. Wood’s light does not accentuate it, and diascopy causes it to merge into the surrounding blanched skin. The patches are usually well defined with irregular edges. Rarely, it may occur in neurofibromatosis, tuberous sclerosis, or as one component of phakomatosis pigmentovascularis. In nevus anemicus the triple response of Lewis lacks a flare, but outside the nevus a flare does develop after rubbing the skin. The underlying defect is an increased sensitivity of the blood vessels to catecholamines.
Nevus oligemicus Nevus oligemicus presents as a patch of livid skin that is cooler than the normal skin, as a result of decreased blood flow. Vasoconstriction of deep vessels is thought to be the underlying defect. Davies MG, et al: Nevus oligemicus. Arch Dermatol 1981; 117:111. Plantin P, et al: Nevus oligemicus. J Am Acad Dermatol 1992; 26:268.
Cutis marmorata telangiectatica congenita (congenital phlebectasia, van Lohuizen syndrome) Cutis marmorata telangiectatica congenita is characterized by the presence of a purplish, reticulated, vascular network with a segmental distribution, usually involving the extremities. The mottling is pronounced and is made more distinct by crying, vigorous activity, and cold; at birth, it may resemble a port wine stain. Lesions usually improve by 2 years of age but may remain stable. The condition occurs sporadically and there is a female preponderance. The segmental distribution suggests mosaicism, and occasional familial occurrence could be explained by paradominant inheritance, where heterozygous individuals are phenotypically normal and the mutation is transmitted unperceived, only becoming manifest when a postzygotic mutation gives rise to loss of heterozygosity. Associated anomalies occur in more than half of patients. Common anomalies include varicosities, nevus flammeus, ulceration, macrocephaly, and hypoplasia and hypertrophy of soft tissue and bone. Unusual associations include generalized congenital fibromatosis, premature ovarian failure, Chiari I malformation, and rectal and genital anomalies. These lesions are associated with Mongolian spots as type 5 phakomatosis pigmentovascularis. They have also been reported in association with features of the Adams–Oliver syndrome (limb abnormalities, scalp defects, skull ossification defects). High copper levels and increased elastolysis have been described. The differential diagnosis includes residual vascular lesions from neonatal lupus and Bockenheimer syndrome.
Bockenheimer syndrome appears in childhood and shows progressive development of large venous ectasias involving one limb. No treatment is required. Many will become less noticeable with time. Hinek A, et al: High copper levels and increased elastolysis in a patient with cutis marmorata telangiectasia congenita. Am J Med Genet A 2008 Oct 1; 146A(19):2520–2527. Imafuku S, et al: Cutis marmorata telangiectatica congenita manifesting as port wine stain at birth. J Dermatol 2008 Jul; 35(7):471–472. Katugampola R, et al: Macrocephaly-cutis marmorata telangiectatica congenita: a case report and review of salient features. J Am Acad Dermatol 2008 Apr; 58(4):697–702.
Nevus flammeus (port wine stain) Nevus flammeus nuchae (stork bite) is a congenital capillary malformation present in 25% of newborns. It may persist in at least 5% of the population. It usually is a pink–red macule situated on the posterior midline between the occipital protuberance and the tip of the spine of the fifth cervical vertebra. The long axis is usually up and down. A similar-appearing midline nevus flammeus (salmon patch or angel’s kiss) on the glabellar region or on one upper eyelid is present in approximately 15% of newborns. It tends to fade during childhood. Other port wine stains occur in an estimated 3 in 1000 children. They are present at birth, and vary in color from pink to dark or bluish red. The lesions are usually unilateral and located on the face and neck, although they may be widespread and involve as much as half the body. The most common site is a unilateral distribution on the face. The mucous membrane of the mouth may be involved (Fig. 28-1). Although the surface of a nevus flammeus is usually smooth, small vascular nodular outgrowths or warty excrescences may develop over time. These lesions often become more bluish or purple with age. Several reports document multiple basal cell carcinomas occurring in adult life over sites of long-standing nevus flammeus. Rarely, nevus flammeus may appear as an acquired condition, usually with onset after trauma. Nevus flammeus in the area supplied by the ophthalmic division of the trigeminal cranial nerve is a component of the Sturge–Weber syndrome (encephalotrigeminal angiomatosis), but the leptomeningeal component is present in only 10% of patients with all or most of the V1 branch of the trigeminal nerve involved. Leptomeningeal angiomatosis may clinically manifest as epilepsy, mental retardation, hemiplegia, hemisensory defects, and homonymous hemianopsia. Characteristic
Cutaneous vascular anomalies
Malformations
Fig. 28-1 Port wine stain.
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calcifications are present in the outer layers of the cerebral cortex; these consist of double-contoured “tram tracks” that follow the brain convolutions. Ocular abnormalities, such as glaucoma, buphthalmos (infantile glaucoma, related to abnormal development of the angle formed by cornea and iris), retinal detachment, and blindness, affect approximately 50% of patients. These may be present without leptomeningeal involvement. The syndrome results from the persistence of the primitive embryonal vascular plexus that develops during the sixth fetal week around the cephalic neural tube and in the region destined to become facial skin. Normally, the plexus regresses during the ninth week, but in the Sturge–Weber syndrome it persists. Fibronectin gene expression is increased in lesional fibroblasts. Overgrowth of soft tissue and underlying bone may occur in an affected extremity, giving rise to the Klippel–Trenaunay– Parkes–Weber syndrome. The Klippel–Trenaunay syndrome is characterized by port wine malformations, and the Parkes– Weber syndrome by deep arteriovenous malformations. Port wine stains are components of many rare congenital disorders. Occasionally, nevus flammeus may be associated with nevus anemicus, nevus spilus, atypical Mongolian spots, or epidermal nevi. Such patients have a condition called phakomatosis pigmentovascularis. The Beckwith–Wiedemann syndrome may comprise facial port wine stain, macroglossia, omphalocele, visceral hyperplasia, occasionally hemihypertrophy, and hypoglycemia. Cobb syndrome (cutaneous meningospinal angiomatosis) is a nonfamilial disorder characterized by a port wine hemangioma or other vascular malformation in a dermatome supplied by a segment of the spinal cord containing a venous or arteriovenous malformation. Kyphoscoliosis is common, and multiple neurologic, gastrointestinal, urologic, and skeletal abnormalities may also be present. Proteus syndrome is characterized by vascular malformations including nevus flammeus, hemihypertrophy, macrodactyly, verrucous epidermal nevus, soft-tissue sub cutaneous masses, and cerebriform overgrowth of the plantar surface. Roberts syndrome consists of a facial port wine stain and hypomelia, hypotrichosis, growth retardation, and cleft lip. The Wyburn–Mason syndrome consists of unilateral retinal arteriovenous malformation associated with ipsilateral port wine stain near the affected eye. This may be present in association with Sturge–Weber syndrome. The TAR syndrome is defined by congenital thrombocytopenia, bilateral absence or hypoplasia of the radius, and port wine stain. Coats’ disease manifests with retinal telangiectasia and ipsilateral facial port wine stain. Lesional skin demonstrates overexpression of vascular endothelial growth factor (VEGF) and its receptor (VEGF-R2). Occasional familial segregation of port wine stains has been noted, and a large associated gene locus, CMC1, has been identified on chromosome 5q. RASA1, a gene encoding p120– RasGAP, is found within this region and heterozygous inactivating RASA1 mutations have been found in affected families. Histologically, port wine stains demonstrate dilatation of capillaries in the subpapillary network. Laser therapy has been used with satisfactory results, but a number of treatments are required and recurrence is common. The flashlamp pulsed dye laser has the best record of safety and efficacy. Commonly, a pulse duration of 0.45 ms is used. A study of cryogen spraycooled laser treatment at wavelengths of 585 versus 595 nm, both with 7 mm spot size in a range of 7–10 J/cm2, demonstrated better blanching at 585 nm. In another study, purple lesions responded best to 585 nm at 0.5 ms, while red and pink lesions showed similar results with either 585 nm at 0.5 ms or 595 nm for 20 ms. In this study, 595 nm at 0.5 ms was less effective than the other settings. Optical–thermal models predict that for vessel diameters of 40, 80, and 120 µm,
effective pulse durations should be approximately 1.5, 6, and 20 ms, respectively. Cryospray cooling and fluence can be varied to produce optimal results. For darker-skinned patients, multiple pulse stacking with multiple cryogen spurts provides better epidermal protection. Intense pulsed light has been effective in some patients resistant to multiple pulsed dye laser treatments. Long-pulse pulsed alexandrite lasers work best for hypertrophic, purple lesions, while pulsed dye lasers work best for flat, pink lesions. The variable pulse pulsed dye laser may be effective in lesions refractory to standard pulse dye laser treatment. Other modalities that have been studied include 810 nm diode and 1064 nm neodymium:yttriumaluminum-garnet (Nd:YAG), as well as intense pulse light systems. Photodynamic therapy shows some promise. Goldberg DJ: Treatment of port wine stains. J Cosmet Laser Ther 2010 Feb; 12(1):1. Jasim ZF, et al: Treatment of pulsed dye laser-resistant port wine stain birthmarks. J Am Acad Dermatol 2007 Oct; 57(4):677–682. Kelly K: Current treatment options for port wine stain birthmarks. Photodiagn Photodyn Ther 2007 Sep; 4(3):147–148. Li L, et al: Comparison study of a long-pulse pulsed dye laser and a long-pulse pulsed alexandrite laser in the treatment of port wine stains. J Cosmet Laser Ther 2008 Mar; 10(1):12–15. MacFie CC, et al: Diagnosis of vascular skin lesions in children: an audit and review. Pediatr Dermatol 2008 Jan–Feb; 25(1):7–12. Stier MF, et al: Laser treatment of pediatric vascular lesions: port wine stains and hemangiomas. J Am Acad Dermatol 2008 Feb; 58(2):261–285. Vural E, et al: The expression of vascular endothelial growth factor and its receptors in port wine stains. Otolaryngol Head Neck Surg 2008 Oct; 139(4):560–564.
Angiokeratoma circumscriptum naeviforme This is a malformation of dermal and subcutaneous capillaries and veins, and is variably classified as a capillary or venous malformation. The vascular malformation is congenital. Over time, a verrucous component appears. The lesions are bluishred and well defined, and occur on the lower extremities mostly, but also on the chest or forearm. Linear segmental lesions have been described. Associated spinal lesions (Cobb syndrome) have been reported. Klippel–Trenaunay syndrome has also been reported in association with verrucous vascular malformation. Superficial ablative therapy is typically followed by recurrence, regardless of whether ablation is performed by excision, laser, cryotherapy, or electrocautery. Full-thickness excision is generally effective, and may be used in combination with laser therapy.
Deep venous malformations including cavernous venous malformation Cavernous venous malformations present as rounded, bright red or deep purple, spongy nodules. They occur chiefly on the head and neck and may involve both the skin and the mucous membranes. There is usually a deep component with a connection to the venous circulation. Calcified phleboliths and localized hyperhidrosis may occasionally be present, but the lesions are generally asymptomatic. The deep components are not amenable to laser therapy. Results of surgical resection are generally poor. Compression may be helpful. Customized, snug-fitting garments are preferable to elastic bandages. Several syndromes are associated with venous malformations. The Bannayan–Riley–Ruvalcaba syndrome is described later in this chapter. Maffucci syndrome, also known as dyschondroplasia with hemangiomata, is characterized by multiple vascular malformations with dyschondroplasia (Fig. 28-2). The dyschondroplasia is manifested by uneven bone growth as a result of the defects of ossification, with enchondromatosis that results in multiple and frequent fractures in the period of bone growth. During the prepubertal
Cutaneous vascular anomalies Fig. 28-3 Blue rubber bleb nevus syndrome.
Fig. 28-2 Maffucci syndrome.
years, 1–2 cm nodules appear on the small bones of the hand or foot. Later, larger nodules, the enchondromas, appear on the long bones. Much later, similar lesions appear on the trunk. Sarcomatous degeneration occurs in 50% of patients. The distribution of the lesions is mostly unilateral. Multiple venous malformations of the skin and mucous membranes are present in this nonhereditary mesodermal dysplasia disorder. Lymphangiomas may also occur. Pigmentary changes, such as vitiligo and café-au-lait macules, have been noted. In Ollier disease, the enchondromatosis is present without the cutaneous abnormalities. Human enchondromatosis has been associated with abnormalities in parathyroid hormone-related protein (PTHrP), its receptor, and the Indian hedgehog (IHH) gene. PTHrP delays differentiation of proliferating chondrocytes, whereas IHH promotes proliferation. The blue rubber bleb nevus syndrome is characterized by cutaneous and gastrointestinal venous malformations. The skin lesions have a cyanotic, bluish appearance with a soft, elevated, nipple-like center, but deeper lesions may also occur. They can be emptied by firm pressure, leaving them flaccid. They are located predominantly on the trunk and arms. Nocturnal pain may occur and is a characteristic symptom. Gastrointestinal hemangiomas are found throughout the gastrointestinal tract (Fig. 28-3), but are numerous in the small intestines. Rupture of a lesion may produce melena. Occasionally, other organs may express venous malformations and symptomatic central nervous system (CNS) lesions have been described. This syndrome generally occurs as a sporadic condition. It may be present as an autosomal-dominant familial trait. Treatment of bleeding or painful lesions is destruction or excision. Minimally invasive surgical techniques are well suited to the treatment of numerous lesions. For patients who continue to have bleeding episodes that require blood transfusions, octreotide, a somatostatin analog known to decrease splanchnic blood flow, may be effective. ε-Aminocaproic acid has also been used. Gorham’s disease (Gorham’s sign) is characterized by cutaneous and osseous venous and lymphatic malformations associated with massive osteolysis or “disappearing bones.” Although multiple areas of the skeletal system may be
involved, usually only a single bone is destroyed. There is complete or partial replacement of the bone with fibrous tissue. The cutaneous malformation may be the initial sign of the disease, which appears commonly in young children, usually in areas adjacent to involved bones. Sinusoidal hemangioma is a vascular malformation that usually presents in adults as a bluish-purple nodule, less than 4 cm in diameter, on the trunk or breasts. Multiple lesions may occur and a facial location has also been reported. Histologically, it appears as a lobular, circumscribed mass with dilated interconnected vascular channels filled with blood. A familial condition of multiple cutaneous and mucosal venous malformations that show abnormal venous channels with decreased or absent smooth muscle has been shown to be the result of an activating mutation in the receptor tyrosine kinase TIE-2 endothelial gene. It is located on chromosome 9p and is the result of a single amino acid substitution in the kinase domain of the TIE-2 receptor. Cerebral cavernomas are vascular malformations that may be inherited in an autosomal-dominant fashion. The gene, CCM1, has been mapped to chromosome 7. Cutaneous malformations are sometimes present, including hyperkeratotic cutaneous capillary venous malformations. Venous malformations (VM) should be distinguished from glomuvenous malformations (GM, glomangioma). VMs are usually sporadic, while GMs are frequently inherited. VM is linked to chromosome 9p21, while GM is linked to 1p21 and loss-of-function mutations in glomulin. GM can be pink at initial presentation, but evolves to blue–black with a cobblestone appearance and minimal hyperkeratosis. Involvement of an extremity is typical and the lesions are often painful if compressed. VM is an isolated mucosal or subcutaneous blue lesion that may involve muscle. The lesion often shrinks with external pressure and is typically painful in the morning due to congestion. Increased pain may be noted at puberty, during menstruation, with pregnancy, or with oral contraceptives. VM may be associated with intravascular coagulopathy. Sclerotherapy is more effective in VM than in GM. Ethanolamine oleate has been reported as a novel sclerotherapy agent. Both soft tissue injury and neuropathy have been reported after various forms of embolization or sclerotherapy. Absence of deeper tissue involvement noted with magnetic resonance imaging (MRI) is associated with a higher rate of skin necrosis and alcohol embolization.
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Fayad LM, et al: Venous malformations: MR imaging features that predict skin burns after percutaneous alcohol embolization procedures. Skeletal Radiol 2008 Oct; 37(10):895–901. Lee KB, et al: Incidence of soft tissue injury and neuropathy after embolo/sclerotherapy for congenital vascular malformation. J Vasc Surg 2008 Nov; 48(5):1286–1291.
Klippel–Trenaunay syndrome (hemangiectatic hypertrophy, angio-osteohypertrophy syndrome) Klippel–Trenaunay syndrome (KTS) is characterized as a triad of nevus flammeus, venous and lymphatic malformations, and soft tissue hypertrophy of the affected extremity (Fig. 28-4). The lower limb is affected in approximately 95% of patients. When there is an associated arteriovenous fistula, Parkes– Weber is appended to the diagnosis. The earliest and most common presenting sign is a nevus flammeus that is confined to the skin of an extremity. The port wine stain often stops abruptly at the midline with a sharp, linear border, but it may be patchy and extend over the buttocks and trunk, and may occasionally be seen with a bilateral or generalized distribution. Varicose veins may be present. The deeper venous malformation in this sporadic syndrome may be confined to the skin; however, it is common for the malformation to extend to muscle and bone. Venous thromboembolism has been reported with an incidence as high as 22%. In other patients, the deep venous system is hypoplastic. The involved limb is usually larger and longer than normal. Other less frequent features include intermittent claudication, venous ulcers, increased skin temperature, diffuse hair loss, hypertrichosis, lymphedema, altered sweating, lacrimation, or salivation. Gait abnormalities are common. Hemihypertrophy of the face; cutaneous lymphangioma; varicose pulmonary, bladder, and colonic veins; and recurrent pulmonary emboli have been reported. Intradural spinal cord arteriovenous malformations, epidural hemangioma, and epidural angiomyo lipoma have been reported to occur at the same segmental level as cutaneous lesions of KTS. Clinical evaluation consists of color duplex ultrasonography to evaluate the patency of the deep venous system, MRI for visualization of hypertrophic muscle and bone, arteriography when an arteriovenous fistula
Fig. 28-4 Klippel–Trenaunay syndrome.
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is suspected, and conventional radiography of both extremities. Early venography may be performed, if the deep venous system is not hypoplastic, to determine whether there are defects that might be amenable to surgical correction. Thickslice dynamic magnetic resonance projection angiography (MRPA) and intra-arterial digital subtraction angiography can be used to detect arteriovenous shunting in Parkes–Weber syndrome. Mutations associated with the angiogenic factor, VG5Q, have been described in KTS. A balanced translocation involving chromosomes 8q22.3 and 14q13 has also been reported. Flashlamp-pumped pulsed dye laser treatments may be used for the nevus flammeus component. The varicosities and malformations may respond to microfoam sclerosis, endovenous thermal ablation, or surgical stripping. Edema is managed through elevation, graded compression pumps, fitted garments, and diuretics. Surgery may be performed to correct the inequality in limb length, to relieve deep venous obstruction, or to correct an associated arteriovenous fistula. Skin ulcers have responded to sunitinib. The Klippel–Trenaunay Support Group website can be found at www.k-t.org. Gloviczki P, et al: Klippel–Trenaunay syndrome: current management. Phlebology 2007; 22(6):291–298. Nguyen S, et al: Skin ulcers in Klippel–Trenaunay syndrome respond to sunitinib. Transl Res 2008 Apr; 151(4):194–196. Redondo P, et al: Microfoam treatment of Klippel–Trenaunay syndrome and vascular malformations. J Am Acad Dermatol 2008 Aug; 59(2):355–356.
Arteriovenous fistulas An arteriovenous (AV) fistula is a route from artery to vein, bypassing the capillary bed. AV fistulas may be congenital or acquired. Congenital AV fistulas occur mostly on the extremities and may be recognized, or at least suspected, in the presence of varicose veins, ulcerations, hemangiomas, and nevus flammeus. They may occur internally as a component of Osler–Weber–Rendu disease (hereditary hemorrhagic telangiectasia). Acquired fistulas are usually the result of trauma (Fig. 28-5), but may be created intentionally for hemodialysis access. The skin over these fistulas is warmer, hair may grow faster, and the affected limb may be larger than the other; thrills and bruits may be discerned in some cases. There may be changes resulting from stasis, a vascular steal syndrome, edema, a vascular mass, increased sweating, or paresthesias. At times, reddish-purple nodules or a plaque may be present with a clinical resemblance to Kaposi sarcoma; this has been called pseudo-Kaposi sarcoma (Stewart–Bluefarb syndrome). It may
Fig. 28-5 Stasis-like changes below an acquired arteriovenous fistula.
Benito-Ruiz J, et al: Steal syndrome of the hand complicating an arteriovenous fistula. Plast Reconstr Surg 2006 Apr; 117(4):1361–1363. Lee S, et al: Stasis dermatitis associated with arteriovenous fistula. Kidney Int 2007 Nov; 72(9):1171–1172.
Prominent inferior labial artery The arteries supplying the lips are normally tortuous to accommodate the movements of the mouth. Howell and Freeman reported a potentially troublesome arterial anomaly of the lower lip characterized by the appearance of a pulsating papule in the lower vermilion, a centimeter or two from the oral commissure, formed by an especially tortuous segment of the inferior labial artery. A similar anomaly may involve the upper lip. Caliber-persistent labial artery may be misdiagnosed as squamous cell carcinoma, and the biopsy may produce significant bleeding. On the lip, it is best to “palpate for pulsation prior to puncture.”
Acral arteriolar ectasia Paslin and Heaton reported a man with purple serpiginous ectatic arterioles on the backs of his fingers, which appeared in the fifth decade of life. Howell JB, Freeman RG: The potential peril from caliber-persistent arteries of the lips. J Am Acad Dermatol 2002; 46:256. Paslin DA, Heaton CL: Acral arteriolar ectasia. Arch Dermatol 1972; 106:906.
Superficial lymphatic malformation (lymphangioma circumscriptum) The old term for superficial lymphatic malformation was lymphangioma circumscriptum; however, this is not a tumor but rather a congenital malformation of the superficial lymphatics. A superficial lymphatic malformation presents as groups of deep-seated, vesicle-like papules (Fig. 28-6), resembling frog spawn, at birth or shortly thereafter. The lesions are usually yellowish but may be pink, red, or dark. When the papules are punctured, they exude clear, colorless lymph. The
Cutaneous vascular anomalies
occur because of congenital malformations, in which case a unilateral purplish discoloration of the skin over or distal to the AV anomaly begins to appear in the second or third decade of life. This type accounts for 80% of cases; the remainder are secondary to fistulas caused by trauma. Iatrogenic AV fistulas, such as those produced to facilitate hemodialysis, may also bring about skin changes, including reactive angioendothelio matosis. Histologically, there is an increase in thick-walled vessels lined by plump endothelial cells, extravasated erythro cytes, and deposits of hemosiderin. Proliferating endothelial cells may occlude the lumen. Cirsoid aneurysms (angioma arteriale racemosum) are uncommon congenital AV fistulas of the scalp or face. They may appear on the skin as a pulsating mass that may extend over the neck and scalp and may penetrate into the cranium, or they may simply manifest as a solitary blue or red papule in the mid-adult period. Diagnosis of an AV fistula is established by plethysmography, thermography, determination of oxygen saturation of venous blood, or arteriography. Treatment of traumatically induced AV fistulas by excision is curative. Because the congenital malformation variety consists of multiple small distal lesions, surgical intervention is not feasible in most cases. Color echo-Doppler ultrasonographyguided sclerotherapy with polidocanol microfoam has been used successfully in this setting. Pressure and elevation as supportive measures may limit ulceration, infection, and other secondary complications. Cirsoid aneurysms of the scalp have been treated by embolization and injection of sodium tetra decyl sulfate.
Fig. 28-6 Superficial lymphatic malformation.
papules are arranged irregularly in groups that may be interconnected by sparsely scattered lymph cysts. The entire process, however, is as a rule localized to one region. The sites of predilection are the abdomen, axillae, genitalia, and mouth, particularly the tongue. The scrotum is subject to multifocal lymphatic malformations presenting as clear, thick-walled, vesicle-like lesions. At times the surface is verrucous, in which instance the color may be brownish, and the lesions may be mistaken for warts. Lesions resembling molluscum contagiosum have also been described. Frequently, the lesions consist of a combination of blood and lymph element, so that purple areas are sometimes seen scattered within the vesicle-like papules. The lesions are also frequently associated with a deep component that occupies the subcutaneous tissues and muscles. In the course of time, these lymphatic malformations show only slight changes. Excision and grafting, fulguration, or coagulation is frequently unsatisfactory because of recurrences resulting from vascular connections between the surface lesions and deepseated lymphatic cisterns. The deeper component should be evaluated by MRI or other suitable radiologic imaging pro cedure to delineate the extent of deep involvement before planned procedures. Vaporization with the CO2 laser may be successful if deeper components are not present. Pulsed dye laser and intense pulse light systems have also been reported as effective. Keloid formation has been described after laser vaporization of genital lymphangiomas. Sclerotherapy has been reported as successful, and radiotherapy has been employed successfully in selected refractory cases. Bikowski JB, et al: Lymphangioma circumscriptum: treatment with hypertonic saline sclerotherapy. J Am Acad Dermatol 2005; 53:442. Bond J, et al: Lymphangioma circumscriptum: pitfalls and problems in definitive management. Dermatol Surg 2008 Feb; 34(2):271–275. Heller M, et al: Lymphangioma circumscriptum. Dermatol Online J 2008 May 15; 14(5):27. Thissen CA, et al: Treatment of lymphangioma circumscriptum with the intense pulsed light system. Int J Dermatol 2007 Nov; 46 Suppl 3:16–18. Yildiz F, et al: Radiotherapy in congenital vulvar lymphangioma circumscriptum. Int J Gynecol Cancer 2008 May–Jun; 18(3):556–559.
Cystic lymphatic malformation Cystic lymphatic malformations are deep-seated, typically multilocular, ill-defined, soft tissue masses that are painless and covered by normal skin. They are most common in the oral cavity and on the extremities, and have been described in Maffucci syndrome. Cystic hygromas are clinically better circumscribed, occurring usually in the neck (Fig. 28-7), axilla, or groin. The posterior neck lesions may be associated with 579
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Fig. 28-7 Cystic hygroma.
Turner syndrome, other chromosomal aneuploidy conditions, hydrops fetalis, or other congenital abnormalities. Cytogenic analysis of children born with cystic hygromas is indicated, as aneuploidy may recur in subsequent pregnancies. Transabdominal or transvaginal sonography can visualize these lesions in utero. Usually these lesions will recur after surgical treatments because of their depth, but injection sclero therapy with agents such as OK-432 (picibanil) may result in regression. Fujino A, et al: A role of cytokines in OK-432 injection therapy for cystic lymphangioma: an approach to the mechanism. J Pediatr Surg 2003; 38:1806. Lille ST, et al: The surgical management of giant cervicofacial lymphatic malformations. J Pediatr Surg 1996; 31:1648. Mosca RC, et al: Cystic hygroma: characterization by computerized tomography. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008 May; 105(5):e65–e69. Woolley SL, et al: Adult cystic hygroma: successful use of OK-432 (Picibanil). J Laryngol Otol 2008 Nov; 122(11):1260–1264.
Lymphangiomatosis Diffuse or multifocal dilated lymphatic channels involving the skin, soft tissues, bone, and parenchymal organs are a rare congenital condition. If an extremity is affected, the prognosis is good; however, when vital internal organs are involved, the prognosis is poor. Skin lesions are presenting signs in 7% of patients with thoracic lymphangiomatosis. These patients have a high incidence of complications, including chylothorax (49%), pulmonary infiltrates (45%), bone lesions (39%), splenic lesions (19%), cervical involvement (15%), and disseminated intravascular coagulation (9%).
Gorham–Stout syndrome Gorham–Stout syndrome is characterized by lymphangiomatosis and chylous effusions, with osteolytic changes resulting in “vanishing bones.” Response to pegylated interferon (IFN)α2b was noted in a 9-year-old boy with systemic disease, Response to bisphosphonates has also been noted. Meltzer E, et al: Diffuse lymphangiomatosis—a fatal case with atypical skeletal features. Am J Med Sci 2008 Nov; 336(5):445–448. Ozeki M, et al: Clinical improvement of diffuse lymphangiomatosis with pegylated interferon alpha-2b therapy: case report and review of the literature. Pediatr Hematol Oncol 2007 Oct–Nov; 24(7):513–524. Wong CS, et al: Clinical and radiological features of generalised lymphangiomatosis. Hong Kong Med J 2008 Oct; 14(5):402–404.
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Fig. 28-8 Venous lake.
Dilation of pre-existing vessels Spider angioma (vascular spider, spider nevus, nevus araneus) The lesion of spider angioma is suggestive of a red spider; hence its name. The ascending central arteriole represents the “body” of the spider, and the radiating fine vessels are suggestive of the multiple legs. These small telangiectases occur singly or severally, most frequently on the face and neck, with decreasing frequency on the upper trunk and upper extremities. In young children, the sites of predilection are the backs of the hands and forearms, and the face. Young children and pregnant women show these lesions most frequently. In pregnant women, palmar erythema is usually present with the vascular spiders. The presence of vascular spiders in otherwise healthy children is common. The vascular spiders of childhood usually involute without treatment; however, several years may elapse before that happens. In pregnant women, most lesions will involute soon after delivery. Vascular spiders also occur in patients with cirrhosis, hepatitis C, malignant disease of the liver, and other hepatic dysfunctions. The common denominator has been shown to be an elevated blood estrogen level. Elevations in VEGF and basic fibroblastic growth factor are also significant predictors for spider angiomas in cirrhotic patients. When vascular spiders occur with palmar erythema and pallid nails with distal hyperemic bands, cirrhosis of the liver should be considered. AV hemangioma has also been reported to be associated with chronic liver disease. If active therapy is to be performed, either obliteration by electrodesiccation of the central punctum or laser treatment produces excellent results. Laser treatment has produced good results in some patients.
Venous lakes Venous lakes (phlebectases) are small, dark blue, slightly elevated blebs (Fig. 28-8). They are easily compressed, and are located on the face, ears, lips, neck, forearms, and backs of the hands. These manifestations of chronic sun damage are
Capillary aneurysms These flesh-colored solitary lesions, resembling an intradermal nevus, may suddenly grow larger and darker and become blue–black or black as a result of thrombosis. They are surrounded by a zone of erythema. The lesions may be clinically indistinguishable from malignant melanoma. Histologically, these are thrombotic, dilated capillaries lying just below the epidermis. Shave excision in stages will expose the clot and eliminate the uncertainty.
Telangiectasia A telangiectasis is a dilated cutaneous blood vessel—venule, capillary, or arteriole. Telangiectases are fine, linear vessels coursing on the surface of the skin; the name given to them collectively is telangiectasia. Telangiectasia may occur in normal skin at any age, in both sexes, and anywhere on the skin and mucous membranes. Fine telangiectases may be seen on the alae nasi of most adults. They are prominent in areas of chronic actinic damage seen in fair-skinned persons. Persons long exposed to wind, cold, or heat are also subject to telangiectasia. Telangiectases can be found in such conditions as radiodermatitis, xeroderma pigmentosum, lupus erythematosus, dermatomyositis, scleroderma and the CREST syndrome, rosacea, cirrhosis of the liver, acquired immunodeficiency syndrome (AIDS), poikiloderma, basal cell carcinoma, necrobiosis lipoidica diabeticorum, sarcoid, lupus vulgaris, adenoma sebaceum, keloid, angioma serpiginosum, angiokeratoma corporis diffusum, ataxia-telangiectasia, pregnancy, Osler– Weber–Rendu disease, and Bloom syndrome. These entities are discussed in other sections with the disease states in which they occur. Altered capillary patterns on the fingernail folds (cuticular telangiectases) are indicative of collagen vascular disease, such as lupus erythematosus, scleroderma, or dermatomyositis. Tortuous glomeruloid loops are characteristic of lupus erythematosus, whereas dilated loops and avascular areas are typical of scleroderma and dermatomyositis. Reticular telangiectatic erythema may occur overlying implantable cardioverter defibrillators. Electrodessication and laser ablation can be effective. Pulsed dye laser and other vascular lasers, such as the 532 nm Nd:YAG laser, are usually well tolerated and associated with a low risk of scarring. Larger vessels require a longer pulse duration. Contact or cryospray cooling can reduce the incidence of complications. Pulse stacking (multiple pulses of low fluences) has been used to reduce the incidence of side effects, such as purpura, hyperpigmentation, hypopigmentation, and scar formation.
Generalized essential telangiectasia Generalized essential telangiectasia (GET) is characterized by the dilation of veins and capillaries over a large segment of the body without preceding or coexisting skin lesions. The telangiectases may be distributed over the entire body or be localized to some large area such as the legs, arms, and trunk. They may be discrete or confluent. Distribution along the course of the cutaneous nerves may occur. This type of telangiectasia is not associated with systemic disease, although patients with a similar appearance may have autoimmune
disease. One report documented gastrointestinal bleeding from a watermelon stomach in a woman with GET. GET develops most frequently in women in their forties and fifties. The initial onset is on the lower legs and then spreads to the upper legs, abdomen, and arms. The dilations persist indefinitely. Generally, this is a sporadic condition, although it has been described in families as an autosomal-dominant condition. In the latter case, it has been termed hereditary benign telangiectasia. It has been reported that GET may be differentiated from telangiectasia associated with systemic disease by the presence of alkaline phosphatase activity. Telangiectatic vessels in GET do not have alkaline phosphatase activity in the endothelium of the terminal arteriole and the arterial portion of the capillary loops. Individual areas may be treated with laser ablation. Highenergy, high-frequency, long-pulse Nd:YAG laser and the 585 nm flashlamp-pumped pulsed dye laser have been reported to produce good results. Tetracycline, ketoconazole, and the treatment of a chronic sinus infection have led to involution in individual reports.
Cutaneous vascular anomalies
markedly dilated, blood-filled spaces that are lined with thin, elongated endothelial cells, and are usually surrounded by prominent solar elastosis. Venous lakes may be treated by light electrocautery, laser ablation, fulguration, infrared coagulation, intralesional injection of 1% polidocanol, and cryotherapy. Sometimes they must be treated because of traumatic bleeding.
Universal angiomatosis Universal angiomatosis, called generalized telangiectasia by Bean, is a bleeding disease that affects the blood vessels of the skin and mucous membranes, as well as other parts of the body. Bean and Rather reported a 13-year-old boy who had frequent nose bleeds, and ear and upper respiratory infections. He had mottled skin, with redness that blanched on pressure. Finely dilated blood vessels were universal, suggesting the term “pink man.” Some irregular white patches were also present. Continual bleeding into the skin was evident despite normal coagulation of the blood. This type of angiomatosis differs from generalized telangiectasia because of its hemorrhagic tendency, especially epistaxis.
Unilateral nevoid telangiectasia In unilateral nevoid telangiectasia, fine, threadlike telangiectases develop in a unilateral, sometimes dermatomal, distribution. The areas most often involved are the trigeminal and C3 and C4 or adjacent areas, with the right side involved slightly more often than the left. In some cases the condition is congenital, but more often it is acquired. Increased estrogen appears to play a role in the onset of acquired cases, e.g. pregnancy, puberty in women, adrenarche in men, and hepatitis/ alcohol-related cases have all been reported. Lesions have responded to pulse dye laser treatment.
Angiokeratomas Angiokeratomas are essentially telangiectases that have an overlying hyperkeratotic surface (Fig. 28-9). These are dilations of pre-existing papillary dermal vessels. Angiokeratoma circumscriptum is discussed in the malformations section above. Angiokeratoma corporis diffusum is discussed in Chapter 26.
Angiokeratoma of Mibelli The lesions of angiokeratoma of Mibelli consist of 1–5 mm red vascular papules, the surfaces of which become hyperkeratotic in the course of time. The papules are dull red or purplishblack, verrucous, and rounded, and are usually situated on the dorsum of the fingers and toes, the elbows, and the knees. Frequently, these are called telangiectatic warts. The patient often has cold, cyanotic hands and feet. This is a rare genodermatosis with an autosomal-dominant trait for vascular lesions located over bony prominences and a family history of chilblains. The condition is most frequently discovered in prepubertal children. 581
Solitary angiokeratoma
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Described by Imperial and Helwig in 1967, solitary angio keratoma is a single small, bluish-black, warty papule that occurs predominantly on the lower extremities. It is not a hereditary lesion and probably follows trauma, with subsequent telangiectasia before the formation of the angiokeratoma. The mode of acquiring this lesion, and its small size, solitary nature, and location, distinguish it from other forms of angio keratoma. Solitary angiokeratoma is to be considered in the differential diagnosis of seborrheic keratosis, melanoma, pigmented basal cell carcinoma, and ordinary hemangioma. Treatment is by electrosurgery, laser ablation, or excision.
Fig. 28-9 Angiokeratoma.
Karabudak O, et al: Acquired unilateral nevoid telangiectasia syndrome. J Dermatol 2006 Nov; 33(11):825–826. Karen JK, et al: Generalized essential telangiectasia. Dermatol Online J 2008 May 15; 14(5):9. Sharma VK, et al: Unilateral nevoid telangiectasia—response to pulsed dye laser. Int J Dermatol 2006 Aug; 45(8):960–964. Wenzel SM, et al: Progressive disseminated essential telangiectasia and erythrosis interfollicularis colli as examples for successful treatment with a high-intensity flashlamp. Dermatology 2008; 217(3):286–290.
Lymphangiectasis (lymphangioma)
Fig. 28-10 Fordyce angiokeratomas.
Histologically, hyperkeratosis, increased thickness of the granular layer, and dilation of the subpapillary vessels to form lacunae are the chief features. In the differential diagnosis of angiokeratomas of the dorsal hands in children is acral pseudolymphomatous angiokera toma in children (APACHE). However, APACHE is unilateral and sporadic in nature, without associated cold sensitivity; on histologic examination there is a dense, nodular, lymphohistiocytic infiltrate with occasional plasma cells, eosinophils, and multinucleated giant cells. It is a variant of pseudolymphoma and not primarily a vascular lesion. Similar lesions may occur in adolescents and adults, and the term acral angiokeratomalike pseudolymphoma has been proposed for these lesions in all age groups. Angiokeratoma may be treated with electrocautery, fulguration, CO2 laser ablation, long-pulse vascular laser therapy, or cryotherapy, with fairly good results.
Angiokeratoma of the scrotum (Fordyce) The angiomas are multiple small vascular papules that stud the scrotum (Fig. 28-10) and sometimes the vulva in middle-aged and elderly individuals. There is often a diffuse redness of the involved area that may be a source of concern to the patient. Urethral or clitoral lesions may also be seen. Infrequently, the keratotic part may be involuntarily scratched off to produce considerable bleeding. Rarely, they may bleed spontaneously. Histologically, the many communicating lacunae in the subpapillary layer are lined with endothelium and connected underneath by dilated veins. Treatment is best accomplished by shave excision, cautery, laser ablation, or fulguration of troublesome lesions. The primary therapy is reassurance. 582
Lymphangiectases are acquired dilations of lymph vessels. Some forms are discussed under malformations (above). Solitary lymphangiomas have an appearance resembling frog’s eggs. Like angiokeratomas, they may be seen adjacent to café-au-lait macules. This may represent a twin spotting phenomenon. Acquired lesions occur on women’s arms, axillae, chest, and back after lymph node dissection and irradiation for breast cancer, and on the scrotum, penis, thighs, and pubic region of men treated aggressively for prostate cancer. Other cancers treated similarly, such as cervical carcinoma, may result in similar lesions. If cancers obstruct outflow from an extremity, lymphangiectases may occur and may be the presenting sign of disease. At times, benign disease, such as scrofuloderma or recurrent erysipelas, which leads to progressive scarring of the lymphatic vessels, may induce lymphangiectasia. Rarely, degenerative changes to the supporting connective tissue may allow lymphangiectasia to develop. A peculiar penicillamine-induced dermopathy may result from damage to the underlying supporting structures of the dermis and allow dilation of lymph vessels within areas of trauma, such as the dorsal hands and knees. Central facial involvement may be seen in variegate porphyria, and sites of chronic high-potency steroid application may develop lymphangiectasia. The lesions are thick-walled, translucent, 2–5 mm white vesicles. They are multiple, and when present on the penis, may mimic condylomata. Spontaneous drainage of a strawcolored to milky-white fluid may occur. Such chylous discharge may induce surface irritation and erythema of the site. At times, recurrent erysipelas may complicate the moist, superficially eroded flexural skin. In penicillamine-induced dermopathy there is a hemorrhagic macular stain that is often surmounted by milia. The method of treatment depends on the cause. If lymph angiectasis results from cancer infiltration and pressure, treatment of the primary process may reopen the lymphatic drainage and lead to resolution. If the condition results from penicillamine or topical steroid application, decreasing the dose or discontinuance may result in improvement. If the underlying process is fibrosis and scarring, and the involved part is amenable to pressure dressings or a pump, the chylous discharge may be improved. If erysipelas is a recurrent complication, long-term oral antibiotic prophylaxis may prevent this.
Hyperplasias Angiolymphoid hyperplasia with eosinophilia Patients with angiolymphoid hyperplasia with eosinophilia (ALHE) usually present with pink to red–brown, domeshaped, dermal papules or nodules of the head or neck, especially about the ears and on the scalp. ALHE may also occur in the mouth, and on the trunk, extremities, penis, and vulva. Grouped lesions merge to form plaques or grapelike clusters. There is a female preponderance, and the average age of onset is 32 years. Symptoms can be pain or pruritus; these may occur after trauma. An underlying AV shunt is present as a result of damage to and repair of an artery or vein. Histologically, central thick-walled vessels with hobnail endothelium are noted. Surrounding hyperplasia of smaller vessels and nodular lymphoid aggregates with eosinophils are present. Lesions do not spontaneously regress. Treatment with surgical excision is successful in 65% of cases. The lesions may recur if the underlying AV shunt is not excised. Intralesional cor ticosteroids, pulsed dye laser therapy with conventional or ultra-long pulsed systems, Nd:YAG laser, cryotherapy, pent oxifylline, indomethacin, imiquimod, and electrodesiccation have been successful in some cases. Difficult cases have been controlled with IFN-α2b, isotretinoin, or vinblastine, and partial responses to intralesional bleomycin have been reported. Much confusion in the literature has centered on distinguishing ALHE from Kimura’s disease (Fig. 28-11). The latter is an inflammatory disorder that presents as massive subcutaneous swelling in the periauricular and submandibular region in young Asian men. Histologically, prominent germinal centers with eosinophils are present in the subcutaneous tissue. Although blood vessels are abundant, changes are less prominent than in ALHE. Additionally, Kimura’s disease is associated with allergic conditions such as asthma, rhinitis, and eczema, and is frequently accompanied by lymphadenopathy, peripheral blood eosinophilia, and an elevated IgE level. Overlap of the two syndromes may occur. Although clonal T-cell gene rearrangement has been reported in both
Fig. 28-11 Kimura’s disease. (Courtesy of Department of Dermatology, Keio University School of Medicine)
ALHE and Kimura’s disease, heteroduplex polymerase chain reaction (PCR) has disproved clonality in some cases positive by conventional PCR. Coexistence of ALHE and peripheral T-cell lymphoma has been reported. Akdeniz N, et al: Intralesional bleomycin for angiolymphoid hyperplasia. Arch Dermatol 2007 Jul; 143(7):841–844. Carlesimo M, et al: Angiolymphoid hyperplasia with eosinophilia treated with isotretinoin. Eur J Dermatol 2007 Nov–Dec; 17(6):554–555. Choi JE, et al: Successful treatment of Kimura’s disease with a 595-nm ultra-long pulsed dye laser. Acta Derm Venereol 2008; 88(3):315–316. Cunha Filho RR, et al: Angiolymphoid hyperplasia with eosinophilia: excellent response to intralesional triamcinolone. Braz J Otorhinolaryngol 2008 Jan–Feb; 74(1):160. Esmaili DD, et al: Simultaneous presentation of Kimura disease and angiolymphoid hyperplasia with eosinophilia. Ophthal Plast Reconstr Surg 2008 Jul–Aug; 24(4):310–311. Gencoglan G, et al: Angiolymphoid hyperplasia with eosinophilia successfully treated with imiquimod. A case report. Dermatology 2007; 215(3):233–235. Gonzalez-Cuyar LF, et al: Angiolymphoid hyperplasia with eosinophilia developing in a patient with history of peripheral T-cell lymphoma: evidence for multicentric T-cell lymphoproliferative process. Diagn Pathol 2008 May 29; 3:22. Kadurina MI, et al: Angiolymphoid hyperplasia with eosinophilia: successful treatment with the Nd:YAG laser. J Cosmet Laser Ther 2007 Jun; 9(2):107–111. Oguz O, et al: Angiolymphoid hyperplasia with eosinophilia responding to interferon-alpha2B. J Eur Acad Dermatol Venereol 2007 Oct; 21(9):1277–1278.
Cutaneous vascular anomalies
Pena JM, et al: Cutaneous lymphangiectases associated with severe photoaging and topical corticosteroid application. J Cutan Pathol 1996; 23:175. Stone MS: Central-facial papular lymphangiectases. J Am Acad Dermatol 1997; 36:493.
Pyogenic granuloma A pyogenic granuloma is a small, eruptive, usually solitary, sessile or pedunculated, friable papule (Fig. 28-12). The lesion is common in children, but may occur at any age. It occurs most often on an exposed surface: on the hands, forearms, or face, or at sites of trauma. The lesion also occurs in the mouth, especially on the gingiva, most often in pregnant women (granuloma gravidarum). On the sole of the foot or nailbed, it may be mistaken for a melanoma. Pyogenic granulomas bleed easily on the slightest trauma and, if cut off superficially, promptly recur. Recurring lesions may have one or many satellite lesions. Pyogenic granulomas may be seen in patients treated with isotretinoin, capecitabine, or indinavir. Isotretinoin treatment of acne vulgaris can be complicated by numerous exuberant pyogenic granuloma-like lesions of the trunk
Fig. 28-12 Pyogenic granuloma.
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or periungual lesions. Some data suggest that patients with pyogenic granuloma have a statistically higher prevalence of Bartonella seropositivity compared with controls, but a definite etiologic role has not been established. Histologically, pyogenic granuloma is a lobular capillary hemangioma, with lobules separated by connective tissue septae. With time, the epidermis becomes thinned, then eroded. Heavy secondary staphylococcal colonization is common. Intravascular pyogenic granuloma appears as a lobular capillary proliferation within a vein. Treatment is by curettage or shave excision, followed by destruction of the base by fulguration or silver nitrate. Silver nitrate alone may be sufficient to treat smaller lesions. Imiquimod under occlusion has been successful, and sclerotherapy with monoethanolamine oleate has also been used successfully. At times, a recalcitrant lesion may require excision or laser ablation. The drug-induced variety will regress after lowering of the dose or discontinuation of the medication. Systemic steroids have been used to treat recurrent giant pyogenic granulomas. Georgiou S, et al: Pyogenic granuloma: complete remission under occlusive imiquimod 5% cream. Clin Exp Dermatol 2008 Jul; 33(4):454–456. Piqué-Duran E, et al: Pyogenic granuloma-like lesions caused by capecitabine therapy. Clin Exp Dermatol 2008 Aug; 33(5):652–653.
Intravascular papillary endothelial hyperplasia Masson described this intravascular papillary proliferation that may mimic angiosarcoma. The lesions appear as red or purplish 5 mm to 5 cm papules or deep nodules on the head, neck, or upper extremities. The condition represents recanalization of a thrombosed vessel. Histologic examination reveals intravascular papillary projections lined by endothelial cells. Thrombi may still be present, and the papillary projections may have a fibrinous or hyaline core. High-resolution ultrasound imaging may be useful in establishing the diagnosis, although the diagnosis is usually made by biopsy. Excision is curative. Schwartz SA, et al: Intravascular papillary endothelial hyperplasia: sonographic appearance with histopathologic correlation. J Ultrasound Med 2008 Nov; 27(11):1651–1653.
point areas of purpura, the so-called cayenne pepper spots, form macules that tend to coalesce and form diffusely pigmented patches. The pigment is hemosiderin. Purpura annularis telangiectodes (Majocchi) is often bilateral and is characterized by acute outbreaks of telangiectatic points that spread peripherally and form small rings. In lichenoid purpuric and pigmentary dermatosis of Gougerot and Blum, the primary lesion is a minute, lichenoid, reddish-brown papule that is sometimes hemorrhagic. It has a tendency toward central involution and residual pigmentation. In angioma serpiginosum, the most important histologic finding is dilated and tortuous capillaries in the dermal papillae and the upper dermis. No inflammatory infiltrate or extravasation of red cells is observed. The dilated capillaries show no alkaline phosphatase activity, in contrast to normal capillaries. Blinkenberg EO, et al: Angioma serpiginosum with oesophageal papillomatosis is an X-linked dominant condition that maps to Xp11.3–Xq12. Eur J Hum Genet 2007 May; 15(5):543–547. Kalisiak MS, et al: Angioma serpiginosum with linear distribution: case report and review of the literature. J Cutan Med Surg 2008 Jul–Aug; 12(4):180–183.
Benign neoplasms Infantile hemangioma (strawberry hemangioma) Strawberry (capillary) hemangiomas, the most common benign tumors of childhood, are present at birth in one-third of cases. The remainder appear shortly thereafter. Sixty percent are on the head and neck, but they may occur anywhere. The dome-shaped lesion is dull to bright red, and when involution begins, streaks or islands of white appear in the lesion as it flattens. The lesions have sharp borders; they are soft and easily compressed (Fig. 28-13). Generally, they tend to grow over the first year or so, remain stable for a period of months, and then slowly involute spontaneously. The period of greatest growth is the first 5 months. Ulceration occurs in nearly 16% of lesions, usually by 4 months of age. Approximately 30% resolve by the third year, 50% by age 5, and 70% by the
Angioma serpiginosum Angioma serpiginosum, first described by Hutchinson in 1889, is characterized by minute, copper-colored to bright red angiomatous puncta that have a tendency to become papular. These puncta occur in groups, which enlarge through the constant formulation of new points at the periphery, whereas those at the center fade. In this manner, linear arrays, small rings, or serpiginous patterns are formed. No purpura is present, but a netlike or diffuse erythema forms the background. In the areas undergoing involution, a delicate tracery of rings and lines, a fine desquamation, and, at times, a semblance of atrophy are seen. Slight lichenification and scaling may be evident in the papular lesions. The eruption predominates on the lower extremities. Although it affects both sexes at all ages, 90% of cases occur in girls under 16. It is usually slowly progressive and chronic, and although involution may occur, it is probably never complete. Treatment with a pulsed dye laser will improve or eliminate such lesions. Angioma serpiginosum following Blaschko’s lines, with associated esophageal papillomatosis, has been reported as an X-linked dominant condition with mild features of Goltz–Gorlin syndrome, including hair and nail dystrophy. The condition maps to Xp11.3–Xq12. Angioma serpiginosum must be differentiated from the progressive pigmentary disease of Schamberg. In the latter, pin584
Fig. 28-13 Infantile hemangioma.
and merosin. Some subgroups, such as rapidly involuting hemangiomas and noninvoluting hemangiomas, lack GLUT-1 staining. Young hemangiomas show evidence of endothelial progenitor cells that stain with CD133 and CD34. In late stages, the endothelium flattens and the lumina are more apparent because of increased blood flow. In time, fibrosis becomes pronounced as involution progresses. In most cases, intervention produces a cosmetic result no better or worse than that achieved with simple observation. Proponents of early treatment point out that many of these hemangiomas remain significant body image factors to children when they enter school. Cryotherapy or laser ablation of early lesions has generally not been successful. The pulsed dye laser can improve the appearance of residual involuted lesions with prominent telangiectasia; however, the depth of the hemangiomas does not allow the lasers to be effective in growing or stable childhood hemangiomas. Vascular lasers have been used to treat ulcerated hemangiomas, but have also caused ulceration. The so-called Cyrano defect, a hemangioma that causes the end of the nose to become bulbous, may be successfully approached surgically in many cases before the patient begins school. Additionally, surgical intervention in small pedunculated hemangiomas and eyelid tumors may also be an excellent option. Finally, compressive wraps may improve extremity hemangiomas. Specific circumstances necessitate treatment. Indications for intervention include severe hemorrhage, thrombocytopenia, threatened cardiovascular compromise from high-output cardiac failure, nasal or auditory canal obstruction, hepatic hemangiomatosis, skin ulceration, or threatened interference with vital functions, such as feeding, respiration, passage of urine or stool, limb function, tissue destruction, or vision. There is a risk of occlusion amblyopia, astigmatism, and myopia from periorbital hemangiomas. Additionally, strong consideration should be given to treatment of those hemangiomas that may lead to permanent disfigurement or long-term psychological consequences, such as large hemangiomas of the ear, nose, glabellar area, or lips. Oral prednisone and beta blockers are used most commonly. Beta blockers can produce rapid involution of hemangiomas, but treatment can be complicated by bradycardia or hypoglycemia. Some very thin hemangiomas may respond to topical beta blockers. Intralesional corticosteroid treatment has been used, but carries some risk of embolization and occlusion of ocular vessels. Injection regularly produces pressures exceeding the systemic arterial pressure, leading to the possibility of embolization. Oral treatment with prednisone requires a dose of 2–4 mg/ kg/day. In the 30% of patients who respond well to treatment, the enlarging hemangioma stops growing in 3–21 days. Ulcerations will heal within 2 weeks. The lesion will usually shrink if treatment is continued for 30–90 days. Laryngeal involvement and stridor, if present, are usually dramatically relieved by treatment. Repeated courses of treatment may be undertaken if rebound of growth occurs on discontinuation of the steroidal agent. Some experts recommend prolonged lowdose oral steroids over a 12-month period to prevent this rebound phenomenon. In another 40%, the clinical situation will stabilize with this treatment; however, the remaining 30% do not respond to treatment with prednisone. Treatment with recombinant IFN-α2a or 2b may result in a good response in 80% of patients, but is rarely used because of the risk of spastic diplegia. Topical imiquimod, low-frequency ultrasound, and selective arterial embolization have also been used. Both Nd:YAG and Potassium Titanyl Phosphate (KTP) lasers have been used to deliver intralesional laser therapy.
Cutaneous vascular anomalies
time the patient is 7 years of age. The skin may appear normal after involution, but more commonly, atrophy, telangiectasia, or anetoderma-type redundancy is present. The majority of these lesions occur sporadically, but kindreds with autosomal-dominant inheritance of infantile hemangiomas and/or vascular malformations have been described. Approximately 7% of hemangiomas may occur in association with structural malformations. One grouping of associated abnormalities is the PHACE syndrome. This acronym, proposed by Frieden et al in 1996, denotes the association of posterior fossa brain malformations (primarily the Dandy–Walker malformation), hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. When sternal clefting and abdominal raphae are present, the designation PHACES is used. The hemangiomas tend to be large, plaquelike, and facial in location, frequently involving more than one dermatome. Frieden et al recommended that brain imaging studies be performed in all infants with such hemangiomas. Solitary segmental hemangiomas of the skin are also associated with visceral hemangiomatosis involving the liver, gastrointestinal tract, lung, brain, and mediastinum; 40% have PHACE(S) syndrome. Multiple hemangiomas, usually 1–10 mm in size, may appear in the first few weeks to months of life and can be large in number. If they are purely cutaneous, they generally involute without sequelae, and the term benign neonatal hemangiomatosis is applied. However, visceral lesions may be present in the CNS, lungs, liver, or other organs. When internal lesions are present, complications may occur, such as gastrointestinal or CNS bleeding, high-output cardiac failure, obstructive jaundice, or respiratory failure; this results in a high mortality rate among untreated patients. This more ominous variant is called diffuse neonatal hemangiomatosis. Flat lumbar hemangiomas are often associated with occult spinal dysraphism. Rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH) are rare vascular tumors that present fully grown at birth and either involute rapidly or fail to involute. Whereas smooth muscle actin (SMA)-positive cells are common in the walls of infantile hemangiomas, they are rare in RICH. Children with RICH or NICH coexisting with infantile hemangioma have been described, as have children with RICH showing rapid but incomplete regression. In these cases, the residuum was NICH. The pathogenesis of infantile hemangiomas is complex. CD133+ stem cells within the hemangioma differentiate into mature blood vessels that express GLUT-1 (a glucose transporter normally restricted to endothelial cells with blood– tissue barrier function, such as in brain and placenta). The vessels proliferate, then involute. Some have suggested that the stem cells could originate from placental trophoblast. Some data suggest that local hypoxia may lead to upregulation of hypoxia-inducible factor-1α responsive chemokines, including stromal cell-derived factor-1α (SDF-1α) and VEGF. These cytokines promote recruitment and proliferation of endothelial progenitor cells. Reduced activity of a pathway involving β1 integrin, the integrin-like receptor tumor endothelial marker-8 (TEM8), VEGF receptor-2 (VEGF-R2), and NFAT has been shown to reduce VEGF receptor-1 (VEGF-R1) expression. This produces a VEGF-dependent activation of VEGF-R2. Histologically, strawberry marks are composed of primitive endothelial cells similar to those found before the embryonic development of true venous channels. Ultrastructurally, they lack typical Weibel–Palade bodies but do have crystalloid inclusions typical of embryonic endothelium and stain for GLUT-1. They also stain for Fc-γ-RII, Lewis Y antigen (LeY),
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Balakrishnan K, et al: Management of airway hemangiomas. Expert Rev Respir Med 2010 Aug; 4(4):455–462. Barry RB, et al: Involution of infantile haemangiomas after imiquimod 5% cream. Clin Exp Dermatol 2008 Jul; 33(4):446–449. Chamlin SL, et al: Multicenter prospective study of ulcerated hemangiomas. J Pediatr 2007 Dec; 151(6):684–689, 689.e1. Chang LC, et al: Growth characteristics of infantile hemangiomas: implications for management. Pediatrics 2008 Aug; 122(2):360–367. Holland KE, et al: Hypoglycemia in children taking propranolol for the treatment of infantile hemangioma. Arch Dermatol 2010 Jul; 146(7):775–778. Pandey A, et al: Evaluation and management of infantile hemangioma: an overview. Ostomy Wound Manage 2008 May; 54(5):16–18, 20, 22–26, 28–29. Pope E, et al: Oral versus high-dose pulse corticosteroids for problematic infantile hemangiomas: a randomized, controlled trial. Pediatrics 2007 Jun; 119(6):e1239–e1247. Serena T: Wound closure and gradual involution of an infantile hemangioma using a noncontact, low-frequency ultrasound therapy. Ostomy Wound Manage 2008 Feb; 54(2):68–71. Sun ZY, et al: Infantile hemangioma is originated from placental trophoblast, fact or fiction? Med Hypotheses 2008 Sep; 71(3):444–448.
Cherry angiomas (senile angiomas, de Morgan spots) These round, slightly elevated, 0.5–6 mm diameter, ruby-red papules are the most common vascular anomalies. It is a rare 30-year-old person who does not have a few, and the number increases with age. Probably every 70-year-old person has some. Most are on the trunk; they are rarely seen on the hands, feet, or face. Early lesions may mimic petechiae. When lesions are surrounded by a purpuric halo, amyloidosis should be suspected. Eruptive lesions have been described after nitrogen mustard therapy. Light electrodesiccation or laser ablation with intense pulsed light (IPL) and long-pulse Nd:YAG systems can be effective. Shave excision can also be performed, but most patients accept reassurance and do not request their removal. Fodor L, et al: A side-by-side prospective study of intense pulsed light and Nd:YAG laser treatment for vascular lesions. Ann Plast Surg 2006 Feb; 56(2):164–170. Ma HJ, et al: Eruptive cherry angiomas associated with vitiligo: provoked by topical nitrogen mustard? J Dermatol 2006 Dec; 33(12):877–879.
Targetoid hemosiderotic hemangioma In 1988, Santa Cruz and Aronberg described a lesion characterized by a central brown or violaceous papule that is surrounded by an ecchymotic halo (Fig. 28-14). The term hobnail hemangioma has been proposed, as many lesions are not targetoid. These acquired hemangiomas occur in the young to
middle-aged and are present on the trunk or extremities. They likely represent trauma to a pre-existing hemangioma, with thrombosis and subsequent recanalization. Histologically, a biphasic growth pattern is seen, with central superficial dilated vascular structures lined by prominent hobnail endothelial cells, and collagen-dissecting, narrow vessels in deeper parts of the lesion. The endothelial cells commonly stain for CD31, but not CD34. D2-40 staining suggests lymphangiomatous proliferation. Carlson et al studied 33 cases and concluded that targetoid hemosiderotic hemangiomas are variants of solitary angiokeratomas. They found episodic changes of swelling, darkening, and/or involution in three patients. Franke FE, et al: Hobnail hemangiomas (targetoid hemosiderotic hemangiomas) are true lymphangiomas. J Cutan Pathol 2004 May; 31(5):362–367. Morales-Callaghan AM, et al: Targetoid hemosiderotic hemangioma: clinical and dermoscopical findings. J Eur Acad Dermatol Venereol 2007 Feb; 21(2):267–269.
Glomeruloid hemangioma This distinctive benign vascular neoplasm was described in 1990 and has been reported in patients with POEMS (poly neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome (Crow–Fukase syndrome) and Castleman’s disease. Some have also been associated with idiopathic thrombocytopenic purpura and Sjögren syndrome. Similar lesions have been reported in patients who are otherwise healthy. POEMS syndrome consists of polyneuropathy (severe sensorimotor), organomegaly (heart, spleen, kidneys), endocrinopathy, M protein, and skin changes (hyperpigmentation, hypertrichosis, thickening, sweating, clubbed nails, leuk onychia, and angiomas). Small, firm, red to violaceous papules appear on the trunk and proximal extremities in approximately one-third of patients. Histologically, the lesions may be microvenular hemangiomas, cherry angiomas, multinucleated cell angiohistiocytomas, or glomeruloid hemangiomas. The latter consist of ectatic vascular structures containing aggregates of capillary loops within a dilated lumen, simulating the appearance of a renal glomerulus. Sequestered degenerating red blood cells are a characteristic finding. Two types of endothelial cell have been noted within the lesions: a capillarytype endothelium with large vesicular nuclei, open chromatin pattern, and a large amount of cytoplasm; and sinusoidal endothelium with small basal nuclei, dense chromatin, and scant cytoplasm. Lesions associated with POEMS syndrome demonstrate increased expression of VEGF and its receptor, Flt-1. Forman SB, et al: Glomeruloid hemangiomas without POEMS syndrome: series of three cases. J Cutan Pathol 2007 Dec; 34(12):956–957. Yamamoto T, et al: Increased expression of vascular endothelial growth factor and its receptor, Flt-1, in glomeruloid haemangioma associated with Crow–Fukase syndrome. J Eur Acad Dermatol Venereol 2007 Mar; 21(3):417–419. Yuri T, et al: Glomeruloid hemangioma. Pathol Int 2008 Jun; 58(6):390–395.
Microvenular hemangioma
Fig. 28-14 Targetoid hemosiderotic hemangioma.
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This recently described, acquired, benign, vascular neoplasm presents as an asymptomatic, slowly growing, 0.5–2.0 cm reddish lesion on the forearms or other sites of young to middle-aged adults. Dermoscopic examination reveals multiple, well-demarcated, red globules. Monomorphous, elongated blood vessels with small lumina involve the entire reticular dermis. In many areas, the podoplanin (D2-40)-negative endothelial cells are surrounded by
Fig. 28-15 Tufted angioma.
pericytes. The main differential diagnosis is that of Kaposi sarcoma. Along with glomeruloid hemangioma, they may sometimes be present in POEMS syndrome. Fernandez-Flores A: Lack of expression of podoplanin by microvenular hemangioma. Pathol Res Pract 2008; 204(11):817–821. Scalvenzi M, et al: Dermoscopy of microvenular hemangioma: report of a case. Dermatology 2007; 215(1):69–71.
Tufted angioma (angioblastoma) This lesion usually develops in infancy or early childhood on the neck and upper trunk. Adult onset has also been described. The lesions present as ill-defined, dull red macules with a mottled appearance; they vary from 2 to 5 cm in diameter. Some show clusters of smaller angiomatous papules superimposed on the main macular area (Fig. 28-15), and associated hypertrichosis has been noted. The lesions are usually sporadic, although familial cases have been reported. Histologic examination reveals small, circumscribed angiomatous tufts and lobules scattered in the dermis in a so-called cannon-ball pattern. Tumors with features of both tufted angioma and kaposiform hemangioendothelioma (KHE) have been described, and transformation between the tumors has also been noted. Immunostaining can be helpful in distinguishing these tumors. Tufted angioma is characterized by a proliferation of CD34+ endothelial cells with few actin-positive cells. KHE shows CD34 staining only in the luminal endothelial cells. In infantile hemangiomas, actin-positive cells outnumber CD34+ cells. Most lesions slowly extend with time, being progressive but benign in nature. Occasional spontaneous regression is documented; however, treatment with pulsed dye laser, intense pulsed light, excision, high-dose steroids, and IFN-α has been successful in individual cases. Lesions associated with Kasabach–Merritt syndrome have also been treated with embolization and vincristine. The term angioblastoma has also been used for a rare pediatric tumor often associated with destruction of regional structures, including bone. Basic fibroblast growth factor has been reported to be elevated, and some patients have responded to treatment with IFN-α2b. Chiu CS, et al: Treatment of a tufted angioma with intense pulsed light. J Dermatolog Treat 2007; 18(2):109–111. Lee B, et al: Adult-onset tufted angioma: a case report and review of the literature. Cutis 2006 Nov; 78(5):341–345. Yesudian PD, et al: Tufted angioma-associated Kasabach–Merritt syndrome treated with embolization and vincristine. Plast Reconstr Surg 2008 Feb; 121(2):692–693.
Kaposiform hemangioendothelioma (KHE) is an uncommon vascular tumor that affects infants and young children. Rare cases have been reported in adults. It was first designated KHE in 1993. Although it frequently occurs in the retroperitoneum, it may present as multinodular soft tissue masses, purpuric macules, plaques, and multiple telangiectatic papules. The lesions extend locally and usually involve the skin, soft tissues, and even bone. The cutaneous variant may be associated with lymphangiomatosis. KHE is locally aggressive and may be complicated by platelet trapping and consumptive coagulopathy (Kasabach–Merritt syndrome), but distant metastases have not yet been reported. It has also been reported in association with Milroy–Nonne disease (primary hereditary lymphedema). Histologically, there are combined features of cellular infantile hemangioma and Kaposi sarcoma. Additionally, in some tumors, lymphangiomatosis is seen sharply separated from the vascular lesion. There is a multilobular appearance that closely resembles that of tufted angioma, but in KHE lesions are larger, less circumscribed, and involve the deep soft tissue and even bone. Transition between these tumors has been described. The transcription factor Prox-1 has been shown to induce proliferation and deep extension in a mouse model of the disease. The prognosis depends on the depth and location of the lesion. Significant morbidity and mortality may occur as a result of the compression and invasion of surrounding structures. If localized to the skin, lesions may be successfully excised. However, because of their tendency for deep and infiltrative growth this is usually not possible. Prednisone may shrink the tumor or limit tumor expansion. Successful treatment has also been reported with IFN-α, vincristine, and radiation. If Kasabach–Merritt phenomenon occurs, prognosis is linked to this complication.
Cutaneous vascular anomalies
Kaposiform hemangioendothelioma
Dadras SS, et al: Prox-1 promotes invasion of kaposiform hemangioendotheliomas. J Invest Dermatol 2008 Dec; 128(12):2798–2806. Harper L, et al: Successful management of a retroperitoneal kaposiform hemangioendothelioma with Kasabach–Merritt phenomenon using alpha-interferon. Eur J Pediatr Surg 2006 Oct; 16(5):369–372. Vetter-Kauczok CS, et al: Kaposiform hemangioendothelioma with distant lymphangiomatosis without an association to Kasabach–Merritt syndrome in a female adult! Vasc Health Risk Manag 2008; 4(1):263–266.
Multifocal lymphangioendotheliomatosis Patients with multifocal lymphangioendotheliomatosis present at birth with hundreds of red–brown plaques as large as several centimeters. Similar lesions may occur in the gastrointestinal tract and are associated with severe bleeding. Severe thrombocytopenic coagulopathy (Kasabach–Merritt syndrome) occurs in affected children. Treatment with cortico steroids and/or IFN-α results in little to no improvement. The histology is distinctive, with delicate thin-walled vessels lined by hobnailed endothelium with papillary tufting. The endothelial cells demonstrate a high proliferative fraction with Ki-67 staining, and are reactive with LYVE-1, suggesting lymphatic differentiation. Piggott KD, et al: Multifocal lymphangioendotheliomatosis with thrombocytopenia: a rare cause of gastrointestinal bleeding in the newborn period. Pediatrics 2006 Apr; 117(4):e810–e813. Yeung J, et al: Multifocal lymphangioendotheliomatosis with thrombocytopenia. J Am Acad Dermatol 2006 May; 54(5 Suppl): S214–S217.
Kasabach–Merritt syndrome (hemangioma with thrombocytopenia) Kasabach-Merritt syndrome (KMS) is seen in infants at an average age of 7 weeks. Before the onset of the acute event, 587
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the infant will often have a reddish or bluish plaque or tumor on the limb or trunk, or in rare instances, no visible lesion at all. The lesions usually have an associated lymphatic component and most are KHEs. KMS also occurs in tufted angiomas and multifocal lymphangioendotheliomatosis, lesions that both demonstrate lymphatic differentiation. It is rarely reported in association with capillary hemangiomas or angio sarcoma. Some patients with venous malformations will have a chronic low-grade consumptive coagulopathy that occurs throughout life, and this is not to be confused with KMS. Infants with KMS suddenly develop a painful violaceous mass in association with purpura and thrombocytopenia. The most striking sign is the bleeding tendency, especially in the hemangioma itself or into the chest or abdominal cavities. The spleen may be enlarged. Hemoglobin, platelets, fibrinogen, and factors II, V, and VIII are all reduced. Prothrombin time and partial thromboplastin time are prolonged, and fibrin split products may be elevated. Cases of microangiopathic hemolytic anemia have also been described. Repeated episodes of bleeding may occur, and although these may be spontaneous, it is not uncommon for bleeding to be precipitated by surgery, directed either at the hemangioma or elsewhere. The mortality may be as high as 30%, most deaths being secondary to bleeding complications. As KMS may be a self-limited disorder, expectant observation may be the best approach initially. Systemic steroids, IFNα2a, vincristine, vinblastine, cyclophosphamide, actinomycin D, embolization, ε-aminocaproic acid, antiplatelet agents, irradiation, excision, and compression therapy have been utilized alone or in combination, but treatment is often difficult and some patients respond poorly to all attempted modalities. Abass K, et al: Successful treatment of Kasabach–Merritt syndrome with vincristine and surgery: a case report and review of literature. Cases J 2008 May 23; 1(1):9. Berkley EM, et al: Consumptive coagulopathy associated with Gorham syndrome and subsequent Kasabach–Merritt syndrome during pregnancy: a case report. J Reprod Med 2007 Dec; 52(12): 1103–1106. Imafuku S, et al: Kasabach–Merritt syndrome associated with angiosarcoma of the scalp successfully treated with chemoradiotherapy. Acta Derm Venereol 2008; 88(2):193–194. Wang Z, et al: Kasabach–Merritt syndrome caused by giant hemangiomas of the spleen in patients with Proteus syndrome. Blood Coagul Fibrinolysis 2007 Jul; 18(5):505–508.
Acquired progressive lymphangioma (benign lymphangioendothelioma) The term acquired progressive lymphangioma was introduced by Wilson-Jones in 1976 to designate a group of lymphangiomas that occur anywhere in young individuals, grow slowly, and present as bruise-like lesions or erythematous macules. Rarely, the lesion is yellow or alopecic. The histologic appearance is that of delicate endothelium-lined spaces dissecting between collagen bundles. A similarity to the plaque stage of Kaposi sarcoma may be striking. Simple excision is curative. Prednisone has caused some extensive lesions to regress. Kim HS, et al: Acquired progressive lymphangioma. J Eur Acad Dermatol Venereol 2007 Mar; 21(3):416–417. Paik AS, et al: Acquired progressive lymphangioma in an HIV-positive patient. J Cutan Pathol 2007 Nov; 34(11):882–885.
Glomus tumor (glomangioma) The solitary glomus or neuromyoarterial tumor is most frequently a skin-colored or slightly dusky blue, firm nodule 1–20 mm in diameter. Subungual tumors show a bluish tinge through the translucent nail plate. The tumor is usually extremely tender and paroxysmal pain occurs frequently. Sensitivity is likely to be present constantly, and when touched, 588
Fig. 28-16 Multiple glomangiomas.
the tumor responds with severe radiating pain. However, nontender glomus tumors are encountered. The characteristic location is subungual, but tumor may occur on the fingers and arms, or elsewhere. Digital lesions are more common in women, and there is a male predominance of nondigital lesions. High-resolution MRI, high-resolution ultrasonography (5–9 MHz), and color duplex sonography may be used to define the limits of the tumor before surgery is undertaken. Progressive growth may lead to ulceration. Multiple glomangiomas are usually nontender and are generally widely distributed over the body. These may be inherited as an autosomal-dominant trait and can be congenital. Clinically, they may resemble lesions of blue rubber bleb nevus (Fig. 28-16). When grouped in one area, they may appear as a confluent mass. Hereditary multiple glomus tumors may represent an autosomal-dominant mosaic trait and may be congenital. The glomus coccygeum is a normal structure that may be seen in pilonidal sinus excision specimens. Histologically, glomus tumors contain numerous vascular lumina lined by a single layer of flattened endothelial cells. Peripheral to the endothelial cells are layers of glomus cells. Generally, these are round and arranged in distinct rows resembling strings of black pearls. Rarely, the cells have a somewhat spindled morphology. Multiple glomangiomas tend to have only one or two layers of glomus cells. Glomangiomyomas have a prominent muscularis media in addition to one or two layers of glomus cells. Both solitary and multiple glomus tumors are related to the arterial segment of the cutaneous glomus, the Sucquet–Hoyer canal. The glomus cells are modified vascular smooth muscle cells and stain with vimentin rather than desmin. Smooth muscle actin is often positive. Treatment of solitary glomus tumors is best carried out by complete excision, which immediately produces relief from pain. The subungual tumors are most difficult to locate and eradicate since they are usually small, seldom more than a few millimeters in diameter. Rare reports of glomangiosarcomas describe large, deeply located extremity lesions that consist of sarcomatous areas intermingled with areas of benign glomus tumor. Anakwenze OA, et al: Clinical features of multiple glomus tumors. Dermatol Surg 2008 Jul; 34(7):884–890. Fong ST, et al: A modified periungual approach for treatment of subungual glomus tumour. Hand Surg 2007; 12(3):217–221. Gombos Z, et al: Glomus tumor. Arch Pathol Lab Med 2008 Sep; 132(9):1448–1452.
Hemangiopericytoma True hemangiopericytomas are rare. The term is now reserved for lesions that demonstrate differentiation towards pericytes
Lesions formerly classified as hemangiopericytomas Various soft tissue tumors can present with a hemangiopericytoma-like staghorn vascular pattern, the most common being solitary fibrous tumor and giant cell angio fibroma. Myofibromas demonstrate nodular, pale blue, hypocellular zones with surrounding hypercellular zones that contain staghorn vessels. Some examples lack the hypocellular zones and present only with a hemangiopericytoma-like pattern. Myopericytoma is a rare mesenchymal neoplasm that typically involves the extremities. The tumor demonstrates concentric perivascular spindle cells with myoid differentiation. Glomangiopericytoma is a closely related lesion composed of perivascular spindle cells with myoid differentiation. The tumor combines features of glomus tumors and a hemangiopericytoma-like vascular pattern. Gengler C, et al: Solitary fibrous tumour and haemangiopericytoma: evolution of a concept. Histopathology 2006 Jan; 48(1):63–74.
Proliferating angioendotheliomatosis Diseases designated angioendotheliomatosis have historically been divided into two groups: a reactive, involuting type and a malignant, rapidly fatal type. “Malignant angioendotheliomatosis” has been shown to be intravascular (angiotropic) lymphoma, rather than a true vascular lesion. The reactive type of angioendotheliomatosis is uncommon. It occurs in patients who have subacute bacterial endocarditis, Chagas’ disease, pulmonary tuberculosis, cryoproteinemia, severe atherosclerotic disease, periodontal disease, and antiphospholipid antibodies, as well as in patients with no identifiable underlying process. Patients present with red– purple patches, plaques, nodules, petechiae, and ecchymoses, usually of the lower extremities. Some may present with a livedoid pattern or lesions resembling atrophie blanche. Diffuse dermal angiomatosis is a variant associated with atherosclerosis. The lesion occurs most often on the thigh in areas of vascular insufficiency (Fig. 28-17) and clears with revascularization. It has also been described in association with an AV fistula and with anticardiolipin antibodies. Histologically, the vessels in benign reactive angioendotheliomatosis are dilated and are filled with proliferating endothelial cells, usually without atypia. Some cases demonstrate a proliferation of capillaries in the dermis, with diffuse, lobular,
Cutaneous vascular anomalies
and cannot be otherwise classified. Many lesions formerly classified as hemangiopericytomas are now classified as examples of solitary fibrous tumor or giant cell angiofibroma. Remaining lesions can often be classified as glomangiopericytoma/myopericytoma or infantile myofibromatosis. Clinically, the typical lesion is a nontender, bluish red tumor that occurs on the skin or in the subcutaneous tissues on any part of the body. The firm, usually solitary nodule may be up to 10 cm in diameter. Histologically, the tumor is composed of endothelium-lined vessels that are filled with blood and surrounded by cells with oval or spindle-shaped nuclei (pericytes). The pericytes often form a concentric perivascular pattern. Staghorn-like ectatic spaces are often encountered. Wide local excision is the treatment of choice, but radiation therapy may produce excellent palliation. It is difficult to distinguish between benign and malignant forms of hemangiopericytoma, although large lesions and those with numerous mitoses are more likely to metastasize. Nearly half of the malignant hemangiopericytomas of deep soft tissues metastasize. The rate of metastasis from lesions of the skin is closer to 20%. The most common cause of death is pulmonary metastasis. Infantile tumors are almost always cutaneous or subcutaneous, and do not metastasize.
Fig. 28-17 Diffuse dermal angiomatosis.
or mixed patterns. Fibrin microthrombi are common, and some cases show amyloid deposits or positive immunohistochemical staining for human herpesvirus (HHV)-8 in lesional endothelial cell nuclei. The course in this type is characterized by involution over 1–2 years. Therapy for the underlying condition has been considered as hastening involution. The malignant type of “angioendotheliomatosis” is actually a large-cell, intravascular lymphoma. This is a rapidly progressive disease; usually death ensues within 10 months of diagnosis. The mean age at onset is 55 years. Reddish-purple plaques, nodules, or patches develop in the skin. Multisystem disease is characteristic, with the CNS often involved. There may be progressive dementia or focal signs that reflect ischemic infarcts. Kidney, heart, lung, and gastrointestinal lesions may occur. Biopsy will show a proliferation of atypical cells that fill the lumen of cutaneous vessels. Immunochemical stains for leukocyte/common antigen have confirmed the lymphomatous nature of these cells. Angioendotheliomatosis is usually B-cell in phenotype, but cases of T-cell lineage have been reported. Some organs may show diffuse large-cell lymphoma. Doxorubicin alone, as well as in combination with vincristine, prednisone, and cyclophosphamide, has been effective in isolated cases. Rituximab has also been useful in CD20+ B-cell intravascular lymphoma. Kawaoka J, et al: Coexistence of diffuse reactive angioendo theliomatosis and neutrophilic dermatosis heralding primary anti phospholipid syndrome. Acta Derm Venereol 2008; 88(4):402–403. Kirke S, et al: Localized reactive angioendotheliomatosis. Clin Exp Dermatol 2007 Jan; 32(1):45–47. Misago N, et al: Simultaneous occurrence of reactive angioendo theliomatosis and leukocytoclastic vasculitis in a patient with periodontitis. Eur J Dermatol 2008 Mar–Apr; 18(2):193–194.
Hemangioendotheliomas Hemangioendotheliomas (HEs) are a group of tumors that spans the spectrum from benign to low-grade malignancy. Composite lesions occur and kaposiform hemangioendotheliomas are associated with tufted angiomas and Kasabach– Merritt syndrome and discussed along with those entities. Spindle cell hemangioma (spindle cell hemangioendothelioma) is a vascular tumor that was first described in 1986. The condition commonly presents in a child or young adult who develops blue nodules of firm consistency on a distal extremity (Fig. 28-18). Usually, multifocal lesions occur within an anatomic region. Histologically, a well-circumscribed dermal nodule will contain dilated vascular spaces with fascicles of spindle cells between them. Areas of the tumor will have an open alveolar pattern resembling hemorrhagic lung tissue. Phleboliths are common. A thrombosed large adjacent vessel 589
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Fig. 28-19 Kaposi sarcoma.
3. African lymphadenopathic KS, an aggressive disease of young patients, chiefly children under age 10 4. KS in patients immunosuppressed by AIDS 5. lymphoma or immunosuppressive therapy.
Clinical features
Fig. 28-18 Spindle-cell hemangioendotheliomas. (Courtesy of Timothy Gardner, MD)
with recanalization may be identified. The lesions appear to represent benign vascular proliferations in response to trauma to a larger vessel. They may repeatedly recur focally after excision. Epithelioid HEs are solid tumors composed of epithelioid cells with intracellular lumens. Retiform HEs resemble rete testis at scan. Both tumors behave as low grade malignancies. Composite hemangioendotheliomas may have epithelioid or retiform features and behave as borderline malignant tumors. Immunoreactivity for Prox-1 suggests lymphatic differentiation. Requena L, et al: Cutaneous composite hemangioendothelioma with satellitosis and lymph node metastases. J Cutan Pathol 2008 Feb; 35(2):225–230. Tejera-Vaquerizo A, et al: Composite cutaneous hemangioendothelioma on the back. Am J Dermatopathol 2008 Jun; 30(3):262–264.
Malignant neoplasms Kaposi sarcoma Moritz Kaposi described this vascular neoplasm in 1872 and called it multiple benign pigmented idiopathic hemorrhagic sarcoma. Since his description, the disease has been reported in five separate clinical settings, with different presentations, epidemiology, and prognoses. The five subtypes are: 1. classic Kaposi sarcoma (KS), an indolent disease seen chiefly in middle-aged men of Southern and Eastern European origin 2. African cutaneous KS, a locally aggressive process affecting middle-aged Africans in tropical Africa 590
Classic Kaposi sarcoma The early lesions appear most commonly on the toes or soles as reddish, violaceous, or bluish-black macules and patches that spread and coalesce to form nodules or plaques (Fig. 28-19). These have a rubbery consistency. There may be brawny edema of the affected leg. Macules or nodules may appear, usually much later, on the arms and hands, and rarely may extend to the face, ears, trunk, genitalia, or buccal cavity, especially the soft palate. The course is slowly progressive and may lead to great enlargement of the lower extremities as a result of lymphedema. However, there may be periods of remission, particularly in the early stages of the disease, when nodules may undergo spontaneous involution. After involution there may be an atrophic and hyperpigmented scar. African cutaneous Kaposi sarcoma Nodular, infiltrating, vascular masses occur on the extremities, mostly of men between the ages of 20 and 50. This form of KS is endemic in tropical Africa, and has a locally aggressive but systemically indolent course. African lymphadenopathic Kaposi sarcoma Lymph node involvement, with or without skin lesions, may occur in children under 10 years of age. The course is aggressive, often terminating fatally within 2 years of onset. AIDS-associated Kaposi sarcoma Cutaneous lesions begin as one or several red to purple–red macules, rapidly progressing to papules, nodules, and plaques. There is a predilection for the head, neck, trunk, and mucous membranes. A fulminant, progressive course with nodal and systemic involvement is expected. This may be the presenting manifestation of human immunodeficiency virus (HIV) infection. Immunosuppression-associated Kaposi sarcoma The lesion’s morphology resembles that of classic KS; however, the site of presentation is more variable.
Internal involvement The gastrointestinal tract is the most frequent site of internal involvement in classic KS. The small intestine is probably the most commonly involved viscus. In addition, the lungs, heart, liver, conjunctiva, adrenal glands, and lymph nodes of the abdomen may be affected. Skeletal changes are characteristic
ularly shaped ectatic vessels with scattered lymphocytes and plasma cells. The endothelial cells of the capillaries are large and protrude into the lumen, like buds. Later lesions show proliferation of vessels around pre-existing vessels and adnexal structures. The pre-existing structure may jut into the vascular space, forming a promontory sign. Dull pink globules, extravasated erythrocytes, and hemosiderin are present. Nodular lesions are composed of spindle cells with erythrocytes that appear to line up between spindle cells with no apparent vascular space.
Treatment
KS is worldwide in distribution. In Europe there are foci of classic KS in Galicia, near the Polish–Russian border, and extending southward to Austria and Italy. In New York City, KS has occurred mostly in elderly male Galician Jewish and southern Italian persons. In Africa, KS occurs largely south of the Sahara. Northeast Congo and Rwanda–Burundi areas have the highest prevalence, and to a lesser extent, West and South Africa. The prevalence of AIDS-related KS has decreased since the 1980s. Most cases are in men who have sex with men. Very few reports have documented the exceptional occurrence of KS in patients with AIDS who acquired their infection from intravenous drug use, or in Haitians, children, or people with hemophilia. Patients at risk for developing KS associated with other causes of immunosuppression include those with iatrogenic suppression from oral prednisone or other chronic immunosuppressive therapies, as may be given to transplant patients. Endemic disease in southern Europe is strongly associated with oral corticosteroid use and diabetes, and inversely associated with cigarette smoking. KS is associated with an increased risk of developing second malignancies, such as malignant lymphomas (Hodgkin disease, T-cell lymphoma, non-Hodgkin lymphoma), leukemia, and myeloma. The risk of lymphoreticular malignancy is about 20 times greater in KS patients than in the normal population.
All types of KS are radiosensitive. Radiation therapy has been used with considerable success, either in small fractionated doses, in larger single doses to limited or extended fields, or by electron beam radiation. Local excision, cryotherapy, alitretinoin gel (Panretin), locally injected chemotherapy or IFN, and laser ablation have been used for troublesome, localized lesions. Vincristine solution, 0.1 mg/mL injected intralesionally, not more than 3 mL at one time and at intervals of 2 weeks, produces involution of tumors, some for as long as 8 months. These studies indicate that adequate control of the lesions may be achieved, at least for periods of 6–12 months. The development of resistance to medication seems to be inevitable. Many other agents have been found to be effective; among the best are IFN, vinblastine, and actinomycin D. The response rate initially is high, but recurrent lesions, which are common, are generally less responsive. Systemic therapy is usually needed if more than ten new KS lesions develop in 1 month, or if there is symptomatic lymphedema, symptomatic pulmonary disease, or symptomatic visceral involvement. In the setting of HIV, protease inhibitors have been shown to have anti-angiogenic effects; however, the results of nonnucleoside reverse transcriptase inhibitor-based regimens are not inferior to protease inhibitor-based therapy in the prevention of KS. This suggests that regression of KS is mediated by an overall improvement in immune function and not by the effects of specific antiretrovirals. Liposomal anthracyclines and paclitaxel have been approved by the US Food and Drug Administration (FDA) as first- and second-line monotherapy, respectively, for advanced KS. Rapamycin (sirolimus), an inhibitor of the mammalian target of rapamycin (mTOR), is an effective immunosuppressant for the prevention of transplant rejection, with benefits as a treatment for Kaposi’s sarcoma. Dual inhibition of PI3Kα and mTOR by PI-103 looks promising.
Etiopathogenesis
Course
Epidemiology
KS is formed by proliferation of abnormal vascular endothelial cells. HHV-8 was first found in tissue of a patient with KS and was reported in 1994. Now it has been found in KS lesional tissue irrespective of clinical type. Detection of HHV-8 in HIVinfected individuals who do not have KS is predictive of the development of KS, usually within 2–4 years. It is considered at this time that sexual or fecal–oral transmission is the most likely means of acquiring this infection. The HHV-8 genome has many open reading frames that encode products that lead to growth dysregulation or evasion of immune surveillance. How these orchestrate the formation and proliferation of spindle cells is under active investigation. Primary effusion lymphoma, solid lymphoma, and Castleman’s disease are other confirmed associations with HHV-8 infection.
Histology There is considerable variation in the histopathology according to the stage of the disease. Early lesions demonstrate irreg-
Cutaneous vascular anomalies
and diagnostic. Bone involvement is always an indication of widespread disease. Changes noted are rarefaction, cysts, and cortical erosion. African cutaneous KS is frequently accompanied by massive edema of the legs and frequent bone involvement. African lymphadenopathic KS has been reported among Bantu children, who develop massive involvement of the lymph nodes, especially the cervical nodes, preceding the appearance of skin lesions. The children also develop lesions on the eyelids and conjunctiva, from which masses of hemorrhagic tissue hang down. Eye involvement is often associated with swelling of the lacrimal, parotid, and submandibular glands, with a picture similar to Mikulicz syndrome. In AIDS-associated KS, 25% of patients have cutaneous involvement alone, whereas 29% have visceral lesions only. The most frequent sites of visceral involvement are the lungs (37%), gastrointestinal tract (50%), and lymph nodes (50%). Visceral involvement ultimately occurs in more than 70% of patients with AIDS-associated KS. Other immunosuppressed patients with KS may have visceral involvement in a variable percentage of cases.
Classic KS progresses slowly, with rare lymph node or visceral involvement. Death usually occurs years later from unrelated causes. African cutaneous KS is aggressive, with early nodal involvement, and death from KS is expected within 1–2 years. AIDS-related KS, although widespread, is almost never fatal; nearly all patients die of intercurrent infection. The course of the disease is variable in patients who develop immunosuppression-related KS from causes other than AIDS. Removal of the immunosuppression may result in resolution of the KS without therapy. Anderson LA, et al: Risk factors for classical Kaposi sarcoma in a population-based case-control study in Sicily. Cancer Epidemiol Biomarkers Prev 2008 Dec; 17(12):3435–3443. Bower M, et al: Immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma. J Clin Oncol 2005; 23:5224. Chaisuparat R, et al: Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi’s sarcoma. Cancer Res 2008 Oct 15; 68(20):8361–8368.
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node metastasis have been noted. Excision is the usual treatment, but response to IFN has been reported.
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Fig. 28-20 Large ulcerated epithelioid hemangioendothelioma. O’Mahony D, et al: Imaging techniques for Kaposi’s sarcoma. J HIV Ther 2008 Sep; 13(3):65–71.
Epithelioid hemangioendothelioma In 1982, Weiss et al described this rare tumor, which, both clinically and histologically, is intermediate between angiosarcoma and hemangioma (Fig. 28-20). It is usually a solitary, slowly growing papule or nodule on a distal area of an extremity. There is a male preponderance, and onset is frequently before the individual is 25 years of age. Histologically, there are two components: dilated vascular channels and solid epithelioid and spindle-cell elements with intracytoplasmic lumens. Some may have cellular pleomorphism and mitotic activity. Wide excision is recommended with evaluation of regional lymph nodes. This is the usual site of metastases, and if they occur here, further surgery may be curative. In the minority of cases in which distant metastatic lesions develop, chemotherapy, radiation, or both may be employed. Of the 31 patients from the original series who had follow-up at an average of 18 months, 20 were alive and well. Epithelioid sarcoma-like hemangioendothelioma demonstrates round to slightly spindled cells in sheets and nests. The cells demonstrate immunohistochemical evidence of endothelial differentiation. Local recurrence and regional soft tissue metastases may occur.
Retiform hemangioendothelioma Retiform hemangioendothelioma is a low-grade angiosarcoma, first described in 1994. It presents as a slow-growing exophytic mass, dermal plaque, or subcutaneous nodule. It most commonly occurs on the upper or lower extremities of young adults. Histologically, there are arborizing blood vessels reminiscent of normal rete testis architecture. HHV-8 DNA sequences have been reported in this tumor. Wide excision is recommended, although local recurrences are common. To date, no widespread metastases have occurred, although regional lymph nodes may develop tumor infiltrates.
Composite hemangioendothelioma This low-grade angiosarcoma typically occurs in adults, although it has been described in infancy. The tumor exhibits a mix of retiform hemangioendothelioma-like, spindle cell hemangioma-like, cavernous hemangioma-like, epithelioid hemangioendothelioma-like, and angiosarcoma-like patterns. Labeling for Prox-1 suggests a lymphatic line of differentiation. The lesions may be associated with Kasabach–Merritt or Maffucci syndrome. Local recurrences and regional lymph 592
Fukunaga M, et al: Composite hemangioendothelioma: report of 5 cases including one with associated Maffucci syndrome. Am J Surg Pathol 2007 Oct; 31(10):1567–1572. Goh SG, et al: Cutaneous vascular tumours: an update. Histopathology 2008 May; 52(6):661–673. Parsons A, et al: Retiform hemangioendotheliomas usually do not express D2-40 and VEGFR-3. Am J Dermatopathol 2008 Feb; 30(1):31–33. Requena L, et al: Cutaneous composite hemangioendothelioma with satellitosis and lymph node metastases. J Cutan Pathol 2008 Feb; 35(2):225–230. Tan D, et al: Retiform hemangioendothelioma: a case report and review of the literature. J Cutan Pathol 2005 Oct; 32(9):634–637. Utaş S, et al: Composite cutaneous haemangioendothelioma treated with interferon. J Eur Acad Dermatol Venereol 2008 Apr; 22(4):503–505.
Endovascular papillary angioendothelioma (Dabska tumor) Endovascular papillary angioendothelioma, a rare low-grade angiosarcoma, presents as a slow-growing tumor on the head, neck, or extremity of infants or young children. It shows multiple vascular channels with papillary plugs of endothelial cells surrounding central hyalinized cores that project into the lumina, sometimes forming a glomeruloid pattern. The entity is controversial, as similar histologic features have been observed in other vascular tumors, such as angiosarcoma, retiform hemangioendothelioma, and glomeruloid hemangioma. The tumor may be a distinct entity, or demonstrate a histologic pattern seen in other vascular tumors. One patient with this histologic pattern developed KMS, and others have developed regional metastasis. Wide excision and excision of the regional lymph nodes, in cases where they are involved, are usually curative. Schwartz RA, et al: The Dabska tumor: a thirty-year retrospect. Dermatology 2000; 201:1.
Angiosarcoma Angiosarcomas of the skin occur in four clinical settings. First and most common are those that occur in the head and neck of elderly people. The male to female ratio is 2:1. The lesion often begins as an ill-defined bluish macule that may be mistaken for a bruise. Distinguishing features are the frequent occurrence of a peripheral erythematous ring, satellite nodules, the presence of intratumoral hemorrhage, and the tendency for the lesion to bleed spontaneously, or after minimal trauma. The tumor progressively enlarges asymmetrically, often becomes multicentric, and develops indurated bluish nodules and plaques. The sudden development of thrombocytopenia may herald metastatic disease or an enlarging primary tumor. Solid sheets of atypical epithelioid cells may be present, but more commonly, the pattern is that of subtle infiltration in the dermis, producing the appearance of cracks between collagen bundles. The spaces are lined by hyperchromatic nuclei. Immunoperoxidase staining for endothelial markers such as CD31, CD34, and Ulex europeus lectin aids in the diagnosis. Virtually all malignant vascular tumors are positive for podoplanin. Early diagnosis and complete surgical excision, followed by moderate-dose, very wide-field radiotherapy, offer the best prognosis for limited disease. Chemotherapy and radiation therapy for extensive disease are often only palliative, especially when dealing with scalp lesions and high-grade lesions. Doxorubicin–ifosfamide chemotherapy produces a modest response rate. Paclitaxel and IFN have shown some response
Buschmann A, et al: Surgical treatment of angiosarcoma of the scalp: less is more. Ann Plast Surg 2008 Oct; 61(4):399–403. Gkalpakiotis S, et al: Successful radiotherapy of facial angiosarcoma. Int J Dermatol 2008 Nov; 47(11):1190–1192. Kikuchi A, et al: Primary cutaneous epithelioid angiosarcoma. Acta Derm Venereol 2008; 88(4):422–423. Köhler HF, et al: Cutaneous angiosarcoma of the head and neck: report of 23 cases from a single institution. Otolaryngol Head Neck Surg 2008 Oct; 139(4):519–524.
Fig. 28-21 Stewart–Treves syndrome.
Fibrous tissue abnormalities Keloid A keloid is a firm, irregularly shaped, fibrous, hyperpigmented, pink or red excrescence. The growth usually arises as the result of a cut, laceration, or burn—or, less often, an acne pustule on the chest or upper back—and spreads beyond the limits of the original injury, often sending out clawlike (cheloid) prolongations. The overlying epidermis is smooth, glossy, and thinned from pressure. The early, growing lesion is red and tender, and has the consistency of rubber. It is often surrounded by an erythematous halo, and the keloid may be telangiectatic. Lesions may be tender, painful, and pruritic, and may rarely ulcerate or develop draining sinus tracts. Keloids are often multiple. They may be as tiny as pinheads or as large as an orange. Those that follow burns and scalds are large. Lesions are often linear, frequently having bulbous expansions at each end. The surface may be larger than the base, so that the edges are overhanging. The most common location is the sternal region, but keloids also occur frequently on the neck, ears, extremities, or trunk, and rarely on the face, palms, or soles. The earlobes are frequently involved as a result of ear piercing, but involvement of the central face is rare. They are much more common, and grow to larger dimensions, in black persons than in other races. Why certain individuals develop keloids still remains unsolved. Trauma is usually the immediate causative factor, but this induces keloids only in those with a predisposition for their development. There is also a regional predisposition. Histologically, a keloid is a dense and sharply defined nodular growth of myofibroblasts and collagen with a whorllike arrangement resembling hypertrophic scar. Centrally, thick hyalinized bundles of collagen are present, and distinguish keloids from hypertrophic scars. There is a paucity of elastic tissue, just as in a scar. By pressure, the tumor causes thinning of the normal papillary dermis and atrophy of adjacent appendages, which it pushes aside. Mucopolysaccharides are increased, and often there are numerous mast cells. Keloids are usually distinctive. They may be distinguished from hypertrophic scars by their clawlike projections (Fig. 28-22), which are absent in the hypertrophic scar, the extension of the lesion beyond the confines of the original injury, and the
Fibrous tissue abnormalities
for scalp and facial angiosarcomas. Because of the multicentricity of lesions, the frequent occurrence on the face or scalp, and the rapid growth with early metastasis, death occurs in most patients within 2 years. Spieth et al reported a dramatic response in a 77-year-old man with recurrent angiosarcoma of the face and scalp after combination treatment with IFN-α2a and 13-cis-retinoic acid. The second classic clinical situation in which angiosarcoma develops is in chronic lymphedematous areas, such as that which occurs in the upper arm after mastectomy, the so-called Stewart–Treves syndrome (Fig. 28-21). This tumor appears approximately 11–12 years after surgery in an estimated 0.45% of patients. The prognosis is poor for these patients, with a mean survival of 19–31 months, and a 5-year survival rate of 6–14%. Metastases to the lungs are the most frequent cause of death. Early amputation offers the best hope. A third setting includes tumors that develop in previously irradiated sites. If the condition for which radiation therapy was given was a benign one, the average interval between radiation and development of angiosarcoma is 23 years. If the preceding illness was a malignant condition, the interval is shortened to 12 years. Again, the prognosis is poor, with survival time generally between 6 months and 2 years after diagnosis. Many patients with the Stewart–Treves syndrome received radiation, and radiation may play a pathogenic role. Angiosarcomas develop in settings other than those previously described, and this small miscellaneous subset comprises the fourth category. An angiosarcoma producing granulocyte colony-stimulating factor was associated with prominent peripheral leukocytosis.
Fig. 28-22 Keloid.
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presence of thick hyalinized collagen bundles histologically. Frequently there is a spontaneous improvement of the hypertrophic scar over a period of months, whereas in the keloid this does not occur. Atypical lesions should be biopsied, as carcinoma en cuirasse may mimic keloid. Initial treatment is usually by means of intralesional injection of triamcinolone suspension alone or in combination with 5-fluorouracil (5-FU). Using a 30-gauge needle on a 1 mL tuberculin Luer syringe, triamcinolone suspension is injected into various parts of the lesion; 40 mg/mL is generally used for initial treatment, although, as the lesion softens, 10–20 mg/ mL may be sufficient to produce involution with less risk of surrounding hypopigmentation and atrophy related to lymphatic spread of the corticosteroid. Injections are repeated at intervals of 6–8 weeks, as required. Flattening and cessation of itching are reliably achieved by this approach, and may sometimes even be achieved with topical corticosteroids. The lesions are never made narrower, however, and hyperpigmentation generally persists. Transforming growth factor (TGF)-β is known to be involved in keloid formation, and triamcinolone acetonide-induced decreases in cellular proliferation and collagen production are associated with a statistically significant decrease in the level of TGF-β1 in both normal and keloid fibroblast cell lines. Anti-TGF-β1 therapy looks promising, as does NF-κB inhibition and green tea polyphenol epigallocatechin-3-gallate. Other approaches to treatment include flashlamp pulsed dye laser treatment, which is also associated with reduced expression of TGF-β1. Cryosurgery (including contact, intralesional needle cryoprobe, and spray cryosurgery), intralesional 5-FU, intralesional etanercept, and calcium channel-blockers have some demonstrated efficacy in the treatment of keloids. Fibroblasts derived from the central part of keloids grow faster than peripheral keloid and nonkeloid fibroblasts. Verapamil has been shown to decrease interleukin (IL)-6 and VEGF in these cultured cells, and to inhibit cell growth. If surgical removal by excision is feasible, and if narrowing of the keloid is a vitally important goal, the keloid may be excised. After the excision, intralesional injection of triamcinolone or IFN-α2b may be combined with postoperative x-ray irradiation or topical application of imiquimod. Silicone sheeting and pressure are other adjunctive methods used to limit recurrences. Results with these modalities have been mixed. Silicone gel-sheet treatment has been shown to reduce lesional mast cell numbers and decrease itching. Banding at the base of the keloid with a suture ligature for a 5-week period has been used successfully to treat pedunculated lesions. Pierced-ear keloids occur with considerable frequency. When the keloid is young, intralesional injection of triamcinolone is frequently sufficient to control the problem. In old keloids, excision of the lesion using lidocaine with triamcinolone, followed by injections at 2-week intervals, produces good results. CO2 laser excision has also been successful in old mature keloids in this site. Berman B, et al: Prevention and management of hypertrophic scars and keloids after burns in children. J Craniofac Surg 2008 Jul; 19(4):989–1006. Berman B, et al: Evaluating the tolerability and efficacy of etanercept compared to triamcinolone acetonide for the intralesional treatment of keloids. J Drugs Dermatol 2008 Aug; 7(8):757–761. Butler PD, et al: Current progress in keloid research and treatment. J Am Coll Surg 2008 Apr; 206(4):731–741 (Epub 2008 Feb 1). Chike-Obi CJ, et al: Keloids: pathogenesis, clinical features, and management. Semin Plast Surg 2009 Aug; 23(3):178–184. Hochman B, et al: Intralesional triamcinolone acetonide for keloid treatment: a systematic review. Aesthetic Plast Surg 2008 Jul; 32(4):705–709.
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Makino S, et al: DHMEQ, a novel NF-kappaB inhibitor, suppresses growth and type I collagen accumulation in keloid fibroblasts. J Dermatol Sci 2008 Sep; 51(3):171–180. Park G, et al: Green tea polyphenol epigallocatechin-3-gallate suppresses collagen production and proliferation in keloid fibroblasts via inhibition of the STAT3-signaling pathway. J Invest Dermatol 2008 Oct; 128(10):2429–2441. Robles DT, et al: Keloids: pathophysiology and management. Dermatol Online J 2007 Jul 13; 13(3):9. Tan KT, et al: The influence of surgical excision margins on keloid prognosis. Ann Plast Surg 2010 Jan; 64(1):55–58.
Dupuytren contracture Dupuytren contracture is a fibromatosis of the palmar aponeurosis. The lesion arises most commonly in men between the ages of 30 and 50 as multiple firm nodules in the palm. Usually, 3–5 nodules about 1 cm in diameter develop, proximal to the fourth finger. Later, the fibromatosis produces contractures, which may be disabling. The condition occurs at times with alcoholic cirrhosis, diabetes mellitus, and chronic epilepsy. It is also associated with Peyronie’s disease, plantar fibromatosis, and knuckle pads. In some cases there is a familial predisposition. The fibrous nodules are composed of myofibroblasts that express androgen receptors. 5-α-Dihydrotestosterone induces an increase in Dupuytren fibroblast proliferation. In contrast to deep fibromatoses, which behave more aggressively, superficial fibromatoses lack β-catenin and adenomatous polyposis coli (APC) gene mutations. Early intralesional triamcinolone may help, but surgical excision of the involved palmar fascia may be the only way to liberate severely contracted fingers. Androgen blockade represents a potential avenue of pharmacologic therapy. As with keloids, matrix metalloproteinase and TGF-β2 inhibition appear promising.
Plantar fibromatosis The plantar analog of Dupuytren contracture, plantar fibromatosis (Ledderhose’s disease) occurs as slowly enlarging nodules on the soles that ultimately cause difficulty in walking or even weight-bearing. The diagnosis is usually made clinically, but both biopsy and MRI can be used to confirm the diagnosis. The usual treatment, as for Dupuytren contracture, is wide excision of the plantar fascia. Subtotal excision is associated with a high rate of recurrence. Although adjuvant radiotherapy is effective in decreasing the recurrence rate, it has a significant complication rate with functional impairment. Improvement by the intralesional injection of triamcinolone acetonide, 30 mg/mL monthly for 5 months, has been reported. The triamcinolone can be diluted with lidocaine solution. Hindocha S, et al: Revised Tubiana’s staging system for assessment of disease severity in Dupuytren’s disease—preliminary clinical findings. Hand (N Y) 2008 Jun; 3(2):80–86. Ostlere S, et al: Masses of the foot closely related to the plantar fascia. Foot Ankle Int 2007 Jan; 28(1):145. Townley WA, et al: Matrix metalloproteinase inhibition reduces contraction by Dupuytren fibroblasts. J Hand Surg [Am] 2008 Nov; 33(9):1608–1616. Zhang AY, et al: Gene expression analysis of Dupuytren’s disease: the role of TGF-β2. J Hand Surg Eur Vol 2008 Dec; 33(6):783–790.
Peyronie’s disease Plastic induration of the penis is a fibrous infiltration of the intercavernous septum of the penis. This fibrosis results in the formation of nodules or plaques. As a result of these plaques, a fibrous chordee is produced, and curvature of the penis occurs on erection, sometimes so severe as to make
Smith JF, et al: Peyronie’s disease: a critical appraisal of current diagnosis and treatment. Int J Impot Res 2008 Sep–Oct; 20(5):445–459. Tran VQ, et al: Review of the surgical approaches for Peyronie’s disease: corporeal plication and plaque incision with grafting. Adv Urol 2008:263450.
Knuckle pads Knuckle pads (heloderma) are well-defined, round, plaquelike, fibrous thickenings that develop on the extensor aspects of the proximal interphalangeal joints (Fig. 28-23) of the toes and fingers, including the thumbs. They develop at any age and grow to be some 10–15 mm in diameter in the course of a few weeks or months, then persist permanently. They are flesh-colored or somewhat brown, with normal or slightly hyperkeratotic epidermis overlying and adherent to them. They are a part of the skin and are freely movable over underlying structures. Knuckle pads are sometimes associated with Dupuytren contracture, clubbing, or camptodactylia (irreducible flexion contracture of one or more fingers). Some cases are familial and some are related to trauma or frequent knuckle cracking. An autosomal-dominant association of knuckle pads, mixed hearing loss (sensorineural and conductive), and total leuko nychia has been reported. Knuckle pads have also been
associated with autosomal-dominant epidermolytic palmoplantar keratoderma with a mutation in keratin 9. Histologically, the lesions are fibromas. They are to be differentiated clinically from the nodular type of neurodermatitis and from the small hemispherical pitted papules that may develop over the knuckles after frostbite or in acrocyanosis, and from rheumatic nodules. Treatment with intralesional injection of corticosteroids may be beneficial. As with keloids, intralesional 5-FU may be beneficial. Akiyama M, et al: A novel GJB2 mutation p.Asn54His in a patient with palmoplantar keratoderma, sensorineural hearing loss and knuckle pads. J Invest Dermatol 2007 Jun; 127(6):1540–1543. Koba S, et al: Knuckle pads associated with clubbed fingers. J Dermatol 2007 Dec; 34(12):838–840. Weiss E, et al: A novel treatment for knuckle pads with intralesional fluorouracil. Arch Dermatol 2007 Nov; 143(11):1458–1460.
Fibrous tissue abnormalities
intromission difficult or impossible. Sometimes pain may be severe. The association of this disease with Dupuytren contracture has been recognized. Injection of IFN-α2b, verapamil, or collagenase has been employed, with the strongest evidence supporting IFN use. Intralesional triamcinolone suspension injected or iontophoresed into the plaques and nodules has shown mixed results. Oral therapies include tocopherol (vitamin E), paraaminobenzoate, colchicine, tamoxifen, and acetyl-L-carnitine, but data supporting oral therapy are weak. Surgical correction tailored to the degree of deformity is often successful. Extracorporeal shock wave therapy may reduce penile pain and improve sexual function, although objective changes in plaque size and curvature have not been demonstrated.
Pachydermodactyly Pachydermodactyly represents a benign fibromatosis of the fingers. There is a fullness of the medial and lateral digit just proximal to the proximal interphalangeal joint. This asymptomatic process is most often first noted in adolescence and usually involves multiple fingers. Five types have been described: classic pachydermodactyly, localized pachydermodactyly, transgrediens pachydermodactyly in which the abnormality extends to the metacarpophalangeal areas, familial pachydermodactyly, and pachydermodactyly associated with tuberous sclerosis. Some instances may result from repetitive tic-like obsessive-compulsive behaviors. Increased collagen or mucin accounts for the swelling. Cases associated with repetitive tics respond to treatment for the obsessivecompulsive disorder. Al Hammadi A, et al: Pachydermodactyly: case report and review of the literature. J Cutan Med Surg 2007 Sep–Oct; 11(5):185–187.
Desmoid tumor Desmoid tumors occur as large, deep-seated, wellcircumscribed masses arising from the muscular aponeurosis. They most commonly occur on the abdominal wall, especially in women during or soon after pregnancy. Desmoid tumors have been divided into five types: abdominal wall, extraabdominal, intra-abdominal, multiple, and those occurring in Gardner syndrome/familial adenomatous polyposis. They recur locally and can kill if they invade, surround, or compress vital structures. The most dangerous, then, are those at the root of the neck and the intra-abdominal type. MRI will aid in the evaluation of soft tissue extension and recurrence following treatment. Mutations in the β-catenin gene correlate with local recurrence. Treatment may be with wide local excision, radiotherapy, or hormonal manipulation. High-dose tamoxifen in combination with sulindac has been effective. Mesenteric desmoid tumors have been treated with anti-angiogenic therapy with toremifene and IFN-α2b. Imatinib mesylate looks promising. Lazar AJ, et al: Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. Am J Pathol 2008 Nov; 173(5):1518–1527.
Collagenous fibroma (desmoplastic fibroblastoma)
Fig. 28-23 Knuckle pads.
This slow-growing, deep-set, benign fibrous tumor is usually located in the deep subcutis, fascia, aponeurosis, or skeletal muscle of the extremities, limb girdles, or head and neck regions. It is characterized by hypocellularity and dense bands of hyalinized collagen that may infiltrate into skeletal muscle. 595
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Despite this, no tumors have been reported to metastasize or recur after excision. Chromosomal translocation (2; 11)(q31; q12) has been reported. Tumor cells stain for vimentin, and may stain for actin, but have been negative for CD34, S-100 protein, keratin, CD68, desmin, and β-catenin. Sakamoto A, et al: Desmoplastic fibroblastoma (collagenous fibroma) with a specific breakpoint of 11q12. Histopathology 2007 Dec; 51(6):859–860. Watanabe H, et al: Desmoplastic fibroblastoma (collagenous fibroma). J Dermatol 2008 Feb; 35(2):93–97.
Aponeurotic fibroma Aponeurotic fibroma has also been called juvenile aponeurotic fibroma (calcifying fibroma). It is a tumor-like proliferation characterized by the appearance of slow-growing, cystlike masses that occur on the limbs, especially the hands and feet. Histologically, the distinctive lesions are sharply demarcated and composed of collagenous stroma showing acid mucopolysaccharides infiltrated by plump mesenchymal cells with oval nuclei. Hyalinized areas are also present, suggesting chondroid or osteoid metaplasia. An aid to the diagnosis is stippled calcification, readily seen on roentgenograms. Surgical excision is the treatment of choice and can be guided by MRI. Morii T, et al: Clinical significance of magnetic resonance imaging in the preoperative differential diagnosis of calcifying aponeurotic fibroma. J Orthop Sci 2008 May; 13(3):180–186.
Infantile myofibromatosis Infantile myofibromatosis is the most common fibrous tumor of infancy. Eighty percent of patients have solitary lesions, with half of these occurring on the head and neck. About 60% are present at or soon after birth. Congenital generalized fibromatosis is an uncommon condition that presents at birth or soon after. It is characterized by multiple, firm, dermal and subcutaneous nodules. Skeletal lesions, primarily of the metaphyseal regions of the long bones, occur in 50% of patients. If only the skin and bones develop fibromas, the prognosis is excellent, with spontaneous resolution of the lesions without complications expected within the first 1–2 years of life. Some refer to this limited disease as congenital multiple fibromatosis. Females more commonly contract the generalized disease. The fibromas may involve the viscera, including the gastrointestinal tract, breast, lungs, liver, pancreas, tongue, serosal surfaces, lymph nodes, or kidney. Autosomal-dominant inheritance has been reported. Histologically, fascicles of spindle cells occur in a whorled pattern. These nodules are composed of myofibroblasts. Mortality in this more widespread subset is high. Eighty percent of affected individuals die from obstruction or compression of vital organs. Those who survive past 4 months have spontaneous regression of their disease. Some life-threatening cases have responded to low-dose chemotherapy.
Aggressive infantile fibromatosis The clinical presentation of this locally recurring, nonmetastasizing lesion involves single or multiple fast-growing masses that are present at birth or occur within the first year of life. Infantile fibromatosis may be seen in any location, although the arms, legs, and trunk are the usual sites. Histologically, it is hypercellular and mimics malignancy. Alaggio R, et al: Morphologic overlap between infantile myofibromatosis and infantile fibrosarcoma: a pitfall in diagnosis. Pediatr Dev Pathol 2008 Sep–Oct; 11(5):355–362. Azzam R, et al: First-line therapy of generalized infantile myofibromatosis with low-dose vinblastine and methotrexate. Pediatr Blood Cancer 2008 Oct 20; 52(2):308. Martín JM, et al: Self-healing generalized infantile myofibromatosis. J Eur Acad Dermatol Venereol 2008 Feb; 22(2):236–238.
Juvenile hyaline fibromatosis and infantile systemic hyalinosis Juvenile hyaline fibromatosis and infantile systemic hyalinosis are allelic autosomal-recessive conditions characterized by multiple subcutaneous skin nodules, hyaline deposition, gingival hypertrophy, osteolytic bone lesions, and joint contractures. Nodular tumors of the scalp, face, and extremities usually appear in early childhood. Pink confluent papules may occur on the paranasal folds, and periauricular (Fig. 28-24) and perianal regions. The gene has been mapped to chromosome 4q21 with at least 15 different mutations in the gene encoding capillary morphogenesis protein 2, a transmembrane protein that is induced during capillary morphogenesis and that binds laminin and collagen IV. Histologically, there are fibroblasts with fine intracytoplasmic eosinophilic granules, embedded in a homogeneous eosinophilic dermal ground substance. Ultrastructurally, the fibroblasts demonstrate defective synthesis of collagen, deposited as fibrillogranular material. Antaya RJ, et al: Juvenile hyaline fibromatosis and infantile systemic hyalinosis overlap associated with a novel mutation in capillary morphogenesis protein-2 gene. Am J Dermatopathol 2007; 29:99.
Diffuse infantile fibromatosis This process occurs within the first 3 years of life and is usually confined to the muscles of the arms, neck, and shoulder area. There is a multicentric infiltration of muscle fibers with fibro blasts resembling those seen in aponeurotic fibromas. Calcification does not occur. Recurrence after excision occurs in about one-third of cases. 596
Fig. 28-24 Juvenile hyaline fibromatosis.
Dhingra M, et al: Juvenile hyaline fibromatosis and infantile systemic hyalinosis: divergent expressions of the same genetic defect? Indian J Dermatol Venereol Leprol 2008 Jul–Aug; 74(4):371–374.
Infantile digital fibromatosis is a rare neoplasm of infancy and childhood that usually occurs on the dorsal or lateral aspects of the distal phalanges of the toes and fingers. The thumb and great toe are usually spared. These asymptomatic, firm, red, smooth nodules occur during the first year of life, 47% in the first month. Rare congenital lesions have been noted. The lesions do not metastasize, but may infiltrate deeply. Histologically, the epidermis is normal, but the dermis is infiltrated with proliferating myofibroblasts and collagen bundles. Eosinophilic cytoplasmic inclusions in many of the fibroblasts are characteristic. Treatment by surgical excision has a high risk of recurrence, and conservative, nonsurgical management is often appropriate. Spontaneous regression is generally noted, but the lesion may cause functional impairment and may infiltrate deeply before regression occurs. Mohs micrographic surgery has been performed successfully using both trichrome staining and smooth muscle actin staining to demonstrate the inclusion bodies within tumor cells. Campbell LB, et al: Mohs micrographic surgery for a problematic infantile digital fibroma. Dermatol Surg 2007 Mar; 33(3):385–387. Grenier N, et al: A range of histologic findings in infantile digital fibromatosis. Pediatr Dermatol 2008 Jan–Feb; 25(1):72–75. Taylor HO, et al: Infantile digital fibromatosis. Ann Plast Surg 2008 Oct; 61(4):472–476.
Fibrous hamartoma of infancy Fibrous hamartoma of infancy is a single dermal or subcutaneous firm nodule of the upper trunk that is present at birth or shortly thereafter. Overlying skin changes are uncommon, but may include increased hair, alteration in pigmentation, and eccrine gland hyperplasia. Most cases are solitary, but multiple tumors have been reported. Ninety-one percent are noted within the first year of life and 23% are congenital. The male to female ratio is 2.4:1. Most lesions occur in the axillary region, upper arm, upper trunk, inguinal region, and external genital area. An association with Williams syndrome has been reported. Biopsy shows an organoid pattern with different types of tissue organized in whorls or bands. In early lesions, lobules of mature fat are interspersed between myxoid and fibrous areas. Myxoid zones have primitive mesenchymal cells with stellate nuclei. Fibrosing areas demonstrate delicate collagen bundles and many elongated fibroblast nuclei. A complex chromosomal translocation (6; 12; 8)(q25; q24.3; q13) has been reported. Over time, both the myxoid and fibrosing areas develop into cell-poor fibrous areas with thick collagen bundles. There is no recurrence after excision. Gupta R, et al: Cytologic diagnosis of fibrous hamartoma of infancy: a case report of a rare soft tissue lesion. Acta Cytol 2008 Mar–Apr; 52(2):201–203. Togo T, et al: Fibrous hamartoma of infancy in a patient with Williams syndrome. Br J Dermatol 2007 May; 156(5):1052–1055.
Fibromatosis colli In fibromatosis colli there is a fibrous tissue proliferation infiltrating the lower third of the sternocleidomastoid muscle at birth. Fine needle aspiration is useful to confirm the diagnosis. Spontaneous remission occurs within a few months. Occasionally, some patients are left with a wryneck deformity; however, this complication is amenable to surgery.
Fibrous tissue abnormalities
Infantile digital fibromatosis (infantile digital myofibroblastoma, inclusion body fibroma)
Fig. 28-25 Giant cell tumor of the tendon sheath.
Nayak SP, et al: Cytodiagnosis of fibromatosis colli. Cytopathology 2007 Aug; 18(4):266–268.
Giant cell tumor of the tendon sheath This tumor, which is most commonly attached to the tendons of the fingers (Fig. 28-25), hands, and wrists, has a predilection for the flexor surfaces. It is firm, measures from 1 to 3 cm in diameter, and does not spontaneously involute. It recurs after excision in approximately 25% of cases. Another tumor of the tendon sheath, fibroma of the tendon sheath, may represent a variant of the giant cell tumor. It also affects the flexural tendons of the fingers and hands, and morphologically, it and the giant cell tumor are identical. The condition tends to occur in younger men (the average age at onset is 30) than does the giant cell variety. When a proliferation similar to giant cell tumor of the tendon sheath occurs in deeper tissues, it is referred to as pigmented villo-nodular tenosynovitis. The pigment is hemosiderin. Histologically, the giant cell tumor consists of lobules of densely hyalinized collagen. The characteristic osteoclast-like giant cells have deeply eosinophilic cytoplasm that moulds to adjacent cells. A variable number of randomly distributed nuclei are present. Lipophages and siderophages may be numerous, and hemosiderin deposition may impart a brown color to the lesions on gross examination. The fibroma of the tendon sheath generally lacks lipophages, siderophages, and giant cells, with the lobules being composed of dense fibrocollagenous tissue. The rate of recurrence depends on the presence or absence of a pseudocapsule, lobulation of the tumor, extra-articular location, and the presence of satellite lesions. Local recurrence has been treated with more extensive surgery, and imaging studies can define the extent of the tumor. Radiation therapy has been reported anecdotally. Gholve PA, et al: Giant cell tumor of tendon sheath: largest single series in children. J Pediatr Orthop 2007 Jan–Feb; 27(1):67–74. Wang Y, et al: The value of sonography in diagnosing giant cell tumors of the tendon sheath. J Ultrasound Med 2007 Oct; 26(10): 1333–1340.
Ainhum Ainhum is also known as dactylolysis spontanea, banko kerend, and sukhapakla. It is a disease affecting the toes, 597
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especially the fifth toe, characterized by a linear constriction around the affected digit, which leads ultimately to the spontaneous amputation of the distal part. It occurs chiefly among black men in Africa. Usually it is unilateral, but it may be bilateral. The disease begins with a transverse groove in the skin on the flexor surface of the toe, usually beneath the first interphalangeal articulation. The furrow is produced by a ringlike fibrosis and an induration of the dermis. It deepens and extends laterally around the toe until the two ends meet, so that the digit becomes constricted, as if in a ligature. The constricted part becomes swollen, soft, and after a time, greatly distended. Ulceration may result in a malodorous discharge, with pain and gangrene. The course of the disease is slow, but in 5–10 years spontaneous amputation occurs, generally at a joint. The cause is unknown. The condition may result from chronic trauma and exposure to the elements by walking barefoot in the tropics. Fissuring followed by chronic inflammation and fibrosis may then result. Treatment in early cases by cutting the constricting band is unsuccessful; in advanced cases amputation of the affected member is advisable. Surgical correction by Z-plasty has produced good results. Intralesional injection of betamethasone (total, 15 injections) has also been successful.
Pseudo-ainhum Pseudo-ainhum has been a term used in connection with certain hereditary and nonhereditary diseases in which annular constriction of digits occurs. Hereditary disorders include hereditary palmoplantar keratodermas, especially Vohwinkel syndrome and mal de Meleda, pachyonychia congenita, Ehlers–Danlos syndrome, erythropoietic protoporphyria, and congenital ectodermal defect. Nonhereditary disorders associated with constriction of digits are ainhum, Hansen’s disease, cholera, ancylostomiasis, scleroderma, Raynaud syndrome, pityriasis rubra pilaris, psoriasis, Olmsted syndrome, Reynold syndrome (scleroderma and primary biliary cirrhosis with antimitochondrial antibodies), syringomyelia, ergot poisoning, and tumors of the spinal cord. Factitial pseudo-ainhum may be produced by self-application of a rubber band, string, or other ligature. Congenital cases have been reported that may affect digits or limbs. It may occur as a familial condition or may be secondary to amniotic bands. Treatment may be with surgery or intralesional injection of corticosteroids, as in ainhum. Retinoids may be used in diseases responsive to them. Almond SL, et al: Pseudoainhum in chronic psoriasis. Br J Dermatol 2003; 149:1064. Rashid RM, et al: Destructive deformation of the digits with autoamputation: a review of pseudo-ainhum. J Eur Acad Dermatol Venereol 2007 Jul; 21(6):732–737.
Connective tissue nevi These uncommon lesions may present as acquired isolated plaques, as multiple lesions—either acquired or congenital, or as one finding in a more generalized disease. Biopsy findings in many cases do not appear very different from normal skin, although in some cases altered amounts of collagen or elastin may be identified. These lesions characteristically occur on the trunk, most often in the lumbosacral area (Fig. 28-26). They may be solitary, but are often multiple, in which case they may show a linear or zosteriform arrangement. Individual lesions are slightly elevated plaques 1–15 cm in diameter, varying in color 598
Fig. 28-26 Connective tissue nevus.
from light yellow to orange, with a surface texture resembling shagreen leather. In Proteus syndrome, the connective tissue nevi are present as plantar, or occasionally, palmar masses with a cerebriform surface. Connective tissue nevi of the acquired type have been classified as eruptive collagenomas, isolated collagenomas, or isolated elastomas, depending on the number of lesions and the predominant dermal fibers present. They cannot be differentiated clinically. Hereditary types of connective tissue nevi include dermatofibrosis lenticularis disseminata in the Buschke–Ollendorff syndrome, familial cutaneous collagenoma, and the shagreen patches seen in tuberous sclerosis. Buschke–Ollendorff syndrome is an autosomal-dominantly inherited disorder in which widespread dermal papules and plaques develop asymmetrically over the trunk and limbs. Elastic fiber thickening, highly variable fiber diameter, and desmosine increases 3–7-fold above normal have been described in these patients. The associated feature of osteo poikilosis is asymptomatic, but it is diagnostic in x-ray evaluation. Focal sclerotic densities are seen, primarily in the long bones, pelvis, and hands. The syndrome is highly variable, and familial inheritance of elastic tissue nevi without evidence of osteopoikilosis has been reported. Papular elastorrhexis is characterized by multiple white, evenly scattered papules, usually occurring on the trunk. There is a decrease of elastic fibers, which may appear thin and fragmented. Most reported cases are sporadic but familial occurrence has been described. Patients with familial cutaneous collagenomas may present with numerous symmetric asymptomatic dermal nodules on the back. The age of onset is usually in the mid- to late teens. In patients with the inherited disease, multiple endocrine neoplasia type I multiple collagenomas were reported in 23 of 32 patients. These were less than 3 mm in diameter and were on the upper torso, neck, and shoulders. They occurred in association with numerous other cutaneous findings, such as angiofibromas, café-au-lait macules, and lipomas. Atrioseptal defect has also been reported in association with familial collagenomas. The collagenomas of tuberous sclerosis are associated with adenoma sebaceum, periungual fibromas, and ash-leaf macules. Because at least half the cases of tuberous sclerosis result from new mutations, all patients with connective tissue nevi should be carefully studied for evidence of tuberous sclerosis, even in the absence of a family history of the disease. Isolated plantar collagenoma may exhibit a cerebriform appearance and resemble plantar fibromas of Proteus syndrome.
Asano Y, et al: Linear connective tissue nevus. Pediatr Dermatol 2007 Jul–Aug; 24(4):439–441. Brazzelli V, et al: Zosteriform connective tissue nevus in a pediatric patient. Pediatr Dermatol 2007 Sep–Oct; 24(5):557–558. Gurel MS, et al: Familial cutaneous collagenoma: new affected family with prepubertal onset. J Dermatol 2007 Jul; 34(7):477–481.
Elastofibroma dorsi Elastofibroma dorsi is a benign tumor usually located in the deep soft tissues in the subscapular region, but sometimes at other sites. The tumor is firm and unencapsulated, and measures up to several centimeters in diameter. It is believed to represent an unusual response to repeated trauma. Histologically, the tumor consists of abundant compact sclerotic collagen mixed with large, swollen, irregular elastic fibers, often appearing as globules of elastic tissue. It commonly appears on nuclear medicine scans, suggesting it is not as uncommon as once believed. Computed tomography (CT) and MRI can define the extent of the lesion, and excision is curative. Mortman KD, et al: Elastofibroma dorsi: clinicopathologic review of 6 cases. Ann Thorac Surg 2007 May; 83(5):1894–1897.
Angiofibromas These skin-colored to reddish papules, which show fibroplasia and varying degrees of vascular proliferation in the upper dermis, may occur as a solitary nonhereditary form, the fibrous papule of the nose, as multiple nonhereditary lesions, pearly penile papules, or as multiple hereditary forms as in tuberous sclerosis, Birt–Hogg–Dube syndrome (in combination with the specific lesion, the fibrofolliculoma), and multiple endocrine neoplasia type I. There have been reports of agminated or segmental angiofibromas that may represent a segmental form of tuberous sclerosis. The multiple hereditary types are discussed in other chapters. Cellular angiofibroma typically occurs in the genital region of older women. It is composed of small spindle cells arranged in short fascicles and relatively abundant small rounded vessels. They may express estrogen and progesterone receptors, and also CD34. Hall MR, et al: Unilateral facial angiofibromas without other evidence of tuberous sclerosis: case report and review of the literature. Cutis 2007 Oct; 80(4):284–288. Val-Bernal JF, et al: Extragenital subcutaneous cellular angiofibroma. Case report. APMIS 2007 Mar; 115(3):254–258.
Fibrous papule of the nose (fibrous papule of the face, benign solitary fibrous papule) These lesions occur in adults as dome-shaped, sessile, skincolored, white or reddish papules, 3–6 mm in diameter, on or near the nose (Fig. 28-27). Fibrous papule is usually solitary, but it is not uncommon for a few lesions to occur. It may be confused with a nevocytic nevus, neurofibroma, granuloma pyogenicum, or a basal cell carcinoma. Like other angiofibromas, fibrous papules demonstrate concentric fibrosis surrounding vessels and adnexal structures. Stellate dermal
Fibrous tissue abnormalities
Eruptive collagenomas may be widespread or localized. They have rarely been associated with infectious diseases such as syphilis. Mucinous nevus is a form of connective tissue nevus characterized by increased ground substance without increases in collagen or elastin. Histologically, collagen bundles are widely separated by mucin and may be attenuated. Overlying follicular induction similar to that seen in dermatofibromas may be present.
Fig. 28-27 Fibrous papule.
dendrocytes are often prominent. Clear cell, granular, and epithelioid variants have been described. They stain for factor XIIIa. Large pyramidal junctional melanocytes are often noted overlying the lesion, and a superficial shave biopsy may be mistaken for a melanocytic lesion. Conservative excision is curative; recurrence is rare. Multiple lesions should prompt a search for other stigmata of tuberous sclerosis. Jacyk WK, et al: Fibrous papule of the face with granular cells. Dermatology 2008; 216(1):56–59. Kucher C, et al: Epithelioid fibrous papule—a new variant. J Cutan Pathol 2007 Jul; 34(7):571–575.
Pearly penile papules This is the term given to pearly-white, dome-shaped papules occurring circumferentially on the coronal margin and sulcus of the glans penis. The lesions may be firm or soft and filiform. Occasionally, lesions are also present on the penile shaft. Pearly penile papules are not uncommon. Patients usually present around the age of 20–30 years, concerned that these are condylomata, or are referred as having treatment-resistant venereal warts. These lesions should be distinguished from papillomas, hypertrophic sebaceous glands, and condyloma acuminatum. No treatment is necessary, only reassurance. If treatment is desired, laser ablation or shave excision is effective.
Acral fibrokeratoma Acral fibrokeratoma, often called acquired digital fibrokeratoma, is characterized by a pinkish, hyperkeratotic, hornlike projection occurring on a finger, toe, or palm. The projection usually emerges from a collarette of elevated skin. The average age of the patient is 40. The lesion resembles a rudimentary supernumerary digit, cutaneous horn, or a neuroma. Onset during immunosuppressive therapy has been reported. Histologic sections show a central core of thick collagen bundles interwoven closely in a vertical position. This is surrounded by capillaries and a fine network of reticulum fibers. Stellate dermal dendrocytes may be present, as in fibrous papule. Simple surgical excision or laser ablation at the level of the skin surface is effective. Qiao J, et al: Acquired digital fibrokeratoma associated with ciclosporin treatment. Clin Exp Dermatol 2009 Mar; 34(2):257–259.
Familial myxovascular fibromas Multiple verrucous papules on the palms and fingers, which on biopsy show focal neovascularization and mucin-like 599
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changes in the papillary dermis, have been described. Clinically, these lesions closely resemble warts. They have been reported in several family members, with a probable autosomal-dominant inheritance.
Superficial acral fibromyxoma Superficial acral fibromyxoma typically appears in the superficial soft tissues of the acral extremity of an adult. Most are painless. Histologically, they are characterized by a moderately cellular proliferation of bland spindled and stellate fibroblasts with a loose storiform or fascicular growth pattern. Mucin and small blood vessels are prominent. Spindle cells commonly express CD34, CD99, and epithelial membrane antigen. CD10 and nestin expression have also been reported. Al-Daraji WI, et al: Superficial acral fibromyxoma: a clinicopathological analysis of 32 tumors including 4 in the heel. J Cutan Pathol 2008 Nov; 35(11):1020–1026. Tardío JC, et al: Superficial acral fibromyxoma: report of 4 cases with CD10 expression and lipomatous component, two previously underrecognized features. Am J Dermatopathol 2008 Oct; 30(5):431–435.
Subungual exostosis Subungual exostosis is closely related to solitary osteochondroma and both are found beneath the distal edge of the nail, most commonly of the great toe. Rarely, the terminal phalanges of other toes, particularly the little toe or even the fingers, may be involved. The exostosis is seen chiefly in women between the ages of 12 and 30. The first appearance is a small pinkish growth projecting slightly beyond the inner free edge of the nail. The overlying nail becomes brittle and either breaks or is removed, after which the tumor, being released, mushrooms upward and distally above the level of the nail. It grows slowly to a maximum diameter of about 8 mm. Pressure of the shoe on the lesion causes great pain. Subungual exostosis must be differentiated from pyogenic granuloma, verruca vulgaris, pterygium inverum unguis, ingrowing nail, and glomus tumor. If subungual exostosis is suspected, the diagnosis can be confirmed by radiographic examination. Complete excision or curettage is the proper method of treatment. Campanelli A, et al: Images in clinical medicine. Subungual exostosis. N Engl J Med 2008 Dec 18; 359(25):e31. Lee SK, et al: Two distinctive subungual pathologies: subungual exostosis and subungual osteochondroma. Foot Ankle Int 2007 May; 28(5):595–601.
Histologically, a zone of eosinophilic necrosis of collagen is flanked by granulation tissue. Overlying acanthosis and hyperkeratosis and central ulceration may be present. The histologic changes resemble those of a decubitus ulcer, but on a smaller scale. Occasionally, bizarre reactive fibroblasts are noted, as in atypical decubital fibroplasia. The lesions may be excised. The underlying cartilage may be excised or fenestrated to reduce pressure on the overlying skin during sleep. The patient may be encouraged to change sleeping positions, but many find this difficult. Pillows with an ear slot are also available. Affleck AG: Surgical treatment of chondrodermatitis nodularis chronica helicis: conservation of normal tissue is important for optimal esthetic outcome. J Oral Maxillofac Surg 2008 Oct; 66(10):2194. Rajan N, et al: The punch and graft technique: a novel method of surgical treatment for chondrodermatitis nodularis helicis. Br J Dermatol 2007 Oct; 157(4):744–747.
Oral submucous fibrosis A distinctive fibrosis of the oral mucosa occurs in the western Pacific basin and south Asia among persons whose diet is heavily seasoned with chili or who chew betel, a compound of the nut of the areca palm, the leaf of the betel pepper, and lime. The irritation produced first causes a thickening of the palate, tonsillar pillars, and fauces secondary to dermal and muscular fibrosis (Fig. 28-28). As the disease progresses, opening of the mouth and protrusion of the tongue develop, such that eating, swallowing, and speech are impaired. Later, ulceration and leukoplakic areas occur, and finally, in approximately 7% of patients, malignant transformation to squamous cell carcinoma develops. Treatment consists of the intralesional injection of dexamethasone and hyaluronidase, and in advanced cases surgical excision and grafting or laser ablation have been used. Discontinuance of the offending substance and physical therapy are also needed. Aziz SR: Oral submucous fibrosis: case report and review of diagnosis and treatment. J Oral Maxillofac Surg 2008 Nov; 66(11):2386–2389. Isaac U, et al: Histopathologic features of oral submucous fibrosis: a study of 35 biopsy specimens. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008 Oct; 106(4):556–560. Nayak DR, et al: Role of KTP-532 laser in management of oral submucous fibrosis. J Laryngol Otol 2008 Oct 10:1–4.
Fascial hernia Evanescent herniations in the form of nodules appear in the skin where the deep and superficial veins meet as they go
Chondrodermatitis nodularis chronica helicis This is a small, nodular, tender, chronic inflammatory lesion occurring on the helix of the ear. Most patients are men. The lesions are not uncommon, and sometimes as many as 12 nodules may arrange themselves along the edge of the upper helix. The lesions are 2–4 mm in diameter, well defined, slightly reddish, and extremely tender. At times, the surface is covered by an adherent scale or a shallow ulcer. After the masses have reached a certain size, growth ceases, but the lesions persist unchanged for years. There is no tendency to malignant change. Similar lesions may occur on the anthelix, predominantly in women. The lesion is produced by ischemic necrosis of the dermis, and generally occurs on the side the patient favors during sleep. There may be a history of frostbite, chronic trauma, or chronic actinic exposure with concomitant actinically induced lesions of the face and dorsal hands. 600
Fig. 28-28 Oral submucous fibrosis. (Courtesy of Shyam Verma, MD)
Harrington AC, et al: Hernias of the anterior tibialis muscle. J Am Acad Dermatol 1990; 22:123.
Perineal skin tag (infantile perianal pyramidal protrusion) Perineal skin tags may be congenital or acquired. They are generally asymptomatic, but may require surgical intervention if inflamed or traumatized. A similar appearance may occur as a manifestation of lichen sclerosus.
Cutaneous pseudosarcomatous polyp and umbilical polyp Cutaneous pseudosarcomatous polyps and umbilical pseudo sarcomatous polyps are benign proliferations with a taglike configuration, but dramatic cytologic atypia and pleomorphism. The cells stain positive for vimentin and variably for CD34 and factor XIIIa. Their clinical behavior is benign. Bord A, et al: Prenatal sonographic diagnosis of congenital perineal skin tag: case report and review of the literature. Prenat Diagn 2006 Nov; 26(11):1065–1067. Cathro HP, et al: Cutaneous pseudosarcomatous polyp: a recently described lesion. Ann Diagn Pathol 2008 Dec; 12(6):440–444.
Acrochordon (cutaneous tag, papilloma colli, fibroma pendulum, cutaneous papilloma, fibroma molluscum, Templeton skin tags, skin tags) Small, flesh-colored to dark brown, pinhead-sized and larger, sessile and pedunculated papillomas commonly occur on the neck, often in association with small seborrheic keratoses. These tags are also seen frequently in the axillae and on the eyelids, and less often on the trunk and groins, where the soft, pedunculated growths often hang on thin stalks. These fleshcolored, teardrop-shaped tags feel like small bags. Occasionally, as a result of twisting of the pedicle, one will become inflamed, tender, and even gangrenous. Both sexes have the same incidence, with nearly 60% of individuals acquiring them by the age of 69. They often increase in number when the patient is gaining weight or during pregnancy, and may be related to the growth hormone-like activity of insulin. They may be associated with diabetes mellitus. In patients preselected for gastrointestinal complaints, skin tags appear to be more prevalent in those with colonic polyps. This association has not been proved for the general population. Histologically, acrochordons are characterized by epidermis enclosing a dermal fibrovascular stalk. The baglike papillomas generally show a flattened epidermis. Smaller lesions often demonstrate seborrheic keratosis-like acanthosis and horn cysts. Small lesions can be clipped off at the base with little or no anesthesia. Aluminum chloride may be applied for hemostasis if needed. Light electrodesiccation can also be effective. For larger lesions, anesthesia and snip excision are preferred. An entity that is frequently reported as perianal acrochordons or skinfolds has now been named infantile perianal pyramidal protrusions. This occurs in young children, usually girls, in the midline anterior to the anus. It reduces with time and no treatment is necessary. Child abuse, genital warts,
hemorrhoids, granulomatous lesions of inflammatory bowel disease, or rectal prolapse must be considered in the differential diagnosis of these lesions. Tag-like basal cell carcinomas in childhood should suggest a diagnosis of nevoid basal cell carcinoma syndrome (NBCCS). Biopsy should be performed on acrochordons in children because the lesions are uncommon in this age group, and they may be the presenting sign of NBCCS.
Dermatofibroma (fibrous histiocytoma) This common skin lesion’s appearance is usually sufficiently characteristic to permit clinical diagnosis. It is generally a single round or ovoid papule or nodule, about 0.5–1 cm in diameter, which is reddish-brown, sometimes with a yellowish hue. The sharply circumscribed nodule is more evident on palpation than expected from inspection. The larger lesions may present an abrupt elevation at the border to form an exteriorized tumor resting on a sessile base. Dermatofibroma may be elevated or slightly depressed. The hard lesion is adherent to the overlying epidermis, which may be thinner from pressure or even indented, so that there is a dell-like depression over the nodule (Fig. 28-29). In such cases only the depression is seen, but on palpation the true nature of the lesion is found. Fitzpatrick proposed the term dimple sign for the depression created over a dermatofibroma when it is grasped gently between thumb and forefinger. Dermatofibromas seldom occur in children; they are encountered mostly in middle-aged adults. Their size generally varies from 4 to 20 mm, although giant lesions greater than 5 cm occur. After they reach this size, growth ceases and the harmless lump remains stationary. The principal locations are on the lower extremities, above the elbows, or on the sides of the trunk. Systemic lupus erythematosus, treatment with prednisone or immunosuppressive drugs, chronic myelogenous leukemia, and HIV infection have been associated with the development of multiple dermatofibromas. It is suspected that many dermatofibromas are initiated by injuries to the skin, such as insect bites or blunt trauma. On histologic examination there is a dermal mass composed of close whorls of fibrous tissue in which there are numerous spindle or histiocytic cells. The cells have features of fibro blasts and myofibroblasts, but are probably of primitive mesenchymal origin. Immunohistochemical studies show that most cells are positive for factor XIIIa and CD10, and negative for MAC387, S-100, and CD34. The tumor is not well circumscribed and may extend into adjacent structures and surround individual collagen bundles at the periphery
Fibrous tissue abnormalities
through the fascia. These herniated nodules, seen most frequently on the lower extremities, become prominent when the underlying muscles contract, and pain may occur with prolonged exertion. Treatment is not indicated unless the area is chronically painful. Light compression may be effective.
Fig. 28-29 Dermatofibroma. (Courtesy of Lawrence Lieblich, MD)
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(collagen trapping). Overlying acanthosis is typical, and induction of primitive epithelial germs or mature follicular structures may be noted. Basal cell carcinoma-like changes commonly overlie dermatofibromas, but true basal cell carcinoma is quite rare. At times, large histiocytic cells within the lesion are strikingly atypical (monster cells). Occasionally, granular cytoplasm may predominate. Hemosiderin may be present, and foam cells and lipid deposits may be seen. The presence of Touton giant cells containing hemosiderin is pathognomonic of dermatofibroma. There is a great variation in the vascular components. Rarely, the vascularization is pronounced and suggests a kind of hemangioma (sclerosing hemangioma). Deep penetrating dermatofibromas may grow into the sub cutaneous tissue via the fibrous septa or with a pushing front of tumor. They lack the extensive lacy and lamellar infiltrative growth pattern of dermatofibrosarcoma protuberans. Deep fascial fibrous histiocytomas may involve the fat or muscle at times. Signet ring and plaque-type variants have been described. A pigmented variant has been described showing histologic overlap with Bednar tumor (pigmented dermato fibrosarcoma protuberans). The lesion stained positive for CD34, a marker usually absent in dermatofibromas. The clinical appearance of the lesion and its location, chiefly on the lower extremities, are distinctive. Clinically, granular cell tumor, dermatofibrosis lenticularis disseminata, clear-cell acanthoma, and melanoma are some of the lesions to be considered. At times only a biopsy can differentiate these. Progressive enlargement beyond 2 or 3 cm in diameter suggests a malignant fibrous histiocytoma or dermatofibrosarcoma protuberans, and excisional biopsy is indicated. These lesions usually are asymptomatic and do not require treatment. Involution may occur after many years if the lesion is left alone. Simple reassurance is suggested.
Epithelioid cell histiocytoma Usually solitary, but occasionally multiple, these lesions appear as dome-shaped papules composed of bland epithelioid cells. They typically stain for factor XIIIa and are considered by many to be closely related to dermatofibromas. Cangelosi JJ, et al: Unusual presentation of multiple epithelioid cell histiocytomas. Am J Dermatopathol 2008 Aug; 30(4):373–376. de Feraudy S, et al: Evaluation of CD10 and procollagen 1 expression in atypical fibroxanthoma and dermatofibroma. Am J Surg Pathol 2008 Aug; 32(8):1111–1122. Garrido-Ruiz MC, et al: Signet-ring cell dermatofibroma. Am J Dermatopathol 2009 Feb; 31(1):84–87. Leow LJ, et al: Plaque-like dermatofibroma: a distinct and rare benign neoplasm? Australas J Dermatol 2008 May; 49(2):106–108. McAllister JC, et al: CD34+ pigmented fibrous proliferations: the morphologic overlap between pigmented dermatofibromas and Bednar tumors. Am J Dermatopathol 2008 Oct; 30(5):484–487.
Dermal dendrocyte hamartoma This presents as a rounded, medallion-like lesion on the upper trunk; it is composed of fusiform CD34, factor XIIIa-positive cells in the mid- and reticular dermis. The lesions are asymptomatic, brown or erythematous in color, and may have a slightly atrophic, wrinkled surface (Fig. 28-30). The major differential diagnosis is congenital atrophic dermatofibrosarcoma protuberans (DFSP), but to date there has been no evidence of chromosomal abnormalities such as the t(17; 22)(q22; q13) translocation with the DFSP fusion gene COL1A1-PDGFB. Marque M, et al: Medallion-like dermal dendrocyte hamartoma: the main diagnostic pitfall is congenital atrophic dermatofibrosarcoma. Br J Dermatol 2009 Jan; 160(1):190–193.
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Fig. 28-30 Dermal dendrocyte hamartoma. Shah KN, et al: Medallion-like dermal dendrocyte hamartoma. Pediatr Dermatol 2007 Nov–Dec; 24(6):632–636.
Nodular fasciitis (nodular pseudosarcomatous fasciitis) Also known as subcutaneous pseudosarcomatous fibromatosis, this benign mesenchymal neoplasm occurs most often on the arms. Clinically, a firm, solitary, sometimes tender nodule develops in the deep fascia, and often extends into the sub cutaneous tissue. It usually measures 1–4 cm in diameter. The lesion appears suddenly over a period of a few weeks, without apparent cause, in normal, healthy persons. Sex distribution is equal and the average age at onset is 40. Microscopic findings consist of well-defined, loose nodules of stellate and spindled cells that may have a myxoid “tissue culture” appearance. Capillary proliferation is typical, and erythrocyte extravasation between spindle cells is common. Nodular lymphoid infiltrates are often noted within the lesion. On electron microscopic examination, the component cells in the neoplasm have proved to be myofibroblasts. Dermal, intravascular, and proliferating variants (proliferative fasciitis) have been described. These are designated when the nodular masses arise in the dermis, in intimate association with blood vessels, or show ganglion-like giant cells and infiltration of collagen. The proper treatment is complete excision. Recurrence is rare and the prognosis is excellent. A rapid response to intralesional corticosteroids has been reported in one case. Cranial fasciitis of childhood is an uncommon variant of nodular fasciitis, manifesting as a rapidly enlarging mass in the subcutaneous tissue of the scalp, which may invade the cranium. It occurs in infants and children, resembles nodular fasciitis histologically, and usually does not recur after surgical excision. Some lesions have demonstrated dysregulation of the Wnt/β-catenin pathway. Proliferative fasciitis and proliferative myositis are closely related entities. Proliferative fasciitis demonstrates irregular extension into the fibrous septae with collagen trapping and ganglion-like nuclei. Proliferative myositis has a similar appearance, but extends into adjacent muscle. Pseudosarcomatous ischemic fasciitis (atypical decubital fibroplasia) is a manifestation of pressure-induced necrosis. The histologic appearance is similar to that of chondrodermatitis nodularis of the ear, only on a much larger scale. A wide zone of fibrinoid necrosis is bordered by granulation tissue
and large atypical fibroblast nuclei that resemble radiation fibroblasts.
Fibrous tissue abnormalities
Hussein MR: Cranial fasciitis of childhood: a case report and review of literature. J Cutan Pathol 2008 Feb; 35(2):212–214. Johnson KK, et al: Diagnosing cranial fasciitis based on distinguishing radiological features. J Neurosurg Pediatrics 2008 Nov; 2(5):370–374. Numajiri T, et al: Nodular fasciitis of the upper eyelid. Eur J Dermatol 2009 Jan–Feb; 19(1):85–86. Rakheja D, et al: A subset of cranial fasciitis is associated with dysregulation of the Wnt/beta-catenin pathway. Mod Pathol 2008 Nov; 21(11):1330–1336. Reitzen SD, et al: Nodular fasciitis: a case series. J Laryngol Otol 2008 Jun 13:1–4.
Solitary fibrous tumor Solitary fibrous tumors occur in the mediastinum, but may also be found in many other parts of the body. They have a diffuse “patternless” growth pattern and stain strongly positive for CD34. Some express progesterone receptor. Their behavior is unpredictable and complete excision is recommended. Spindle cell lipomas with few or no lipocytes (“low-fat” and “non-fat” spindle cell lipomas) may be misinterpreted as solitary fibrous tumors because they are also CD34-positive. Billings SD, et al: Diagnostically challenging spindle cell lipomas: a report of 34 “low-fat” and “fat-free” variants. Am J Dermatopathol 2007 Oct; 29(5):437–442. Insabato L, et al: Extrapleural solitary fibrous tumor: a clinicopathologic study of 19 cases. Int J Surg Pathol 2009 Jun; 17(3):250–254.
Plexiform fibrohistiocytic tumor This rare tumor arises primarily on the upper extremities of children and young adults. There is a strong female predisposition. It presents as a slowly growing, painless growth in the subcutaneous tissue. There is usually extension into the dermis or the underlying skeletal muscle. Histologically, it is a distinctly biphasic tumor, with a fibroblastic component mixed with aggregates of mononuclear histiocyte-like cells and multinucleated osteoclast-like cells. The multinucleated cells label for vimentin and CD68, while the spindle cells express smooth muscle actin but not factor XIIIa. While most patients are cured with excisional surgery, some tumors will recur locally, and uncommonly, regional and systemic metastases can occur. Moosavi C, et al: An update on plexiform fibrohistiocytic tumor and addition of 66 new cases from the Armed Forces Institute of Pathology, in honor of Franz M. Enzinger, MD. Ann Diagn Pathol 2007 Oct; 11(5):313–319.
Dermatofibrosarcoma protuberans Dermatofibrosarcoma protuberans (DFSP) is characterized by bulky, protuberant, neoplastic masses. Between 50 and 60% occur on the trunk, with less common involvement of the proximal extremities and the head and neck. The disease begins with one or multiple elevated, erythematous, firm nodules or plaques, often associated with a purulent exudate or with ulceration. Patients, usually middle-aged, complain of a firm, painless lump in the skin that has been slowly increasing in size for several years. The course is slowly progressive, with pain becoming prominent as the lesion grows, and frequent recurrence after initial conservative surgical intervention (Fig. 28-31). In untreated patients, severe pain and contractures may result. There is little tendency to metastasize, although wide dissemination has been reported. Histologically, the tumor shows a subepidermal fibrotic plaque with uniform spindle cells and variable vascular
Fig. 28-31 Recurrent dermatofibrosarcoma protuberans.
spaces. In many instances, there is a pronounced matlike woven pattern of spindle cells. Cytogenetic studies commonly demonstrate a t(17; 22)(22; q13) fusion involving the COL1A1 gene on chromosome 17 and the PDGFB gene on chromosome 22. Giant cells may be present in small numbers. Pigmented DFSPs, in which the cells contain melanin, predominantly affect persons of color and are called Bednar tumors. CD34, nestin, and stromelysin 3 positivity are characteristic and serve as markers to distinguish DFSP from dermatofibroma. S-100 is negative and may be used to separate spindle cell melanoma from a Bednar tumor. Recurrent DFSP can be myxoid and resembles the diffuse type of neurofibroma histologically. A juvenile variant, called giant cell fibroblastoma, is characterized by a loose arrangement of spindle cells, and by multi nucleated giant cells adjacent to dilated spaces that resemble dilated lymphatic vessels. The differential diagnosis, especially in the early stage, is that of keloid and a large dermatofibroma. CD34-positive myxoid dermatofibrohistiocytoma of the skin occurs as an indolent post-traumatic tumor. It resembles myxoid DFSP. Mohs surgical excision technique is the treatment of choice for DFSP. In a series of 50 patients the recurrence rate was 2%; with wide local excision, recurrence is 11–50%. A preoperative MRI may assist in planning successful clearance. Imatinib mesylate has been effective in some unresectable tumors. Al-Quran SZ, et al: CD34-positive myxoid dermatofibrohistiocytoma of the skin: an indolent post-traumatic tumor that can be mistaken for dermatofibrosarcoma protuberans. J Cutan Pathol 2009 Jan; 36(1):84–86. Dimitropoulos VA: Dermatofibrosarcoma protuberans. Dermatol Ther 2008 Nov–Dec; 21(6):428–432. Kimmel Z, et al: Peripheral excision margins for dermatofibrosarcoma protuberans. Ann Surg Oncol 2008 Sep; 15(9):2617. Lemm D, et al: Remission with imatinib mesylate treatment in a patient with initially unresectable dermatofibrosarcoma protuberans—a case report. Oral Maxillofac Surg 2008 Dec; 12(4):209–213. Mori T, et al: Expression of nestin in dermatofibrosarcoma protuberans in comparison to dermatofibroma. J Dermatol 2008 Jul; 35(7):419–425. Nelson RA, et al: Mohs micrographic surgery and dermatofibrosarcoma protuberans: a multidisciplinary approach in 44 patients. Ann Plast Surg 2008 Jun; 60(6):667–672. Thomison J, et al: Hyalinized collagen in a dermatofibrosarcoma protuberans after treatment with imatinib mesylate. J Cutan Pathol 2008 Nov; 35(11):1003–1006.
Atypical fibroxanthoma Atypical fibroxanthoma (AFX) of the skin is a low-grade malignancy that occurs chiefly on the sun-exposed parts of the head or neck in white persons over age 50. Most cases appear 603
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Fig. 28-32 Atypical fibroxanthoma. (Courtesy of Daniel Loo, MD)
Fig. 28-33 Epithelial sarcoma.
to be related to undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma), which it resembles histologically. Its smaller size and more superficial location account largely for its more favorable prognosis. Some cases probably represent spindled or anaplastic squamous cell carcinoma that has lost the ability to express keratin. Clinically, the tumor begins as a small, firm nodule, often with an eroded or crusted surface without characteristic morphologic features (Fig. 28-32). A distinct clinical variant has a different presentation as a slowly enlarging tumor on a covered area, in patients with an average age of 39. This variant accounts for 25% of cases. The lesion develops in the dermis and is separated from the epidermis by a thin band of collagen. The tumor consists of bizarre spindle cells mingled with atypical histiocytic cells. The cytoplasm may be vacuolated and resembles the xanthoma cell. Mitotic figures, prominent eosinophilic nucleoli, and the presence of a biphasic tumor cell population are characteristic findings, but purely spindle cell variants also occur. S-100 staining is sparse when compared with melanoma, and prekeratin staining is negative; this helps to distinguish AFX from squamous cell carcinoma. Variants with clear cells, granular cells, and osteoclast-type cells have been described. Tumor cells stain for CD10, S100A6, and procollagen I, but none of these markers is specific for the tumor. The treatment of choice is complete surgical excision. Mohs microsurgery results in fewer recurrences and smaller defects than conventional excision. Although the prognosis is excellent, local recurrence after inadequate excision is usual, and cases of metastasizing AFX have been reported.
Pleomorphic cellular elements and bizarre mitotic figures are characteristic. AFXs are smaller and more superficial tumors of the dermis, compared with the deeper location of malignant fibrous histiocytoma (MFH). Epithelioid sarcoma lacks the large, bizarre, multinucleated cells often seen in MFH. The prognosis in MFH is related to the site; deeper and more proximally located tumors have a poorer prognosis. The myxoid variant is less likely to metastasize. An especially poor prognosis attends tumors arising in sites of radiodermatitis. Local recurrence after excision occurs in 25%, 35% metastasize, and the overall survival rate is 50%. Mohs surgical removal may result in fewer recurrences. The angiomatoid type may have a different presentation on the extremities of children as a slowly growing dermal or subcutaneous mass. It has been separated, as it has a relatively good prognosis.
de Feraudy S, et al: Evaluation of CD10 and procollagen 1 expression in atypical fibroxanthoma and dermatofibroma. Am J Surg Pathol 2008 Aug; 32(8):1111–1122. Marcet S: Atypical fibroxanthoma/malignant fibrous histiocytoma. Dermatol Ther 2008 Nov–Dec; 21(6):424–427.
Undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma) This is the most common soft tissue sarcoma of middle and late adulthood. It arises deeply and is more likely to appear in deep fascial planes than in subcutaneous tissue. One-third occur on the thigh or buttock. Peak incidence is in the seventh decade. They sometimes arise in an area of radiodermatitis or in a chronic ulceration. Several histologic variants have been described, including myxoid, inflammatory, and giant cell types. Gene expression profiling is now being used to define subtypes of pleomorphic sarcoma. Cell staining is positive for vimentin and factor XIIIa. 604
Cutaneous myxofibrosarcoma The diagnosis of cutaneous myxofibrosarcoma is often delayed because the tumor may appear indolent clinically and may mimic an interstitial granuloma histologically. Areas of atypical spindle cells within a prominent myxoid stroma and pleomorphic multinucleated cells suggest the diagnosis. Kwong RA, et al: Histopathological evolution of a cutaneous myxofibrosarcoma. Australas J Dermatol 2008 Aug; 49(3):169–172. Park SW, et al: Malignant fibrous histiocytoma of the head and neck: CT and MR imaging findings. Am J Neuroradiol 2009 Jan; 30(1):71–76.
Epithelioid sarcoma Epithelioid sarcoma occurs chiefly in young adults, with onset usually being from 20 to 40 years of age. Two-thirds of cases are in men. Nearly all lesions are on the extremities, half of them on the hands or wrists (Fig. 28-33). They have, however, been reported from a wide variety of locations, including the genital region (“proximal type”). The tumor grows slowly among fascial structures and tendons, often with central necrosis of the tumor nodules and ulceration of the overlying skin. Initial clinical diagnoses may include granuloma annulare, rheumatoid nodule, or ganglion cyst. Histologically, irregular nodular masses of large, deeply acidophilic polygonal cells merge with spindle cells in a biphasic pattern. Central necrosis within masses of epithelioid cells may give the impression of a palisaded granuloma. Absence of staining for CD68 (KP-1) and co-expression of keratins and vimentin confirm the diagnosis. Absence of INI1
Chbani L, et al: Epithelioid sarcoma: a clinicopathologic and immunohistochemical analysis of 106 cases from the French sarcoma group. Am J Clin Pathol 2009 Feb; 131(2):222–227.
Myxomas Cutaneous myxomas may be solitary, and appear as fleshcolored nodules on the face, trunk, or extremities. They may also occur as part of Carney complex. This has also been reported under the acronyms NAME (nevi, atrial myxoma, myxoid neurofibromas, and ephelides) and LAMB (lentigines, atrial myxoma, mucocutaneous myxomas, blue nevi), and simply as cutaneous lentiginosis with atrial myxoma. The Carney complex consists of patients who have two or more of the following: 1. cardiac myxomas (79%) 2. cutaneous myxomas (not myxoid neurofibromas) (45%) 3. mammary myxoid fibromas (30%) 4. spotty mucocutaneous pigmentation, including lentiginoses (not ephelides) and blue nevi, often of a distinctive epithelioid variety (65%) 5. primary pigmented nodular adrenocortical disease (45%), which results in Cushing syndrome 6. testicular tumors (56% of male patients) 7. pituitary growth hormone-secreting tumors (10%). A peculiar type of schwannoma featuring melanin and psammoma bodies may also be present. The cutaneous myxomas occur as small (5) or a BCC before age 30 (Fig. 29-20) 2. odontogenic keratocysts of the jaws 3. pitted depressions on the hands and feet (palmar plantar pits) (two or more) 4. lamellar calcification of the falx under age 20 5. first-degree relative with NBCCS. Minor criteria include: 1. childhood medulloblastoma 2. lympho-mesenteric or pleural cysts 3. macrocephaly (97th percentile) 4. cleft lip/palate 5. vertebral/rib abnormalities 6. preaxial or postaxial polydactyly 7. ovarian/cardiac fibromas 8. ocular abnormalities. The diagnosis is made if the affected individual has two major criteria and one minor criterion, or one major criterion and three minor criteria. Genetic testing has revealed that some 637
patients in childhood. Among the many BCCs an NBCCS patient may have, some sit indolently and others may grow more aggressively.
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Jaw cysts Jaw cysts occur in approximately 90% of patients. They occur as early as age 5 years and rarely after age 30. Both the mandible and the maxilla may show cystic defects on x-ray, with mandibular involvement occurring twice as often. Jaw cysts most commonly present as painless swelling. They usually have a keratinized lining (keratocysts) but uncommonly a cyst may be an ameloblastoma.
Pits of palms and soles Fig. 29-20 Multiple basal cell carcinomas in nevoid basal cell carcinoma syndrome.
persons carrying the genetic mutation do not meet the diagnostic criteria. Essentially, all cases of NBCCS are due to mutations in the PTCH (or PTCH1) gene. One family with a mutation in the SUFU gene has been reported. SUFU mutations have been reported with meduloblastoma susceptibility. Mutations occur throughout the PTCH gene and there does not appear to be a correlation between the site of the mutation and the clinical phenotype. Most mutations result in premature termination and production of shortened gene product. Loss of the PTCH gene can also occur by deletions of part of the long arm of chromosome 9, where the PTCH gene is located (region q22). This represents about 6% of NBCCS patients The clinical findings seen with this syndrome are dependent on two characteristics: the race of the patient and the form of mutation (nucleotide point mutation or chromosome deletion). Of 105 patients reported in one series, 80% were white. The first tumor developed by the mean age of 23 years for white patients. Palmar pits were seen in 87%. Jaw cysts were found in 74%, with 80% manifested by the age of 20. The total number of cysts ranged from 1 to 28. Medulloblastomas developed in four patients and three had cleft lip or palate. Physical findings in this series included “coarse face” (54%), macrocephaly (50%), hypertelorism (42%), frontal bossing (27%), pectus deformity (13%), and Sprengel deformity (11%). In Japanese and African American patients with NBCCS, palmar and plantar pits, odontogenic keratocysts, and skeletal abnormalities are most common, with BCCs not appearing until much later in life. Those patients with NBCCS due to deletions of chromosome 9q22 have all the stigmata of typical NBCCS patients, and in addition often have severe mental retardation, hyperactivity, overfriendliness with strangers, short stature, and less commonly, neonatal hypotonia, epicanthic folds, short neck, pectus, scoliosis, and epilepsy.
Skin tumors The BCCs occur at an early age or any time thereafter as multiple lesions, usually numerous. The usual age of appearance is between 17 and 35 years. Although any area of the body may be affected, there is a marked tendency toward involvement of the central facial area, especially the eyelids, periorbital area, nose, upper lip, and cheeks. Persons with fair skin (type 1) and prior excessive UV exposure are particularly prone to develop many BCCs. Lesions typically appear as 1–10 mm, hyperpigmented or skin-colored, dome-shaped papules. They have a striking resemblance to typical compound or intradermal nevi. Polypoid BCC or acrochordon-like BCC is a more unusual variant that tends to occur in NBCCS 638
An unusual pitting of palms and soles is a distinguishing feature of the disease. This usually becomes apparent in the second decade of life. Up to 87% of patients with NBCCS will have pits. Histologically, they show basaloid proliferation, but the lesions do not progress or behave like a BCC.
Skeletal defects/birth defects Most NBCCS patients have skeletal anomalies that are easily detected by x-ray. Macrocephaly is the first feature observed, and explains the high rate of cesarian section delivery of NBCCS-affected fetuses. Other skeletal defects include bifid, fused, missing, or splayed ribs; scoliosis; and kyphosis. Radiographic evidence of multiple lesions is highly suggestive of this syndrome; and since most are present congenitally, radiology may be useful in diagnosing this syndrome in patients too young to manifest other abnormalities. Cleft lip/ palate is seen in 5% of patients, lamellar calcification of the falx will be evident in 90% of patients by age 20, and polydactyly also occurs. Numerous ocular findings have been reported, and if NBCCS is suspected or confirmed, an ophthalmologic evaluation should be performed. Spina bifida is, fortunately, uncommon.
Histopathology The histology of BCCs arising in syndrome patients is identical to that arising in nonsyndromic patients, with the solid and superficial types being most common.
Differential diagnosis Several other unique types of BCC presentation should not be confused with NBCCS. One is the linear unilateral BCC syndrome, in which a linear arrangement of close-set papules, sometimes interspersed with comedones, is present at birth. Biopsy reveals basal cell epitheliomas; however, they do not increase in size with the age of the patient. The second type, referred to as Bazex syndrome, is an X-linked dominantly inherited disease comprising follicular atrophoderma of the extremities, localized or generalized hypohidrosis, hypotrichosis, and multiple BCCs of the face, which often arise at an early age. The third type consists of multiple hereditary infundibulocystic BCCs; this is an autosomal-dominant syndrome. It is distinguished from NBCCs by the absence of palmar pits and jaw cysts in most cases. Clinically, patients appear to have multiple trichoepitheliomas. Numerous skincolored pearly papules affect the central face, accentuated in the nasolabial folds. The generalized basaloid follicular hamartoma syndrome differs from NBCCS by having basaloid follicular hamartomas instead of BCCs. It is reported from a large kindred in the southeastern US (see below). Tiny palmar pits are present. Histologically, infundibulocystic BCC and basaloid follicular hamartoma may be indistinguishable, so
Treatment Genetic counseling is essential. Strict sun avoidance and maximum sun protection, as recommended for xeroderma pigmentosum patients, is advised. Treatment involves very regular monitoring and biopsy of suspicious lesions. Topical therapy with tazarotene and imiquimod may be of some use in preventing and treating the superficial tumors. Oral retinoid therapy may reduce the frequency of new BCCs appearing, and the existing small BCCs stop growing. However, once the oral retinoids are stopped, the lesions again begin to grow. Surgical treatments are used for most lesions, either curettage and desiccation or excisions. At times, megasessions, with removal of multiple tumors under general anesthesia in the operating room, are needed to keep up with the large number of BCCs that these patients develop. Photodynamic therapy appears to be particularly beneficial when used to treat areas that have had multiple BCCs in the past. Abe S, et al: Coincident two mutations and one single nucleotide polymorphism of the PTCH1 gene in a family with naevoid basal cell carcinoma syndrome. Acta Derm Venereol 2008; 88:635. Bañuls J, et al: Tissue and tumor mosaicism of the myotonin protein kinase gene trinucleotide repeat in a patient with multiple basal cell carcinomas associated with myotonic dystrophy. J Am Acad Dermatol 2004; 50:S1. Dalati T, Zhou H: Gorlin syndrome with ameloblastoma: a case report and review of the literature. Cancer Invest 2008; 26:975. de Ravel TJ, et al: Early detection of chromosome 9q22.32q31.1 microdeletion and the nevoid basal cell carcinoma syndrome. Eur J Med Genet 2009; 52:145. El Sobky RA, et al: Successful treatment of an intractable case of hereditary basal cell carcinoma syndrome with paclitaxel. Arch Dermatol 2001; 137:827. Evans DG, Farndon PA, et al: Nevoid basal cell carcinoma syndrome (updated January 25, 2008). In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997–2010. Available at http://www.genetests.org. Feito-Rodriguez M, et al: Dermatoscopic characteristics of acrochordon-like basal cell carcinomas in Gorlin–Goltz syndrome. J Am Acad Dermatol 2009; 60:857. Gilchrest BA, et al: Photodynamic therapy for patients with basal cell nevus syndrome. Dermatol Surg 2009; 35:1576. Glaessl A, et al: Sporadic Bazex–Dupré–Christol-like syndrome: early onset basal cell carcinoma, hypohidrosis, hypotrichosis, prominent milia. Dermatol Surg 2000; 26:152. Kimonis VE, et al: Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 1997; 69:299. Kulkarni P, et al: Nevoid basal cell carcinoma syndrome in a person with dark skin. J Am Acad Dermatol 2003; 49:332. Lo Muzio L: Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis 2008; 3:32. Micali G, et al: The use of imiquimod 5% cream for the treatment of basal cell carcinoma as observed in Gorlin’s syndrome. Clin Exp Dermatol 2003; 28:19. Nakamura M, Tokura Y: A novel missense mutation in the PTCH1 gene in a premature case of nevoid basal cell carcinoma syndrome. Eur J Dermatol 2009; 19:262. Pastorino L, et al: Identification of a SUFU germline mutation in a family with Gorlin syndrome. Am J Med Genet A 2009; 149A:1539. Requena L, et al: Multiple hereditary infundibulocystic basal cell carcinomas. Arch Dermatol 1999; 135:1227. Takahashi C, et al: Germline PTCH1 mutations in Japanese basal cell nevus syndrome patients. J Hum Genet 2009; 54:403.
van der Geer S, et al: Treatment of basal cell carcinomas in patients with nevoid basal carcinoma syndrome. J Eur Acad Dermatol Venereol 2009; 23:308. van der Geer S, et al: Treatment of the patient with nevoid basal cell carcinoma syndrome in a megasession. Dermatol Surg 2009; 35:709. Vered M, et al: The immunoprofile of odontogenic keratocyst (keratocystic odontogenic tumor) that includes expression of PTCH, SMO, GLI-1 and bcl-2 is similar to ameloblastoma but different from odontogenic cysts. J Oral Pathol Med 2009; 38:597. Wheeler CE, et al: Autosomal dominantly inherited generalized basaloid follicular hamartoma syndrome: report of a new disease in a North Carolina family. J Am Acad Dermatol 2000; 43:189. Yamamoto K, et al: Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome: report of two cases and review of the literature. Congenit Anom (Kyoto) 2009; 49:8.
Squamous cell carcinoma
the two familial syndromes may be difficult to separate. Rombo syndrome, reported in one large Swedish family, has multiple BCCs, vermiculate atrophoderma, and hypotrichosis. A patient with multiple BCCs and myotonic dystrophy has been reported, suggesting yet another genodermatosis associated with multiple BCCs.
Squamous cell carcinoma Squamous cell carcinoma (SCC) is the second most common form of skin cancer. Most cases of SCC of the skin are induced by UVR. Chronic, long-term sun exposure is the major risk factor, and areas that have had such exposure (the face, scalp, neck, and dorsal hands) are favored locations. SCC becomes relatively more common as the annual amount of UVR increases, so SCC is more common in Texas than in Minnesota, for example. Immunosuppression greatly enhances the risk for the development of SCC, with azathioprine exposure especially associated with greater risk for development of cutaneous SCC. Sorafenib and possibly the tumor necrosis factor (TNF) inhibitors may be associated with increased risk of cutaneous SCC. High-risk genital human papillomaviruses (HPV16, 18, 31, and 35, primarily) play a role in SCCs that develop on the genitalia and periungually. A chronic ulcer, hidradenitis suppurativa, prior x-radiation exposure, PUVA treatment, recessive dystrophic epidermolysis bullosa, lesions of discoid lupus, and erosive lichen planus are skin conditions or treatments that appear to enhance the risk for the development of SCC. Metastasis, with a mortality rate of 18%, is very uncommon for SCCs arising in sites of chronic sun damage, whereas it is relatively high (20–30%) in SCCs occurring in the various scarring processes. Patients with epidermodysplasia verruciformis (EDV) also develop SCCs on sun-exposed sites, associated with unique HPV types. These unique EDV HPV types (HPV-5, 8, and others) may also play a role in SCCs that develop in immunosuppressed persons. SCC of the oral mucosa is discussed in Chapter 34. Because the vast majority of cutaneous SCCs are induced by UVR, sun protection, with avoidance of the midday sun, protective clothing, and the regular application of a sunblock of SPF 30, is recommended. Some researchers have suggested that smoking is also a risk factor for cutaneous SCC, but this is controversial.
Clinical features Frequently, SCC begins at the site of actinic keratosis on sunexposed areas such as the face and backs of the hands. BCCs far outnumber SCCs on the facial skin, but SCCs on the hand occur three times more commonly than BCCs. The lesion may be superficial, discrete, and hard, and arises from an indurated, rounded, elevated base (Fig. 29-21). It is dull-red and contains telangiectases. In the course of a few months the lesion becomes larger, deeply nodular, and ulcerated. The ulcer is at first superficial and is hidden by a crust. When this is removed, a well-defined, papillary base is seen, and on palpation a discrete hard disk is felt. In the early phases this tumor is localized, elevated, and freely movable on the underlying structures; later it gradually becomes diffuse, more or less depressed, and fixed. The growth eventually invades the underlying tissues. The tumor above the level of the skin may 639
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Fig. 29-21 Squamous cell carcinoma, preauricular ulceration in a patient with AIDS.
is the late sixties. SCCs occurring on the lower lip metastasize approximately 10–15% of the time. SCC of the lip may also occur in areas of discoid lupus erythematosus (DLE) in black patients. Neoplastic transformation into SCC may develop in 0.3–3% of patients with DLE of the lip. Periungual SCC frequently presents with signs of erythema and scaling, which can superficially appear as a wart. The patient may even have periungual warts on other digits. Early on, pain and ulceration are uncommon. Fifty percent of those x-rayed show changes in the terminal phalanx. There is a low rate of metastases (3%), but local excision with Mohs microsurgery is recommended, as it reduces the risk of recurrence. Periungual SCC is strongly associated with genital HPV types, primarily 16, 18, 31, and 35. Given the numerous presentations of SCC on the skin, there should be a low threshold for biopsy of any suspicious keratotic, ulcerated or nodular lesions, especially on the background of chronic sun exposure.
Histopathology SCC is characterized by irregular nests, cords, or sheets of neoplastic keratinocytes invading the dermis to various depths. Thickness is an important risk factor for metastasis, with thickness >2 mm associated with 4% metastases and >6 mm with a 16% metastatic rate. Less than 5% of patients with metastatic SCC had a primary cutaneous SCC 4.0 mm in thickness • T4a: No ulceration • T4b: Ulceration • N0: No regional lymph node metastasis • N1: Metastasis in one lymph node • N1a: Clinically occult • N1b: Clinically apparent • N2: Two to three regional nodes or in-transit metastasis • N2a: Clinically occult • N2b: Clinically apparent • N2c: Satellite or in-transit metastases • N3: Four or more nodes, matted nodes or in-transit metastasis with positive nodes • M0: No distant metastases • M1: Distant metastases • M1a: Skin or nodes • M1b: Lung • M1c: All other viscera or any distant metastases with elevated lactic acid dehydrogenase (LDH)
• • • •
Stage Stage Stage Stage
I (T1 or T2a, N0, M0): >80% II (T2b–4, N0, M0): 60–80% III (N1–3, M0): 10–60% IV (M1): 6/mm2 is worst) • ulceration (adverse effect) • location (hair-bearing limbs yield a better prognosis than when lesions are present on the trunk, head, neck, palm, or sole) • sex (women have a better prognosis than men) • age (younger patients have a better prognosis) • the presence of leukoderma at distal sites (improves the prognosis) • regression (associated with a poorer prognosis).
Melanoma
CNS metastasis is the most common cause of death. Although most metastatic spread occurs in the first 5 years after diagnosis, late-onset metastases occur, especially in premenopausal women. Melanemia, melanuria, and cachexia are likely to occur in terminal disease. In extreme cases, the entire integument may become deeply pigmented (generalized melanosis), with melanin in melanophages, endothelial cells, and tissue histiocytes. Occasionally, patients present with metastatic melanoma from an unknown source. Full-body skin examination may reveal a depigmented or irregularly pigmented atrophic patch consistent with a regressed primary lesion. Such patients are estimated to have a 40% chance of 5-year survival. Estrogen receptors may play a role in melanoma progression and metastasis, with lower levels of expression of receptors in thicker lesions.
Multivariant analysis shows that some are not independently predictive and others are of variable significance in different series. Pregnancy does not have an adverse effect on survival in patients with clinically localized melanoma. Tumor thickness, ulceration, and lymph node involvement have the greatest predictive value and are used to determine therapy. The presence or absence of melanoma in regional lymph nodes is the single most important prognostic factor for melanoma. Sentinel lymph node dissection using lymphoscintigraphy with 99mTc-labeled colloids is widely used for the staging of clinically node-negative melanomas. The success rate in localizing the sentinel lymph node approaches 98% at centers experienced in the technique. When combined with the vital blue dye technique the success rate can approach 99%. About 20% of patients with melanoma between 1.5 and 4 mm in depth will have metastasis in their sentinel node(s). For desmoplastic and neurotropic melanoma (mean Breslow depth, 4.0 mm; median, 2.8 mm), published data suggest that up to 12% have at least one positive sentinel lymph node, although recent data suggests those with metastases are likely to be hybrid tumors rather than pure desmoplastic melanomas. Tumor thickness and ulceration are the major independent predictors of sentinel lymph node metastases. Age and axial tumor location are also significant. Patients with larger metastases to the sentinel node (metastatic deposits greater than 2 mm in diameter) have significantly decreased survival. Local recurrence related to a positive margin should not be equated with local recurrence representing dermal in-transit lymphatic metastasis. The latter is associated with a poor prognosis, while the former may be cured in many cases by re-excision.
Work-up and follow-up There is no definite proof that any routine laboratory work or imaging studies affect longevity. Some advocate only ordering studies as prompted by signs or symptoms. Other guidelines recommend limited studies varying by stage. For all stages, studies should be ordered if signs or symptoms occur. Lactic acid dehydrogenase (LDH) is not a sensitive screening tool, but has prognostic value. The yield of computed tomography (CT), MRI, and positron emission tomography (PET) is low. There is broad consensus that no x-rays or blood work are routinely indicated for those with stage 0 or Ia melanoma. For stages Ib and II, a baseline chest x-ray and LDH level are optional in the NCCN guidelines. For stage IIIa disease, a chest x-ray and LDH are recommended by NCCN guidelines. For 689
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stage IIIb or IIIc disease, fine needle aspiration should be attempted to confirm nodal involvement. A chest x-ray and LDH are recommended by NCCN guidelines. A pelvic CT scan is recommended in those with inguinofemoral lymph adenopathy. For stage IV disease, the work-up should be similar to that for stage IIIb disease, along with consideration of abdominal and pelvic CT scan, head MRI, or PET. The highest yield for CT scans is in the area adjacent to nodal disease. As glucose metabolism is increased in malignant tumors, PET using the glucose analog fluorine-18-fluorodeoxyglucose (F18-FDG) can be used to detect metastases. Periodic skin examinations are important to detect second primary tumors, as well as metastatic disease. Skin and lymph node examination should be performed at least yearly. Tumor recurrence occurs sooner in patients with thick melanomas than those with thin melanomas. Some authors have suggested follow-up schedules based on AJCC staging, to include annual examinations for patients with stage I disease, 6-monthly examinations for 2 years and then annually for those with stage IIa disease, and 4-monthly examinations for 2 years, 6-monthly in the third year and annually thereafter, for those with stage IIb–IIc disease. Those with other risk factors may need more frequent examinations.
Treatment
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Early excision remains the most important determinant of outcome. Most published guidelines are based on data that relate largely to superficial spreading melanoma, and may not be applicable to all melanomas. A margin of 0.5 cm is recommended for excision of a melanoma in situ, a 1.0 cm margin for melanomas less than or equal to 1.0 mm thick, a 1–2 cm margin for those less than or equal to 2 mm, and a 2 cm margin for those thicker than 2.0 mm. In the case of lentigo maligna and acral lentiginous melanoma, subclinical extension of the in situ tumor commonly exceeds 0.5 cm, and asymmetrical growth is common. In such cases, a symmetrical “standard” margin may do a disservice to the patient. It may result in a positive lateral margin, and difficult closure because excessive uninvolved skin was sacrificed. Mohs micrographic surgery may be useful in this setting. Although H&E-stained frozen sections have been used, immunostains such as MelanA or MITF are easier to interpret. “Slow Mohs” staged excision with permanent sections is another option. In patients who are poor surgical candidates, nonsurgical treatments such as topical imiquimod and radiotherapy may be utilized. Nail apparatus melanoma may necessitate amputation of a digit or skin grafting. This is another setting where Mohs micrographic surgery may be considered as a tissue-sparing technique. Sentinel node biopsy (SNB) should be discussed with patients whose melanomas are 1 mm or greater in thickness. SNB should be considered for thinner lesions in patients who have ulceration, Clark level IV or V invasion, regression, a vertical growth phase, or a positive deep margin on initial biopsy. Dual-basin drainage from the trunk is not independently associated with an increased risk of nodal metastases, but each basin must be identified and sampled. Those with a positive SNB or nodal metastasis confirmed by fine needle aspiration should receive counseling regarding dissection of the remainder of the nodal basin. An analysis of SNB results in 422 Swedish patients with a mean thickness of 3.2 mm suggests that SN-negative patients have better disease-free survival (p < 0.0001), but the false-negative rate may be as high as 14%. Ipilimumab blocks the CTLA-4 protein, reducing tumor tolerance. It has shown impressive results in some patients with melanoma and trials of this agent with other immunomodulat-
ing drugs and vaccines are ongoing. Oncogenic mutations in KIT occur in mucosal and acral melanomas, as well as those on chronically sun-damaged skin. Imatinib may have a role in treating tumors in these sites. For in-transit metastases, surgical excision, interferon (IFN), hyperthermic isolated limb perfusion with melphalan, CO2 laser ablation, and intralesional bacille Calmette–Guérin (BCG) are used. Dinitrochlorobenzene in the setting of in-transit melanoma metastases has been reported to induce local remission but did not prevent metastatic lymph node and liver involvement. For stage IV disease, treatment options include resection, radiation, dacarbazine, temozolomide, interleukin-2, paclitaxel, and combination chemotherapy. Before surgical intervention, a period of observation to rule out more widespread metastasis may be reasonable. Adjuvant therapy should be discussed with patients who have positive nodes or node-negative melanoma that is 4 mm thick, or ulcerated or Clark’s level IV or V. IFN-α 2b is Food and Drug Administration (FDA)-approved as adjuvant therapy and is used most commonly. Although meta-analysis suggests that IFN therapy may increase relapse-free survival, an advantage for overall survival is uncertain. Systemic symptoms may require discontinuation of therapy in some patients, and lipodystrophy has been reported with IFN therapy. The results of trials have been mixed. Reports of long-term survival after resection of distant melanoma metastases suggest that cytoreductive surgery may play a role in selected patients. Clinical vaccine trials are ongoing and some have shown promising results. However, despite numerous trials, only a few patients have been shown to exhibit strong antigenspecific cellular responses. Barnhill RL, et al: Unusual variants of malignant melanoma. Clin Dermatol 2009; 27(6):564–587. Braun RP, et al: The furrow ink test: a clue for the dermoscopic diagnosis of acral melanoma vs nevus. Arch Dermatol 2008 Dec; 144(12):1618–1620. Busam KJ, et al: Distinction of conjunctival melanocytic nevi from melanomas by fluorescence in situ hybridization. J Cutan Pathol 2010 Feb; 37(2):196–203. Cadili A, et al: Predictors of sentinel lymph node metastasis in melanoma. Can J Surg 2010; 53(1):32–36. Carlson JA, et al: New techniques in dermatopathology that help to diagnose and prognosticate melanoma. Clin Dermatol 2009 Jan–Feb; 27(1):75–102. Curtin JA, et al: Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24:4340–4346. de Giorgi V, et al: Estrogen receptor expression in cutaneous melanoma: a real-time reverse transcriptase-polymerase chain reaction and immunohistochemical study. Arch Dermatol 2009 Jan; 145(1):30–36. Driscoll MS, et al: Hormones, nevi, and melanoma: an approach to the patient. J Am Acad Dermatol 2007 Dec; 57(6):919–931. Driscoll MS, et al: Nevi and melanoma in the pregnant woman. Clin Dermatol 2009; 27(1):116–121. Erickson C, et al: Treatment options in melanoma in situ: topical and radiation therapy, excision and Mohs surgery. Int J Dermatol 2010 May; 49(5):482–491. Forman SB, et al: Is superficial spreading melanoma still the most common form of malignant melanoma? J Am Acad Dermatol 2008 Jun; 58(6):1013–1020. Francken AB, et al: Follow-up schedules after treatment for malignant melanoma. Br J Surg 2008 Nov; 95(11):1401–1407. Gambichler T, et al: Minichromosome maintenance proteins are useful adjuncts to differentiate between benign and malignant melanocytic skin lesions. J Am Acad Dermatol 2009; 60(5):808–813. Ghosh P, et al: Genetics and genomics of melanoma. Expert Rev Dermatol 2009; 4(2):131–143. Hansson J: Familial cutaneous melanoma. Adv Exp Med Biol 2010; 685:134–145. Hodi FS, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711–723.
Q-switched ruby laser and Q-switched neodymium-doped yttrium aluminium garnet (Nd:YAG) lasers have been used to treat Mongolian spots. Application of bleaching creams should be considered prior to treatment to reduce overlying pigmentation. The outcome of laser treatment tends to be better for lesions treated before the age of 20. Kagami S, et al: Laser treatment of 26 Japanese patients with Mongolian spots. Dermatol Surg 2008 Dec; 34(12):1689–1694. Leung AK, et al: Superimposed Mongolian spots. Pediatr Dermatol 2008 Mar–Apr; 25(2):233–235.
Nevus of Ota (oculodermal melanocytosis)
The Mongolian spot is a bluish-gray macule that varies in diameter from 2 to 8 cm. It occurs typically in the sacral region of the newborn (Fig. 30-19), in 80–90% of Asian, southern European, American black, and Native American persons. The Mayan Indians uniquely take great pride in it as an indicator of pure Mayan inheritance. The Mongolian spot may be situated in other locations. Multiple spots may occur in a widespread distribution, and overlapping spots have been described. These have been called generalized dermal melanocytosis or dermal melanocytic hamartomas. They may occur in phakomatosis pigmentovascularis types II, IV, and V, and have been described in the setting of Sjögren–Larsson syndrome. Extensive Mongolian spots have been associated with Hunter syndrome and with trisomy 20 mosaicism. Histologically, the Mongolian spot shows elongated dendritic dermal melanocytes, widely scattered among normal collagen bundles. It usually disappears during childhood, although rarely, it may persist into adulthood.
This nevus is also known as nevus fuscoceruleus ophthalmo maxillaris. It is usually present at birth in the two-thirds of patients who have ocular involvement. Other lesions may not appear until the teen years. The conjunctiva and skin about the eye supplied by the first and second branch of the trigeminal nerve, as well as the sclera, ocular muscles, retrobulbar fat, periosteum, and buccal mucosa, may be involved. On the skin, brown, slate gray, or blue–black macules grow slowly larger and deeper in color (Fig. 30-20). It persists throughout life. Eighty percent occur in females; 5% are bilateral. Glaucoma or ipsilateral sensorineural hypoacusia may also occasionally complicate nevus of Ota. Malignant melanoma rarely occurs in nevus of Ota. Malignant degeneration is more frequent in white patients. The most common site of malignancy is the choroid. Histologically, elongated dendritic dermal melanocytes are seen scattered in the upper portion of the dermis. Acquired unilateral nevus of Ota-like macules are known as Sun nevus. Some express hormone receptors. Q-switched lasers have been used successfully to treat nevus of Ota. Nd:YAG laser at 1064 nm is suitable for use in a wide range of skin types. Acquired dermal melanocytosis (acquired bilateral nevus of Ota-like macules or Hori nevus) is recalcitrant to laser therapy compared with nevus of Ota. Good results have been reported after treatment with Q-switched ruby laser. Initial topical bleaching with 0.1% tretinoin and a 5% hydroquinone ointment containing 7% lactic acid can be used to reduce epidermal melanin prior to laser treatment. Epidermal cooling has been advocated in the past, but some data suggest an increased incidence of hyperpigmentation with epidermal
Fig. 30-19 Mongolian spot.
Fig. 30-20 Nevus of Ota.
Dermal melanocytic lesions Mongolian spot
Dermal melanocytic lesions
Jen M, et al: Childhood melanoma. Clin Dermatol 2009; 27(6):529–536. Mattsson J, et al: Sentinel node biopsy in malignant melanoma: Swedish experiences 1997–2005. Acta Oncol 2008; 47(8):1519–1525. Menzies SW, et al: Dermoscopic evaluation of amelanotic and hypomelanotic melanoma. Arch Dermatol 2008 Sep; 144(9): 1120–1127. Orlandi A, et al: Relation between animal-type melanoma and reduced nuclear expression of glutathione S-transferase pi. Arch Dermatol 2009 Jan; 145(1):55–62. Rivers JK, et al: The case for early detection of melanoma. J Cutan Med Surg 2010; 14(1):24–29. Shokrollahi K, et al: Malignant melanoma: perspectives, diagnostics and treatment. Ann Plast Surg 2010 Feb; 64(2):132–133. Spatz A, et al: The biology of melanoma prognostic factors. Discov Med 2010 Jul; 10(50):87–93. Takata M, et al: Molecular pathogenesis of malignant melanoma: a different perspective from the studies of melanocytic nevus and acral melanoma. Pigment Cell Melanoma Res 2010; 23(1):64–71. Tucker MA: Melanoma epidemiology. Hematol Oncol Clin North Am 2009; 23(3):383–395. Weedon D: Lentiginous melanoma. J Cutan Pathol 2009; 36(11):1232.
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cooling. Q-switched ruby laser has also been used after epidermal ablation using a scanned CO2 laser. Lesions of phakomatosis pigmentovascularis have been treated successfully with Q-switched ruby laser and Q-switched alexandrite laser, with flashlamp pumped pulsed dye laser for the vascular component. Intense pulse light systems have been combined with the Q-switched ruby laser for complex dyspigmentation among Asian patients. Fractional photothermolysis using a fractionated 1440 nm Nd:YAG laser has also been reported as successful.
Nevus of Ito Also known as nevus fuscoceruleus acromiodeltoideus, the nevus of Ito has the same features as nevus of Ota except that it occurs in the distribution of the posterior supraclavicular and lateral cutaneous brachial nerves, to involve the shoulder, side of the neck, and supraclavicular areas. Ee HL, et al: Characteristics of Hori naevus: a prospective analysis. Br J Dermatol 2006 Jan; 154(1):50–53. Harrison-Balestra C, et al: Clinically distinct form of acquired dermal melanocytosis with review of published work. J Dermatol 2007 Mar; 34(3):178–182. Kouba DJ, et al: Nevus of Ota successfully treated by fractional photothermolysis using a fractionated 1440-nm Nd:YAG laser. Arch Dermatol 2008 Feb; 144(2):156–158. Long TF, et al: Androgen, estrogen and progesterone receptors in acquired bilateral nevus of Ota-like macules. Pigment Cell Melanoma Res 2010 Feb; 23(1):144–146. Manuskiatti W, et al: Effect of cold air cooling on the incidence of postinflammatory hyperpigmentation after Q-switched Nd:YAG laser treatment of acquired bilateral nevus of Ota-like macules. Arch Dermatol 2007 Sep; 143(9):1139–1143. Park JM, et al: Combined use of intense pulsed light and Q-switched ruby laser for complex dyspigmentation among Asian patients. Lasers Surg Med 2008 Feb; 40(2):128–133.
Blue nevus Blue nevi appear as well-defined blue papules or nodules (Fig. 30-21). Histologically, they share the silhouette of a bulbous finger-like or wedge-shaped protrusion into the dermis. All variants show little maturation, and no dispersion of melanocytes in the deep portion of the lesion. All except epithelioid blue nevi and some cellular blue nevi are associated with a dense sclerotic stroma. They commonly occur as combined nevi (combinations of various types of blue nevus, blue nevus combined with banal nevus, or blue nevus combined with Spitz nevus).
Blue nevus of Jadassohn–Tiche (common blue nevus, nevus ceruleus) The typical lesion is a steel-blue papule or nodule that begins in early life. Some may be large and congenital. The slowly growing lesion is rarely more than 2–10 mm in diameter, and occurs most frequently on the dorsal hands, feet, and face. Histologically, the lesion is composed of dendritic dermal melanocytes and melanophages. The sclerotic stroma is particularly prominent in this variant.
Cellular blue nevus Usually, a cellular blue nevus is a large, firm, blue or blue– black nodule. It is most frequently seen on the buttock and sacrococcygeal region, and occasionally is present at birth. Women have cellular blue nevus 2.5 times as frequently as men, and the average age of the patient seen with this lesion is 40 years. Uncommonly, these may invade underlying structures such as the skull in scalp lesions. Occasionally, cellular blue nevi may occur on the eyelids. Histologically, in addition to deeply pigmented melanophages, islands of cells are observed with large fusiform vesicular nuclei, prominent nucleoli, and abundant pale cytoplasm. The cellular islands contain little or no pigment. Important diagnostic criteria for benign blue nevi include a low mitotic rate, absence of necrosis, a low Ki-67-+ proliferative fraction, and uniform HMB45 label ing. Cytologic atypia may be present in benign blue nevi, but mitotic figures should not been seen. Such “ancient” blue nevi frequently demonstrate edematous stromal areas and hyaline changes in vessels, suggesting a degenerative phenomenon.
Epithelioid blue nevus Epithelioid blue nevi are mostly seen in patients with the Carney complex (myxomas, spotty skin pigmentation, endocrine overactivity, and schwannomas). They occur on the extremities and trunk, and less frequently on the head and neck. They may also be noted in the absence of Carney complex, and may occur on the genital mucosa. The lesions are composed of large polygonal and epithelioid melanocytes often laden with melanin. These cells are admixed with heavily pigmented dendritic melanocytes, spindled melanocytes, and melanophages. Some melanocytes are situated among the dermal collagen bundles singly, in short rows, and small groups. The nuclei are vesicular with very pale chromatin and a single prominent nucleolus. They may demonstrate moderate pleomorphism and rare mitotic figures. In contrast with other blue nevi, they lack the usual sclerotic stroma. Some have grouped these lesions with dendritic and epithelioid melanomas under the designation pigmented epithelioid melanocytoma, which they regard as a borderline malignancy or low-grade melanoma. One problem with this designation is the lack of data suggesting that the lesions in patients with the Carney complex behave in a malignant fashion.
Deep penetrating nevus This unique type of nevus is commonly seen in combination with other forms of blue nevus. The fascicles of cells have small hyperchromatic nuclei with a smudged chromatin pattern and inconspicuous nucleoli. Adjacent melanophages are noted.
Amelanotic blue nevus (hypomelanotic blue nevus)
Fig. 30-21 Blue nevus.
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In the amelanotic or hypomelanotic variant of cellular blue nevus, mild cytologic atypia and pleomorphism may be present. Mitotic activity (up to three mitoses/mm) may also be observed. It is important to recognize the entity so as not to confuse it with a malignant lesion.
The term “malignant blue nevus” has been used to refer to melanomas arising in a blue nevus (usually a cellular blue nevus). It has also been used for de novo melanoma resembling a cellular blue nevus. When melanoma occurs in a blue nevus, an abrupt transition can be seen between the nevus and the melanoma. The melanoma demonstrates a sheet-like growth pattern, mitoses, necrosis, and nuclear atypia.
Treatment Excision is the mainstay of treatment for blue nevi. Successful results have been reported with the Q-switched ruby laser. Treatment of the malignant variety is the same as for a malignant melanoma. Intratumoral therapy with IFN-β has also been used. Berman EL, et al: Multifocal blue nevus of the conjunctiva. Surv Ophthalmol 2008 Jan–Feb; 53(1):41–49. Cerroni L, et al: “Ancient” blue nevi (cellular blue nevi with degenerative stromal changes). Am J Dermatopathol 2008 Feb; 30(1):1–5. Fleming MG: Pigmented lesion pathology: what you should expect from your pathologist, and what your pathologist should expect from you. Clin Plast Surg 2010; 37(1):1–20. Murali R, et al: Blue nevi and related lesions: a review highlighting atypical and newly described variants, distinguishing features and diagnostic pitfalls. Adv Anat Pathol 2009; 16(6):365–382.
von Moos R, et al: Intratumoral therapy with interferon-alpha in a locoregional advanced malignant blue nevus: a brief communication. J Immunother 2010; 33(1):92–95. Wang Q, et al: Cellular blue nevi of the eyelid: a possible diagnostic pitfall. J Am Acad Dermatol 2008 Feb; 58(2):257–260.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. Fig. Fig. Fig. Fig. Fig. Fig. Fig. Fig. Fig. Fig. Fig. Fig. Fig.
30-1 Solar lentigines. 30-2 Benign nevi. 30-3 Medium-sized congenital nevus. 30-4 Spitz nevus. 30-5 Multiple spindle cell nevi. 30-6 Fried egg appearance of a dysplastic nevus. 30-7 Melanoma. 30-8 Palatal melanoma. 30-9 Congenital common blue nevus. 30-10 Nevus spilus. 30-11 Becker nevus. 30-12 Halo nevus. 30-13 Spitz nevus. 30-14 Amelanotic malignant melanoma.
Dermal melanocytic lesions
“Malignant blue nevus”
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Bonus images for this chapter can be found online at http://www.expertconsult.com
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Macrophage/Monocyte Disorders
Palisaded granulomatous dermatoses Granuloma annulare Granuloma annulare (GA) is a relatively common idiopathic disorder of the dermis and subcutaneous tissue. It occurs in all races and at all ages, but much more frequently affects women (2 : 1). GA may exhibit the isomorphic response of Koebner, affect healed areas of herpes zoster, and may be restricted to sun-exposed areas. While most cases spontaneously resolve, leaving entirely normal skin, loss of elastic tissue may occur, leaving atrophic lesions resembling middermal elastolysis or anetoderma. GA lesions will sometimes spontaneously resolve when biopsied. Long-term follow-up of at least 20 years in patients with GA reveals that lesions usually heal, and that the patients remain healthy and do not develop unusual diseases. Case reports of associations as described below demonstrate that GA can be a reactive condition associated with a variety of underlying disorders and medications. In most patients, however, it is a benign, self-limited (although not soon enough for the dermatologist or patient) condition affecting only the skin. Many clinical morphologies of GA exist. Usually, patients exhibit primarily one clinical type during the course of their illness, except in the subcutaneous form, in which typical papular or localized GA may also occur.
nevus may be affected. Lesions are erythematous, fawncolored or violaceous, thinly bordered plaques or papules, which slowly spread peripherally, at the same time undergoing central involution, so that roughly annular lesions are formed. The overlying skin usually remains completely normal. Lesions may coalesce and sometimes form scalloped patterns or firm plaques. The lesions never ulcerate and on resolving virtually always leave no residua. They develop slowly and often involute spontaneously. Although more than
Localized granuloma annulare This form of GA tends to affect children and young to middleaged adults. Usually only one or a few lesions are present at any one time. Localized GA usually appears on the lateral or dorsal surfaces of the fingers or hands, elbows, dorsal feet, and ankles (Figs 31-1 to 31-3). Rarely, the eyelid or even a Becker
Fig. 31-2 Granuloma annulare, annular, localized type.
Fig. 31-1 Granuloma annulare, dermal papule on the knuckle.
Fig. 31-3 Granuloma annulare, annular plaque composed of coalescing papules.
Fig. 31-5 Granuloma annulare, subcutaneous and dermal lesion.
50% of patients clear within 2 years, lesions will recur in 40%. Autoimmune thyroiditis may be present in women with localized GA.
major clinical problem occurs when the initial pathologic interpretation is rheumatoid nodule and an unnecessary extensive rheumatologic work-up is performed. An unusual variant is one that remains localized to the penis or scrotum, an atypical location for GA in general. Adult women without rheumatoid arthritis may develop similar lesions around the joints.
Generalized granuloma annulare This form of GA affects mostly women in the fifth and sixth decades, adolescents and children. The association of generalized GA with diabetes mellitus has been questioned. The eruption presents as a diffuse but symmetrical, papular or annular eruption of more than 10 lesions, and often hundreds. Lesions favor the nape of the neck, upper trunk, and proximal upper extremities, and rarely exceed 5 cm in diameter. The palms, soles, and eyelids may be affected. The face and genital area are usually spared. In some cases sun exposure seems to be a trigger (see section on actinic granuloma below). Some patients are completely asymptomatic, whereas others complain of severe pruritus. Spontaneous clearing usually occurs but at variable times. The average duration is 3–4 years but may be as short as 4 months or longer than a decade.
Patch-type or macular granuloma annulare This form of GA is significantly more common in women, usually between 30 and 70 years of age. Flat or only slightly palpable erythematous or red–brown lesions occur (Fig. 31-4), especially on the upper medial thighs and in bathing-trunk distribution. Lesions may closely simulate cutaneous T-cell lymphoma or morphea. Individual lesions average at least several centimeters in diameter but may be much larger. On careful palpation, small papules can be felt in some cases and on stretching the skin the papules or small annular lesions can be seen. Such papules are the most fruitful sites for biopsies. Both well-formed necrobiotic granulomas and the interstitial pattern of GA may be seen on biopsy.
Subcutaneous granuloma annulare (deep granuloma annulare, pseudorheumatoid nodule) Subcutaneous GA is most common in children, with boys affected twice as frequently as girls. Childhood cases appear at any age from 1 year to adolescence, with one congenital case reported. Lesions tend to occur on the lower legs, especially the dorsal foot, but may also occur on the distal upper extremity or scalp. Multiple lesions are usually present. There is often a history of trauma to the affected area preceding the appearance of a lesion. Typically, lesions are skin-colored, deep dermal or subcutaneous nodules, up to several centimeters in diameter (Fig. 31-5). Superficial papular lesions are present in about one-quarter of patients with subcutaneous GA. Lesions in general are asymptomatic and resolve over a few years. The
Palisaded granulomatous dermatoses
Fig. 31-4 Granuloma annulare, macular lesion of the medial thigh.
Perforating granuloma annulare Perforating GA usually appears on the dorsal hands and presents as papules with a central keratotic core. This core represents transepidermal elimination of the degenerated material in the center of GA lesions and clinically can resemble a pustule.
Acute-onset painful acral granuloma annulare This recently described clinical variant of GA does not resemble other forms of the disease. Female patients present with the sudden onset of painful lesions on the hands and feet, and a scattering of lesions at other sites. The lateral, dorsal, and marginal hands and, to less extent, the feet are affected. Palm and sole lesions are characteristic. Lesions are tender to palpation and, when present on the palms, are dusky and may vaguely resemble erythema multiforme. Patients may have associated arthralgias and diarrhea, and feel feverish, features of a “cytokine storm.” The erythrocyte sedimentation rate (ESR) may be elevated, even above 50 mm/hr. Lesions resolve over months, at times after having been treated with systemic corticosteroids or hydroxychloroquine. The authors have seen one such case associated with Hodgkin disease.
Granuloma annulare in human immunodeficiency (HIV) disease GA may occur in persons with HIV infection at all stages of disease. Lesions are typically papular and generalized GA is more common (60%) than localized GA (40%). Photodistributed and perforating lesions may also occur. The histology is identical to GA in the normal host. The natural history of GA in HIV is unknown.
Granuloma annulare and malignant neoplasms The occurrence of GA and a cancer in the same patient is rare, but has been reported many times. Most of these patients are between 35 and 75, older than the typical GA patient. Half the cases occur in lymphoma/leukemia patients and half in solid tumor patients. The diagnosis of the neoplasm usually predates the diagnosis of GA, but may precede it. In some cases, lesions are described as “atypical” in that they may be painful (see above). 695
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Other conditions associated with granuloma annulare Since these reports are anecdotal, causality cannot be ascribed in every case. However, these cases do show trends that parallel our concept of the pathogenesis of GA. Numerous medications have been reported to cause GA. Many of these medications are immunomodulatory—interferon (IFN)-α, IFN-β, and tumor necrosis factor (TNF) inhibitors. GA may follow a bee sting, waxing in a patient with pseudofolliculitis, and injections at a medispa for mesotherapy. Two groups of infectious diseases have been described as having GA-like lesions either histologically or clinically: borreliosis and tuberculosis. Both Lyme disease in the USA and Borrelia infections in Europe have been described rarely as demonstrating interstitial granulomatous inflammation; clinically, however, at least in Europe, the lesions resemble morphea rather than GA. Despite laboratory evidence of infection, treatment of the patient with appropriate antibiotics may not lead to resolution of the skin lesions. A tuberculid can closely resemble disseminated GA, although histologically caseous necrosis may be seen in the center of the granulomas. Treatment for tuberculosis leads to resolution of the skin lesions. In the appropriate patient evaluation for tuberculosis and anti-tuberculous treatment may be indicated.
Granuloma annulare and eye disease Anterior and chronic intermediate uveitis has been described in patients with localized GA. The uveitis can be unilateral or bilateral, may be mild and respond to topical therapy, or may be aggressive, resulting in visual impairment. The frequency of uveitis in patients with GA seems to be too low to recommend that all patients with GA be screened by an ophthalmologist. However, GA patients should be questioned about visual symptoms, including reduced visual acuity. If these are present, ophthalmologic evaluation would be appropriate.
Histology Because there are many clinical patterns of GA, skin biopsies are often performed to confirm the diagnosis. In general, there are two histopathologic patterns that often coexist in the same patient. The classic pattern of GA is a palisading granuloma characterized by histiocytes and epithelioid cells surrounding a central zone of altered collagen. In well-developed lesions, there is mucin deposition within the foci of altered collagen. Fibrin and nuclear dust may also be present in the degenerated foci. Lesions are most typically located in the upper and midreticular dermis, but may involve the deep dermis or subcutaneous tissue. At the periphery of lesions a leukocytoclastic vasculitis may rarely be found. IgM and C3 in the blood vessels of the skin lesions are found in about half of patients. The second pattern of GA is the interstitial pattern. Lesions may be entirely interstitial, or an interstitial pattern may be seen adjacent to well-formed palisaded lesions. A patchy dermal infiltrate of histiocytes and other mononuclear cells with occasional neutrophils is interspersed between collagen bundles. The patchy distribution within the dermis is best appreciated at scanning magnification. Interstitial mucin is often present in the affected areas, and is best demonstrated with a colloidal iron stain. Although these features are sufficient to confirm the diagnosis of GA, further sectioning may reveal typical palisaded granulomas. If the number of histiocytes in the infiltrate is small and lymphocytes predominate, the diagnosis of interstitial cutaneous T-cell lymphoma should be considered.
Treatment Patients regularly report that a biopsy of the lesion will cause its involution. Because the lesions are often asymptomatic and 696
spontaneous involution occurs, no treatment is required in many mild cases. Numerous modalities have been reported to improve GA, suggesting that no one treatment is uniformly efficacious and the “treatment of choice.” It is best to develop a therapeutic ladder for both localized and generalized cases of GA. For localized cases, the intralesional injection of triamcinolone suspension is effective and is a reasonable initial treatment. Most cases relapse within 3–7 months. Superpotent topical steroids or topical calcineurin inhibitors, or imiquimod, may be effective in some patients, especially those with more macular lesions. Localized phototherapy in the form of pulsed dye laser, high-intensity UV therapy with a laser designed to treat psoriasis, PUVA, photodynamic therapy, or even fractional photothermolysis could be considered. Generalized cases represent a major therapeutic challenge. Although systemic steroids may be very effective, the high doses required and the usual immediate relapse as the steroids are tapered make this approach untenable in most situations. In addition, because diabetes may be present, systemic steroids may complicate the management of the diabetes. Many systemic agents have been reported as effective, but few have been tested in large numbers of cases or in blinded or controlled fashion. For any treatment, 3–6 months of therapy appear to be necessary for efficacy or failure to be demonstrated. With all treatments, the GA may clear, only to recur when the treatment is stopped. Antibiotics such as doxycycline; the combination of rifampin, ofloxacin, and minocycline, once monthly; pentoxiphylline, 400 mg three times daily; or high-dose nicotinamide, potassium iodide, or dapsone, 100 mg per day, can be effective. Fumaric acid esters over 1–18 months have also shown efficacy. Oral retinoids, especially isotretinoin, can be considered at a dose of 0.5 mg/kg or slightly more. Hydroxychloroquine in very high doses (9 mg/kg initially) reportedly cleared all nine patients so treated. Phototherapy in the form of NB-UVB, PUVA, or UVA-1 can be effective in selected patients. With UVA-1 about half of treated patients have a “satisfactory response”; however, stopping treatment led to relapse. Photodynamic therapy will clear or “almost clear” some lesions and can be used for multiple lesions in a localized area. For patients with severe or disabling disease, TNF inhibitors can be considered. Etanercept, infliximab, and adalimumab have all been reported to be effective. It is of interest that these medications can also cause GA. Systemic agents, such as cyclosporine, IFN-γ, and hydroxyurea, have been reported to be effective in small series of patients. The potential toxicity of these medications limits their use to patients with significant GA. Adams BB, Mutasim DF: Colocalization of granuloma annulare and mid-dermal elastolysis. J Am Acad Dermatol 2003; 48:S25. Adams DC, Hogan DJ: Improvement of chronic generalized granuloma annulare with isotretinoin. Arch Dermatol 2002; 138:1518. Asano Y, et al: Generalized granuloma annulare treated with short-term administration of etretinate. J Am Acad Dermatol 2006; 54:S245. Badavanis G, et al: Successful treatment of granuloma annulare with imiquimod cream 5%: a report of four cases. Acta Derm Venereol 2005; 85:547. Barzilai A, et al: Pseudorheumatoid nodules in adults: a juxta-articular form of nodular granuloma annulare. Am J Dermatopathol 2005; 27:1. Baskan EB, et al: A case of granuloma annulare in a child following tetanus and diphtheria toxoid vaccination. J Eur Acad Dermatol Venereol 2005; 19:639. Baskan EB, et al: A case of generalized granuloma annulare with myelodysplastic syndrome: successful treatment with systemic isotretinoin and topical pimecrolimus 1% cream. J Eur Acad Dermatol Venereol 2007; 21:693. Batchelor R, Clark S: Clearance of generalized papular umbilicated granuloma annulare in a child with bath PUVA therapy. Pediatr Dermatol 2006; 23:72.
Marcus DV, et al: Granuloma annulare treated with rifampin, ofloxacin, and minocycline combination therapy. Arch Dermatol 2009; 145:787. Marie I, et al: Rosai–Dorfman disease and granuloma annulare. Acta Derm Venereol 2007; 87:375. Mehta LR, Rose JW: Recurrent granuloma annulare during treatment with daclizumab. Mult Scler 2009; 15:527. Moreno C, et al: Interstitial granulomatous dermatitis with histiocytic pseudorosettes: a new histopathologic pattern in cutaneous borreliosis. Detection of Borrelia burgdorferi DNA sequences by a highly sensitive PCR-ELISA. J Am Acad Dermatol 2003; 48:376. Nebesio CL, et al: Lack of an association between granuloma annulare and type 2 diabetes mellitus. Br J Dermatol 2002; 146:122. Neto Pimentel DR, et al: Multiple deep granuloma annulare limited to the cephalic segment in childhood. Pediatr Dermatol 2008; 25:407. Özkan S, et al: Anetoderma secondary to generalized granuloma annulare. J Am Acad Dermatol 2000; 42:335. Pasmatzi E, et al: Temporary remission of disseminated granuloma annulare under oral isotretinoin therapy. Int J Dermatol 2005; 44:169. Piaserico S, et al: Generalized granuloma annulare treated with methylaminolevulinate photodynamic therapy. Dermatology 2009; 218:282. Reddy HS, et al: Granuloma annulare anterior uveitis. Ocul Immunol Inflamm 2008; 16:55. Requena L, Fernandez-Figueras MT: Subcutaneous granuloma annulare. Semin Cutan Med Surg 2007; 25:96. Sandwich JT, Davis LS: Granuloma annulare of the eyelid: a case report and review of the literature. Pediatr Dermatol 1999; 16:373. Schnopp C, et al: UVA1 phototherapy for disseminated granuloma annulare. Photodermatol Photoimmunol Photomed 2005; 21:68. Setoyama M, et al: Granuloma annulare associated with Hodgkin’s disease. Int J Dermatol 1997; 36:445. Shimizu S, et al: Atypical generalized granuloma annulare associated with two visceral cancers. J Am Acad Dermatol 2006; 54:S236. Shupack J, Siu K: Resolving granuloma annulare with etanercept. Arch Dermatol 2006; 142:394. Sidwell RU, et al: Subcutaneous granuloma annulare of the penis in 2 adolescents. J Pediatr Surg 2005; 40:1329. Simon M, et al: Antimalarials for control of disseminated granuloma annulare in children. J Am Acad Dermatol 1994; 31:1064. Sliger BN, et al: Treatment of granuloma annulare with the 595 nm pulsed dye laser in a pediatric patient. Pediatr Dermatol 2008; 25:196. Smith JB, et al: Potassium iodide in the treatment of disseminated granuloma annulare. J Am Acad Dermatol 1994; 30:791. Sniezek PJ, et al: Treatment of granuloma annulare with the 585 nm pulsed dye laser. Dermatol Surg 2005; 31:1370. Spadino S, et al: Disseminated granuloma annulare: efficacy of cyclosporine therapy. Int J Immunopathol Pharmacol 2006; 19:433. Strahan JE, et al: Granuloma annulare as a complication of mesotherapy: a case report. Dermatol Surg 2008; 34:836. Takayama K, et al: Papular granuloma annulare with subcutaneous granulomatous reaction induced by a bee sting. Acta Derm Venereol 2008; 88:519. Toro JR, et al: Granuloma annulare and human immunodeficiency virus infection. Arch Dermatol 1999; 135:1341. Tsai J, et al: Cutaneous tuberculid clinically resembling generalized granuloma annulare. Clin Exp Dermatol 2007; 32:450. Uenotsuchi T, et al: Seasonally recurrent granuloma annulare on sun-exposed areas. Br J Dermatol 1999; 141:367. Vázquez-López F, et al: Localized granuloma annulare and autoimmune thyroiditis in adult women: a case-control study. J Am Acad Dermatol 2003; 48:517. Villegas RG, et al: Pustular generalized perforating granuloma annulare. Br J Dermatol 2003; 149:866. Voulgari PV, et al: Granuloma annulare induced by anti-tumour necrosis factor therapy. Ann Rheum Dis 2008; 67:567. Webber HO, et al: Treatment of disseminated granuloma annulare with low-dose fumaric acid. Acta Derm Venereol 2009; 89:295. Weinberg JM, et al: Granuloma annulare restricted to Becker’s nevus. Br J Dermatol 2004; 151:245. Weisenseel P, et al: Photodynamic therapy for granuloma annulare: more than a shot in the dark. Dermatology 2008; 217:329. Weiss JM, et al: Treatment of granuloma annulare by local injections with low-dose recombinant human interferon gamma. J Am Acad Dermatol 1998; 39:117.
Palisaded granulomatous dermatoses
Brey NV, et al: Acute-onset, painful acral granuloma annulare: a report of 4 cases and a discussion of the clinical and histologic spectrum of the disease. Arch Dermatol 2006; 142:49. Brey NV, et al: Association of inflammatory eye disease with granuloma annulare? Arch Dermatol 2008; 144:803. Cannistraci C, et al: Treatment of generalized granuloma annulare with hydroxychloroquine. Dermatology 2005; 211:167. Chiu ML, Tang MB: Generalized granuloma annulare associated with gastrointestinal stromal tumour: case report and review of clinical features and management. Clin Exp Dermatol 2008; 33:469. Cohen PR: Granuloma annulare, relapsing polychondritis, sarcoidosis, and systemic lupus erythematosus: conditions whose dermatologic manifestations may occur as hematologic malignancy-associated mucocutaneous paraneoplastic syndromes. Int J Dermatol 2006; 45:70. Czarnecki DB, et al: The response of generalized granuloma annulare to dapsone. Acta Dermatol Venereol (Stockh) 1986; 66:82. Dadban A, et al: Widespread granuloma annulare and Hodgkin’s disease. Clin Exp Dermatol 2008; 33:465. Dahl MV: Granuloma annulare: long-term follow-up. Arch Dermatol 2007; 143:946. De Aloe G, et al: Congenital subcutaneous granuloma annulare. Pediatr Dermatol 2005; 22:234. Duarte AF, et al: Generalized granuloma annulare—response to doxycycline. J Eur Acad Dermatol Venereol 2009; 23:84. Forman SB, et al: Penile granuloma annulare of an adolescent male—case report and review of the literature. Pediatr Dermatol 2008; 25:260. Frigerio E, et al: Multiple localized granuloma annulare: ultraviolet A1 phototherapy. Clin Exp Dermatol 2007; 32:762. Grundmann-Kollmann M, et al: Cream psoralen plus ultraviolet A therapy for granuloma annulare. Br J Dermatol 2001; 144:996. Gualco F, et al: Interstitial granuloma annulare and borreliosis: a new case. J Eur Acad Dermatol Venereol 2007; 21:1117. Hacihamdioglu B, et al: Subcutaneous granuloma annulare in a child: a case report. Clin Pediatr 2008; 47:306. Hall CS, et al: Treatment of recalcitrant disseminated granuloma annulare with hydroxyurea. J Am Acad Dermatol 2008; 58:525. Herron MD, Florell SR: Disseminated granuloma annulare accompanying mycobacterium tuberculosis lymphadenitis. Int J Dermatol 2004; 43:961. Hertl MS, et al: Rapid improvement of recalcitrant disseminated granuloma annulare upon treatment with the tumour necrosis factor-α inhibitor, infliximab. Br J Dermatol 2005; 152:552. Hinckley MR, et al: Generalized granuloma annulare as an initial manifestation of chronic myelomonocytic leukemia: a report of 2 cases. Am J Dermatopathol 2008; 30:274. Hsu S, et al: Granuloma annulare localized to the palms. J Am Acad Dermatol 1999; 41:287. Inui S, et al: Disseminated granuloma annulare responsive to narrowband ultraviolet B therapy. J Am Acad Dermatol 2005; 53:533. Karsai S, et al: Fractional photothermolysis for the treatment of granuloma annulare: a case report. Lasers Surg Med 2008; 40:319. Kawakami T, et al: Granuloma annulare-like skin lesions as an initial manifestation in a Japanese patient with adult T-cell leukemia/ lymphoma. J Am Acad Dermatol 2009; 60:848. Kiremitci U, et al: Generalized granuloma annulare resolving to anetoderma. Dermatol Online J 2006; 12:16. Kluger N, et al: Generalized interstitial granuloma annulare induced by pegylated interferon-alpha. Dermatology 2006; 213:248. Knoell KA: Efficacy of adalimumab in the treatment of generalized granuloma annulare in monozygotic twins carrying the 8.1 ancestral haplotype. Arch Dermatol 2009; 145:610. Levin NA, et al: Resolution of patch-type granuloma annulare lesions after biopsy. J Am Acad Dermatol 2002; 46:426. Li A, et al: Granuloma annulare and malignant neoplasms. Am J Dermatopathol 2003; 25:113. Lopez-Navarro N, et al: Successful treatment of perforating granuloma annulare with 0.1% tacrolimus ointment. J Dermatolog Treat 2008; 19:376. Ma A, et al: Response of generalized granuloma annulare to high-dose niacinamide. Arch Dermatol 1983; 119:836. Madan V, et al: Multiple asymptomatic scrotal nodules. Clin Exp Dermatol 2009; 34:433.
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Macrophage/Monocyte Disorders
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Fig. 31-7 Granuloma annulare, generalized papular lesions localized to sun-exposed sites.
Fig. 31-6 Granuloma annulare, annular elastolytic giant cell granuloma (Meischer), atrophic annular plaque. Whelan JP, Zembowicz A: Case records of the Massachusetts General Hospital. Case 19-2000: a 22-month-old boy with the rapid growth of subcutaneous nodules. N Engl J Med 2006; 254:2697. Wu H, et al: Granuloma annulare with a mycosis fungoides-like distribution and palisaded granulomas of CD68-positive histiocytes. J Am Acad Dermatol 2004; 51:39. Young HS, Coulson IH: Granuloma annulare following waxing induced pseudofolliculitis—resolution with isotretinoin. Clin Exp Dermatol 2000; 25:274. Ziemer M, et al: Granuloma annulare—a manifestation of infection with Borrelia? J Cutan Pathol 2008; 35:1050.
Annular elastolytic giant cell granuloma (Meischer’s) and actinic granuloma (O’Brien) Annular elastolytic giant cell granuloma (AEGCG) and actinic granuloma are unified by their histopathologic appearance. Non-diabetes-associated necrobiosis lipoidica of the face has been included in this category. It is currently unclear whether they simply represent variants of GA occurring on sundamaged skin or are distinct diseases. AEGCG have been reported in two patterns. One is a single, asymptomatic, atrophic-appearing, yellow, thin plaque on the forehead (Meischer’s Granuloma) (Fig. 31-6). Fine wrinkling and loss of elasticity characterize the skin within the ring. Clinically, this pattern resembles facial necrobiosis lipoidica more than GA. The second variant is of multiple extensor upper extremity and sometimes trunk lesions, and occurs more frequently in women and largely in sun-exposed areas. In these cases the lesions have an active erythematous border with central clearing. A papular variant has been described. While the vast majority of cases occur in adults, children and even an infant have been affected. Except for temporal arteritis as described below, most patients are otherwise well. However, AEGCG has been described in association with acute myelogenous leukemia (which resolved with remission and recurred with relapse of the leukemia) and pleomorphic cutaneous T-cell lymphoma, At times, as in GA, the lesions may heal with loss of elastic tissue and clinical features of skin laxity and anetoderma. The condition is chronic. Actinic granuloma, as described by O’Brien, may represent the same disorder as AEGCG. It presents as papules and plaques on sun-exposed skin (Fig. 31-7). Lesions are frequently numerous and may coalesce to cover much of the exposed 698
skin. A history of onset after significant sun exposure and the distribution on physical examination should lead to suspicion of the diagnosis. A few lesions may occur on sun-protected sites or spill over from affected areas to more photoprotected sites. Rarely, open comedones, scarring, and milia formation may be present clinically. This may be associated with transepidermal elimination of damaged connective tissue or loss of elastic tissue surrounding the follicular ostia, leading to a Favre–Racouchot-like appearance. This condition affects older adults (usually over age 50) and can be intensely pruritic. It is not associated with diabetes mellitus, but there are numerous reports of it occurring in patients with temporal arteritis. It is speculated that the vasculitis is also due to actinic injury to the connective tissue surrounding the temporal artery. Histologically, all these conditions show a characteristic histology. The dermal infiltrate of macrophages is largely interstitial and well-formed palisaded granulomas are uncommon. Multinucleated giant cells, often quite large, are numerous. Mucin is scant or lacking. The macrophages characteristically contain fragments of actinically damaged elastic tissue (elasto phagocytosis). When this typical histology is seen in concert with the classic clinical features noted above, it may be reasonable to make these specific diagnoses. These conditions cannot, however, be diagnosed on clinical or histologic grounds alone. Some cases with the clinical features of AEGCG or actinic granuloma will show a histology more characteristic of typical GA, suggesting that there is a spectrum of both clinical and histologic features in these patients. Treatment of these conditions has been difficult. Cases with an active erythematous border tend to respond to systemic steroids, but relapse immediately when the steroids are tapered or discontinued. Tranilast, 300 mg/day, and chloroquine, 250 mg/day, have been reported as effective. Insulin improved diabetic control and the actinic granuloma in one case. Other anecdotal treatments include oral retinoids, fumaric acid, PUVA, pentoxiphylline, cyclosporine, and methotrexate. Boussault P, et al: Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma associated with an annular elastolytic giant cell granuloma. Br J Dermatol 2009; 160:1126. Davies MG, et al: Actinic granuloma in a young woman following prolonged sunbed usage. Br J Dermatol 1997; 136:797. Garg A, et al: Annular elastolytic giant cell granuloma heralding onset and recurrence of acute myelogenous leukemia. Arch Dermatol 2006; 142:532. Gass JK, et al: Generalized granuloma annulare in a photosensitive distribution resolving with scarring and milia formation. Clin Exp Dermatol 2009; 34:e53.
Interstitial granulomatous drug reaction Interstitial granulomatous drug reaction (IGDR) is an uncommon, and increasingly recognized, pattern of adverse reactions to medication. While it may occur within a few days of starting the medication, most patients with IGDR have been on the offending medication for months to years. A wide variety of medications have been implicated, including calcium channelblockers (most common cause reported), lipid-lowering agents, angiotensin-converting enzyme (ACE) inhibitors, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, anticonvulsants, antidepressants, allopurinol, thalidomide, lenalidomide, darifenacin, anakinra, ganciclovir, strontium ranelate, sennoside (a common over-the-counter laxative), Chinese herbs, and even soy. The TNF inhibitors have been implicated as causal in IGDR in many cases, mostly in patients being treated for rheumatoid arthritis. Since rheumatoid arthritis patients may develop similar lesions independent of medication exposure, it suggests that rheumatoid arthritis patients may be predisposed to developing this reaction pattern. In cases of IGDR from TNF inhibitors, stopping the medication led to resolution of the eruption over several months, strongly supporting the association. Clinically, the lesions are erythematous annular plaques with an indurated border and sometimes a tendency to central clearing. Lesions favor the creases (groin, axillae, popliteal fossae), but may also affect the trunk, proximal extremities, palms, and soles. Lesions may be photodistributed, affecting the face and dorsal extensor forearm and hands. Pruritus is minimal or absent. Mucous membranes are spared. Histologically, there is a diffuse deep dermal infiltrate that is perivascular but has a prominent interstitial component. The inflammatory infiltrate is centered in the lower two-thirds of the dermis; it contains neutrophils, eosinophils, histiocytes, and multinucleated giant cells. Degenerated collagen bundles may be surrounded by histiocytes, neutrophils, and eosino phils, forming “Churg–Strauss” granulomas, and mucin is usually scant or absent. Necrobiotic granulomas are usually incomplete, but have at times been reported to resemble those seen in GA. Unique features that should suggest IGDR over GA include an interface component and “atypical” lymphocytes in the infiltrate. The histologic differential diagnosis includes interstitial granulomatous dermatitis associated with arthritis, palisaded neutrophilic granulomatous dermatitis, papular eruption of methotrexate, and interstitial GA. Lesions resolve over months once the offending ingestant is stopped.
Chen YC, et al: Interstitial granulomatous drug reaction presenting as erythroderma: remission after discontinuation of enalapril maleate. Br J Dermatol 2008; 158:1143. Deng A, et al: Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor alpha inhibitors. Arch Dermatol 2006; 142:198. Dyson SW, et al: Interstitial granulomatous dermatitis secondary to soy. J Am Acad Dermatol 2004; 51:S105. Fujita Y, et al: A case of interstitial granulomatous drug reaction due to sennoside. Br J Dermatol 2004; 150:1028. Groves C, et al: Interstitial granulomatous reaction to strontium ranelate. Arch Dermatol 2008; 144:268. Lee HW, et al: Interstitial granulomatous drug reaction caused by Chinese herbal medication. J Am Acad Dermatol 2005; 52:712. Lim AC, et al: A granuloma annulare-like eruption associated with the use of amlodipine. Australas J Dermatol 2002; 45:24. Marcollo Pini A, et al: Interstitial granulomatous drug reaction following intravenous ganciclovir. Br J Dermatol 2008; 158:1391. Mason HR, et al: Interstitial granulomatous dermatitis associated with darifenacin. J Drugs Dermatol 2008; 7:895. Regula CG, et al: Interstitial granulomatous drug reaction to anakinra. J Am Acad Dermatol 2008; 59:S25. Yazganoglu KD, et al: Interstitial granulomatous drug reaction due to thalidomide. J Eur Acad Dermatol Venereol 2009; 23:490.
Palisaded granulomatous dermatoses
Klemke CD, et al: Generalized annular elastolytic giant cell granuloma. Dermatology 2003; 207:420. Lau H, et al: Actinic granuloma in association with giant cell arteritis. Pathology 1997; 29:260. Lee HW, et al: Annular elastolytic giant cell granuloma in an infant: improvement after treatment with oral tranilast and topical pimecrolimus. J Am Acad Dermatol 2005; 53:S244. Morita K, et al: Papular elastolytic giant cell granuloma: a clinical variant of annular elastolytic giant cell granuloma or generalized granuloma annulare? Eur J Dermatol 1999; 9:647. Muller FB, Groth W: Annular elastolytic giant cell granuloma: a prodromal stage of mid-dermal elastolysis? Br J Dermatol 2007; 156:1377. Özkaya-Bayazit E, et al: Annular elastolytic giant cell granuloma: sparing of a burn scar and successful treatment with chloroquine. Br J Dermatol 1999; 140:525. Sniezek PJ, et al: Annular atrophic plaques on the arms of a 57-year-old woman. Arch Dermatol 2006; 142:775. Stein JA, et al: Actinic granuloma. Dermatol Online J 2007; 13:19. Sudy E, et al: Open comedones overlying granuloma annulare in a photoexposed area. Photodermatol Photoimmunol Photomed 2006; 22:273.
Granuloma multiforme (Leiker) Granuloma multiforme is seen most commonly in central Africa, where it is a common disorder, and rarely elsewhere. It affects adults aged over 40 and is more common in females. Lesions are most frequently found on the upper trunk and arms, and in sun-exposed areas. It begins as small papules that evolve within a year into round or oval plaques up to 15 cm in diameter. The active edge of lesions may be elevated to as much as 4 mm in height and the center may be slightly depressed and hypopigmented. Pruritus can occur and coalescing lesions may form unusual polycyclic shapes. The course is chronic. It is, most importantly, separated from tuberculoid leprosy. Histologically, it resembles GA, but multinucleated giant cells are prominent. Giant cells typically contain phagocytosed connective tissue and elastic tissue is decreased in the areas affected by the granulomas. GM shares many features with AEGCG and actinic granuloma/GA of sun-exposed skin, and in fact may be considered identical to those disorders. Kumari R, et al: Granuloma multiforme: a report from India. Indian J Dermatol Venereol Leprol 2009; 75:296.
Necrobiotic xanthogranuloma Necrobiotic xanthogranuloma is an uncommon multisystem disease with prominent skin findings. The cause is unknown. Disease is gradually progressive, affecting men and women equally, and beginning on average at around age 50 (range 25–80 years or more). The most common site affected is the periorbital area (65–80% of cases). Multicentric involvement is typical. The characteristic skin lesions are yellow (xanthomatous) plaques and nodules. Periorbitally, they may be mistaken for xanthelasma, but they are deep, firm, and indurated, and may extend into the orbit. The trunk and proximal extremities may have orange–red plaques that have an active red border and an atrophic center with superficial telangiectasias (Fig. 31-8). These plaques may grow to 25 cm in diameter. The skin lesions ulcerate in 50% of cases, leading to atrophic scarring. Acral nodules may also occur, some localized solely to the subcutaneous tissue. Extracutaneous involvement most commonly affects the eyes. Patients may complain of burning, itching, or pain around or in the eyes. Diplopia and inflammation in various compartments of the eye can occur, including 699
Newman B, et al: Aggressive histiocytic disorders that can involve the skin. J Am Acad Dermatol 2007; 56:302 Spicknall, KE, Mehregan DA: Necrobiotic xanthogranuloma. Int J Dermatol 2009; 48:1. Venencie PY, et al: Recombinant interferon alfa-2b treatment of necrobiotic xanthogranuloma with paraproteinemia. J Am Acad Dermatol 1995; 32:666. Wood AJ, et al: Necrobiotic xanthogranuloma: a review of 17 cases with emphasis on clinical and pathologic correlation. Arch Dermatol 2009; 145:279. Yasukawa K, et al: Necrobiotic xanthogranuloma: isolated skeletal muscle involvement and unusual changes. J Am Acad Dermatol 2005; 52:729.
Macrophage/Monocyte Disorders
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Sarcoidosis
Fig. 31-8 Necrobiotic xanthogranuloma.
conjunctivitis, keratitis, scleritis, uveitis, iritis, ectropion, or proptosis. Ulceration and scarring of the plaques and distortion of the eye may lead to visual occlusion. Blindness may result. Lymphadenopathy, hepatosplenomegaly, and mucosal, myocardial, and pulmonary lesions may occur. There is a monoclonal IgG (usually κ) paraproteinemia in 80% of cases, and rarely an IgA paraproteinemia (one patient had both). Thrombocytopenia, neutrophilia, neutropenia, and eosinophilia may be present. The bone marrow may show leukopenia, plasmacytosis (25–50% of patients), or frank myeloma (10–20% of patients). In some cases a myelodysplastic syndrome may be present or develop (chronic lymphocytic lymphoma, Hodgkin or non-Hodgkin lymphoma). The necrobiotic xanthogranuloma predates the development of the myeloma or myelodysplastic syndrome by an average of 2.5 years. Histologically, there are extensive zones of degenerated collagen surrounded by palisaded macrophages. These macrophages are of various forms—foamy, Touton cells, epithelioid, and giant cells, sometimes with more than 50 nuclei. Atypical multinucleated giant cells with multiple nuclei clustered at one end of the cell (polarized nuclei) are seen in 80% or more of cases. The process extends into the fat, obliterating fat lobules. Cholesterol clefts and extracellular lipid deposits are prominent. Within this process is a perivascular and interstitial infiltrate of lymphocytes and plasma cells. Lymphoid follicles are present. In the skin, the lymphoid aggregates are polytypic. The histologic differential diagnosis includes necrobiosis lipoidica and other histiocytoses. Necrobiotic xanthogranuloma has more atypical and Touton giant cells, lymphoid nodules, and cholesterol clefts. The treatment is usually directed at the paraprotein or underlying malignancy and consists of systemic corticosteroids, alkylating agents (including chlorambucil, cyclophosphamide, and melphalan), plasmapheresis, or local radiation therapy (for eye lesions). Anecdotally, high dose intravenous immunoglobin (0.5 g/kg/d for 4 consecutive days 2 g/kg total) at 4 week intervals, IFN-α 2b, 3–6 MU three times a week, in combination with systemic corticosteroids, and pulse cytoxan with dexamethasone both led to improvement. Simple excision is an option, but lesions may recur. Chave TA, et al: Recalcitrant necrobiotic xanthogranuloma responding to pulsed high-dose oral dexamethasone plus maintenance therapy with oral prednisolone. Br J Dermatol 2001; 144:158. Flann S, et al: Necrobiotic xanthogranuloma with paraproteinaemia. Clin Exp Dermatol 2006; 31:248. Hallerman C, et al: Successful treatment of necrobiotic xanthogranuloma with intravenous immunoglobin. Arch Dermatol 2010; 146:957. Meyer S, et al: Cyclophosphamide-dexamethasone pulsed therapy for treatment of recalcitrant necrobiotic xanthogranuloma with paraproteinemia and ocular involvement. Br J Dermatol 2005; 153:443.
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Sarcoidosis is a systemic granulomatous disease that involves the skin and many of the internal organs with an acute or persistent course. In addition to the skin, which is involved in approximately 25% of cases, other sites of involvement are the lungs, mediastinal and peripheral lymph nodes, eyes, phalangeal bones, myocardium, central nervous system (CNS), kidneys, spleen, liver, and parotid glands. Sarcoidosis occurs worldwide. In Europe it is most prevalent in Scandinavia, especially in Sweden, with a prevalence of 64 in 100 000. In the UK, the rate is 20 in 100 000, and in France and Germany about 10 in 100 000, with lower rates in Spain and Japan of 1.4 in 100 000. In the US the southeastern states and certain urban centers (New York City, Detroit, and Washington DC) show the highest prevalence. In the US there is a marked racial variation with a rate of 10–14 in 100 000 for white persons and 35–64 in 100 000 for African Americans. The highest annual incidence is in African American women between the ages of 30 and 39, who have an annual incidence of 107 in 100 000. The lifetime risk for the development of sarcoidosis is 0.85% for white US residents, and 2.4% for African Americans. The disease begins most frequently between the ages of 20 and 40, and is slightly more common in women. Children may also develop sarcoidosis. There are two distinct forms of pediatric sarcoidosis. Early-onset disease, usually before the age of 4, is unique and characterized by the triad of skin lesions, uveitis, and arthritis. It is due to a defined genetic deficiency. It may be confused with juvenile rheumatoid arthritis. Older children, aged 8–14, present similarly to adults, with lymphadenopathy and pulmonary disease. Several genetic associations have been made with sarcoidosis, but the underlying cause still remains a mystery. HLADQB1*0201 and HLA-DRB1*0301 are strongly associated with acute disease and a good prognosis. The butyrophilin-like 2 (BTNL2) gene is associated with sarcoidosis, but the mechanism of this association is unknown. Mutations in the promoter region of TNF are associated with erythema nodosum in sarcoidosis in white Caucasians, and a variant in intron 1 of the lymphotoxin alpha (LTA) gene is associated with erythema nodosum in Caucasian female sarcoidosis patients. Cutaneous involvement in sarcoidosis may be classified as specific, which reveals granulomas on biopsy, or nonspecific, which is mainly reactive, such as erythema nodosum. In about 20% of cases the skin lesions appear before the systemic disease, in 50% there is simultaneous appearance of the skin and systemic lesions, and in 30% the skin lesions appear up to 10 years after the systemic disease has occurred. This is often coincidental with the tapering of systemic steroids for pulmonary sarcoidosis. The cutaneous manifestations of sarcoidosis are quite varied and numerous morphologic lesion types have been described. The morphology of the lesions in sarcoidosis might include papules, nodules, plaques, subcutaneous nodules, scar sarcoidosis, erythroderma, and ulcerations. The lesions may be verrucous, ichthyosiform, hypomelanotic, psoriasiform, or alopecic. They are usually multiple, firm, and
Sarcoidosis Fig. 31-10 Sarcoidosis, annular plaque. Fig. 31-9 Sarcoidosis, characteristic papules on the nares.
elastic when palpated. They extend to involve the entire thickness of the dermis. The overlying epidermis may be slightly thinned, discolored, telangiectatic, or scaly. The color is faint, showing dull tints of red, purple, brown, or yellow according to the stage of development. Usually the lesions are asymptomatic, but approximately 10–15% of patients itch. There is a racial difference in the frequency of cutaneous lesions in sarcoidosis. Among white patients erythema nodosum is as frequent as the specific cutaneous manifestations and both types of cutaneous involvement occur in about 10% of white patients with sarcoidosis. In black patients, erythema nodosum is much less common; however, specific cutaneous manifestations occur in 50% or more of patients. The skin lesions in general do not correlate with the extent or nature of systemic involvement or with prognosis. The exceptions are erythema nodosum, which is associated with a good prognosis, and subcutaneous sarcoidosis and lupus pernio. The morphologic types of sarcoidosis are discussed below, and when possible, the relationship to systemic sarcoidosis is discussed.
Erythema nodosum in sarcoidosis Erythema nodosum is the most common nonspecific cutaneous finding in sarcoidosis. Sarcoidosis may first appear with fever, polyarthralgias, uveitis, bilateral hilar adenopathy, fatigue, and erythema nodosum. This combination, known as Lofgren syndrome, occurs frequently in Scandinavian white persons and is uncommon in American blacks. The typical red, warm, and tender subcutaneous nodules of the anterior shins are distinctive and are most frequently seen in young women. The face, upper back, and extensor surfaces of the upper extremities may less commonly be involved. There is a strikingly elevated ESR, frequently above 50 mm/hr. Erythema nodosum is associated with a good prognosis, with the sarcoidosis involuting within 2 years of onset in 80% of cases. Conversely, the absence of erythema nodosum is a risk factor for persistent disease activity. Sweet’s syndrome may also rarely be seen in association with sarcoidosis as a non-specific finding.
Papular sarcoid Papules are the most common morphology of cutaneous sarcoidosis and are usually less than 1 cm in diameter. Lesions may be localized or generalized, in which case small papules predominate (Fig. 31-9). This is also known as miliary sarcoid.
The papules are especially numerous over the face, eyelids, neck, and shoulders. Plaques may occur by the expansion or coalescence of papules. In time the lesions involute to faint macules. Hyperkeratosis may rarely be prominent, giving the lesions a verrucous appearance. “Papular sarcoidosis of the knee” is distinctive, in that disease is often limited to this site. In this region the sarcoidal granulomas often contain foreign bodies. In Caucasians it often occurs in the context of Lofgren syndrome (see above) and has a good prognosis. Papular lesions along the alar rim in African Americans, in contrast, may be the first evidence of lupus pernio (see below) and portend a bad prognosis.
Annular sarcoidosis Papular lesions may coalesce or be arranged in annular patterns, usually with a red–brown hue (Fig. 31-10). On palpation the lesions are indurated. Central clearing with hypopigmentation, atrophy, and scarring may occur. Lesions favor the head and neck, and are usually associated with chronic sarcoidosis. Alopecia may result in the center of the lesion. Annular plaques of sarcoidosis can preferentially develop in sun-exposed areas.
Hypopigmented sarcoidosis Hypopigmentation may be the earliest sign of sarcoidosis and is usually diagnosed in darkly pigmented races. Lesions vary from a few millimeters to more than a centimeter in diameter and favor the extremities. Although they appear macular by visual inspection, on palpation a dermal or subcutaneous component is often palpable in the center of the lesion.
Lupus pernio Lesions typically are brown to violaceous, smooth, shiny plaques on the head and neck, especially the nose (Fig. 31-11), cheeks, lips, forehead, and ears. They can be very disfiguring. Involvement of the nasal mucosa and underlying bone may occur and lead to nasal perforation and collapse of the nasal bridge. Upper aerodigestive tract involvement is also common. Ear, nose, and throat (ENT) evaluation is recommended. In three-quarters of cases of lupus pernio, chronic fibrotic respiratory tract involvement is found. In 43% of cases, lupus pernio is associated with granulomas in the bones (punchedout cysts), most commonly of the fingers. Chronic ocular lesions occur in 37% of cases. Sarcoid involving the sinus is 701
extremity have a tendency to form indurated linear bands from the elbow to the hand on the cubital side of the forearm. The amount of subcutaneous involvement in the upper extremity may be so extensive as to simulate chronic cellulitis. A biopsy is usually required to confirm the diagnosis. About 90% of patients will have systemic involvement, usually bilateral hilar adenopathy, but the overall prognosis is good.
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Plaques These distinctive lesions are flat-surfaced, slightly elevated plaques that appear with greatest frequency on the cheeks, limbs, and trunk symmetrically. Superficial nodules may be superimposed and coalescence of plaques may lead to serpiginous lesions. Involvement of the scalp may lead to permanent alopecia. The finding of alopecia in an annular plaque with a raised border should raise the diagnostic consideration of sarcoidosis.
Erythrodermic sarcoidosis
Fig. 31-11 Sarcoidosis, lupus pernio with rhinophymatous nasal changes.
associated with lupus pernio 50% of the time. Lupus pernio is typically seen in women in their fourth or fifth decade of life. The skin lesions rarely involute spontaneously. At times, lupus pernio may resemble rhinophyma. It is important to make the correct diagnosis, as ulceration of sarcoidal lesions may occur with laser treatment, even with pulsed dye laser.
Ulcerative sarcoidosis Ulcerative sarcoidosis is very rare, affecting about 0.5% of patients with sarcoidosis. It affects primarily blacks, but it is also well recognized in Japanese. It is 2–3 times more common in women than men. In one-third of cases it is the presenting finding of sarcoidosis, except in Japan where it is commonly a late finding in patients with known sarcoidosis. The ulcerations may occur de novo or in sarcoidal plaques. Lesions favor the lower extremities, but most patients have lesions in more than one anatomic region. Trauma may be the inciting event. The clinical appearance may not be specific, but skin biopsies are diagnostic. Lupus pernio may also be present. Many patients have multisystem sarcoidosis, although uncommonly no other evidence of sarcoidosis is found. Biopsies may show necrosis in the center of sarcoidal granulomas. Methotrexate, which can be therapeutic in sarcoidosis, may also lead to ulceration in sarcoidosis patients.
Subcutaneous sarcoidosis About 10% of patients with cutaneous sarcoidosis will have subcutaneous lesions. They may also have other types of specific lesion, along with subcutaneous lesions. Subcutaneous sarcoidosis is also known as Darier–Roussy sarcoid and consists of a few to numerous 0.5–3 cm, deep-seated nodules on the trunk and extremities; only rarely do they appear on the face. The overlying epidermis may be normal (30%), erythematous (50%), or slightly violaceous (10%). The lesions are usually asymptomatic. Ninety percent of patients will have multiple lesions, and the upper extremity is most frequently affected (virtually 100% of patients). Lesions on the upper 702
Erythrodermic sarcoidosis is an extremely rare form of sarcoidosis. A diffuse infiltrative erythroderma of the skin usually begins as erythematous, scaling patches that merge to involve large portions of the body. A biopsy is confirmatory, but the diagnosis can be clinically suspected if small apple jelly papules are seen on diascopy throughout the erythroderma.
Ichthyosiform sarcoidosis Ichthyosiform sarcoidosis resembles ichthyosis vulgaris or acquired ichthyosis, with fine scaling usually on the distal extremities (Fig. 31-12). It is virtually always seen in non-white persons, especially African Americans. Nearly all patients have or will develop systemic disease. In 75% of patients, the skin lesions follow or occur at the same time as the diagnosis of systemic sarcoidosis. Although the lesions have no palpable component, a biopsy will reveal dermal noncaseating granulomas.
Alopecia Alopecia on the scalp due to sarcoidosis can have multiple morphologies. Plaques may extend into and involve the scalp, leading to scarring hair loss (Fig. 31-13). More rarely, macular lesions from one to several centimeters in diameter appear on the scalp and closely resemble alopecia areata. This form may be permanent or reversible. Diffuse alopecia, scaly plaques resembling seborrheic dermatitis, and cicatricial lesions resembling discoid lupus erythematosus or pseudopelade may also occur. A biopsy of all forms of alopecic sarcoid will reveal dermal granulomas and sometimes loss of follicular structures. Scalp sarcoidosis is virtually always seen in African or African American women. In cases where sarcoidosis affects the scalp, causing alopecia, the patient virtually always has other cutaneous lesions and the vast majority of cases will demonstrate systemic involvement.
Morpheaform sarcoidosis Very rarely, specific cutaneous lesions of sarcoidosis may be accompanied by substantial fibrosis and simulate morphea. Less than 10 cases have been described to date. Most typically, the lesions are localized and resemble linear morphea. Skin biopsy will demonstrate noncaseating granulomas. African American women are most commonly affected. This form of sarcoidosis responds favorably to antimalarial therapy.
Sarcoidosis Fig. 31-13 Sarcoidosis, scarring alopecia of the scalp.
Fig. 31-12 Sarcoidosis, ichthyosiform type; biopsy showed noncaseating granuloma, although there was no palpable dermal component to the lesions.
Sarcoidosis in scars (scar sarcoid) Infiltration and elevation of tattoos and old flat scars are two variants of scar sarcoid. Previously flat scars become raised and may become erythematous or violaceous. These lesions may be confused with hypertrophic scars. Infiltration of tattoos may be the first manifestation of sarcoidosis and can be confused with a granulomatous hypersensitivity reaction to the tattoo pigment (Fig. 31-14). Cosmetic tattooing, as may be performed in a dermatology office, may result in sarcoidal granulomas in patients with pulmonary sarcoidosis. Hyaluronic acid injections can also be complicated by the development of sarcoidal lesions in patients with sarcoidosis. As noted below, patients with hepatitis C virus (HCV) infection receiving IFN therapy are at high risk for developing sarcoidosis and can develop disfiguring sarcoidal reactions following cosmetic filler injections. Similar granulomatous reactions may occur in the earlobe following ear piercing, and represent granulomatous dermatitis to metals introduced by the procedure or the earring. Titanium, nickel, cobalt, zinc, gold, and palladium can all be the allergen. From 22 to 77% of biopsies from patients with cutaneous sarcoidosis will contain polarizable foreign material, suggesting that scar sarcoidosis is very common. The foreign material seems to be a nidus that favors the development of sarcoidal granulomas when sarcoidosis develops. Scar sarcoid may sometimes occur in patients with acute disease and erythema nodosum, especially if the lesions are small papules on the knees. It may also occur in patients with chronic sarcoidosis. The presence of polarizable material in a granulomatous
Fig. 31-14 Sarcoidosis, papules and plaques arising in a tattoo.
process does not confirm the diagnosis of “foreign body granuloma,” but rather should result in evaluation of the patient for evidence of systemic sarcoidosis. When foreign material is found, infection must be carefully excluded if no other features of sarcoidosis are found.
Mucosal sarcoidosis The lesions in the mouth are characterized by pinhead-size papules that may be grouped and fused together to form a flat plaque. The hard palate, tongue, buccal mucosa, or posterior pharynx may be involved. They may simulate Fordyce spots. In lupus pernio the nasal mucosa is frequently involved. Rarely, in ulcerative sarcoidosis, the oral mucosa may be involved. Sarcoidosis may also infiltrate the gingiva, causing “strawberry gums” that simulate Wegener’s granulomatosis.
Systemic sarcoidosis Sarcoidosis may involve virtually every internal organ and its presentations are protean. Many instances of sarcoidosis are asymptomatic and it is only when routine radiographs of the chest reveal some abnormality that sarcoidosis is suspected. Fever may be the only symptom of the disease or be accompanied by weight loss, fatigue, and malaise. Intrathoracic lesions, including parenchymal lung lesions and hilar adenopathy, are the most common manifestation of 703
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the disease, occurring in 90% of cases of sarcoidosis. Pulmonary changes are staged as follows: Stage 0: normal Stage I: bilateral hilar and/or paratracheal adenopathy Stage II: adenopathy with pulmonary infiltrates Stage III: pulmonary infiltrates only Stage IV: pulmonary fibrosis. Transbronchial lung biopsy and needle aspiration have a high yield in confirming the diagnosis of sarcoidosis, even in patients with only stage I changes on chest x-ray. Gallium-67 scanning is useful in the diagnosis of sarcoidosis since typical patterns of uptake are seen. The panda sign correlates with gallium uptake in the nasopharynx and lacrimal and parotid glands; the lambda sign correlates with uptake in the paratracheal lymph nodes. These characteristic findings, plus a skin biopsy demonstrating typical sarcoidal granulomas, can be used as presumptive evidence for sarcoidosis. Lymphadenopathy, especially of the mediastinal and hilar nodes, and generalized adenopathy, or adenopathy confined to the cervical or axillary areas, may be an initial sign of sarcoidosis or may occur during the course of the disease. Polyarthralgias may be seen with acute sarcoidosis or as a component of chronic disease. Chronic arthritis may occur (Fig. 31-15). Osseous involvement is often present in chronic disease. The most characteristic changes are found radiographically in the bones of the hands and feet, particularly in the phalanges. They consist of round, punched-out, lytic, cystic lesions. These are seen frequently in patients with lupus pernio. The bone lesions represent epithelioid granulomas. Ocular involvement is present in 30–50% of patients, with granulomatous uveitis the most characteristic lesion. The lacrimal gland may be involved unilaterally or bilaterally by painless nodular swellings. Lesions of the iris are nodular and painless. There may also be lesions of the retina, choroid, sclera, and optic nerve. Ophthalmic disease is highly correlated with systemic involvement. All patients, even those who have no ocular symptoms, should be seen by an ophthalmologist. Sarcoidal involvement of the eye can progress to blind-
ness. Conjunctival biopsy is positive in about 50% of patients with sarcoidosis, making it an easy site to sample and confirm the diagnosis. Parotid gland and lacrimal gland enlargement with uveitis and fever may occur in sarcoidosis; this is known as uveo parotid fever or Heerfordt syndrome, and usually lasts 2–6 months if not treated. Facial nerve palsy and CNS disease are frequently seen in this syndrome. Mikulicz syndrome is bilateral sarcoidosis of the parotid, submandibular, sublingual, and lacrimal glands. Clinically apparent hepatic involvement occurs in about 20% of patients; however, a blind liver biopsy will reveal granulomas in 60% of cases. Hepatomegaly with elevation of serum alkaline phosphatase, biliary cirrhosis with hypercholesterol emia, and portal hypertension with esophageal varices are some of the manifestations. Liver biopsy showing hepatic granulomas is an excellent means of confirming the diagnosis of sarcoidosis. Renal disease may be due to direct involvement with granulomas or secondary to hypercalcemia. Hypercalcemia is due to the macrophage in the granulomas having large amounts of 25-hydroxyvitamin D-1α-hydroxylase, which converts 25-hydroxyvitamin D to the more active 1,25 dihydroxyvitamin D. Nephrolithiasis may result. Cardiac involvement occurs in 5% of cases, but in a higher percentage of autopsy cases. Neurosarcoidosis occurs in 5–10% of patients. It can present in numerous ways, from focal cranial nerve involvement (most commonly facial nerve palsy) to aseptic meningitis, seizures, psychiatric changes, stroke, and space-occupying lesions. Neurosarcoidosis tends to be chronic and relapsing, with a higher mortality rate. Vision loss in sarcoidosis after heat exposure is called the Uhthoff phenomenon. Magnetic resonance imaging (MRI) with gadolinium is useful for detecting CNS lesions of sarcoidosis and following therapy. Treatment is recommended with corticosteroids and an immunosuppressive agent until all MRI-visible lesions are eradicated. Measuring ACE levels in sarcoidosis patients has little utility. ACE levels may be elevated in all granulomatous diseases, including infectious granulomatous disorders. An elevated ACE level is suggestive of, but not diagnostic for granulomatous inflammation. A normal ACE level cannot be used to rule out sarcoidosis and an elevated level does not necessarily indicate the presence of multisystem involvement. The use of 18FDG positron emission tomography (PET) is more accurate in identifying extent of involvement and monitoring response to treatment.
Pediatric sarcoidosis
Fig. 31-15 Sarcoidosis, fusiform swelling of the digits.
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Childhood sarcoidosis is rare. The clinical features are very age-dependent. In children under 4 years, the triad of skin, joint, and eye involvement is characteristic, and often confused with juvenile rheumatoid arthritis. In older children, lung, lymph node, and eye involvement is typical. Calcium abnormalities are present in 30% of children with sarcoidosis. Older children develop specific sarcoidal skin lesions at the same rate as adults, about 30% of the time. One presentation resembles granulomatous peri-orificial dermatitis. Blau syndrome is due to mutations in the NOD2 gene and is associated with early-onset sarcoidosis (age 20 mm) types. The small-type lesions are more numerous than the large type. However, often one patient will have both types of lesion, and the proposed increased risk for ocular involvement in the 707
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Papular xanthomas, diffuse normolipemic plane xanthomas
Monomorphous and generalized
Generalized eruptive histiocytoma Benign cephalic histiocytosis and mononuclear xanthogranuloma
Monomorphous and localized
Fig. 31-16 Schematic drawing of unifying concept of non-X histiocytoses.
Xanthelasma, papular and verruciform xanthoma
Polymorphous
xanthomatized
vacuolated
Scalloped Xanthoma cell xantho- disseminatum granuloma
Xanthogranulomas
- juvenile - adult scalloped
spindleshaped Spindle cell xanthogranuloma
oncocytic Reticulohistiocytoma
Progressive nodular histiocytosis
Multicentric reticulohistiocytosis
Fig. 31-18 Juvenile xanthogranuloma, multiple small papules.
Fig. 31-17 Juvenile xanthogranuloma, solitary.
micronodular type and other internal involvement in the macronodular type has been refuted. Skin lesions regress spontaneously within 3–6 years in children. In adults, lesions are usually persistent. Hyperpigmentation, atrophy, or anetoderma may remain after lesions resolve. Multiple atypical presentations have been described. These include hyperkeratotic nodules; macronodular tumors from 2 to 10 cm in diameter; clustered (agminated) forms; linear lesions; flat, plaque-like lesions; and pedunculated or cylindrical exophytic lesions. Atypical sites of involvement include the genitalia, lips, palms, soles, earlobes, and fingers. The most common location for JXGs after the dermis is the subcutaneous tissue, again most commonly on the head and neck. About 15% of JXGs present in this manner, usually as a solitary 708
Fig. 31-19 Juvenile xanthogranuloma, multiple nodules.
nuclear cells with abundant amphophilic cytoplasm that is poorly lipidized or vacuolated. Later, the cells become more vacuolated and multinucleated forms appear. In mature lesions, foam cells, multinucleated foam cells (Touton giant cells), and foreign-body giant cells are present. Touton giant cells are characteristic of JXG but not specific for it. The inflammatory infiltrate consists of lymphocytes, eosinophils, and neutrophils, and lacks plasma cells. Fibrosis occurs in the older lesions. The histology described above is characteristic of cutaneous JXGs. Soft-tissue and visceral JXGs present with more monomorphous cytology, may have very few of the characteristic Touton giant cells, and can have a prominent spindle cell appearance. Immunohistochemistry is especially valuable in confirming the diagnosis of extracutaneous JXG. The cells of JXG of all anatomic locations stain with factor XIIIa, vimentin, fascin, MS-1, and CD68, not with CD1, S-100, or other specific markers for Langerhans cells. The treatment for most cases of JXG is observation. By age 6 most lesions have resolved, often leaving normal or only slightly hyperpigmented skin. In adults spontaneous involution is slower, and local removal with surgery or CO2 laser could be considered. It is noteworthy that the patterns of involvement by JXG and LCH are similar, with childhood onset and primary cutaneous involvement; when visceral disease occurs, the liver, bone, and lungs are commonly involved. Without histologic confirmation, isolated JXG of the bone would be most likely diagnosed as isolated LCH, a much more common condition. These clinical similarities between JXG and LCH may be explained by the fact that both diseases are caused by antigen-presenting dendritic cells. JXG is a proliferation of dermal dendrocytes and LCH is a proliferation of Langerhans cells. The clinical features favoring JXG include lack of crusting or scale and the distribution and uniformity of size of lesions. Histologic evaluation is definitive in difficult cases, since JXGs are negative for the Langerhans cell marker CD1. Unlike LCH, JXGs are usually negative for S-100, although a few S-100-positive JXGs have been reported. Benign cephalic histiocytosis (BCH) may be difficult to distinguish both clinically and histologically, but in BCH lesions tend to be flatter and are mainly on the head and neck. Papular xanthoma can be distinguished histologically. Clinically, mastocytosis will urticate when scratched (Darier’s sign) and can be distinguished histologically. Solitary JXG appearing in a child must be distinguished from a Spitz nevus, usually requiring a biopsy.
Histiocytoses
mobile mass up to 3 cm in diameter. Subcutaneous JXG most commonly appears before age 1 and often before age 3 months. Oral JXG may develop in infancy or childhood, and is most frequently a solitary lesion of the tongue, lip, or palate. Extracutaneous JXG is uncommon and occurs as visceral involvement, in association with either multiple cutaneous lesions or a solitary extracutaneous lesion. Visceral disease of both types accounts for only 4% of childhood JXGs, and for 5–10% of all JXG cases. Ocular involvement occurs in about 0.3–0.4% of children with multiple JXGs, and 41% of children with ocular JXGs have skin lesions. Skin lesions appear after eye lesions in 45% of cases. In 92% of cases, eye lesions occur during the first 2 years of life. The most common location is the iris, where JXG can present as a tumor, unilateral glaucoma, unilateral uveitis with spontaneous hyphema, or as heterochromia iridis. The eyelid or posterior eye may also be involved. Ocular screening is recommended for all children with multiple cutaneous lesions before the age of 2 years. Mass lesions of the nasal, orbital, and paranasal sinus region can occur and can cause erosion of the orbit and extend to the skull. Other extracutaneous sites and their presentations, in order of frequency, include the lung (respiratory distress and nodular opacities on chest radiograph), liver (hepatomegaly and, rarely, fatal giant cell hepatitis), testis (mass), and rarely, the CNS, kidney, spleen, and retroperitoneum. Other evaluations for extracutaneous JXGs are not indicated unless there are symptoms or findings suggesting their presence. Extracutaneous lesions also spontaneously regress. If surgical intervention is required, extracutaneous lesions tend not to recur, even if they are incompletely excised. Rarely, the burden of visceral JXGs may be so great that the patient’s life is threatened. These cases have been called “disseminated JXG,” “systemic JXG,” or “systemic xanthogranuloma.” In 25% of these cases, no skin lesions are found. Progressive CNS, liver, or bone marrow involvement usually mandates aggressive therapy. These cases may simulate hemophagocytic lymphohistiocytosis syndrome. Locally aggressive tumors may be radiated. Systemic steroids, chemotherapy, and even liver or bone marrow transplantation may be required. Even more rarely, a visceral lesion may behave malignantly, spreading to previously unaffected organs and killing the patient. JXGs have been reported in association with neurofibromatosis (NF-1) and juvenile myelomonocytic leukemia (JMML). Patients with NF-1 and JXG are 20–32 times more likely to develop JMML. JMML and NF-1 are known to be linked, but since JMML occurs in infancy or early childhood, often caféau-lait macules are the only findings of NF-1 at the time. Sometimes all three conditions affect the same patient, with males having a 3 : 1 predominance and commonly a maternal history of NF-1. Children with JXG should be examined for stigmata of NF-1. If these stigmata are found, especially in a boy with a maternal history of NF-1, the pediatrician should be alert to the possible, although uncommon, occurrence of JMML. Rarely, JXG in childhood may be associated with mastocytosis or childhood acute lymphoblastic leukemia. Multiple xanthogranulomas are rare in adults and it is quite unusual for them to occur in an eruptive manner. At least six cases have been associated with hematologic malignancy (chronic lymphocytic leukemia, essential thrombocytosis, large B-cell lymphoma, adult T-cell lymphoma/leukemia, and monoclonal gammopathy). Lesions appear histologically as nonencapsulated but circumscribed proliferations in the upper and mid-reticular dermis, and may extend more deeply into the subcutaneous tissue or abut directly on the epidermis with no Grenz zone. Epidermotropism does not occur. Classically, it has been proposed that the histopathology varies in accordance with the age of the lesion. Very early lesions are composed of mono
Aparicio G, et al: Eruptive juvenile xanthogranuloma associated with relapsing acute lymphoblastic leukemia. Pediatr Dermatol 2008; 25:487. Bowling JC, et al: Solitary anogenital xanthogranuloma. Clin Exp Dermatol 2005; 30:716. Bradford RK, Choudhary AK: Imaging findings of juvenile xanthogranuloma of the penis. Pediatr Radiol 2009; 39:176. Chantorn R, et al: Severe congenital systemic juvenile xanthogranuloma in monozygotic twins. Pediatr Dermatol 2008; 25:470. Chantranuwat C: Systemic form of juvenile xanthogranuloma: a report of a case with liver and bone involvement. Pediatr Dev Pathol 2004; 7:646. Clayton TH, et al: Congenital plaque on the chest. Diagnosis: solitary giant congenital juvenile xanthogranuloma. Clin Exp Dermatol 2007; 32:613. Dehner LP: Juvenile xanthogranulomas in the first two decades of life: a clinicopathologic study of 174 cases with cutaneous and extracutaneous manifestations. Am J Surg Pathol 2003; 27:579. Dincaslan HU, et al: An infant with giant juvenile xanthogranuloma presenting as an axillary mass. Pediatr Blood Cancer 2008; 51:713. Dolken R, et al: Treatment of severe disseminated juvenile systemic xanthogranuloma with multiple lesions in the central nervous system. J Pediatr Hematol Oncol 2006; 28:95. Gamo R, et al: Anetoderma developing in juvenile xanthogranuloma. Int J Dermatol 2005; 44:503.
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Gunson TH, Birchall NM: Symmetrical giant facial plaque-type juvenile xanthogranuloma. J Am Acad Dermatol 2008; 59:S56. Hara T, et al: Prolonged severe pancytopenia preceding the cutaneous lesions of juvenile xanthogranuloma. Pediatr Blood Cancer 2006; 47:103. Haughton AM, et al: Disseminated juvenile xanthogranulomatosis in a newborn resulting in liver transplantation. J Am Acad Dermatol 2008; 58:S12. Hirata M, et al: A case of adult limbal xanthogranuloma. Jpn J Ophthalmol 2007; 51:302. Hsiao PF, et al: An infant with juvenile xanthogranuloma, multiple café-au-lait macules, acute myeloid leukaemia: an incomplete, rare form of triple association? J Eur Acad Dermatol Venereol 2008; 22:1378. Hu JY, et al: An infant with extensive cutaneous nodular juvenile xanthogranuloma and hyperlipidemia. J Am Acad Dermatol 2007; 56:S54. Hughes DB, et al: Juvenile xanthogranuloma of the finger. Pediatr Dermatol 2006; 23:53. Imiela A, et al: Juvenile xanthogranuloma: a congenital giant form leading to a wide atrophic sequela. Pediatr Dermatol 2004; 21:121. Janssen D, Harms D: Juvenile xanthogranuloma in childhood and adolescence: a clinicopathologic study of 129 patients from the Kiel pediatric tumor registry. Am J Surg Pathol 2005; 29:21. Kaur MR, et al: Disseminated clustered juvenile xanthogranuloma: an unusual morphological variant of a common condition. Clin Exp Dermatol 2008; 33:575. Kim EJ, et al: Juvenile xanthogranuloma of the finger: an unusual localization. J Dermatol 2007; 34:590. Kiopelidou D, et al: Linear-agminated juvenile xanthogranulomas. Int J Dermatol 2008; 47:387. Kirke S, et al: Juvenile xanthogranuloma associated with contralateral lymphadenopathy. Pediatr Dermatol 2005; 22:424. Klemke CD, et al: Multiple juvenile xanthogranulomas successfully treated with CO laser. J Dtsch Dermatol Ges 2007; 5:30. Kolivras A, et al: Congenital disseminated juvenile xanthogranuloma with unusual skin presentation and renal involvement. J Cutan Pathol 2009; 36:684. Liang S, et al: Juvenile xanthogranuloma with ocular involvement. Pediatr Dermatol 2009; 26:232. Matcham NJ, et al: Systemic juvenile xanthogranulomatosis imitating a malignant abdominal wall tumor with lung metastases. J Pediatr Hematol Oncol 2007; 29:72. Mocan MC, et al: Juvenile xanthogranuloma of the corneal limbus: report of two cases and review of the literature. Cornea 2008; 27:739. Motegi S, et al: An unusual presentation of juvenile xanthogranuloma. Pediatr Dermatol 2007; 24:576. Mowbray M, Schofield OM: Juvenile xanthogranuloma en plaque. Pediatr Dermatol 2007; 24:670. Nishi T, et al: A case of juvenile limbal xanthogranuloma. Jpn J Ophthalmol 2007; 51:301. Orsey A, et al: Central nervous system juvenile xanthogranuloma with malignant transformation. Pediatr Blood Cancer 2008; 50:927. Rajendra B, et al: Successful treatment of central nervous system juvenile xanthogranulomatosis with cladribine. Pediatr Blood Cancer 2009; 52:413. Redbord KP, Sheth AP: Multiple juvenile xanthogranulomas in a 13-year-old. Pediatr Dermatol 2007; 24:238. Rubegni P, et al: Juvenile xanthogranuloma: dermoscopic pattern. Dermatology 2009; 218:380. Savasan S, et al: Successful bone marrow transplantation for lifethreatening xanthogranuloma disseminatum in neurofibromatosis type-1. Pediatr Transplant 2005; 9:534. Shoo BA, et al: Xanthogranulomas associated with hematologic malignancy in adulthood. J Am Acad Dermatol 2008; 59:488. Sidwell RU, et al: Is disseminated juvenile xanthogranulomatosis benign cephalic histiocytosis? Pediatr Dermatol 2005; 22:40. Stover DG, et al: Treatment of juvenile xanthogranuloma. Pediatr Blood Cancer 2008; 51:130. Torrelo A, et al: Multiple lichenoid juvenile xanthogranuloma. Pediatr Dermatol 2009; 26:238. Tsutsui K, et al: Urticaria pigmentosa occurring with juvenile xanthogranuloma. Br J Dermatol 1999; 140:990. Unuvar E, et al: Successful therapy of systemic xanthogranuloma in a child. J Pediatr Hematol Oncol 2007; 29:425.
Vendal Z, et al: Glaucoma in juvenile xanthogranuloma. Semin Ophthalmol 2006; 21:191.
Benign cephalic histiocytosis BCH is a rare condition affecting boys and girls of all races equally. The onset is between 2 and 34 months of age (rarely up to 5 years), with 50% of cases beginning between ages 5 and 12 months. The disease begins initially on the head in virtually all cases, often the cheeks, eyelids, forehead, and ears. Lesions may later appear on the neck and upper trunk, and less commonly more caudad. There are always multiple lesions, but often few in number (5–20), although they can number more than 100. Individual lesions are slightly raised, reddish-yellow papules, 2–4 mm in diameter. Lesions may coalesce to give a reticulate appearance. The lesions cause no symptoms. The mucosa and viscera are not involved. Lesions spontaneously involute over 2–8 years, leaving behind hyperpigmented macules. Some cases of BCH have evolved to become JXGs, and one patient later developed generalized eruptive histiocytoma many years after the involution of BCH. This supports the concept outlined above that these conditions lie along a spectrum and all derive from the same cell type, a dermal dendritic cell. Histologically, there is a diffuse dermal infiltration of monomorphous macrophages, which stain positively for CD68 and factor XIIIa and negatively with S-100 and CD1a. Dadzie O, et al: Benign cephalic histiocytosis in a British-African child. Pediatr Dermatol 2005; 22:444. Hasegawa S, et al: Japanese case of benign cephalic histiocytosis. J Dermatol 2009; 36:69. Jih DM, et al: Benign cephalic histiocytosis: a case report and review. J Am Acad Dermatol 2002; 47:908.
Generalized eruptive histiocytoma (generalized eruptive histiocytosis) Generalized eruptive histiocytosis (GEH) is a rare disease, usually presenting in young adulthood. The diagnostic criteria are: 1. widespread, erythematous, essentially symmetrical papules, particularly involving the trunk and proximal extremities, sparing the flexors, and rarely involving the mucous membranes (there is no visceral involvement) 2. progressive development of new lesions, often in crops, over several years with eventual spontaneous involution to hyperpigmented macules 3. a benign histologic picture of monomorphous, vacuolated macrophages. Lesions appear in crops, and may be grouped or clustered. (Since Winkelmann’s initial report of this entity, several cases with grouped lesions have been reported, so finding grouped lesions does not exclude the diagnosis of GEH.) They are skincolored, brown, or violaceous. GEH is rare in childhood. It may be difficult to distinguish from widespread BCH in childhood, if indeed it is a separate condition. In adults and children, GEH may suddenly appear several weeks following a bacterial or viral illness; in adults it may be associated with underlying malignancy, usually leukemia or lymphoma. GEH is distinguished from xanthoma disseminatum by the lack of visceral disease, the benign course, and by the scalloped appearance of the macrophages in xanthoma disseminatum. Histologically, there is a dermal infiltrate of monomorphous vacuolated macrophages and mononuclear histiocytes. The GEH cells stain positively for vimentin, CD68, and usually factor XIIIa, and negatively for S-100, and CD1a. The natural history of GEH is unpredictable, with complete resolution in some cases and persistence in others. Some cases have progressed to widespread xanthogranulomas, xanthoma
Deng YJ, et al: Generalized eruptive histiocytosis: a possible therapeutic cure? Br J Dermatol 2004; 150:155. Fernandez-Jorge B, et al: A case of generalized eruptive histiocytosis. Acta Derm Venereol 2007; 87:533. Klemke C, et al: Atypical generalized eruptive histiocytosis associated with acute monocytic leukemia. J Am Acad Dermatol 2003; 49:233. Lan Ma H, et al: Successful treatment of generalized eruptive histiocytoma with PUVA. J Dtsch Dermatol Ges 2007; 5:131. Misery L, et al: Generalized eruptive histiocytoma in an infant with healing in summer: long-term follow-up. Br J Dermatol 2001; 144:435. Seward JL, et al: Generalized eruptive histiocytosis. J Am Acad Dermatol 2004; 50:116. Tamiya H, et al: Generalized eruptive histiocytoma with rapid progression and resolution following exanthema subitum. Clin Exp Dermatol 2005; 30:300.
Xanthoma disseminatum (Montgomery syndrome) Xanthoma disseminatum (XD) is a very rare, potentially progressive non-LCH that preferentially affects males in childhood or young adulthood. It is characterized by the insidious onset of small, yellowish-red to brown papules and nodules that are discrete and disseminated. They characteristically involve the eyelids and flexural areas of the axillary and inguinal folds, and the antecubital and popliteal fossae. Over years the lesions increase in number, forming coalescent xanthomatous plaques and nodules. About 30–50% of cases have mucous membrane involvement, most commonly of the oropharynx (causing dysphagia), larynx (causing dysphonia and airway obstruction), and conjunctiva and cornea (causing blindness). Diabetes insipidus, usually transient, occurs in 40%. CNS involvement, with epilepsy, hydrocephalus, and ataxia, can occur. Synovitis and osteolytic bone lesions have been described. In some cases, the disease may spontaneously involute. The serum lipids are abnormal in 20% of cases, which may lead to confusion with hyperlipidemic xanthomatosis. Histologic examination of early lesions shows surprisingly nonfoamy, scalloped macrophages. Later lesions show xanthoma cells, Touton giant cells, and frequently, a mild inflammatory cell infiltrate of lymphocytes, plasma cells, and neutrophils. The macrophages stain with CD68 and factor XIIIa. Disseminated xanthosiderohistiocytosis is a variant of XD in which there is a keloidal consistency to the lesions; they have annular borders, a cephalad distribution, and extensive iron and lipid deposition in the macrophages and connective tissue. Progressive XD can produce considerable morbidity and can even be fatal. Therefore, aggressive therapy may be indicated. Systemic steroids have led to improvement in one case. In a patient with XD and dyslipidemia, the combination of rosiglitazone, simvastatin, and acipimox led to partial remission and stabilization of mucosal and osseous disease. Cyclophosphamide has led to dramatic improvement in two of three patients so treated. Eisendle K, et al: Inflammation and lipid accumulation in xanthoma disseminatum: therapeutic considerations. J Am Acad Dermatol 2008; 58:S47. Goodenberger ME, et al: Xanthoma disseminatum and Waldenstrom’s macroglobulinemia. J Am Acad Dermatol 1990; 23:1015. Heald P, et al: Xanthoma disseminatum. N Engl J Med 1998; 338:1138. Seaton ED, et al: Treatment of xanthoma disseminatum with cyclophosphamide. Br J Dermatol 2004; 150:346. Yusuf SM, et al: Xanthoma disseminatum in a black African woman. Int J Dermatol 2008; 47:1145.
Progressive nodular histiocytosis Progressive nodular histiocytosis (PNH) is a very rare disorder that affects men and women equally and usually begins between the ages of 40 and 60 years. The characteristic clinical feature is the development of two types of lesion: superficial papules and deeper, larger, subcutaneous nodules. The superficial lesions are small xanthomatous papules up to 5 mm in diameter. They are diffusely distributed on the body, but spare the flexors. The larger deep lesions can be up to 5 cm in diameter and are associated with pain, ulceration, and disfigurement. On the face, lesions may coalesce, giving the patient a leonine facies and creating ectropion. New lesions progressively appear and spontaneous resolution does not occur. Most patients have no mucosal or visceral lesions, although one patient had a hypothalamic lesion leading to precocious puberty and growth hormone deficiency. Histologically, the superficial lesions show foamy macrophages and the deeper lesions a densely cellular proliferation of spindle-shaped histiocytes with multinucleated giant cells. It is the development of these deep lesions composed of primarily spindled histiocytes that is the diagnostic feature of PNH. Local excision may be used for symptomatic lesions.
Histiocytoses
disseminatum, or progressive nodular histiocytosis, again supporting the concept that these diseases all fall along a spectrum and derive from the same cell type. In childhood, no treatment may be required. In adulthood, treatment with PUVA or isotretinoin could be considered.
Beswick SJ, et al: Progressive nodular histiocytosis in a child with a hypothalamic tumour. Br J Dermatol 2002; 146:138. Gonzalez A, et al: Progressive nodular histiocytosis accompanied by systemic disorders. Br J Dermatol 2000; 143:628. Lufti M, et al: Progressive nodular histiocytosis—rare variant of cutaneous non-Langerhans cell histiocytosis. J Dtsch Dermatol Ges 2006; 4:236. Nogueras SV, et al: An indolent and progressive papulonodular eruption. Int J Dermatol 2009; 48:751. Watanabe T, et al: Progressive nodular histiocytosis—a five-year follow up. Eur J Dermatol 2008; 18:200.
Papular xanthoma Papular xanthoma (PX) is a rare form of non-LCH that is poorly defined. The disease can occur at any age, but usually appears in early childhood or after adolescence. PX usually presents as a solitary lesion favoring men 4 : 1 over women. The primary lesion is a small, yellow papule from 1 to 10 mm in diameter. If there are multiple lesions they are generalized, not grouped, and do not favor the flexors. There is no visceral involvement and no abnormalities are found on lipid profile examination. Histologically, there are aggregates of xanthoma tized foamy macrophages in the dermis, with Touton giant cells. Inflammatory cells are scant or absent. Cells stain positively for markers of monocytes/macrophages such as CD68, but are negative for factor XIIIa. The differential diagnosis includes normolipemic plane xanthomas and normolipemic papuloeruptive xanthomatosis. In infants the natural history is for spontaneous involution. In one adult patient, treatment with doxycycline was effective. Bastida J, et al: Adult disseminated primary papular xanthoma treated with doxycycline. Arch Dermatol 2007; 143:667. Breier F, et al: Papular xanthoma: a clinicopathological study of 10 cases. J Cutan Pathol 2002; 29:200. Chen CG, et al: Primary papular xanthoma of children. Am J Dermatopathol 1997; 19:596. Kim SH, et al: Congenital papular xanthoma. Br J Dermatol 2000; 142:569. Singla A: Normolipemic papular xanthoma with xanthelasma. Dermatol Online J 2006; 12:19.
Erdheim–Chester disease This rare non-LCH is primarily a visceral disorder with cutaneous manifestations. It can begin at any age from childhood to the ninth decade. The characteristic feature is bilateral and symmetrical sclerosis of the metaphyseal and diaphyseal 711
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regions of the long bones. These radiologic findings are considered pathognomonic. Diabetes insipidus from involvement of the pituitary and retroperitoneal fibrosis affecting the kidneys may occur. Despite a normal gross appearance, many internal organs are affected. The course is progressive with infiltration of many visceral organs, followed by fibrosis. This is often fatal, usually from pulmonary fibrosis and cardiac failure. In one series, 60% of patients had died, 36% within 6 months of diagnosis, with a mean survival of less than 3 years. Skin lesions occur in 25% of patients, typically presenting as red–brown or xanthomatous 2–15 mm papules or nodules. Lesions favor the eyelids, axilla, groin, neck, trunk (inframammary areas), and face. As opposed to plane xanthomas and xanthelasmas, the lesions can be elevated or tubelike, resembling sausages or keloids. Dickson BC, et al: Systemic Erdheim–Chester disease. Virchows Arch 2008; 452:221. Taguchi T, et al: Erdheim–Chester disease: report of a case with PCR-based analysis of the expression of osteopontin and surviving in xanthogranulomas following glucocorticoid treatment. Endocr J 2008; 55:217. Vanichaniramol N, et al: Erdheim–Chester disease. Intern Med 2008; 47:1633.
Progressive mucinous histiocytosis in women Progressive mucinous histiocytosis is an autosomal-dominant or X-linked hereditary disorder described only in women. The skin lesions consist of a few to numerous skin-colored to red– brown papules, ranging from pinhead- to pea-sized, which tend to appear on the face, arms, forearms, hands, and legs. Onset is in the second decade of life, with slow progression and no tendency to spontaneous involution. Visceral and mucosal lesions have not been reported. Histologically, in the mid-dermis there is a proliferation of spindle-shaped and epithelioid monocytes. Superficial telangiectatic vessels and increased mast cells are found. Abundant mucin is demonstrated by alcian blue staining, indicating the presence of acid mucopolysaccharides. This condition can be distinguished from the other non-LCHs by its familial pattern, lack of lipidized and multinucleated cells, and presence of mucin. Immunoperoxidase studies have been conflicting, but most consistently show positivity for factor XIIIa and CD68, and negativity for CD1a, S-100, and CD34. Sass U, et al: A sporadic case of progressive mucinous histiocytosis. Br J Dermatol 2000; 142:133. Young A, et al: Two sporadic cases of adult-onset progressive mucinous histiocytosis. J Cutan Pathol 2006; 33:166.
Reticulohistiocytosis Two distinct forms of reticulohistiocytosis occur: reticulohistiocytoma and multicentric reticulohistiocytosis. The two forms have identical histology but distinct clinical manifestations.
Reticulohistiocytoma Reticulohistiocytoma usually occurs as a solitary, firm dermal lesion of less than 1 cm in diameter. Lesions favor the trunk and extremities. Multiple lesions may rarely occur and can be quite extensive and diffuse. Solitary lesions and multiple lesions without systemic involvement, in contrast to multicentric reticulohistiocytosis, have been described, mainly in adult men and rarely in children.
Multicentric reticulohistiocytosis Multicentric reticulohistiocytosis (MRH) is a multisystem disease beginning usually around age 50 (range 6–86). It is twice as common in women as in men and affects all races. The primary manifestations are skin lesions and a potentially 712
Fig. 31-20 Multicentric reticulohistiocytosis.
destructive arthritis. In 40% of cases the joint disease occurs first, in 30% the skin lesions precede the joint symptoms, and in 40% the joint and skin disease appear simultaneously. Clinically, there may be a few to a few hundred firm, skincolored to red–brown papules and nodules, mostly 2–10 mm in diameter, but some reaching several centimeters in size (Fig. 31-20). These occur most frequently on the fingers and hands, with a tendency to cause paronychial lesions. In about half the cases, lesions will be arranged about nailfolds, giving a so-called “coral bead” appearance, which may be associated with nail dystrophy. The upper half of the body, including the arms, scalp, face, ears, and neck, are also common sites. Ninety percent of patients have lesions on the face and hands. Nodular and papular involvement of the pinnae and a symmetrical distribution of the lesions, especially over joints, are characteristic. The nodules on the arms, elbows, and knees may resemble rheumatoid nodules. Diffuse erythematous lesions can occur, at times simulating erythroderma. Lesions may ulcerate. Xanthelasma occurs in 30% of patients. Atypical patchy areas of hypopigmentation over the face and upper limbs have been noted. About 10% of MRH patients may complain of pruritus. The itching is not localized to the lesions and may precede the appearance of the skin lesions. Mucous membrane involvement is seen in one-third of cases and is most common on the lips and tongue; other sites are the gingiva, palate, buccal mucosa, nasopharynx, larynx, and sclera. Lesions of the esophagus can lead to dysphagia. Onethird of cases have hypercholesterolemia and xanthelasma. Rheumatoid factor is usually negative. Osteoarticular changes are the most important aspect of MRH. There is no association between the extent, size, or severity of the skin eruption and the course of the joint disease. The associated arthropathy is an inflammatory, symmetrical, polyarticular arthritis that can affect many joints, including the hands, knees, shoulders, wrists, hips, ankles, elbows, feet, and spine. The arthritis can be rapidly destructive and mutilating, with absorption and telescopic shortening of the phalanges and digits—doigts en lorgnette (opera-glass fingers). In older reports at least 50% of cases developed arthritis mutilans, but this has been reduced to about 11%. The infiltrating cells in the skin and joints are identical on microscopic examination and immunophenotypic evaluation. The clinical course varies. In many instances there is complete involution after about 8 years. The joint destruction is permanent, however, and is a cause of severe disability. The joint involvement may resemble
bisphosphonate, or a TNF inhibitor could be considered if symptoms are severe. Baghestani S, et al: Multicentric reticulohistiocytosis presenting with papulonodular skin eruption and polyarthritis. Eur J Dermatol 2005; 15:196. Bogle MA, et al: Multicentric reticulohistiocytosis with pulmonary involvement. J Am Acad Dermatol 2003; 49:1125. Chen CH, et al: Multicentric reticulohistiocytosis presenting with destructive polyarthritis, laryngopharyngeal dysfunction, and a huge reticulohistiocytoma. J Clin Rheumatol 2006; 12:252. Codriansky KA, et al: Multicentric reticulohistiocytosis: a systemic osteoclastic disease? Arthritis Rheum 2008; 59:444. Gajic-Veljic M, et al: Multicentric reticulohistiocytosis—a case with minimal articular changes. J Eur Acad Dermatol Venereol 2006; 20:108. Goto H, et al: Successful treatment of multicentric reticulohistiocytosis with alendronate. Arthritis Rheum 2003; 48:3538. Ho SG, Yu RC: A case of multicentric reticulohistiocytosis with multiple lytic skull lesions. Clin Exp Dermatol 2005; 30:515. Hsiung SH, et al: Multicentric reticulohistiocytosis presenting with clinical features of dermatomyositis. J Am Acad Dermatol 2003; 48:S11. Hsu S, et al: Multicentric reticulohistiocytosis with neurofibroma-like nodules. J Am Acad Dermatol 2001; 44:373. Kalajian AH, Callen JP: Multicentric reticulohistiocytosis successfully treated with infliximab: an illustrative case and evaluation of cytokine expression supporting anti-tumor necrosis factor therapy. Arch Dermatol 2008; 144:1350. Kishikawa T, et al: Multicentric reticulohistiocytosis associated with ovarian cancer. Mod Rheumatol 2007; 17:422. Liu YU, Fang K: Multicentric reticulohistiocytosis with generalized systemic involvement. Clin Exp Dermatol 2004; 29:373. Lovelace K, et al: Etanercept and the treatment of multicentric reticulohistiocytosis. Arch Dermatol 2005; 141:1167. Luz FB, et al: Multicentric reticulohistiocytosis: a proliferation of macrophages with tropism for skin and joints, part I. Skinmed 2007; 6:172. Mavragani CP, et al: Alleviation of polyarticular syndrome in multicentric reticulohistiocytosis with intravenous zoledronate. Ann Rheum Dis 2005; 64:1521. McIlwain KL, et al: Multicentric reticulohistiocytosis with prominent cutaneous lesions and proximal muscle weakness masquerading as dermatomyositis. J Rheumatol 2005; 32:193. Miettinen M, Fetsch JF: Reticulohistiocytoma (solitary epithelioid histiocytoma): a clinicopathologic and immunohistochemical study of 44 cases. Am J Surg Pathol 2006; 30:521. Millar A, et al: Multicentric reticulohistiocytosis: a lesson in screening for malignancy. Rheumatology (Oxford) 2008; 47:1102. Morris-Jones R, et al: Multicentric reticulohistiocytosis associated with Sjögren’s syndrome. Br J Dermatol 2000; 143:649. Outland JD, et al: Multicentric reticulohistiocytosis in a 14-year-old girl. Pediatr Dermatol 2002; 19:527. Poochareon VN, et al: Multiple pink papules in the setting of arthritis and fever. Multicentric reticulohistiocytosis (MRH). Arch Dermatol 2008; 144:1383. Rentsch JL, et al: Prolonged response of multicentric reticulohistiocytosis to low dose methotrexate. J Rheumatol 1998; 25:1012. Satoh M, et al: Treatment trial of multicentric reticulohistiocytosis with a combination of prednisolone, methotrexate and alendronate. J Dermatol 2008; 35:168. Shannon SE, et al: Multicentric reticulohistiocytosis responding to tumor necrosis factor-alpha inhibition in a renal transplant patient. J Rheumatol 2005; 32:565. Simpson EM, et al: Multicentric reticulohistiocytosis: diagnosis at the nailbeds. J Rheumatol 2008; 35:2272. Webb-Detiege T, et al: Infiltration of histiocytes and multinucleated giant cells in the myocardium of a patient with multicentric reticulohistiocytosis. J Clin Rheumatol 2009; 15:25. Yang HJ, et al: Multicentric reticulohistiocytosis with lungs and liver involved. Clin Exp Dermatol 2009; 34:183.
Histiocytoses
rheumatoid arthritis and psoriatic arthritis. Weight loss and fever occur in one-third of patients. About 15% of patients with MRH have associated auto immune disorders. Thyroiditis, Sjögren’s, ulcerative colitis, and vitiligo have all been reported. At least six patients have been described with myopathy closely simulating dermatomyositis. About 25% of reported cases have had an associated malignancy. Given this high rate of malignancy, every patient with MRH should have a complete age-appropriate cancer screening, repeated at regular intervals (similar to the protocol followed for patients with dermatomyositis). No specific tumor type has been associated. There are reports involving breast, colon, cervix, stomach, melanoma, and ovary, as well as leukemia and lymphoma. The skin lesions usually appear before the diagnosis of the malignancy, but synchronous behavior of the skin lesions and the underlying malignancy is only occasionally reported. In one case, tuberculosis was identified, and treatment of the tuberculosis led to resolution of the MRH. Other organs and tissues may be involved, such as bone, muscle, lymph nodes, liver, myocardium, pericardium, lungs, pleura, and stomach. Myocardial involvement may be fatal. Gallium is a method to screen for extent of disease. Histologically, the skin lesions are usually centered in the mid-dermis and tend to occupy much or all of the dermis. The infiltrating cells are mononuclear and multinucleate monocyte/ macrophages. The giant cells are most characteristic, with an abundant smooth or slightly granular, eosinophilic or amphophilic, “ground-glass” cytoplasm. Their cytoplasm is darker in the center than at the periphery. These cells stain positive for periodic-acid Schiff (PAS) after diastase digestion. The overlying epidermis may be thinned but is usually separated from the dermal process by a narrow zone of collagen (Grenz zone). Characteristically, there is a polymorphous infiltrate of lymphocytes, neutrophils, eosinophils, and plasma cells within the lesions. By immunohistochemistry the monocyte/macrophage cells stain positively for CD68, vimentin, and CD163. In MRH the cells in the skin and joints stain positively for acid phosphatase that is tartrate-resistant (TRAP) and cathepsin K, markers for osteoclasts. This may explain the response of MRH to bisphosphonates, which cause apoptosis of osteoclasts and are taken up by cells in the reticuloendothelial system. Given the aggressive nature of the arthritis, early and adequate treatment should be considered. However, associated malignancy is frequent and can be worsened by immunosuppressive therapy. The same would be true if there were underlying asymptomatic tuberculosis. Initially, the patient should be screened for these two conditions and they should be adequately treated if found. In patients free of neoplasia and tuberculosis, the treatment is individualized. Spontaneous remissions are common, making efficacy of treatment hard to determine. The major goal of treatment is to prevent the destruction of the joints that are the cause of disability. If systemic therapy is considered, two approaches can be taken. One is the use of the combination of systemic steroids, methotrexate, and a TNF inhibitor. In the case of TNF inhibitors, infliximab has proven more effective than etanercept and should probably be the initial agent used. The other approach is to use a combination of immunosuppressives and a bisphosphonate. Since the infiltrating cells in MRH seem phenotypically to be osteoclastic in behavior, this therapy is logical and appears to be joint-sparing. In refractory cases, the use of a bisphosphonate and TNF inhibitor with methotrexate and systemic steroids could be considered. For patients with skin lesions only, therapy is not required. PUVA, antimalarials, topical nitrogen mustard, and low-dose methotrexate, a
Indeterminate cell histiocytosis Indeterminate cells are felt to represent dermal precursors of Langerhans cells. They are positive for S-100 and CD1a but do 713
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not contain Birbeck granules. Indeterminate cell histiocytosis (ICH) is the term used to describe disorders that are composed of cells that immunophenotypically stain as Langerhans cells but lack Birbeck granules. Since electron microscopy is rarely employed, it is difficult to use this criterion to establish the diagnosis of a disorder. Langerin immunostaining might be substituted. ICH cases are quite rare, and there is little homogeneity among the reports to reassure one that all these cases actually describe a single disease. In addition, S-100 staining is variable in the various non-Langerhans cell histiocytoses (NLCH), making S-100 positivity a soft criterion to use. In addition, reactive conditions are associated with tissue infiltration by S-100-positive cells. Indeterminate cells may be found as a minor component of the dermal infiltrate in nodular scabies and rarely following pityriasis rosea. Some authors favor classifying ICH as a generalized eruptive histiocytosis. This being said, it appears that both children and adults are affected by ICH, with males outnumbering females. Solitary and multiple lesions may occur, and the color of lesions varies from yellow to red–brown. Lesions may be papules, plaques, or nodules from 3 mm to 10 cm in size. These clinical features are not specific, and resemble the papular lesions seen in many forms of NLCH. Conjunctival involvement has been reported. Solitary malignant tumors with similar immunohistochemistry have been described, clinically resembling atypical fibro xanthoma. Histologically, while the cells in these cases do stain with S-100 and at times with CD1a, the staining is never as intense as in Langerhans cells. ICH seems to have a benign course in the vast majority of cases, and no therapy is required. Broad-band UVB, PUVA, and total skin electron beam have each been effective in limited number(s) of cases with severe skin involvement. Many cases have been treated with numerous chemotherapeutic agents similar to those used for LCH, including cyclophosphamide, etoposide, vinblastine, systemic corticosteroids, and 2-chlorodeoxyadenosine, but therapeutic response has been equivocal. Acute myelogenous leukemia has followed some of these courses of chemotherapy. Solitary lesions with malignant histology should be managed with surgical excision ensuring adequate margins. The utility of adjunctive therapy and sentinel lymph node sampling is not known. Amo Y, et al: A case of solitary indeterminate cell histiocytosis. J Dermatol 2003; 30:751. Calatayud M, et al: Ocular involvement in a case of systemic indeterminate cell histiocytosis: a case report. Cornea 2001; 20:769. Caputo R, et al: Chemotherapeutic experience in indeterminate cell histiocytosis. Br J Dermatol 2005; 153:206. Ferran M, et al: Acquired mucosal indeterminate cell histiocytoma. Pediatr Dermatol 2007; 24:253. Frater JL, et al: Histiocytic sarcoma with secondary involvement of the skin and expression of CD1a: evidence of indeterminate cell differentiation? J Cutan Pathol 2006; 33:437. Hashimoto K, et al: Post-scabietic nodules: a lymphohistiocytic reaction rich in indeterminate cells. J Dermatol 2000; 27:181. Ishibashi M, et al: Indeterminate cell histiocytosis successfully treated with ultraviolet B phototherapy. Clin Exp Dermatol 2008; 33; 301. Malhomme de la Roche H, et al: Indeterminate cell histiocytosis responding to total skin electron beam therapy. Br J Dermatol 2008; 158:838. Ratzinger G, et al: Indeterminate cell histiocytosis: fact or fiction? J Cutan Pathol 2005; 32:552. Rezk SA, et al: Indeterminate cell tumors: a rare dendritic neoplasm. Am J Surg Pathol 2008; 32:1868. Rodriguez-Jurado R, et al: Indeterminate cell histiocytosis: clinical and pathologic study in a pediatric patient. Arch Pathol Lab Med 2003; 127:748. Rosenberg AS, Morgan MB: Cutaneous indeterminate cell histiocytosis: a new spindle cell variant resembling dendritic cell sarcoma. J Cutan Pathol 2001; 28:531.
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Vener C, et al: Indeterminate cell histiocytosis in association with later occurrence of acute myeloblastic leukaemia. Br J Dermatol 2007; 156:1357. Wollenberg A, et al: Long-lasting “Christmas tree rash” in an adolescent: isotopic response of indeterminate cell histiocytosis in pityriasis rosea? Acta Derm Venereol 2002; 82:288.
Sea-blue histiocytosis Sea-blue histiocytosis may occur as a familial inherited syndrome or as an acquired secondary or systemic infiltrative process. The characteristic and diagnostic cell is a histiocytic cell containing cytoplasmic granules that stain blue–green with Giemsa stain and blue with May–Gruenwald stain. The disorder is characterized by infiltration of these cells into the marrow, spleen, liver, lymph nodes, and lungs, as well as the skin in some cases. Skin lesions include papules or nodules, facial waxy plaques, eyelid swelling, and patchy gray pigmentation of the face and upper trunk. Similar histologic findings have occurred in patients with myelogenous leukemia, light chain deposition disease, adult Niemann–Pick disease (type B), sphingomyelinase deficiency, or mutations in the apolipoprotein E gene, and following the prolonged use of intra venous fat supplementation. The unifying feature in all these conditions is an abnormal lipid metabolism by the infiltrating histiocytes. This condition has been seen in the infiltrate of a case of cutaneous T-cell lymphoma. Bigorgne C, et al: Sea-blue histiocyte syndrome in the bone marrow secondary to total parenteral nutrition. Leukemia Lymphoma 1998; 28:523. Candoni A, et al: Sea-blue histiocytosis secondary to Niemann–Pick disease type B: a case report. Ann Hematol 2001; 80:620. Caputo R, et al: Unusual variants of non-Langerhans cell histiocytosis. J Am Acad Dermatol 2007; 57:1031. Naghashpour M, Cualing H: Splenomegaly with sea-blue histiocytosis, dyslipidemia, and nephropathy in a patient with lecithin-cholesterol acyltransferase deficiency: a clinicopathologic correlation. Metabolism 2009; 58:1459. Newman B, et al: Aggressive histiocytic disorders that can involve the skin. J Am Acad Dermatol 2007; 56:302. Suzuki O, Abe M: Secondary sea-blue histiocytosis derived from Niemann–Pick disease. J Clin Exp Hematop 2007; 47:19.
X-type histiocytoses (Langerhans cell histiocytosis—LCH) This group of disorders is caused by infiltration of the skin, and in some cases other organs, by Langerhans cells. The spectrum of disease is broad, with solitary, usually benign and autoinvoluting lesions at one end, and multicentric, multi organ visceral and skin disease at the other. While not completely worked out, it appears that most cases of LCH demonstrate clonality. In addition, the Langerhans cells in LCH demonstrate telomere shortening. Clonality and telomere shortening are features of preneoplastic conditions and cancer. Histologically, in all cases of LCH in the skin, there is a dense dermal infiltrate of Langerhans cells. This can be superficial and immediately below the epidermis (usually corresponding to small papules or scaly patches clinically), folliculocentric, or deep and diffuse (in papular and nodular lesions). The Langerhans cells are recognized by their abundant, amphophilic cytoplasm and eccentric round or kidney beanshaped nucleus. There is frequently exocytosis of the abnormal cells into the overlying epidermis. If this is extensive, macroscopic vesicles can be seen, and erosion can occur secondarily. The dermal infiltrate is accompanied by many other inflammatory cells, including neutrophils, eosinophils, lymphocytes, and plasma cells. Dermal edema and hemorrhage are characteristically present. In larger and older lesions the infiltrating histiocytic cells become foamy and fibrosis may be present.
Congenital self-healing reticulohistiocytosis (Hashimoto–Pritzker disease) Congenital self-healing reticulohistiocytosis (CSHR) is an autoinvoluting, self-limited form of LCH. It can be considered as one end of the spectrum of LCH, and although cases continue to be described, it is best approached as a variant of LCH, not a separate entity. CSHR is usually present at birth or appears very soon thereafter, although a case in an 8-yearold has been reported. It has been described in two forms: a solitary and a multinodular variant. Solitary or generalized lesions can affect any part of the cutaneous surface. Lesions range from 0.2 to 2.5 cm in diameter (Fig. 31-21). Lesions may grow postnatally. Exceptionally large tumors up to 8 cm in diameter can occur. At presentation the lesions can be papules or nodules, with or without erosion or ulceration. Individual lesions are red, brown, pink, or dusky. Lesions may rarely appear as hemorrhagic bullae. Lesions greater than 1 cm characteristically ulcerate as they resolve. Lesions are asymptomatic and spontaneously involute over 8–24 weeks, leaving atrophic scarring from the ulcerated nodules. Internal involvement is not found. Histologically, the skin lesions are composed of Langerhans cells and no histological features identify this variant of LCH. Because LCH with systemic involvement may present in identical fashion, systemic evaluation is recommended, including a physical examination, complete blood count, liver function tests, and radiological evaluation of the bones. The affected child must be followed regularly because, as in other forms of LCH, late recurrences can occur.
Fig. 31-21 Congenital self-healing reticulohistiocytosis, solitary lesion.
Belhadjali H, et al: Self-healing Langerhans cell histiocytosis (Hashimoto–Pritzker disease): two Tunisian cases. Acta Dermatovenerol Alp Panonica Adriat 2008; 17:188. Inuzuka M, et al: Congenital self-healing reticulohistiocytosis presenting with hemorrhagic bullae. J Am Acad Dermatol 2003; 48:S75. Kapur P, et al: Congenital self-healing reticulohistiocytosis (Hashimoto–Pritzker disease): ten-year experience at Dallas Children’s Medical Center. J Am Acad Dermatol 2007; 56:290. Nakahigashi K, et al: Late-onset self-healing reticulohistiocytosis: pediatric case of Hashimoto–Pritzker type Langerhans cell histiocytosis. J Dermatol 2007; 34:205. Riva B, et al: Two cases of a solitary congenital ulcerated nodule. Pediatr Dermatol 2009; 26:473. Thong HY, et al: An unusual presentation of congenital self-healing reticulohistiocytosis. Br J Dermatol 2003; 149:191. Weidner KR, et al: JAAD Grand Rounds quiz. Necrotic, ulcerated papules on a newborn male. J Am Acad Dermatol 2009; 61:544. Zwerding T, et al: Congenital, single system, single site, Langerhans cell histiocytosis: a new case, observations from the literature, and management considerations. Pediatr Dermatol 2009; 26:121.
Histiocytoses
The histologic features of the Langerhans cells, such as nuclear atypia and mitotic indices, do not predict prognosis and are not reproducible. Histology is not predictive of biological behavior. Immunohistochemistry is useful in confirming the diagnosis. The infiltrating cells in LCH are positive for S-100 and CD1a. Langerin is a protein expressed in the Birbeck granule and stained with CD207. Electron microscopy is rarely required to diagnose LCH due to this panel of Langerhans cell “characteristic” markers.
Langerhans cell histiocytosis (LCH) LCH is a rare disease characterized by proliferation of Langerhans cells in many organs. The rarity of the disease and a lack of understanding of how to manage patients appropriately have inspired the formation of the “Histiocyte Society.” Many patients throughout the world are entered in large standardized treatment protocols (LCH-I to IV). This has led not only to standardized approaches to management, but also to standardized terminology and classification of patients. It is clear that age of onset is an important determinant of the nature of the disease, and childhood and adult forms of LCH are considered separately. It is also quite clear that patients may begin with any pattern of disease and evolve or relapse to another pattern. This is especially true of younger children. Up to 50% of children under the age of 1 year diagnosed with skin-limited LCH progress to have multisystem disease. Repeated evaluation and close follow-up are required.
Childhood LCH In childhood LCH, boys are slightly more commonly affected than girls. The incidence in children is about 2.6 cases per million, with a greater rate in children under 1 year of age (9 cases per million), 5 cases per million in 1–4-year-olds, and about 1 per million in 5–14-year-olds. Neonatal disease occurs in 6% of cases but at times is unrecognized, especially if it were to involve an internal organ asymptomatically but not affect its function. Thus many of the neonatal cases have predominantly cutaneous lesions. Overall, in childhood LCH bone lesions represent about two-thirds of cases and skin disease about one-third. Only 10% of cases have neither skin nor bone involvement. In children under 1 year of age, the skin is involved in three-quarters of cases, with ear and bone being involved in about one-third of cases. Two-thirds of children under 1 year of age have multisystem disease, with half having involvement of liver, lungs, or bone marrow. In children aged 1–4, bone disease is most common, but two-thirds or more have multisystem disease. In children aged 5–14, bone disease is almost always seen, and multisystem disease is seen in less than 20%. Skin lesions About 10% of children have single-organ disease involving only the skin and 50% of children with multisystem LCH have skin involvement, making skin the second most commonly involved organ in childhood LCH. Almost 90% of children less than 1 year old with multisystem LCH have skin lesions. The pattern of skin disease does not predict the presence or extent of systemic disease. The most common form of skin disease in children is that described in Abt–Letterer–Siwe disease. The skin lesions are tiny red, 715
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Fig. 31-22 Langerhans cell histiocytosis, erythematous eruption accentuated in the groin folds.
Fig. 31-24 Langerhans cell histiocytosis, bullous lesions.
Fig. 31-23 Langerhans cell histiocytosis, seborrheic dermatitis-like eruption with hemorrhage.
Fig. 31-25 Langerhans cell histiocytosis, xanthomatous nodule in a patient with diabetes insipidus.
red–brown, or yellow papules that are widespread but favor the intertriginous areas, behind the ears, and the scalp (Figs 31-22 and 31-23). There is a superficial resemblance to seborrheic dermatitis, but on careful inspection the lesions are individual papules and there is focal hemorrhage in the lesions. The papules are often folliculocentric. Lesions may erode or weep. In children this pattern is frequently associated with multisystem disease. A rare variant of this pattern of LCH is one in which vesicles appear (Fig. 31-24), usually in infants. The vesicles rupture easily, resulting in widespread erosions. This presentation may be confused with other bullous diseases, especially congenital candidiasis, herpes virus infections, bullous impetigo, bullous mastocytosis, primary immunobullous diseases, and epidermolysis bullosa. The vesicles are due to large intraepidermal collections of Langerhans cells, and a Tzanck smear may lead to suspicion of the diagnosis. A less common presentation is with slightly larger papules up to 1 cm in diameter. These lesions tend to be yellow–red and resemble xanthomas or xanthogranulomas (Fig. 31-25). They can be numerous and widespread. A rare variant resembling lichen planopilaris has been reported. Congenital lesions with hemorrhage have been reported as resembling “blueberry muffin” babies, but the biopsies show typical LCH. Nail changes can occur, but are uncommon and can include longitudinal grooving, purpuric striae, hyperkeratosis, sub
ungual thinning, deformities, loss of nail plate, and paronychia. Both fingernails and toenails may be affected. Most patients with nail involvement have multisystem disease. LCH restricted to the genitalia is rare, but vulvar, inguinal, and perianal disease may be the initial manifestation of LCH. It tends to be painful and ulcerative, and may simulate hidradenitis suppurativa, since axillary and scalp involvement may also be present. Oral mucosa lesions The oral mucosa may be involved. Lesions may be mucosal ulcerations that are painful and inflamed. They affect primarily the buccal mucosa. Most oral disease is due to alveolar bone lesions. These osteolytic lesions can lead to significant periodontitis. Gingival ulceration can result (Fig. 31-26). Teeth detach from the underlying bone and on x-ray appear to be “floating.” Palpable masses and gingival lesions should be looked for and a dental evaluation completed in all patients. Cervical adenopathy is common. Bilateral parotid swelling may occur. Visceral involvement The most commonly involved organ is the bone (Fig. 31-27). The lesions may be asymptomatic or cause pain. The skull is most commonly involved, followed by the long bones, then the flat bones. Bony lesions tend to occur in older children and young adults. Lesions are treated with curettage, intralesional corticosteroids, or radiation. Endocrine dysfunction occurs, usually in the form of diabetes insipidus, which is more common in patients with bone disease of the
1. Monosystem disease a. Focal disease of bone, skin, or lymph node b. Multifocal disease of skeleton or lymph nodes 2. Multisystem disease a. Low risk—age over 2, without involvement of lungs, liver, spleen, or hematopoietic system b. High risk—age under 2 and involvement of multiple organs, or age over 2 years and involvement of lungs, liver, spleen, or hematopoietic system
Histiocytoses
Box 31-1 Classification system for Langerhans cell histiocytosis (LCH)
Fig. 31-26 Langerhans cell histiocytosis, gingival lesions.
Pulmonary LCH occurs on average at age 33 years. A diffuse micronodular pattern on chest radiograph may progress to cyst formation (honeycomb lung), large bullae, and pneumo thorax. More than 90% of adults with pulmonary LCH are tobacco or marijuana smokers. Pneumothorax occurs in 25% of cases. High-resolution CT is useful for diagnosis. Five-year survival is 88%. Lung transplantation may be required. It is unclear if isolated pulmonary LCH is a reactive process or a variant of LCH.
Treatment/prognosis
Fig. 31-27 Langerhans cell histiocytosis, eosinophilic granuloma of rib that eroded through to the skin.
skull and in patients with extensive disease. Diabetes insipidus is one of the common long-term sequelae of children recovering from LCH. Lymph nodes are characteristically involved, especially the cervical nodes. The bone marrow may be affected, resulting in cytopenias. This may present as purpura in the skin. The liver may be involved directly by infiltration with Langerhans cells, or may be affected indirectly by enlarged nodes in the porta hepatis, leading to obstructive disease. Either pattern can lead to biliary cirrhosis. Pulmonary disease with diffuse micro nodular infiltrates and cysts occurs less commonly in childhood LCH than in adults with LCH.
Adult LCH In adults the peak age of presentation is between 20 and 35 years, with multisystem disease in between one-third and two-thirds of adults with LCH. Bones are the most common organ involved in adults with LCH, and 12% of adult LCH patients have disease limited to one or several bones. Skin and mucosal involvement is the second most common manifestation in adults. In the skin, lesions can be papular or diffuse, sometimes with both forms of lesion present at different sites. Acneiform lesions of the chest and back, identical clinically to acne vulgaris, can occur. Xanthomatous lesions may be found. A pattern that has been repeatedly reported in the skin of adults with LCH is a red, erosive, intertriginous eruption, with a close resemblance to deficiency dermatitis. It favors the groin and inframammary areas, especially in elderly women.
In childhood LCH, outcome is determined by the extent of involvement and, more importantly, the function of affected organs. Children younger than 1 year with multisystem disease have the worst prognosis, with mortality approaching 50%, children aged 1–4 have a 30% or lower mortality, and mortality is only 6% in children 5 years or older. Not only is the organ system involved important, but also the extent of involvement. Liver function tests greater than five times normal are associated with a 5-year survival of only 25%, with most deaths occurring within 1 year. Without liver involvement, the 5-year survival is more than 75%. Involvement of the ear and lung is also a poor prognostic finding in patients with multisystem disease. Early initial response to multidrug chemotherapy in childhood multisystem LCH is an important predictor of survival, with survival of 92% of responders and 11% of nonresponders after 6 weeks of treatment. Baseline and repeated evaluation is important. Lesions in one organ system may resolve while disease progresses in another organ. Skin lesions may spontaneously resolve, only for the disease to recur, even years later, so patients must be followed regularly. For treatment children with LCH are classified into four groups (Box 31.1). Monosystem disease 1a and 1b involves local therapies to the skin, and surgery alone for bone lesions. These patients may be observed, as spontaneous resolution may occur. Treatment is not required. Low-risk patients are treated with a combination of vinblastine and prednisone over months. High-risk patients receive prednisone and vinblastine as initial treatment, followed by maintenance therapy with methotrexate and 6-mercaptopurine. Multisystem LCH in adults has a 5-year survival of more than 90%. Pulmonary LCH in adults can be progressive and fatal, especially in smokers. Adults with multisystem disease who require treatment are given a combination of vinblastine and prednisone induction, followed by maintenance treatment with 6-mercaptopurine and methotrexate. Relapses or progression may be treated with 2-chlorodeoxyadenosine. Imatinib mesylate, thalidomide, cyclosporine, and anti-TNF agents can be considered experimental approaches. Rarely, hematopoietic stem cell transplantation and solid organ (liver, lung) 717
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transplantation have been performed as life-saving measures in refractory or progressing patients. Various skin-directed treatments have been reported for children and adults with skin-predominant disease, who do not require systemic therapy. These include topical nitrogen mustard, topical steroids, imiquimod, systemic steroids, PUVA, narrow-band UVB, excimer laser, isotretinoin, thalidomide, low-dose methotrexate, and IFN-α. Associated lymphomas, solid tumors, and myelodysplasias have occurred in patients with LCH, with acute lymphoblastic leukemia and myelodysplastic syndrome preceding the appearance of LCH, and acute myelogenous leukemia and acute lymphoblastic leukemia following it. The role of the preceding lymphoma or myelodysplasia in the appearance of LCH in adults is unknown. The appearance of acute leukemia and possibly solid tumors following the diagnosis of LCH is felt to be a complication of the chemotherapeutic regimens and is seen predominantly in LCH patients so treated. In some cases of cutaneous and systemic lymphomas, aggregates of polyclonal Langerhans cells are seen in the tissue affected by the lymphoma. Whether this represents the coexistence of LCH and lymphoma (unlikely) or a reactive proliferation of Langerhans cells within the tissue affected by the lymphoma (more likely) is unknown. Reactive proliferations of histiocytes resembling sarcoidosis can also be seen in lymphoma, suggesting this is a reactive phenomenon.
Differential diagnosis The diffuse small papular form is frequently misdiagnosed as seborrheic dermatitis. The yellow color of the lesions and the presence of hemorrhage in the small papules, if present, should suggest the diagnosis of LCH. Nodular lesions of scabies can closely simulate LCH. This includes the finding of Langerhans or indeterminate cells in the dermal infiltrate by electron microscopy and S-100 and CD1a staining. The larger papules resemble juvenile xanthogranulomas and xanthomas. Erosive genital disease may simulate deficiency dermatitis. Alston RD, et al: Incidence and survival of childhood Langerhans cell histiocytosis in Northwest England from 1954 to 1998. Pediatr Blood Cancer 2007; 48:555. Aviner S, et al: Langerhans cell histiocytosis in a premature baby presenting with skin-isolated disease: case report and literature review. Acta Paediatr 2008; 97:1751. Avram MM, et al: Case records of the Massachusetts General Hospital. Case 20-2007: a newborn girl with skin lesions. N Engl J Med 2007; 357:1327. Aydogan K, et al: Adult-onset Langerhans cell histiocytosis confined to the skin. J Eur Acad Dermatol Venereol 2006; 20:890. Bechan GI, et al: Telomere length shortening in Langerhans cell histiocytosis. Br J Haematol 2008; 140:420. Billings SD, et al: Langerhans cell histiocytosis associated with myelodysplastic syndrome in adults. J Cutan Pathol 2006; 33:171. Broekaert SM, et al: Multisystem Langerhans cell histiocytosis: successful treatment with thalidomide. Am J Clin Dermatol 2007; 8:311. Campanati A, et al: Purely cutaneous Langerhans’ cell histiocytosis in an adult woman. Acta Derm Venereol 2009; 89:299. Campos MK, et al: Langerhans cell histiocytosis: a 16-year experience. J Pedatri (Rio J) 2007; 83:79. Chander R, et al: Pulmonary disease with striking nail involvement in a child. Pediatr Dermatol 2008; 25:633. Chi DH, et al: Eruptive xanthoma-like cutaneous Langerhans cell histiocytosis in an adult. J Am Acad Dermatol 1996; 34:688. Chiles LR, et al: Langerhans cell histiocytosis in a child while in remission for acute lymphocytic leukemia. J Am Acad Dermatol 2001; 45:S233. Christie LJ, et al: Lesions resembling Langerhans cell histiocytosis in association with other lymphoproliferative disorders: a reactive or neoplastic phenomenon? Hum Pathol 2006; 37:32. Escardó-Paton JA, et al: Late recurrence of Langerhans cell histiocytosis in the orbit. Br J Ophthalmol 2004; 88:838.
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Fernandez Flores A, Mallo S: Langerhans cell histiocytosis of vulva. Dermatol Online J 2006; 12:15. Hagiuda J, et al: Langerhans cell histiocytosis on the penis: a case report. BMC Urol 2006; 6:28. Hancox JG, et al: Adult onset folliculocentric Langerhans cell histiocytosis confined to the scalp. Am J Dermatopathol 2004; 26:123. Hatakeyama N, et al: An infant with self-healing cutaneous Langerhans cell histiocytosis followed by isolated thymic relapse. Pediatr Blood Cancer 2009; 53:229. Honda R, et al: Langerhans’ cell histiocytosis after living donor liver transplantation: report of a case. Liver Transpl 2005; 11:1435. Imafuku S, et al: Cutaneous Langerhans cell histiocytosis in an elderly man successfully treated with narrowband ultraviolet B. Br J Dermatol 2007; 157:1277. Iqbal Y, et al: Langerhans cell histiocytosis presenting as a painless bilateral swelling of the parotid glands. J Pediatr Hematol Oncol 2004; 26:276. Kartono F, et al: Crusted Norwegian scabies in an adult with Langerhans cell histiocytosis: mishaps leading to systemic chemotherapy. Arch Dermatol 2007; 143:626. Kwong YL, et al: Widespread skin-limited Langerhans cell histiocytosis: complete remission with interferon alfa. J Am Acad Dermatol 1997; 36:628. Lau L, et al: Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer 2006; 46:66. Madrigal-Martinez-Pereda C, et al: Langerhans cell histiocytosis: literature review and descriptive analysis of oral manifestations. Med Oral Patol Oral Cir Bucal 2009; 14:E222. Mataix J, et al: Nail changes in Langerhans cell histiocytosis: a possible marker of multisystem disease. Pediatr Dermatol 2008; 25:247. McElligott J, et al: Spontaneous regression of Langerhans cell histiocytosis in a neonate with multiple bony lesions. J Pediatr Hematol Oncol 2008; 30:85. Moravvej H, et al: An unusual case of adult disseminate cutaneous Langerhans cell histiocytosis. Dermatol Online J 2006; 12:13. Mosterd K, et al: Neonatal Langerhans’ cell histiocytosis: a rare and potentially life-threatening disease. Int J Dermatol 2008; 47:10. Mottl H, et al: Treatment results of Langerhans cell histiocytosis according to the LCH II protocol. Cas Lek Cesk 2005; 144:753. Nagarajan R, et al: Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 2001; 23:629. Pollono D, et al: Reactivation and risk of sequelae in Langerhans cell histiocytosis. Pediatr Blood Cancer 2007; 48:696. Querings K, et al: Clinical spectrum of cutaneous Langerhans’ cell histiocytosis mimicking various diseases. Acta Derm Venereol 2006; 86:39. Sankilampi U, et al: Congenital Langerhans cell histiocytosis mimicking a “blueberry muffin baby”. J Pediatr Hematol Oncol 2008; 30:245. Satter EK, et al: Langerhans cell histiocytosis: a case report and summary of the current recommendations of the Histiocyte Society. Dermatol Online J 2008; 14:3. Satter EK, et al: Diffuse xanthogranulomatous dermatitis and systemic Langerhans cell histiocytosis: a novel case that demonstrates bridging between non-Langerhans cell histiocytosis and Langerhans cell histiocytosis. J Am Acad Dermatol 2009; 60:841. Saven A, et al: 2-chlorodeoxyadenosine-induced complete remission in Langerhans-cell histiocytosis. Ann Intern Med 1994; 121:430. Shaffer MP, et al: Langerhans cell histiocytosis presenting as blueberry muffin baby. J Am Acad Dermatol 2005; 53; S143. Steen AE, et al: Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol 2001; 145:137. Stefanos CM, et al: Langerhans cell histiocytosis in the elderly. J Am Acad Dermatol 1998; 39:375. Tantiwongkosi B, et al: Congenital solid neck mass: a unique presentation of Langerhans cell histiocytosis. Pediatr Radiol 2008; 38:575. Tatevossian R, et al: Adults with LCH—orphans with an orphan disease. Clin Med 2006; 6:404. Teng CL, et al: Rapidly fatal Langerhans’ cell histiocytosis in an adult. J Formos Med Assoc 2005; 104:955. Vogel CA, et al: Excimer laser as adjuvant therapy for adult cutaneous Langerhans cell histiocytosis. Arch Dermatol 2008; 144:1287.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 31-1 Granuloma annulare, generalized small papules and annular plaques. Fig. 31-2 Sarcoidosis, hypopigmented papules. Fig. 31-3 Sarcoidosis, hypopigmented and annular plaques.
Histiocytoses
Von Stebut E, et al: Successful treatment of adult multisystemic Langerhans cell histiocytosis with psoralen-UV-A, prednisone, mercaptopurine, and vinblastine. Arch Dermatol 2008; 144:649. Wagner C, et al: Langerhans cell histiocytosis: treatment failure with imatinib. Arch Dermatol 2009; 145:949. Yazc N, et al: Langerhans cell histiocytosis with involvement of nails and lungs in an adolescent. J Pediatr Hematol Oncol 2008; 30:77.
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Cutaneous Lymphoid Hyperplasia, Cutaneous T-cell Lymphoma, Other Malignant Lymphomas, and Allied Diseases
Cutaneous lymphoid hyperplasia (lymphocytoma cutis, lymphadenosis benigna cutis, pseudolymphoma) The term cutaneous lymphoid hyperplasia refers to a group of benign disorders characterized by collections of lymphocytes, macrophages, and dendritic cells in the skin. These processes can be caused by known stimuli (such as medications, injected foreign substances, infections, or the bites of arthropods) or they may be idiopathic. They may have a purely benign his tologic appearance or resemble cutaneous lymphoma. If there is a histologic resemblance to lymphoma, the term pseudo lymphoma is sometimes used. Most cases contain a mixed population of T and B cells, but they may contain mostly T cells. By standard techniques, most cases of cutaneous lym phoid hyperplasia will be found to lack clonality. Cases of monoclonal B- and T-cell cutaneous lymphoid hyperplasia do occur. Thus, a finding of monoclonality does not equate to the diagnosis of malignancy or lymphoma, nor does it predict biologic behavior. A subset of polyclonal or monoclonal (T- or B-cell) cutaneous lymphoid hyperplasias does progress to cutaneous B-cell and, less commonly, T-cell lymphoma. Even when the initial evaluation detects a T-cell rich infiltrate (>90%), which may be monoclonal, the lymphoma that eventu ates from this form of cutaneous lymphoid hyperplasia may be B-cell. Thus, as in many cancer syndromes, cutaneous lym phoid hyperplasia represents the benign end of a spectrum of cutaneous lymphoid proliferation, with cutaneous lymphoma at the other end, and cases falling everywhere along that spec trum of progression. Unfortunately, current techniques cannot always predict which cases will progress. Two clinical patterns of cutaneous lymphoid hyperplasia exist. The nodular form consists of nodular and diffuse dermal aggregates of lymphocytes, macrophages, and dendritic cells. The clinical and histologic differential diagnosis is cutaneous B-cell lymphoma. The diffuse type is usually associated with drug exposure or photosensitivity (actinic reticuloid). Histologically, it is to be distinguished from cutaneous T-cell lymphoma.
Cutaneous lymphoid hyperplasias—nodular B-cell pattern The nodular pattern of cutaneous lymphoid hyperplasia is the most common pattern. It usually presents in adults and is 2–3 times more common in women. It favors the face (cheek, nose, or earlobe), and the majority of cases present as a solitary or localized cluster of asymptomatic, erythematous to violaceous papules or nodules (Fig. 32-1). Less commonly, lesions may affect the trunk (36%) or extremities (25%). At times, the lesions may coalesce into a plaque or be widespread in one region, in which case they present as miliary papules. Systemic
symptoms are absent and, except for rare cases with regional lymphadenopathy, there are no other physical or laboratory abnormalities. It is usually idiopathic, but can be caused by tattoos, Borrelia infections, herpes zoster scars, antigen injec tions, acupuncture, and, in rare cases, drug reactions, tumor necrosis factor (TNF)-α inhibitors, and persistent insect bite reactions. Lesions that result from a known stimulus tend to be localized to the site of the original process—tattoo, injection, or insect bite. Borrelia-induced cutaneous lymphoid hyperplasia is an uncommon manifestation of this infection, occurring in 0.6–1.3% of cases reported from Europe. The lack of borrelial pseudolymphoma in the US compared with Europe may relate to the fact that there are different borrelial species in Europe, specifically Borrelia afzelii, that cause borreliosis. Lesions occur at the site of the tick bite or close to the edge of a lesion of erythema migrans. They may appear up to 10 months after infection. Lesions may be multiple and favor the earlobes, nipple and areola, nose, and scrotal area, and vary from 1 to 5 cm in diameter. Usually, there are no symptoms, but associ ated regional lymphadenopathy may be present. Late mani festations of Borrelia infection are uncommon. The diagnosis is suspected from a history of a tick bite or erythema migrans, the location (earlobe or nipple), and the histologic picture. The diagnosis is confirmed by an elevated anti-Borrelia antibody (present in 50% of cases) and the finding of borrelial DNA in the affected tissue. The treatment is penicillin. Some cases progress to true lymphoma. Histologic examination of nodular cutaneous lymphoid hyperplasia reveals a dense, nodular infiltrate that occupies primarily the dermis and lessens in the deeper dermis and subcutaneous fat, i.e. it is “top-heavy.” The process is usually separated from the epidermis by a clear Grenz zone. The infiltrate is composed chiefly of mature small and large lymphocytes, histiocytes, plasma cells, dendritic cells, and eosinophils. In the deeper portions, well-defined germinal centers are usually seen, with central large lymphoid cells with abundant cytoplasm and tingible body macrophages, and a peripheral cuff of small lymphocytes. A plasma cellpredominant variant has been described. Reactive hyperplasia of adnexal epithelium is common and characteristic, but may also occasionally be seen in true lymphomas. Germinal centers are symmetrical and surrounded by a mix of B and T cells. BCL-6 and CD10 expression is limited to the germinal centers, which also have an intact CD21+ network of dendritic cells. Typically, more than 90% of the cells in the germinal center express the proliferative marker Ki-67 (MIB-1). There is no evidence of light chain restriction by in situ hybridization. CD30+ cells may occasionally be prominent, raising concern about the development of a CD30+ lymphoproliferative disorder. As most lesions are asymptomatic, treatment is often not required. If the process has been induced by a medication, use of the medication should be discontinued. Infection should be
Fig. 32-1 Reactive lymphoid hyperplasia.
treated and localized foci of infection removed. Intralesional steroidal agents are sometimes beneficial, but lesions may recur in a few months. Potent topical steroids may also be tried for superficial lesions. Intralesional corticosteroids, cryosur gery, thalidomide, 100 mg/day for a few months, interferon (IFN)-α, IFN-α 2b, laser ablation, and surgical excision can all produce good results. Low-dose radiation therapy is usually very effective and may be used on refractory facial lesions that cannot be satisfactorily removed surgically. If monoclonality is detected in a localized lesion, complete removal and local radiation have been recommended, but there is no evidence that this improves outcome, and lesions that are not initially monoclonal may also progress to lymphoma.
Cutaneous lymphoid hyperplasias—bandlike T-cell pattern Cutaneous lymphoid hyperplasias may histologically show a bandlike and perivascular dermal infiltrate, at times with epidermotropism. They may be idiopathic, or caused by photosensitivity (formerly called actinic reticuloid; now called chronic actinic dermatitis), medications (usually anticonvul sants, but also many others), or contact dermatitis (so-called lymphomatoid contact dermatitis). Clinically, these patients have lesions that clinically resem ble mycosis fungoides: widespread erythema with scaling. Thicker plaques may occur as well and these cases are fre quently caused by medications. The treatment is to stop any implicated medication. If stopping the medication is ineffec tive, topical and intralesional steroids, PUVA, and, for persist ent localized lesions, radiotherapy may be considered. Histologically, a T cell-rich band of lymphocytes is present. Epidermotropism, atypia, and even clonality may suggest mycosis fungoides, but the lesions resolve when the drug or other inciting agent is withdrawn.
Jessner lymphocytic infiltrate of the skin The existence of this entity has recently been challenged. Even the coauthors of the original paper feel their cases would now best be classified as a variant of lupus erythematosus. Clinically, Jessner infiltrate is a persistent papular and plaquelike eruption that is photosensitive and occurs primarily on the face. Histologically, there is a superficial and deep perivas cular and periadnexal lymphocytic infiltrate. Interface derma titis is absent. The infiltrating lymphocytes are suppressor T cells (CD8+). Features that suggest this may be distinct from
Cutaneous lymphomas
other forms of cutaneous lupus erythematosus include the absence of an interface dermatitis, lack of mucin, and negative direct immunofluorescence. Tumid lupus erythematosus also lacks interface dermatitis but has ample mucin. Polymorphous light eruption (PMLE) is distinguished from Jessner infiltrate by having edematous papules and plaques that are more tran sient, and by the presence of dermal edema. In PMLE the infiltrating cells are CD8+. There may still exist true cases of lymphocytic infiltration of the skin. To distinguish them clearly from lupus erythematosus and PMLE, the lesions must contain predominantly CD8+ suppressor T cells, lack dermal mucin and dermal edema, and be fixed (not transient like PMLE); patients must have negative direct immunofluores cence and serologic testing for lupus erythematosus. Both Jessner and chronic cutaneous lupus erythematosus can respond to antimalarials. Belousova IE, et al: Atypical histopathological features in cutaneous lymphoid hyperplasia of the scrotum. Am J Dermatopathol 2008 Aug; 30(4):407–408. Böer A, et al: Pseudoclonality in cutaneous pseudolymphomas: a pitfall in interpretation of rearrangement studies. Br J Dermatol 2008 Aug; 159(2):394–402. Cerroni L, et al: Cutaneous B-cell pseudolymphoma at the site of vaccination. Am J Dermatopathol 2007 Dec; 29(6):538–542. Guis S, et al: Cutaneous pseudolymphoma associated with a TNF-alpha inhibitor treatment: etanercept. Eur J Dermatol 2008 Jul–Aug; 18(4):474–476. Kazakov DV, et al: Hyperplasia of hair follicles and other adnexal structures in cutaneous lymphoproliferative disorders: a study of 53 cases, including so-called pseudolymphomatous folliculitis and overt lymphomas. Am J Surg Pathol 2008 Oct; 32(10):1468–1478. Nervi SJ, et al: Plasma cell predominant B cell pseudolymphoma. Dermatol Online J 2008 Oct 15; 14(10):12. Shin JB, et al: Cutaneous T cell pseudolymphoma at the site of a semipermanent lip-liner tattoo. Dermatology 2009; 218(1):75–78. Tomar S, et al: Treatment of cutaneous pseudolymphoma with interferon alfa-2b. J Am Acad Dermatol 2009 Jan; 60(1):172–174.
Cutaneous lymphomas Because cutaneous Hodgkin disease is very rare, the term nonHodgkin lymphoma has little meaning when speaking of a lymphoma in the skin, because virtually all cutaneous lym phomas are “non-Hodgkin lymphomas.” Cutaneous lym phoma can be considered to be either primary or secondary. Primary cutaneous lymphomas are those that occur in the skin and where no evidence of extracutaneous involvement is found for some period after the appearance of the cutaneous disease. Secondary cutaneous lymphoma includes cases that have simultaneous or preceding evidence of extracutaneous involvement. These cases are best classified and managed as lymph node-based lymphomas with skin involvement. This conceptual separation is not ideal, but it has been important in developing classification schemes and determining progno sis in cutaneous lymphomas. For many years classification of lymphomas has been based on their histologic appearance, and lesions from all organ systems were classified histomorphologically in an identical manner to lymphomas arising in lymph nodes. It had been recognized that these classification schemes have major short comings when applied to extranodal lymphomas. Specifically, they did not uniformly predict clinical behavior. The new World Health Organization (WHO) classification scheme rec ognizes distinct forms of primary cutaneous lymphoma. Cutaneous lymphomas are classified based on their cell type. There are B-cell lymphomas and T-cell lymphomas, but B-cell lymphomas can be T cell-rich. In such cases, atypia is restricted to the B-cell population and immunoglobulin gene rearrangements are detected. Histologic features used in the 721
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classification system include cell size (large versus small), nuclear morphology (cleaved or non-cleaved), and immuno phenotype. Because appropriate classification may be prognostically important, experienced dermatopathology con sultation should be sought in cases of cutaneous lymphoma.
Primary cutaneous T-cell lymphomas A major insight into cutaneous lymphoma was the finding that the majority of lymphomas in the skin were of T-cell origin. This is logical, since T cells normally traffic through the skin and are important in “skin-associated lymphoid tissue.” Unfortunately, dermatologists frequently use the term cutane ous T-cell lymphoma synonymously with mycosis fungoides. Although mycosis fungoides represents the large majority of primary cutaneous T-cell lymphomas, up to 30% of primary cutaneous T-cell lymphomas are not mycosis fungoides. The following discussion is divided into mycosis fungoides and related conditions, Sézary syndrome, lymphomatoid papulo sis, and non-mycosis fungoides primary cutaneous T-cell lymphomas.
Mycosis fungoides Mycosis fungoides is a malignant neoplasm of T-lymphocyte origin, almost always a memory T-helper cell. The incidence has been cited as 1 in 300 000 per year, but has been increasing. Mycosis fungoides affects all races. In the US black persons are relatively more commonly affected than white persons. The condition is twice as common in males as in females.
Natural history In most cases, mycosis fungoides is a chronic, slowly progres sive disorder. It usually begins as flat patches (patch stage), which may or may not be histologically diagnostic of mycosis fungoides. This inability to diagnose early cases has more to do with the limits of diagnostic capabilities, rather than a transformation from some non-neoplastic (premycotic) condi tion to mycosis fungoides, and these cases are best considered mycosis fungoides from the onset. Pruritus, sometimes severe, is usually present at this stage. Over time, sometimes years, the lesions become more infiltrated, and the diagnosis is usually confirmed with repeated histologic evaluation. Infiltrated plaques occur eventually (plaque stage). In some cases, tumors may eventually appear (tumor stage). Some patients may present with or progress to erythroderma. Most rarely, patients may present with tumors de novo, the so-called d’emblée form. With immunophenotyping, many of these cases are now recognized as non-mycosis fungoides T-cell lymphomas. Eventually, in some patients, noncutaneous involvement is detected. This is most commonly first identi fied in lymph nodes. Peripheral blood involvement and vis ceral organ involvement may also occur. In general, mycosis fungoides affects elderly patients and has a long evolution. However, once tumors develop or lymph node involvement occurs, the prognosis is guarded and mycosis fungoides can be fatal. In most fatal cases the patient dies of septicemia. Early, aggressive chemotherapy in an attempt to “cure” mycosis fungoides is associated with exces sive morbidity and mortality, and is not indicated.
Evaluation and staging
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The North American Mycosis Fungoides Cooperative Group has developed a staging system. Because mycosis fungoides is a systemic disease from the onset (as lymphocytes naturally traffic throughout the body), concepts used for solid tumors, such as tumor burden and metastasis, cannot be readily applied. The TNMB system scores involvement in the skin (T), lymph node (N), viscera (M), and peripheral blood (B), and is
in evolution. Skin involvement is divided into less than 10% (T1), more than 10% (T2), tumors (T3), and erythroderma (T4). Node involvement is normal clinically and pathologically (N0), palpable but pathologically not mycosis fungoides (N1), not palpable but pathologically mycosis fungoides (N2), or clinically and pathologically involved (N3). Viscera and blood are either not involved (M0 and B0) or involved (M1 and B1). • Stage IA is T1,N0,M0. • Stage IB is T2,N0,M0. • Stage IIA is T1–2,N1,M0. • Stage IIB is T3,N0–1,M0. • Stage IIIA is T4,N0,M0. • Stage IIIB is T4,N1,M0. • Stage IVA is T1–4, N2–3,M0. • Stage IVB is T1–4,N0–3,M1. The “B” or blood status does not alter staging of the disease. A staging work-up would include a complete history and physical examination, with careful palpation of lymph nodes and mapping of skin lesions; a complete blood cell count with assays for circulating atypical cells (Sézary cells); serum chem istries, including renal and liver function tests with lactic dehydrogenase; a chest radiograph evaluation; and a skin biopsy. If lymph nodes are palpable, they should be examined histologically. Fine-needle aspiration is not an ideal mode of evaluation, since early lymph node involvement may be local ized to certain areas of the affected nodes, and architectural evaluation is often required to detect early lymph node involvement. If any abnormalities are detected through the above evaluations, they should be pursued. Computed tom ography (CT) can be performed to assess chest, abdominal, and pelvic lymph nodes, and visceral organs. These are useful in patients with stage II–IV disease, but are not indicated in patients with stage IA disease. Whether patients with stage IB disease should undergo these tests is unknown. The value of this staging system is confirmed in large series. Stage IA patients have a life expectancy identical to that of a control population; only 8–9% progress to have more advanced disease; and only 2% die of their disease. By contrast, patients with T2 disease have a shorter survival time than control subjects (median survival of 11.7–15.6 years). Twenty-four percent of T2 patients progress to more advanced disease. T3 patients have a median survival of 3.2–8.4 years, and T4 patients 1.8–3.7 years. Palpable adenopathy is associated with a median survival of only 7.7 years, whereas patients without adenopathy have a survival of 21.8 years. Lymphadenopathy, tumors, and cutaneous ulceration are cardinal prognostic factors; no patient dies without having developed one of them and patients with all three (in any order) survive a median of 1 year.
Clinical features In the early patch/plaque stage, the lesions are macular or slightly infiltrated patches or plaques varying in size from 1 to 5 cm or more. Folliculotropic disease can resemble lichen nitidus. Except for the folliculotropic variant, lesions >5 cm in size are virtually always present in true cases of mycosis fun goides. In contrast, most histologic simulators present with smaller skin lesions. The eruption may be generalized or begin localized to one area and then spread. The lower abdomen, buttocks, upper thighs, and breasts of women are preferen tially affected. The lesions may have an atrophic surface, or present as true poikiloderma with atrophy, mottled dyspig mentation, and telangiectasia. Poikiloderma vasculare atroph icans most commonly represents a clinical form of patch-stage mycosis fungoides. Likewise, large-plaque parapsoriasis and cases of small-plaque parapsoriasis with poikilodermatous change are early patch-stage lesions of mycosis fungoides. In
and leads to discoid patches or extensive plaques, which may be as wide as 30 cm. Eventually, through coalescence of the various plaques, the involvement becomes widespread, but there are usually patches of apparently normal skin interspersed. When the involvement is advanced, painful superficial ulcerations may occur. During this phase, enlarged lymph nodes usually develop. They are nontender, firm, and freely movable. The tumor stage is characterized by large, various-sized and shaped nodules on infiltrated plaques and on apparently normal skin. These nodules have a tendency to break down early and to form deep oval ulcers, whose bases are covered with a necrotic grayish substance and which have rolled edges (Fig. 32-4). The lesions generally have a predilection for the trunk, although they may be seen anywhere on the skin or may involve the mouth and upper respiratory tract. Uncommonly, tumors may be the first sign of mycosis fungoides. The erythrodermic variety of mycosis fungoides is a general ized exfoliative process, with universal redness. The hair is scanty, nails are dystrophic, palms and soles are hyperkera totic, and at times there may be generalized hyperpigmenta tion (Fig. 32-5). Erythroderma may be the presenting feature. Alopecia mucinosa The infiltrating cells of mycosis fun goides can demonstrate a predilection for involving the hair follicle (Fig. 32-6). This may be observed simply by
Fig. 32-2 Mycosis fungoides, hypopigmented patches.
Fig. 32-4 Tumor-stage mycosis fungoides. (Courtesy of Ellen Kim, MD)
Fig. 32-3 Plaque stage mycosis fungoides. (Courtesy of Ellen Kim, MD)
Fig. 32-5 Erythrodermic mycosis fungoides.
Cutaneous lymphomas
contrast, typical digitate dermatosis probably never evolves into mycosis fungoides. “Invisible” mycosis fungoides is gen eralized skin involvement that is not visible to the naked eye but can be documented histologically. With current diagnostic methods, this can usually be confirmed. In general, the patchstage lesions resemble an eczema, being round or ovoid, but annular, polycyclic, or arciform configurations can occur. Less common forms are the verrucous or hyperkeratotic form, the hypopigmented form (Fig. 32-2), lesions resembling a pig mented purpura, and the vesicular, bullous, or pustular form. The hypopigmented form seems to be more common in persons of color and is a common presentation for adolescents and children with mycosis fungoides. Subtle lesions of mycosis fungoides may manifest clinically during anti-TNF therapy. In the plaque stage, lesions are more infiltrated and may resemble psoriasis (Fig. 32-3), a subacute dermatitis, or a gran ulomatous dermal process such as granuloma annulare. The palms and soles may be involved, with hyperkeratotic, pso riasiform, and fissuring plaques. The infiltration of the plaques, at first recognized by light palpation, may be present in only a few of the lesions. It is a manifestation of diagnostic impor tance. Different degrees of infiltration may exist even in the same patch and sometimes it is more pronounced peripher ally, the central part of the plaque being depressed to the level of the surrounding skin. The infiltration becomes more marked
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Fig. 32-6 Follicular mycosis fungoides.
about 7 years. Any other evidence of visceral involvement is a grave prognostic sign. An abnormal result on liver–spleen scan, chest radiograph or CT evaluation, abdominal or pelvic CT scans, or bone marrow biopsy is associated with a survival of about 1 year. The prognosis is worse in non-Caucasian patients with early-onset mycosis fungoides, especially African American women.
Pathogenesis
Fig. 32-7 Alopecia mucinosa.
folliculotropism of the cells (pilotropic or follicular mycosis fungoides) or by the appearance of follicular mucinosis (Fig. 32-7). In all cases of follicular mucinosis, the histologic speci men should be carefully examined and the diagnosis of mycosis fungoides considered. Among patients older than 40 years of age who have follicular mucinosis, a large percent age will have mycosis fungoides or go on to develop it. However, the finding of a T-cell clone in lesions of follicular mucinosis without mycosis fungoides is not predictive of the development of cutaneous T-cell lymphoma. Selective tropism of the cutaneous T-cell lymphoma cells to the sweat glands and ducts is termed syringotropic cutaneous T-cell lymphoma (Fig. 32-8). This is often seen in conjunction with follicular involvement. Syringolymphoid hyperplasia may be seen in these cases histologically and may mimic eccrine carcinoma. Cases previously termed “syringolym phoid hyperplasia with alopecia” are now considered to be cutaneous T-cell lymphoma. Clinically, the lesions present as discrete follicular and nonfollicular erythema, along with alo pecia, milia, and follicular cysts. The initial clinical diagnosis in such cases is often discoid lupus erythematosus. The prog nosis in mycosis fungoides with adnexal involvement is as predicted by the staging system for other forms of mycosis fungoides.
Systemic manifestations Mycosis fungoides as a form of malignant lymphoma may progress to include visceral involvement. Lymph node involve ment is most common; it predicts progression of the disease in at least one-quarter of patients and reduces survival to 724
Fig. 32-8 Syringotropic mycosis fungoides.
Mycosis fungoides is a neoplasm of memory helper T cells in most cases. Rare cases of suppressor cell (CD8+) mycosis fun goides have been reported. These CD8+ cases may behave indolently, like mycosis fungoides, or aggressively. The latter aggressive subset tends to present with plaques rather than patches. The events leading to the development of the malig nant T cells are unknown. It has been speculated that it is caused by chronic exposure to an antigen, but this has yet to be confirmed. Patients with atopic dermatitis appear to be at increased risk for the development of mycosis fungoides, sug gesting that persistent stimulation of T cells may lead to devel opment of a malignant clone. The inflammatory nature of the skin lesions has led to investigation of the interactions of the malignant T cells and both keratinocytes and antigen-presenting cells (including Langerhans cells) in mycosis fungoides. Mycosis fungoides skin lesions have many features of skin that is immunologi cally “activated.” Mycosis fungoides cells express cutaneous lymphocyte antigen (CLA), the ligand for E selectin, which is expressed on the endothelial cells of inflamed skin. This allows the malignant cells to traffic into the skin from the peripheral blood. CCR4, another homing molecule, is expressed on mycosis fungoides cells, and the ligand for this receptor is on basal keratinocytes. Antigen-presenting cells are increased in mycosis fungoides lesions and have increased functional capacity to activate T cells. There is increased expression of major histocompatibility complex (MHC) class II antigens on the surface of the antigen-presenting cells. Through cytokines, infiltration of neoplastic and reactive T cells is increased. The pattern in early mycosis fungoides is more T-helper 1 (Th1)like and the non-neoplastic infiltrating cells (tumor infiltrating lymphocytes [TILs]) may play a role in downregulating and controlling the neoplastic cells. There are more CD8+ cells in these early lesions and these TILs may control the malignant clone. In fact, mycosis fungoides patients with more than 20% CD8+ cells in their skin survive longer than those with less than 15%. In summary, early mycosis fungoides is a condition in which host immunity is intact and the host immune system effectively limits proliferation of the malignant T-cell clone. In more advanced mycosis fungoides and in Sézary syndrome,
Histopathology Perhaps more than in any other situation in dermatopathol ogy, the ability to diagnose mycosis fungoides histologically correlates closely with the skill, training, and experience of the reviewing pathologist. When the clinician is considering a diagnosis of mycosis fungoides, consultation with a skilled dermatopathologist should be strongly considered if original histologic reports are nonconfirmatory or nonspecific. In patch-stage lesions there is subtle epidermotropism of lymphocytes that resembles a vacuolar interface dermatitis with a lymphocyte in every vacuole. As lesions progress, there is a distinct bandlike distribution of lymphocytes with epider motropism. At this stage, there is a large dark lymphocyte in every vacuole. The lymphocytes within the epidermis may be numerous or few in number, but are typically larger, darker, and more angulated than those in the dermis. Papillary dermal fibrosis is typically present. The superficial perivascular lym phoid infiltrate that surrounds the postcapillary venule is typi cally more prominent above the vessel than below the vessel (bare under-belly sign). Plaques of mycosis fungoides show a more prominent superficial bandlike lymphoid infiltrate and a deeper perivas cular dermal component than patch-stage lesions. Papillary dermal fibrosis is more prominent and the subpapillary plexus is shifted downward. Epidermotropism is much more marked and is typically associated with very little spongiosis. This helps distinguish patch-stage mycosis fungoides from spongi otic dermatitis. Vesicular variants are an exception to this rule. In vesicular variants, spongiosis is prominent and results in intraepidermal and subcorneal vesiculation. Eosinophils are common in folliculotropic mycosis fungoides (with or without follicular mucinosis), but are uncommon in other forms of mycosis fungoides. In thick plaques and tumors, epidermotropism may be sub stantially diminished. The diagnosis is confirmed by the pres ence of dense sheets of infiltrating lymphocytes in the dermis and subcutaneous fat. These cells may have cerebriform nuclei. Cardinal features that should suggest a diagnosis of mycosis fungoides include the following: • solitary or small groups of lymphocytes in the basal cell layer
• epidermotropism of lymphocytes, with disproportionately scant spongiosis • more lymphocytes within the epidermis than would normally be seen in an inflammatory dermatosis, with little accompanying acanthosis or spongiosis • lymphocytes in the epidermis larger than those in the dermis • papillary dermal fibrosis with bundles of collagen arranged haphazardly • prominent folliculotropism or syringotropism of the lymphocytes, especially with intrafollicular mucin deposition (follicular mucinosis).
Cutaneous lymphomas
perhaps through interleukin (IL)-4 and 10, a Th2 environment exists. This downregulates suppressor cell function and allows the malignant clone to proliferate. In addition, the Th2dominant environment reduces effective helper T-cell func tion, explaining the increased risk of infection and secondary cancer in patients with advanced cutaneous T-cell lymphoma. Correcting the aberrant immune response in advanced cutane ous T-cell lymphoma is the basis of some treatment approaches. Common chromosomal alterations in mycosis fungoides include gain of 7q36 and 7q21–7q22, and loss of 5q13 and 9p21. This characteristic pattern differs from that seen in Sézary syndrome, suggesting that the two disorders are distinct. Low levels of human herpesvirus (HHV) 8 have been detected in large-plaque parapsoriasis as well as mycosis fungoides, but an etiologic link has not been established. As mycosis fungoides advances, the number of circulating malignant T cells increases. Standard cytologic evaluation (the Sézary preparation) is expensive and not very accurate, even when enhanced by specific labeling techniques. Use of stand ard laboratory tests, such as the CD4/CD8 ratio test, which increases as mycosis fungoides progresses, and assessment of the number of CD4+,CD7− or CD4+,CD26− circulating cells, which relatively specifically identify mycosis fungoides cells, yield indicators of tumor burden with advanced disease but are of limited value in early disease.
Features that should suggest a diagnosis of inflammatory dermatosis over mycosis fungoides include the following: • prominent upper dermal and papillary edema • marked epidermal spongiosis • accumulation of the intraepidermal inflammatory cells in flask-shaped collections, with the top open to the stratum corneum. Immunohistochemistry is of some value in assessing mycosis fungoides. Mycosis fungoides cells characteristically are CD4+, but lose the CD7 and CD26 antigens, i.e. they are CD4+,CD7−,CD26−. This phenotype is very unusual for nonmalignant T cells and thus is useful in evaluating biopsy specimens and peripheral blood lymphocytes. Loss of CD7 expression within the large dark lymphocytes in the epider mis, with normal expression in the benign recruited lym phocytes in the infiltrate below, suggests a diagnosis of mycosis fungoides. DNA hybridization or a Southern blot test is frequently performed in equivocal cases to detect clonal rearrangement of the T-cell receptor (TCR). However, these data must be interpreted with caution; clonality does not confirm a diagnosis of malignancy. Benign processes may contain clonal TCR rearrangements. In early lesions of mycosis fungoides, the number of infiltrating cells may be insufficient for a clone to be detected, so a negative test does not exclude the diagnosis of mycosis fungoides. Testing with fresh tissue is somewhat more sensitive than with fixed tissue using current methods. Similar techniques can be used to evaluate lymph nodes in mycosis fungoides patients. Lymph node involvement can be detected by these molecular methods, while the routine histologic evaluation yields normal results. Patients with more advanced disease are more likely to have clones in their lymph nodes, and the presence of clonality is predictive of shorter survival.
Differential diagnosis In the early patch stage, mycosis fungoides may be difficult to diagnose. The skin lesions usually resemble a nondescript form of eczema with some scale. Interestingly, despite the itching, scratch marks and lichenification are usually absent. Mycosis fungoides presenting as papuloerythroderma of Ofuji is an obvious exception. The multiple morphologies of mycosis fungoides make the differential diagnosis vast. Plaque-like lesions may resemble subacute dermatitis or psoriasis. Tumors must be differentiated from other forms of lymphoreticular malignancy and metastases.
Treatment Effective therapy that reliably prolongs survival has not yet been documented. Many forms of therapy induce remissions of variable length. The choice between them depends on extent of disease, the patient’s overall health and physical status, the physician’s experience and preference, and the availability of various options. Topical steroids, topical nitrogen mustard or 1,3-bis (2-chloroethyl)-l-nitrosourea (carmustine) (BCNU), 725
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bexarotene gel 1%, and PUVA (or narrow-band UVB) are gen erally good choices for stages IA, IB, and IIA disease. Patchstage mycosis fungoides has responded to alefacept. Total skin electron beam (TSEB) therapy can be used for refractory stage IIA and IIB cases. Single-agent chemotherapy or photophore sis can be employed as initial management for stage III patients. Low-dose methotrexate may control the skin lesions of mycosis fungoides, but has been associated with the development of a secondary aggressive lymphoma in a few patients. Pegylated liposomal doxorubicin and combinations of IFN-α, retinoids (bexarotene or isotretinoin), photophoresis, IFN-γ, skindirected PUVA, sargramostim (granulocyte macrophage colony-stimulating factor), alemtuzumab, and perhaps IL-2, IL-12, and IFN-α may be effective in stage IV disease, and for patients who have failed the above therapies for stages IIB and III mycosis fungoides. Multiagent systemic chemotherapy is used much less commonly with the advent of immunomodu latory treatments for mycosis fungoides. It should only be considered when all other treatment options have failed. Treatment of early-stage disease is in general restricted to skindirected treatments. More advanced disease is treated with different modalities at different institutions. Combinations of agents are often used, and those combinations and their order of use vary from one institution to the next. In general, thera pies that also enhance the patient’s immune system are favored in persons with more advanced disease. Complete remission has been noted following a severe reaction to combined therapy with bexarotene, vorinostat, and high-dose fenofi brate. The reaction included fever, extensive skin necrosis, and granuloma formation. Topical corticosteroids The availability of superpotent class I topical corticosteroids has led to a reassessment of their pos sible role in the management of early (patch-stage, T1 and T2) mycosis fungoides. Zackheim reported a 63% complete remis sion for patients with T1 disease and a total response rate of 94% in T1 patients. In T2 patients, complete responses were only 25% but total responses were 82%. The predominant side effect was a temporary and reversible suppression of the hypothalamic–pituitary axis in about 13% of patients. The responses were short-lived if therapy was stopped, but given the limited toxicity, this is not necessary in many patients. The adjunctive value of topical corticosteroids in T1 mycosis fun goides requires reappraisal because the response rates are similar to other modalities used for early mycosis fungoides and the toxicity is very low. Topical nitrogen mustard The contents of a 10 mg vial of mechlorethamine hydrochloride (Mustargen-MSD) are dis solved in 60 mL of tap water and applied to the entire skin surface, except the face, axillae, and genitalia, with a 2 inch paint brush or gauze pad. The last milliliter may be diluted to half-strength or greater dilution for application to the face, axillae, and genitalia. Daily applications are made until com plete clearing occurs, which usually takes several months or longer, and may be continued indefinitely. Such treatment leads to complete responses in 80% of patients with stage IA disease, 68% in patients with stage IB, 61% in stage IIA, 49% in stage IIB, and 60% in stage III patients. About 10% of patients obtain a durable and long-lasting remission of over 8 years. The major side effects of topical nitrogen mustard (NH2) therapy are cutaneous intolerance, which occurs in almost 50% of patients, and allergic contact dermatitis, which occurs in 15%. Short (1 h) contact does not reduce this rate of sensitiza tion. This can be reduced by the use of an ointment formula tion, but response rates have been reported to be inferior with the ointment form. At least half of patients will relapse when therapy is stopped, but frequently will respond again to NH2. The duration of maintenance therapy after achieving remission varies in different centers. Some treat for an additional 6 months and others taper treatment over a year
or more, or continue treatment indefinitely. In many centers, topical nitrogen mustard has been a proven mainstay of therapy for patch- or plaque-stage mycosis fungoides without lymphadenopathy. Topical BCNU (carmustine) BCNU, 2 mg/mL in 150 mL aliquots, dissolved in ethanol, is dispensed to the patient. From this stock solution the patient takes 5 mL and adds it to 60 mL of water at room temperature. This is applied once a day to the whole body, sparing the folds, genitals, hands, and feet (if they do not have lesions). If the extent of disease is limited, only the affected areas are treated. The average treat ment course is 8–12 weeks. If, after 3–6 months, the patient’s condition is not responding, the concentration may be doubled and the treatment repeated for 12 weeks. For small or persist ent lesions, the straight stock solution may be applied daily. Patients tolerate BCNU better than nitrogen mustard, contact sensitization is uncommon, and responses are more rapid. Complete blood counts should be monitored monthly during treatment, but marrow suppression occurs in less than 10% of patients treated with the low concentrations. Telangiectasia, which may be persistent and severe, can occur after prolonged BCNU therapy or following an adverse cutaneous reaction to the medication. Ultraviolet therapy Both UVB (narrow- or broad-band) and PUVA (systemic or bath) have been effective in the manage ment of mycosis fungoides. About 75% of patients with patchstage disease will have a complete clinical remission with UVB therapy. Home therapy is successful. PUVA has been used more extensively and, because of its deeper penetration, is perhaps better suited to the treatment of a disorder with a dermal component. Complete clearing is seen in 88% of patients with limited patch/plaque disease and in 52% of patients with extensive disease. Tumor-stage patients do not clear. Erythrodermic patients have poor tolerance for PUVA. Up to 50% of patients with a complete response to PUVA may have a remission of up to 10 years. Retinoids and IFN-α may be added to PUVA. Retinoids may reduce the total number of PUVA treatments required. Low-dose IFN-α plus PUVA may be used in patch-stage patients in whom topical therapy and PUVA alone are ineffective. The excimer laser may be used once or twice a week to deliver the phototherapy if the patient has a limited number of lesions. On average, 5–6 weeks of treatment are required, and remissions of up to 2 years or more can be achieved. Extracorporeal photochemotherapy (photophoresis, ECP) is a therapeutic modality in which the circulating cells are extracted and treated with UVA outside the body; the patient ingests psoralen before the treatment. Complete responses are seen in a small percentage of mycosis fungoides patients, about 20%, and a partial response occurs in a similar percent age of patients. In the original reports, the overall response rate for erythrodermic patients was 80%, but many of these patients failed to have at least the 50% clearing required to be considered a partial response. In one comparative trial, stand ard PUVA was significantly more effective than photophoresis alone, and photophoresis was judged ineffective in plaquestage (T2) mycosis fungoides. ECP is now used in combination with other agents, especially IFN-α, and appears to have better efficacy. Insulin-dependent diabetics respond poorly. Radiation TSEB therapy in doses in excess of 3000 Gy is very effective in the management of mycosis fungoides. Stage T1 patients have a 98% complete response; stage T2, 71%; stage T3, 36%; and stage T4, 64%. Long-term remissions occur in about 50% of T1 patients and 20% of T2 patients. Erythrodermic patients tolerate TSEB therapy poorly; other modalities should be attempted initially. Adjuvant therapy with a topical agent or PUVA can be considered if the patient relapses, which is a frequent occurrence. The most common side effects of TSEB therapy are erythema, edema, worsening of lesions, alopecia,
protocols noted above. A number of new agents are being evaluated for the treatment of mycosis fungoides. Histone deacetylase inhibitors including vorinostat demonstrate responses in a subgroup of patients. Forodesine is a novel inhibitor of purine nucleoside phosphorylase and pralatrexate is a novel targeted antifolate agent. Fusion toxin DAB389IL-2 is the fusion of a portion of the diphtheria toxin to recombinant IL-2. This selectively binds to cells expressing the IL-2 receptor and leads to their death. A series of mycosis fungoides cases that expressed the IL-2 receptor demonstrated a response rate of 37%, including a complete response in 14% of cases. These patients had failed conventional therapies. Patients in stages I–III achieved response, but no patient with stage IV disease did so. Fever, chills, hypotension, nausea, and vomiting were common and at high doses a vascular leak syndrome occurred. This agent is reserved for advanced-stage patients who have failed other modalities.
Cutaneous lymphomas
and nail loss. Persistent hyperpigmentation and chronically dry skin are also problems after TSEB therapy. Orthovoltage radiation may be used to control tumors or resistant thick plaques in patients whose conditions have been otherwise controlled with another modality. Biologic response modifiers (multimodality immunomodulatory therapy) The appearance of circulating malignant T cells in mycosis fungoides may indicate failure of the host immune system to control the disease. Immunomodulatory agents are used in an attempt to enhance host immune function and gain control of the disease. It is often combined with treatments that increase malignant cell apoptosis, so that the “tumor antigens” released will be recognized and immunologically “attacked” by the host immune system. These immunomodulatory agents both activate antigen-presenting cells and enhance Th1 immune function directed against the malignant T-cell clone. IFN-α and IFN-γ have been shown to have efficacy against mycosis fungoides. IFN-α is associated with a positive response in about 60% of patients and a complete response in 19%. If it is used as a single agent, toxicity is high and includes fever, chills, myalgias, neutropenia, and depression. Low-dose IFN-α and IFN-γ treatments and granulocyte macrophage colonystimulating factor are now used in an adjunctive fashion in combination with retinoid therapy, phototherapy, and other modalities. This is termed multimodality immunomodulatory therapy. IL-2 and 12 may be used in a similar fashion in the future. Retinoids Both isotretinoin and etretinate have efficacy in the treatment of mycosis fungoides. A clinical response is noted in about 44% of patients. Dosage of isotretinoin is about 1 mg/kg/day to start, and may be increased up to 3 mg/kg/ day as tolerated. Retinoids may be effective in stage IB (T2) and stage III patients, and as a palliative treatment in those with stage IVA disease. Bexarotene (Targretin), a synthetic retinoid that is bound preferentially by the retinoid X receptor (RXR), is felt to work by inducing apoptosis in the malignant T cells. It is available as a 1% topical gel and as an oral tablet. Topical therapy is used in patients with stage IA–IIA cutane ous T-cell lymphoma. Patients improve about 50% with this treatment. Oral bexarotene at a dose of 300 mg/m2 also has a response rate of about 50% in early-stage cutaneous T-cell lymphoma. This dose is complicated by hypercholesterolemia, marked hypertriglyceridemia (at times complicated by pan creatitis), central hypothyroidism, and leukopenia. It may be combined with PUVA and other forms of treatment at a lower dose. Systemic chemotherapy For most forms of cancer, combi nations of chemotherapeutic agents are given. In mycosis fun goides, however, multidrug chemotherapy often exacerbates the ongoing immune imbalance and may prevent the patient’s immune system from attacking the malignant T cells. For this reason, and due to the enhanced efficacy of combination immunomodulatory treatment regimens, systemic chemother apy is now very uncommonly used for mycosis fungoides. Methotrexate, in doses from 5 to 125 mg/week, is effective for the management of T3 patients. In these patients, Zackheim et al demonstrated that 41% had a complete response, and an additional 17% a partial response, giving a total response of 58%. The median overall survival was 8.4 years and 69% of patients were alive at 5 years. For advanced mycosis fun goides, higher doses of methotrexate with citrovorum-factor rescue were successful in obtaining a response, which was then maintained with lower doses of methotrexate, not requir ing rescue. Similarly, pentostatin, etoposide, fludarabine, and 2-chlorodeoxyadenosine have been used. Systemic chemo therapy beyond methotrexate, especially multiagent chemo therapy, is best managed by an oncologist. Systemic chemotherapy is only indicated in stage III and IVA patients who have failed all the available immunoenhancing treatment
Arulogun SO, et al: Long-term outcomes of patients with advancedstage cutaneous T-cell lymphoma and large cell transformation. Blood 2008 Oct 15; 112(8):3082–3087. Carter J, et al: Phototherapy for cutaneous T-cell lymphoma: online survey and literature review. J Am Acad Dermatol 2009 Jan; 60(1):39–50. Enke CA: New options in diagnosis and management of mycosis fungoides and Sézary syndrome. Oncology (Williston Park) 2010 May; 24(6):507–508. Galper SL, et al: Diagnosis and management of mycosis fungoides. Oncology (Williston Park) 2010 May; 24(6):491–501. Gerami P, et al: Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma. Arch Dermatol 2008 Jun; 144(6):738–746. Green WH, et al: Patch-stage mycosis fungoides in remission after therapy with alefacept. J Am Acad Dermatol 2008 May; 58(5 Suppl 1): S110–S112. Kempf W, et al: Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization for Research and Treatment of Cancer (EORTC). Arch Dermatol 2008 Dec; 144(12):1609–1617. Lansigan F, et al: Current and emerging treatment strategies for cutaneous T-cell lymphoma. Drugs 2010 Feb 12; 70(3):273–286. Lafaille P, et al: Exacerbation of undiagnosed mycosis fungoides during treatment with etanercept. Arch Dermatol 2009 Jan; 145(1):94–95. McGirt LY, et al: Predictors of response to extracorporeal photopheresis in advanced mycosis fungoides and Sézary syndrome. Photodermatol Photoimmunol Photomed 2010 Aug; 26(4):182–191. Novelli M, et al: Flow cytometry immunophenotyping in mycosis fungoides. J Am Acad Dermatol 2008 Sep; 59(3):533–534. Olsen E, et al: Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization for Research and Treatment of Cancer (EORTC). Blood 2007 Sep 15; 110(6):1713–1722. Quereux G, et al: Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome. Arch Dermatol 2008 Jun; 144(6): 727–733. Steinhoff M, et al: Complete clinical remission of tumor-stage mycosis fungoides after acute extensive skin necroses, granulomatous reaction, and fever under treatment with bexarotene, vorinostat, and high-dose fenofibrate. J Am Acad Dermatol 2008 May; 58(5 Suppl 1):S88–91. Sun G, et al: Poor prognosis in non-Caucasian patients with early-onset mycosis fungoides. J Am Acad Dermatol 2009 Feb; 60(2):231–235.
Pagetoid reticulosis Localized epidermotropic reticulosis, Pagetoid reticulosis, or Woringer–Kolopp disease is an uncommon lymphoprolifera tive disorder considered be a form of mycosis fungoides. Other terms suggested for these cases have been acral mycosis fungoides or mycosis fungoides palmaris et plantaris. In large mycosis fungoides clinics, such cases represent about 0.6% of all mycosis fungoides cases. Pagetoid reticulosis is divided
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into classic Woringer–Kolopp, which usually describes soli tary lesions, and cases with multiple lesions (Ketron–Goodman variant). The unique features of Woringer–Kolopp disease are clinical. The disease presents as a solitary lesion that is often located on an extremity and frequently has a keratotic rim. If there is more than a single lesion, there is often a propensity for lesions to involve both the palms and soles. Frequently, over months to years, the lesion gradually enlarges, reaching a size of over 10 cm. In some cases, the lesions spontaneously come and go over many years. Twenty percent of cases occur in patients who are younger than 15 years of age. The long duration without progression has been a clinical hallmark of Woringer–Kolopp disease. Histologically, there is prominent epidermotropism of lymphocytes, with many lining up in the basal cell layer. This histologic pattern correlates with strong αE–β7 and α4–β7 integrin expression by the infiltrating cells. This integrin expression is also seen in the epidermotropic cells of classic mycosis fungoides and contact dermatitis. In mycosis fungoides, most cases are CD4+, but in the acral mycosis fungoides cases they may be CD4+, CD8+, or negative for both. TCR gene rearrangements can be detected in many cases of Woringer–Kolopp disease. Therapeutically, local exci sion and radiation therapy have been “curative” in many cases. Topical and systemic PUVA has also proved effective. Local recurrence is possible.
Sézary syndrome Sézary syndrome is the leukemic phase of mycosis fungoides. The characteristic features are generalized erythroderma, superficial lymphadenopathy, and atypical cells in the circu lating blood. Although patients with classic mycosis fungoides may progress to Sézary syndrome, usually patients with Sézary syndrome are erythrodermic from the onset. The skin shows a generalized or limited erythroderma of a typical fiery red color. Associated features can include leonine facies, eyelid edema, ectropion, diffuse alopecia, hyperkeratosis of the palms and soles, and dystrophic nails. Some patients develop lesions identical to vitiligo, especially on the lower legs. The symptoms are those of severe pruritus and burning, with epi sodes of chills. Prognosis is poor, with an average survival of about 5 years. Superficial lymphadenopathy is usually found in the cervi cal, axillary, and inguinal areas. Leukocytosis up to 30 000/ mm3 is usually present. In the peripheral blood, skin infiltrate, and lymph nodes, helper T cells with deeply convoluted nuclei are found—the so-called Sézary cells. Chromosomal aberra tions are common, but differ from the typical pattern seen in mycosis fungoides. Resistance to Fas-ligand and TNF-related apoptosis has been demonstrated. Histologically, and by immunohistochemistry, there are no reproducible differences between cases of mycosis fungoides and Sézary syndrome. In a fair number of cases of the latter, the cutaneous histology may be nonspecific, showing a spon giotic dermatitis. Additional hematologic evaluation may be necessary to confirm the diagnosis in the erythrodermic patient. T-cell gene rearrangement studies are frequently used to confirm the diagnosis of Sézary syndrome. In addition, an increased CD4/CD8 ratio in the blood, with an increase in the number of CD3+/CD4+/CD7−/CD26− circulating cells, is suggestive of leukemic mycosis fungoides. The erythroderma of Sézary syndrome must be distin guished from chronic lymphocytic leukemia (CLL), psoriasis, atopic dermatitis, photodermatitis, seborrheic dermatitis, contact dermatitis, drug reaction, and pityriasis rubra pilaris. This is done primarily by histopathologic and immunopatho logic examination. In Sézary syndrome, the infiltrating T cells in the skin have a Th2 phenotype, and Th2 cytokines are pro duced by these cells. This explains the reduced delayed-type
hypersensitivity, elevated IgE, and eosinophilia seen in these patients. Sézary syndrome is difficult to treat. Low-dose methotrexate has a reasonable response rate of about 50% and an overall survival of 101 months, suggesting a survival benefit with its use. Photophoresis, used in combination with other agents, is effective in some patients, but the median survival time is only between 39 and 60 months (see above). TSEB radiation has produced some complete cutaneous responses, as well as improvement in the blood burden of malignant cells. Zanolimumab has also been used in this setting. Arulogun S, et al: Extracorporeal photopheresis for the treatment of Sézary syndrome using a novel treatment protocol. J Am Acad Dermatol 2008 Oct; 59(4):589–595. Contassot E, et al: Resistance to FasL and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in Sézary syndrome T-cells associated with impaired death receptor and FLICE-inhibitory protein expression. Blood 2008 May 1; 111(9):4780–4787. Dores GM, et al: Assessment of delayed reporting of mycosis fungoides and Sézary syndrome in the United States. Arch Dermatol 2008 Mar; 144(3):413–414. Introcaso CE, et al: Total skin electron beam therapy may be associated with improvement of peripheral blood disease in Sézary syndrome. J Am Acad Dermatol 2008 Apr; 58(4):592–595.
Granulomatous slack skin Granulomatous slack skin is a rare variant lymphoma that typically presents in middle-aged adults and gradually progresses over years. It occurs more often in men. Lesions are erythematous, atrophic, bulky, infiltrated, pendulous, and redundant plaques in the axillae and groin (Fig. 32-9). Unusual presentations may resemble Hansen’s disease or acquired ichthyosis. Histologically, there is a lymphohistio cytic infiltrate extending through the dermis into the subcuta neous fat. Focal collections of huge, multinucleated cells with 20–30 nuclei arranged in a wreath-like pattern are characteristic. Elastophagocytosis is prominent and elastic tissue is absent in areas of inflammation. Lymphocytes are also found within the multinucleate giant cells and are arranged around them. Epidermotropic lymphocytes are also seen. Immunohistologically, the cells are CD4+. T-cell gene re arrangements can be detected. In most patients, the condition evolves into mycosis fungoides, but about one-third of patients with granulomatous slack skin develop Hodgkin disease after years to decades. Hsiao PF, et al: Granulomatous slack skin presenting as acquired ichthyosis and muscle masses. Am J Clin Dermatol 2009; 10(1):29–32. Pratchyapruit W, et al: Granulomatous slack skin clinically and histologically masquerading as borderline leprosy in its early stages. Eur J Dermatol 2009 Jan–Feb; 19(1):88–89.
Fig. 32-9 Granulomatous slack skin.
Lymphomatoid papulosis (LyP) is an uncommon, but not rare disorder. It occurs at any age, including childhood, but is most common in adults with a mean age of 44. In most typical cases, the lesions and course are very similar to that of Mucha– Habermann disease (pityriasis lichenoides et varioliformis acuta), except that the lesions tend to be slightly larger and fewer in number, and have a greater propensity to necrosis. Symptoms are usually minimal. The primary lesion is a red papule up to about 1 cm in diameter (Fig. 32-10). The lesions evolve to papulovesicular, papulopustular, or hemorrhagic, then necrotic papules over days to weeks. They typically heal spontaneously within 8 weeks, somewhat longer in larger lesions. Lesions are usually generalized, although cases limited to one anatomic region have been reported. There may be crops of lesions or a constant appearance of a few lesions. In most patients, however, the condition tends to be chronic, and lesions are present most of the time if no treat ment is given. The average number of lesions present at any one time is usually 10–20, but cases with more than 100 lesions occur. Lesions heal with varioliform, hyperpigmented, or hypopigmented scars. Cases previously reported as solitary, large nodules of lymphomatoid papulosis would now be clas sified as CD30+ large-cell lymphomas or as overlaps between LyP and lymphoma, termed borderline cases. Localized agmi nated LyP may be seen in areas typical for mycosis fungoides. The diagnosis of LyP is confirmed histologically. There is a dermal infiltrate that is wedge-shaped, patchy, and perivascu lar. In larger lesions, the infiltrate may occupy the whole dermis. It may also be bandlike. The infiltrate may involve the epidermis, with epidermotropism of inflammatory cells. As lesions evolve, epidermal necrosis and ulceration may occur. The dermal vessels may demonstrate fibrin deposition and, more rarely, a lymphocytic “vasculitis.” The dermal infiltrate is composed of lymphoid cells, eosinophils, neutrophils, and larger mononuclear cells. Atypical large or small lymphoid cells are present and may represent up to 50% of the infiltrate. Histologically, lesions have been classified into type A, type B, and type C lesions. Type A lesions contain atypical large cells with abundant cytoplasm and prominent nuclei, with prominent eosinophilic nucleoli. If these cells contain two nuclei, they closely resemble Reed–Sternberg cells. In type B lesions, the atypical cells are smaller, with a smaller cerebriform, hyperchromatic nucleus. These resemble the atypical cells of mycosis fungoides. In both types of lesion, atypical mitotic figures may be observed.
Immunophenotypically, the large atypical cells mark as T cells, usually of the helper type. The atypical cells, especially those of the type A lesions, stain for the activation marker Ki-1 or CD30. Bcl-2 expression occurs in about 50% of cases. When clonal rearrangement studies are performed, clonal rearrange ments may be found in up to 40% of LyP lesions, but this finding is not predictive of the behavior of that lesion or the case in general. Type C lesions overlap with primary cutane ous large-cell lymphoma with no clear distinction between the two. CD8+ LyP is a rare variant in which the Tc2 subset of CD8+ T cells proliferates and attracts eosinophils. Lymphomatoid papulosis types A and B are associated with lymphoma. In the general literature this number is about 5–10%, but some reports have documented rates as high as 20%, and at the University of California at San Francisco (UCSF) up to 40% of cases of LyP have an associated lym phoma. The lymphoma may occur before, concurrently with, or after the appearance of the LyP. In most cases, the LyP precedes the development of lymphoma, sometimes by a long period—up to 20 years. The associated lymphoma is most commonly mycosis fungoides (40%), a CD30+ T-cell lym phoma (30%), or Hodgkin disease (25%). The lymphoma and LyP may behave quite independently. If the lymphoma is suc cessfully treated and cleared, the LyP typically continues. Despite this independent behavior, the lymphoma and the LyP may contain the same clonal TCR gene rearrangement. Patients with pure type B lesions are much less likely to develop lymphoma than patients with type A lesions. Lesions of LyP may occur on a background of mycosis fungoides and must be distinguished from CD30-positive large-cell transfor mation of mycosis fungoides. Papular lesions of LyP tend to occur in crops. Even though the LyP lesions may demonstrate the same clonal rearrangements as the mycosis fungoides, they often continue to appear in crops, even when the mycosis fungoides lesions respond to therapy. Therapy may not be necessary; there is no evidence that treatment of LyP prevents the development of secondary lym phoma. When any therapy is stopped, the LyP invariably returns. Therefore, patients only need to be treated if they are moderately symptomatic and the treatment has fewer poten tial complications than the benefits gained. Superpotent topical corticosteroids have been beneficial in some childhood cases. Topical bexarotene may abort early lesions, and oral bexaro tene may suppress lesion formation. PUVA systemically or topically may be effective, although maintenance treatment is usually required. Both narrow- and broad-band UVB may be successful. Of all the systemic agents, methotrexate gives the most dependable response, with up to 90% of LyP patients improving significantly. It is given in weekly doses similar to those used for rheumatoid arthritis—usually 7.5–15 mg/week. Higher doses may be required in some patients. Response is rapid. Some patients treated with methotrexate may have remissions of the LyP. In most, however, maintenance therapy is required.
Cutaneous lymphomas
Lymphomatoid papulosis
Heald P, et al: Persistent agmination of lymphomatoid papulosis: an equivalent of limited plaque mycosis fungoides type of cutaneous T-cell lymphoma. J Am Acad Dermatol 2007 Dec; 57(6):1005–1011. Kamstrup MR, et al: Potential involvement of Notch1 signalling in the pathogenesis of primary cutaneous CD30-positive lymphoproliferative disorders. Br J Dermatol 2008 Apr; 158(4):747–753. Slone SP, et al: IL-4 production by CD8+ lymphomatoid papulosis, type C, attracts background eosinophils. J Cutan Pathol 2008 Oct; 35(Suppl 1):38–45.
Pityriasis lichenoides Fig. 32-10 Lymphomatoid papulosis. (Courtesy of M. Rosenbach, MD)
Both the acute and chronic forms of pityriasis lichenoides are lymphocytic vasculitides. The lymphoid infiltrate may contain 729
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a clonal proliferation. However, progression to cutaneous lymphoma is rare.
Pityriasis lichenoides et varioliformis acuta (Mucha–Habermann disease) Pityriasis lichenoides et varioliformis acuta (PLEVA) is a dis order that usually appears suddenly in children or young adults. Individual lesions are erythematous macules, papules, or papulovesicles. Lesions tend to be brownish-red and evolve through stages of crusting, necrosis, and varioliform scarring. Lesions tend to appear in crops, and may number from a few to more than 100 (Fig. 32-11). In general, PLEVA patients have more and smaller lesions than patients with LyP. The trunk is favored, but even the palms and soles may infrequently be involved. The patient feels otherwise well. The natural history is benign, with spontaneous involution occurring over 1–3 years. In children, diffuse cases resolved more quickly than cases that were purely central; cases with primarily peripheral lesions took almost twice as long to resolve. Histologically, PLEVA is characterized by epidermal necro sis, together with prominent hemorrhage and a dense perivas cular infiltrate in the upper and mid-dermis in a wedge-shaped pattern. Lymphocytic vasculitis may be seen. T-cell gene re arrangements may be detected, but the significance of that finding is unclear at this time. Treatment of PLEVA may include oral erythromycin or tetracyclines and phototherapy (broad- or narrow-band UVB, PUVA, or photodynamic therapy). Topical tacrolimus may be effective. Low-dose methotrexate, 5.0–15 mg/week, may be required in severe cases. A rapid response to azithromycin has been reported. Etanercept has been reported as effective, but infliximab has been reported to cause pityriasis lichenoides. An unusually severe form of PLEVA (febrile ulceronecrotic Mucha–Habermann disease) is characterized by the acute onset of diffuse, coalescent, large, ulceronecrotic skin lesions associated with high fever and constitutional symptoms. The condition may begin as typical PLEVA, but the ulceronecrotic lesions usually begin to appear within a few weeks. Skin necrosis may be extensive, especially in the intertriginous regions. Associated symptoms include gastrointestinal and central nervous system (CNS) symptoms, pneumonitis, myo carditis, and even death (in adult cases). The condition favors boys who are l8 years of age or younger. This severe form of PLEVA usually lasts several months with successive out breaks, then resolves or converts to more classic PLEVA. Reported triggers include viral infections and radiocontrast injection. Treatment is systemic steroids, and if response is limited, methotrexate. Dapsone may also be useful, for main tenance and as a steroid-sparing agent.
Pityriasis lichenoides chronica Pityriasis lichenoides chronica (PLC) is a chronic form of pit yriasis lichenoides, related to PLEVA by its common histol ogy. Lesions are erythematous, scaly macules and flat papules with very slow evolution. Lesions each last several months. The eventual resolution of lesions of PLC distinguishes it from guttate parapsoriasis, which it may resemble clinically. Lesions of small-plaque parapsoriasis do not spontaneously resolve. Lesions of PLC favor the lateral trunk and proximal extremi ties. Patients may have from 10 to hundreds of lesions, but usually fewer than 50. Resolution may leave persistent areas of hypopigmentation, which last for months to years. In many patients, the hypopigmented macules are the most prominent clinical finding. Unlike PLEVA, PLC tends to last for many years. Lesions may occur at any age. The condition commonly affects children, and onset at birth has been described. Histologically, the changes are similar to PLEVA but much more subtle. A mild interface or perivascular lymphocytic infiltrate with overlying parakeratosis may be present. T-cell gene rearrangement studies may demonstrate monoclonality; however, the meaning of this finding is unclear at this time. Treatment with phototherapy (natural sunlight, UVB, UVA1, or PUVA) is most effective. Topical steroids or tacrolimus may be tried. No treatment is required. PLC is generally a benign disease. There are rare patients who have progressed to develop cutaneous T-cell lymphoma. The authors recommend that patients with PLC be followed regularly and changes in lesion morphology, including indu ration, erosion, atrophy, persistent erythema, or poikiloderma, should trigger repeat pathologic evaluation. Aydogan K, et al: Narrowband UVB (311 nm, TL01) phototherapy for pityriasis lichenoides. Photodermatol Photoimmunol Photomed 2008 Jun; 24(3):128–133. Ersoy-Evans S, et al: Narrowband ultraviolet-B phototherapy in pityriasis lichenoides chronica. J Dermatolog Treat 2008 Nov; 14:1–5. Fernandes NF, et al: Pityriasis lichenoides et varioliformis acuta: a disease spectrum. Int J Dermatol 2010 Mar; 49(3):257–261. Fernández-Guarino M, et al: Pityriasis lichenoides chronica: good response to photodynamic therapy. Br J Dermatol 2008 Jan; 158(1):198–200. López-Ferrer A, et al: Pityriasis lichenoides chronica induced by infliximab, with response to methotrexate. Eur J Dermatol 2010 Jul–Aug; 20(4):511–512. Nikkels AF, et al: Etanercept in therapy multiresistant overlapping pityriasis lichenoides. J Drugs Dermatol 2008 Oct; 7(10):990–992. Skinner RB, et al: Rapid resolution of pityriasis lichenoides et varioliformis acuta with azithromycin. J Am Acad Dermatol 2008 Mar; 58(3):524–525. Smith JJ, et al: Febrile ulceronecrotic Mucha–Habermann disease associated with herpes simplex virus type 2. J Am Acad Dermatol 2009 Jan; 60(1):149–152. Sotiriou E, et al: Febrile ulceronecrotic Mucha–Habermann disease: a case report and review of the literature. Acta Derm Venereol 2008; 88(4):350–355.
Primary cutaneous T-cell lymphomas other than mycosis fungoides
Fig. 32-11 Mucha–Habermann disease.
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Once a cutaneous lymphoma has been identified as being of T-cell origin and the diagnosis of mycosis fungoides and its variants has been excluded, the most important evaluation is to determine the CD30-staining pattern. CD30 is a marker found on some activated, but not resting T and B cells. It also marks the Reed–Sternberg cells of Hodgkin disease. Monoclonal antibodies Ki-1 and Ber H2 are used to identify CD30 positiv ity. A cutaneous lymphoma is considered to be CD30+ if there are large clusters of CD30+ cells or more than 75% of the ana plastic T cells are CD30+. Systemic CD30+ lymphoma with cutaneous involvement has a poor prognosis. Those cases that
CD30+ cutaneous T-cell lymphoma (primary cutaneous anaplastic large-cell lymphoma) Clinically, these lymphomas present as solitary or localized skin lesions that have a tendency to ulcerate (50%), spontane ously regress (25%), and relapse. They are rare in children and occur with slightly greater frequency in males. Lesions are usually firm, red to violaceous tumors up to 10 cm in diameter (Fig. 32-12). Tumors may grow in a matter of weeks. There is no favored anatomic site. Onset has been reported during glatiramer acetate treatment of multiple sclerosis. Relapses in the skin are common, but the development of extracutaneous, bone marrow, or lymph node involvement is uncommon. Clonal populations may occasionally be demon strated in peripheral blood, but differ from those in the skin. Lymph node involvement is associated with a poorer progno sis. The “pyogenic lymphoma” of the skin is a neutrophil-rich CD30+ lymphoma with skin lesions that clinically resemble Sweet syndrome, pyoderma gangrenosum, halogenoderma, leishmaniasis, or deep fungal infection. IL-8 overexpression by the anaplastic CD30+ cells causes the neutrophilic infiltration. The number of neutrophils present may make histologic inter pretation difficult. Cases with features of both lymphomatoid
papulosis and CD30+ anaplastic T-cell lymphoma have been described, sometimes under the designation type C lympho matoid papulosis. Histologically, there is a dense dermal non epidermotropic infiltrate with atypical tumor cells whose large nuclei have one or several prominent nucleoli and abundant cytoplasm. The malignant cells can be further characterized as anaplastic, pleomorphic, and immunoblastic, but this distinc tion may be difficult and has yet to be determined to be of prognostic or therapeutic value. This form of primary cutane ous T-cell lymphoma has an excellent prognosis, with a 5-year survival of 90%. Lesions are highly responsive to radiother apy. Early individual lesions can even be surgically excised. Topical imiquimod has been therapeutically successful. Chemotherapy causes regression of lesions, but a rapid relapse usually occurs. Other than low-dose methotrexate, chemo therapy generally has little role in the treatment of this disease. Local hyperthermia has been used successfully, as has inhibi tion of the mammalian target of rapamycin.
Cutaneous lymphomas
express anaplastic lymphoma kinase (ALK-1) associated with a 2:5 translocation have a somewhat better prognosis. Primary cutaneous large T-cell lymphomas that are CD30+ are typically ALK-1-negative, have a very good prognosis, and tend to run a relapsing course similar to that of lymphomatoid papulosis. Individual lesions respond to irradiation and the relapsing course may remit with low-dose methotrexate. Large-cell lym phomas of the skin have similar histologic and clinical fea tures, so immunophenotyping is essential for prognosis. Clonal TCR gene rearrangements are present in large-cell T-cell lymphoma. The group of T-cell lymphomas that are not large-cell and CD30+ are classified in the WHO system as peripheral T-cell lymphomas. CD56 is rapidly becoming the second most important immunophenotypic marker for cutaneous lymphomas. Four important variants of CD56+ cutaneous lymphomas have been identified: a subset of subcutaneous panniculitis-like T-cell lymphoma; natural killer (NK)/T-cell lymphoma; blastic NK cell lymphoma; and CD8+ aggressive epidermotrophic cyto toxic T-cell lymphoma. Peripheral T-cell lymphoma is a heterogeneous grouping that includes primary cutaneous CD30+ nonanaplastic largecell lymphoma, primary cutaneous CD30− anaplastic and nonanaplastic large-cell lymphoma, and primary cutaneous CD30− pleomorphic small-/medium-cell lymphoma.
Secondary cutaneous CD30+ large-cell lymphoma CD30+ large-cell lymphomas may arise in cases of mycosis fungoides, in patients with lymphomatoid papulosis, and in patients who have documented extracutaneous disease (sec ondary cutaneous anaplastic large-cell lymphoma). Skin lesions of pyogenic lymphoma may be seen secondary to a pyogenic lymphoma of other organs. The prognosis is poor in patients who have extracutaneous disease preceding or near the time of cutaneous involvement. Among those with sys temic disease, the expression of Alk-1 associated with a t(2; 5) translocation is a favorable prognostic feature. Kempf et al reported that MUM1 expression is common in secondary ana plastic large-cell lymphoma and in LyP, but uncommon in primary cutaneous anaplastic large-cell lymphoma. Other authors have disputed that MUM1 is a useful marker. Patients with lymphomatoid papulosis, who develop cutaneous CD30+ lymphoma and who do not have systemic lymphoma or mycosis fungoides, typically have an excellent prognosis. The prognosis for patients with mycosis fungoides who develop CD30+ anaplastic large-cell lymphoma is poor.
Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma Non-mycosis fungoides CD30− cutaneous large T-cell lym phomas usually present as solitary or generalized plaques, nodules, or tumors of short duration. There is no preceding patch stage that distinguishes it from mycosis fungoides. The prognosis is poor, with a 5-year survival rate of 15%. The malignant cells are pleomorphic large or medium cell types or are immunoblastic. The cells may be cerebriform and epidermo tropism may be present. Some cases previously called d’emblée mycosis fungoides are better classified in this group. Multiagent chemotherapy is recommended.
Pleomorphic T-cell lymphoma (non-mycosis fungoides CD30− pleomorphic small/medium-sized cutaneous T-cell lymphoma)
Fig. 32-12 Large-cell anaplastic lymphoma.
This group comprises about 3% of all primary cutaneous lym phomas. Pleomorphic small/medium-sized cutaneous T-cell lymphoma is distinguished from the large-cell type by having less than 30% large pleomorphic cells. It is distinguished from mycosis fungoides by clinical features (lack of patch or plaque lesions). These primary cutaneous lymphomas usually present with one or several red–purple papules, nodules, or tumors (5 mm to 15 cm in size). Immunophenotypically, they are usually of helper T-cell origin and clonal rearrangements of the TCR gene are usually present. A CD4 phenotype, as opposed to a CD8 phenotype, is associated with a more 731
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favorable prognosis, but a CD4/CD56 phenotype has a poorer prognosis. The presence of a mixed population of suppressor cells, B cells, and histiocytes usually favors the diagnosis of reactive lymphoid hyperplasia. The overall prognosis is inter mediate, with a 5-year survival rate of 62%. The optimal therapy for this form of lymphoma has not been determined. Therapeutically, localized lesions have been treated with radi ation therapy or surgical excision. Chemotherapy, retinoids, interferons, and monoclonal antibodies have been used in widespread or progressive disease.
Lennert lymphoma (lymphoepithelioid lymphoma) Lennert lymphoma is a rare CD4+ systemic T-cell lymphoma. Cutaneous lesions occur in less than 10% of cases and present as papules, plaques, or nodules. The skin lesions may not represent lymphoma cutis because palisaded granulomatous and nonspecific dermal infiltrates may occur. The clinical and histologic appearance may resemble granuloma annulare very closely. The course is low-grade until the lymphoma trans forms to a high-grade, large-cell lymphoma.
Subcutaneous (panniculitis-like) T-cell lymphoma Clinically, patients are usually young adults who present with subcutaneous nodules (Fig. 32-13), usually on the lower extremities, and are frequently diagnosed as having erythema nodosum or some other form of panniculitis. Weight loss, fever, and fatigue are common and may herald the onset of a rapidly progressive hemophagocytic syndrome, which is often fatal. Extracutaneous involvement is rare, even in fatal cases. An indolent chronic course can also be seen, but even in these cases the prognosis is poor. This variant of lymphoma may also rarely be seen in childhood. Histologically, there is a lace-like infiltration of the lobules of adipocytes, mimicking panniculitis, especially lupus pro fundus. A characteristic feature is rimming of neoplastic cells around individual adipocytes. The infiltrate contains prima rily small cells with hyperchromatic, irregular nuclei and large anaplastic cells in varying proportions. The small cells are atypical, karyorrhexis is prominent, and mitotic figures are
frequent. Benign histiocytes are present in large or small numbers and demonstrate erythrophagocytosis (bean-bag cells). Immunophenotypically, the neoplastic cells mark as T cells (CD2+, CD3+). Most cases are derived from α/β T cells and are CD56−. They have a less aggressive course. A subset of subcutaneous T-cell lymphomas are derived from γ/δ T cells and are CD56+. These cases have been misdiagnosed as lupus profundus or alopecia areata; histologically prominent dermal and even epidermal (interface) involvement may be seen. They have a more aggressive course and are now classi fied separately. SPTCL may evolve from the benign variant of cytophagic histiocytic panniculitis, which may also have a hemophagocytic syndrome. Multiagent chemotherapy is rec ommended, at times with stem-cell support. Denileukin difti tox (Ontak) was reported to produce a favorable response.
Nasal/nasal-type NK/T-cell lymphoma (angiocentric lymphoma) NK/T-cell lymphoma most frequently presents in extranodal tissue and is characterized by a high incidence of nasal involvement. It is more common in Asia, where it affects pri marily women with a mean age of 40. In Korea it is reported to be the most common form of cutaneous lymphoma after mycosis fungoides. It is uncommon in the US. It presents clini cally as dermal or subcutaneous papules or nodules that may ulcerate. Lesions are usually widespread and involve the lower extremities. A hydroa vacciniforme-type has been described in children in Mexico and in adults and children in Japan and Korea. Skin lesions are facial and extremity papulo vesicles ulcerate and heal with scarring. Skin lesions are exac erbated by sun exposure and are reproduced with UVA irradiation. Histologically, the dermis and subcutaneous fat are infil trated with intermediate-sized, atypical lymphocytes, within and around the walls of small and medium-sized vessels. Epidermotropism may be noted. The lymphoma cells express a spectrum of T- and NK-cell immunophenotypic markers, variably expressing CD2, CD3, CD4, CD8, and the NK-cell marker CD56. CD56 is not cell lineage-specific, and a subset of CD56 cutaneous lymphoma cases is classified under the SPTCL category. Epstein–Barr virus is present in the NK vari ants and variably present in the T-cell variants. T-cell clonality is detected if the T-cell immunophenotype is present. The prognosis is poor.
Blastic plasmacytoid dendritic cell neoplasm (blastic NK-cell lymphoma, CD4, CD56+ hematodermic neoplasm) The majority of patients are males, with a mean age of about 60 years. All patients present with multiple, rapidly expanding plaques and/or nodules on noncontiguous sites. Lesions are characteristically purple in color. The course is aggressive in most patients, with rapid cutaneous relapse after chemother apy with systemic involvement. Histologically, the cells infil trate the dermis or subcutaneous fat, with a tendency for the neoplastic cells to “Indian file” in dermal collagen. There is usually a Grenz zone below the epidermis. The lymphoma cells are small/medium to large blastic lymphocytes. Angiocentricity may be noted, but is not prominent. Immunophenotyping is usually CD4+,CD56+. MIB-1 shows a proliferation activity of over 50%. T-cell gene rearrangements are negative. A response to pralatrexate has been reported, but in general the results with radiation therapy and chemother apy have been poor. Bone marrow transplantation (BMT) may play an important role in therapy. Fig. 32-13 Subcutaneous T-cell lymphoma.
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Benner MF, et al: Bone marrow examination has limited value in the staging of patients with an anaplastic large cell lymphoma first
Cutaneous B-cell lymphoma Primary cutaneous B-cell lymphomas (Fig. 32-14) occur less commonly than cutaneous T-cell lymphomas (25% of cases of primary cutaneous non-Hodgkin lymphomas are B-cell in origin). Although the morphologic appearance of the malig nant lymphocytes composing these primary cutaneous lym phomas is identical to lymphomas based in lymph nodes, they have a distinctly different clinical behavior and immuno phenotypic profiles. This renders the classification systems based on lymph node histology of limited benefit in the diag nosis of primary cutaneous B-cell lymphomas. More simpli fied schemes have thus been proposed that apply to primary cutaneous lymphomas only. While most entities classified by the European Organization for Research and Treatment of Cancer (EORTC) have now been accepted in the WHO classification, some remain provisional entities. The great majority of primary cutaneous B-cell lymphomas are composed of cells with the morphologic characteristics of the B cells normally found in the marginal zone or germinal centers of lymph nodes. Classification schemes used primarily for lymph node-based lymphomas divide these lymphomas into multiple types based on histomorphology. Secondary cutaneous involvement can occur with all forms of B-cell lym phoma based primarily in lymph node or other sites. The clinical features are similar to those of primary cutaneous lymphoma, with violaceous papules or nodules (Fig. 32-15). Typically, the histologic structure of secondary lesions in the skin is similar to that of the lymphoma at the site of origin, usually the lymph nodes. The pattern in the skin may not, however, be sufficient to classify the lymphoma, making lymph node biopsy necessary in most cases. In secondary cutaneous B-cell lymphomas the prognosis is generally poor. It is therefore critical to evaluate any patient suspected of having primary cutaneous B-cell lymphoma to exclude involvement at another site. Radiation is most commonly used for indolent forms of cutaneous B-cell lymphoma, but excision, rituximab, intralesional corticosteroids, and systemic chemo therapy have also been used in selected cases. Higher-grade lymphomas, including leg-type lymphoma, primary cutane ous follicle center lymphoma occurring on the leg, and precur sor B-cell lymphoblastic lymphoma, are typically treated with systemic chemotherapy regimens including combinations of anthracycline-containing chemotherapies and rituximab.
Cutaneous B-cell lymphoma
presenting in the skin. Retrospective analysis of 107 patients. Br J Dermatol 2008 Nov; 159(5):1148–1151. Chumsri S, et al: Inhibition of the mammalian target of rapamycin (mTOR) in a case of refractory primary cutaneous anaplastic large cell lymphoma. Leuk Lymphoma 2008 Feb; 49(2):359–361. Ehst BD, et al: Primary cutaneous CD30+ anaplastic large cell lymphoma responds to imiquimod cream. Eur J Dermatol 2008 Jul–Aug; 18(4):467–468. Fernández-Torres R, et al: Extranodal NK/T-cell lymphoma, nasal type presenting as a pyogenic granuloma-like on a fingertip. Eur J Dermatol 2009 Jan–Feb; 19(1):79–80. Fujita H, et al: Primary cutaneous anaplastic large cell lymphoma successfully treated with low-dose oral methotrexate. Eur J Dermatol 2008 May–Jun; 18(3):360–361. Herling M, et al: CD4+/CD56+ hematodermic tumor: the features of an evolving entity and its relationship to dendritic cells. Am J Clin Pathol 2007 May; 127(5):687–700. Honma M, et al: Primary cutaneous anaplastic large cell lymphoma successfully treated with local thermotherapy using pocket hand warmers. J Dermatol 2008 Nov; 35(11):748–750. Humme D, et al: Dominance of nonmalignant T-cell clones and distortion of the TCR repertoire in the peripheral blood of patients with cutaneous CD30+ lymphoproliferative disorders. J Invest Dermatol 2009 Jan; 129(1):89–98. Kempf W, et al: MUM1 expression in cutaneous CD30+ lymphoproliferative disorders: a valuable tool for the distinction between lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Br J Dermatol 2008 Jun; 158(6):1280–1287. Leitenberger JJ, et al: CD4+ CD56+ hematodermic/plasmacytoid dendritic cell tumor with response to pralatrexate. J Am Acad Dermatol 2008 Mar; 58(3):480–484. Madray MM, et al: Glatiramer acetate-associated, CD30+, primary, cutaneous, anaplastic large-cell lymphoma. Arch Neurol 2008 Oct; 65(10):1378–1379. Massone C, et al: The morphologic spectrum of primary cutaneous anaplastic large T-cell lymphoma: a histopathologic study on 66 biopsy specimens from 47 patients with report of rare variants. J Cutan Pathol 2008 Jan; 35(1):46–53. Parveen Z, et al: Subcutaneous panniculitis-like T-cell lymphoma: redefinition of diagnostic criteria in the recent World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas. Arch Pathol Lab Med 2009 Feb; 133(2):303–308. Querfeld C, Khan I, Mahon B, Nelson BP, Rosen ST, Evens AM: Primary cutaneous and systemic anaplastic large cell lymphoma: clinicopathologic aspects and therapeutic options. Oncology (Williston Park) 2010 Jun; 24(7):574–587. Savage KJ: Prognosis and primary therapy in peripheral T-cell lymphomas. Hematology Am Soc Hematol Educ Program 2008; 2008:280–288. Savage KJ, et al: ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008 Jun 15; 111(12):5496–5504.
Adult T-cell leukemia/lymphoma Infection with human lymphotropic virus type 1 (HTLV-1) may lead to acute T-cell leukemia/lymphoma (ATL) in 0.01– 0.02% of infected persons. This virus is endemic in Japan, Southeast Asia, the Caribbean, Latin America, and equatorial Africa. ATL usually has an acute onset, with leukocytosis, lymphadenopathy, and HOTS (hypercalcemia, osteolytic bone lesions, T-cell leukemia, and skin lesions). Lesions resemble mycosis fungoides, except that patches are uncommon and plaques and nodules predominate. Histologically, the skin lesions contain lichenoid infiltrates of medium-sized lym phocytes with convoluted nuclei. Epidermotropism and involvement around and within adnexa occur. Granuloma formation may occur in the dermis. ATL cells are usually CD4+/CD7− and show T-cell gene rearrangements.
Fig. 32-14 Lymphoma, B-cell.
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Fig. 32-15 Secondary cutaneous B-cell lymphoma.
Primary cutaneous marginal zone lymphoma (PCMZL, MALT-type lymphoma, including primary cutaneous immunocytoma) These lymphomas present as solitary or multiple dermal or subcutaneous nodules or tumors primarily on the upper part of the body, trunk, or extremities. Widespread lesions suggest secondary skin involvement by systemic lymphoma. Women are affected more than men. Immunocytomas are associated with European Borrelia and occur as tense, shiny, pink to red nodules on the legs of older patients. Histologically, the infiltrate may be nodular or diffuse. The neoplastic cells are medium-sized gray cells with predomi nantly cleaved nuclei that proliferate within the space sur rounding and between benign germinal centers. Plasma cells are typically present and may be numerous. Light chain restriction is easiest to identify in the plasma cell population by means of in situ hybridization. The lymphoma cells may contain “Dutcher bodies,” intranuclear collections of immuno globulin. Initially, the malignant cells may represent a very small proportion of the infiltrate and an incorrect diagnosis of pseudolymphoma may be made. Over time, the “marginal zone” cells predominate and the germinal centers are dimin ished. Immunophenotypically, the cells are CD20+, CD79+, and BCL-2+. Clonal immunoglobulin gene rearrangements can usually be demonstrated. The prognosis is excellent, with 5-year survival close to 100%. Local radiation therapy, or exci sion if lesions are few, is recommended. In some Borreliaendemic areas in Europe, immunocytomas are common. They present with sheets of plasmacytoid B cells with Dutcher bodies. Treatment is similar to other forms of PCMZL.
Primary cutaneous follicle center cell lymphoma (PCFCCL, diffuse and follicular types) Clinically, most patients present with single or multiple papules, plaques, or nodules, with surrounding erythema, in one anatomic region. About two-thirds of cases present on the trunk, about one-fifth on the head and neck (the vast majority of these on the scalp), and about 15% on the leg. These lym 734
phomas are more common in men than women. Males outnumber females 4:1 in trunk lesions, whereas women disproportionately have head and leg lesions. Untreated, the lesions gradually increase in size and number, but extracuta neous involvement is uncommon. The prognosis is excellent, 5-year survival with treatment approaching 100%. Secondary cutaneous involvement of systemic follicular lymphoma has a poor prognosis. Histologically, the neoplasm is composed of centroblasts (uncleaved nuclei with a peripheral nucleolus) and centrocytes (cleaved nuclei with a peripheral nucleolus). The diffuse form is more common than the follicular form. In the diffuse form, the neoplastic cells retain the normal BCL-6+ phenotype of a follicle center cell, but typically lose expression of CD10. The follicular growth pattern is composed of irregularly shaped asymmetrical follicles that crowd together like pieces of a jigsaw puzzle. The cells typically stain for both BCL-6 and CD10, and these stains demonstrate neoplastic cells that have “wandered” beyond the confines of the follicle center. Elongated “carrot-shaped” nuclei are often present within the follicular centers, and CD21 staining shows defects in the net of dendritic cells in the follicle center. In early lesions, the neoplastic cells are of smaller size and there is a substantial portion of normal T cells surrounding and mixed with the neoplastic B cells. Over time, the neoplas tic B cells become a more predominant portion of the infiltrate, the neoplastic cells are larger in size, and tumor-infiltrating T cells diminish. Immunophenotypically, the neoplastic cells stain with B-cell markers (CD20) and may be monotypic for immunoglobulin production, i.e. they stain for either κ or λ light chains, but not both. Immunoglobulin staining is com monly negative in tumorous lesions, but clonal rearrangement of the immunoglobulin gene can be demonstrated by polymer ase chain reaction (PCR). The absence of expression of BCL-2, lack of adenopathy, and lack of involvement of the bone marrow help to exclude nodal follicular center lymphoma. Nodal follicular lymphoma usually expresses BCL-2 and there is a t(14 : 18) translocation in more than 80% of cases. BCL-2 expression is usually lacking in primary cutaneous follicular lymphoma. Radiation therapy totaling 30–40 Gy and including all ery thematous skin and a 2 cm margin of normal skin is very effective for lesions of the head and trunk. A combination of intralesional IFN-α, 5 MU every 4 weeks, and topical bexaro tene gel, 1% twice, has also been used. Anthracycline-based chemotherapy or rituximab may be used for relapses, as well as for more aggressive lesions of the leg. In Europe, a few cases of PCFCL are associated with Borrelia infection and may arise in lesions of acrodermatitis chronica atrophicans.
Diffuse large B-cell lymphoma (primary cutaneous large B-cell lymphoma) Clinically, lesions present as solitary or localized red or purple papules, nodules, or plaques. In general, solitary or localized lesions are typical of primary disease, and widespread lesions suggest secondary cutaneous involvement of primary nodal lymphoma. Lesions on the head and neck have an excellent prognosis. Lesions on the leg have a poorer prognosis, with a 5-year survival of about 50%, and are considered in some clas sifications as a separate entity (Fig. 32-16). This group of lymphomas is composed of large lymphocytes. Tumors made up of sheets of centroblasts and immunoblasts (non-cleaved nuclei with peripheral or central nucleoli, respec tively) should be stained for MUM1, a marker for leg-type lymphoma. If the tumor cells express MUM1, the prognosis is worse. Immunophenotypically, cells usually express CD20 and
Cutaneous B-cell lymphoma Fig. 32-16 B-cell lymphoma of the leg.
monotypic immunoglobulin, and leg-type lymphoma expresses BCL-2. Secondary cutaneous involvement with nodal large B-cell lymphoma is also associated with a poor prognosis. Richter transformation of chronic lymphocytic leukemia into a high-grade lymphoma occurs in 3–10% of patients with chronic lymphocytic leukemia. Its onset is often heralded by fever, night sweats, and weight loss. The lymphoma com monly arises in the lymph nodes or bone marrow, but can also present in the skin or internal organs.
Intravascular large B-cell lymphoma (malignant “angioendotheliomatosis,” angiotropic large-cell lymphoma) Clinically, these patients present with variable cutaneous morphologies, often very subtle and nonspecific. Some cases resemble classic lymphoma with violaceous papules or nodules. Others more closely resemble intravascular throm botic disorders, with livedo reticularis-like lesions or telangiec tatic patches. Sclerotic plaques may also occur. Even normal skin can show the characteristic changes on biopsy. Patients often present with fever of unknown origin. CNS symptoms are prominent, with progressive dementia or multiple cere brovascular ischemic events that may precede skin findings by many months. Histologically, the features are characteristic and diagnostic. Dermal and subcutaneous vessels are dilated and filled with large neoplastic cells. Focal extravascular accumulations may be seen. The neoplastic cells are CD20+ and CD79a+, and monotypic for immunoglobulin. Clonal immunoglobulin gene rearrangements may be detected. Despite the large number of intravascular cells in the skin and other affected organs, the peripheral blood smears and bone marrow may be normal histologically. The prognosis is very poor. Multiagent chemo therapy is recommended. Rare cases of intravascular lym phoma may be of T-cell origin. Adam DN, et al: Review of intravascular lymphoma with a report of treatment with allogenic peripheral blood stem cell transplant. Cutis 2008 Oct; 82(4):267–272. Gerami P, et al: Applying the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome in primary cutaneous marginal zone lymphoma. J Am Acad Dermatol 2008 Aug; 59(2):245–254. Grange F, et al: Primary cutaneous diffuse large B-cell lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases. Arch Dermatol 2007 Sep; 143(9):1144–1150.
Fig. 32-17 Plasmacytoma extending from the sternum. Hallermann C, et al: New prognostic relevant factors in primary cutaneous diffuse large B-cell lymphomas. J Am Acad Dermatol 2007 Apr; 56(4):588–597. Morales AV, et al: Indolent primary cutaneous B-cell lymphoma: experience using systemic rituximab. J Am Acad Dermatol 2008 Dec; 59(6):953–957. Senff NJ, et al: Results of radiotherapy in 153 primary cutaneous B-cell lymphomas classified according to the WHO-EORTC classification. Arch Dermatol 2007 Dec; 143(12):1520–1526. Senff NJ, et al: European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 2008 Sep 1; 112(5):1600–1609. Shafer D, et al: Cutaneous precursor B-cell lymphoblastic lymphoma in 2 adult patients: clinicopathologic and molecular cytogenetic studies with a review of the literature. Arch Dermatol 2008 Sep; 144(9):1155–1162. van Tuyll van Serooskerken AM, et al: Coincidence of cutaneous follicle center lymphoma and diffuse large B-cell lymphoma. Int J Dermatol 2008 Nov; 47(Suppl 1):21–24. Yamazaki ML, et al: Primary cutaneous Richter syndrome: prognostic implications and review of the literature. J Am Acad Dermatol 2009 Jan; 60(1):157–161.
Plasmacytoma (multiple myeloma) True cutaneous plasmacytomas are seen most commonly in the setting of myeloma. They are, however, rare, occurring in only 2% of myeloma cases. These cases are called secondary cutaneous plasmacytoma. They may also occur by direct extension from an underlying bone lesion (Fig. 32-17). They may appear at sites of trauma, such as biopsies or intra venous catheters (inflammatory oncotaxis). Most commonly, secondary cutaneous plasmacytomas occur in the setting of advanced myeloma and the prognosis is poor. Less commonly, the skin lesions may be the initial clinical finding, leading to the diagnosis of myeloma. Many cutaneous lesions formerly classified as primary cutaneous plasmacytomas are now clas sified as plasma cell-rich primary cutaneous marginal zone lymphoma. Anetoderma may show plasmacytoma on biopsy. A rare manifestation of a solitary plasmacytoma of bone is an overly ing erythematous skin patch that may be 10 cm or more in diameter. The chest is the most common location. Lymphadenopathy is present and some of the patients have or develop POEMS syndrome (polyneuropathy, organomeg aly, endocrinopathy, monoclonal protein, and skin changes). This syndrome has been called adenopathy and extensive skin patch overlying a plasmacytoma, or AESOP. 735
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Histologically, there are nodular and diffuse collections of plasma cells with varying degrees of pleomorphism and atypia. The degree of atypia may predict prognosis. The cells are monotypic for immunoglobulin production and produce the same light chain as the myeloma. The immunoglobulin produced is most commonly IgG or IgA, and rarely IgD or IgE. CD79 is positive, but CD19 and CD20 are negative. In addition to plasmacytomas, patients with myeloma may develop a vast array of cutaneous complications. These include normolipemic plane xanthomas, amyloidosis, vasculitis, and calcinosis cutis. An unusual but characteristic skin finding in myeloma is multiple follicular spicules of the nose, forehead, cheeks, and chin. They are yellowish and firm to palpation, and can be removed without bleeding. Numerous small ulcer ations may occur on the trunk. Both the spicules and ulcers contain an eosinophilic material composed of the abnormal monoclonal protein produced by the malignant cells. The spi cules are not made of keratin. Clinically similar cutaneous spicules composed of keratin can be seen in vitamin A defi ciency, chronic renal failure, acquired immunodeficiency syndrome (AIDS), Crohn’s disease, and other malignant diseases. The appropriate treatment of plasmacytomas is determined by the presence or absence of associated systemic disease. Solitary or paucilesional primary cutaneous plasmacytomas have been treated successfully with local surgery and radia tion therapy. Systemic chemotherapy may be required if these modalities fail. The treatment for secondary plasmacytomas and for patients with numerous primary cutaneous plasma cytomas is chemotherapy.
Cutaneous and systemic plasmacytosis Cutaneous plasmacytosis and systemic plasmacytosis occur largely in Asians, slightly favoring males. They typically occur between the ages of 20 and 55. These conditions are character ized by polyclonal proliferations of plasma cells and hyper globulinemia, and were originally considered variants of Castleman’s disease. Cutaneous plasmacytosis affects only the skin but patients may have lymphadenopathy and systemic symptoms of fever and malaise. Systemic plasmacytosis has involvement in two or more organ systems, usually, in addi tion to skin, the lung, bone marrow, and liver. Dyspnea may occur due to interstitial pneumonia. Uncommonly, cases of systemic plasmacytosis may progress to lymphoma. The course is chronic and benign, and response to various cyto static and immunosuppressive treatments has been poor. PUVA and topical tacrolimus have been reported to be effec tive for skin lesions. The skin lesions in cutaneous and sys temic plasmacytosis are identical. They consist of multiple brown–red plaques, mostly of the central upper trunk, but also of the face. Lesions range from 1 to 3 cm in diameter. They are often considered simply postinflammatory hyperpigmenta tion until they are palpated. Histologically, they show a dense perivascular infiltrate of mature plasma cells, which stain for both κ and λ light chains (polyclonality). Elevated IL-6 has been reported in some patients.
Hodgkin disease The vast majority of reports of cutaneous Hodgkin disease actually represent type A lymphomatoid papulosis (LyP). These two diseases have a considerable number of overlap ping features. The type A cells of LyP have similar morphol ogy and share immunophenotypic markers with Reed–Sternberg cells. LyP can be seen in patients with Hodgkin disease. Primary cutaneous Hodgkin disease without nodal 736
involvement is thus difficult to prove and is very, very rare, if it exists. Most cases of Hodgkin disease of the skin usually originate in the lymph nodes, from which extension to the skin is either retrograde through the lymphatics or direct. Lesions present as papules or nodules, with or without ulceration. Lesions resembling scrofuloderma may occur. Miliary dissemination to the skin can occur in advanced disease. Nonspecific cutaneous findings are common in patients with Hodgkin disease. Generalized, severe pruritus may precede other findings of Hodgkin disease by many months or may occur in patients with a known diagnosis. Secondary prurigo nodules and pigmentation may occur as a result of scratching. An evaluation for underlying lymphoma should be consid ered in any patient with severe itching, no primary skin lesions, and no other cause identified for the pruritus. Acquired ichthyosis, exfoliative dermatitis, and generalized and severe herpes zoster are other cutaneous findings in patients with Hodgkin disease.
Malignant histiocytosis (histiocytic medullary reticulosis) Most cases considered to be malignant histiocytosis in the past are now considered to be other forms of lymphoma or lym phomas with large components of reactive histiocytes. Very rare cases of true malignancies of histiocytes may still occur and can have cutaneous lesions, most characteristically ery thematous nodules. Often, the bone marrow examination in these patients is initially normal, but cases are rapidly progres sive and fatal, and the bone marrow becomes involved. Introcaso CE, et al: Cutaneous Hodgkin disease. J Am Acad Dermatol 2008 Feb; 58(2):295–298.
Leukemia cutis Clinical features Cutaneous eruptions seen in patients with leukemia may be divided into specific (leukemia cutis) and nonspecific lesions (reactive and infectious processes). Overall, about 30% of biop sies from patients with leukemia will show leukemia cutis. All forms of leukemia can be associated with cutaneous findings, but skin disease is more common in certain forms of leukemia. Myeloid leukemia with monocytic differentiation involves the skin more commonly than other types of myeloid leukemia. CD68 and lysozyme immunostains can be helpful in distin guishing this form of leukemia. Dermatologic manifestations are commonly seen in patients with acute myelogenous leuke mia (AML) and myelodysplastic syndrome (MDS). AML includes types M1–M5. In AML and MDS patients, only about 25% of skin biopsies will show leukemia cutis, the remainder showing complications of the leukemia. These include infec tions, graft versus host disease, drug reactions, or the reactive conditions associated with leukemia that are sometimes referred to as leukemids. By contrast, in patients with acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL), about 50% of biopsies will show leukemia cutis. Lesion presentation may be subtle, and may include macular erythema, hyperpigmen tation, or morbilliform rash.
Specific eruptions The most common morphology of leukemic infiltrations of the skin in all forms of leukemia is multiple papules or nodules
Leukemia cutis Fig. 32-20 Gingival involvement in leukemia. Fig. 32-18 Leukemia cutis.
Fig. 32-19 Leukemia cutis.
(60% of cases) or infiltrated plaques (26%). These lesions are usually flesh-colored, erythematous, or violaceous (plumcolored) (Figs 32-18 and 32-19). They are rubbery on palpation and ulceration is uncommon. Extensive involvement of the face may lead to a leonine facies. Less common manifestations of leukemia cutis are subcuta neous nodules resembling erythema nodosum or panniculitis, arciform lesions (in juvenile CML), ecchymoses, palpable purpura, erythroderma, ulcerations (which may resemble pyoderma gangrenosum or venous stasis ulceration), and urticaria-like, urticaria pigmentosa-like (in ALL), and guttate psoriasis-like lesions. Rare manifestations are a lesion resem bling Sister Mary Joseph nodule and cutaneous sarcoidal lesions. Myelogenous leukemia may be complicated by lesions resembling stasis dermatitis or chilblains. Gingival infiltration causing hypertrophy is common in and relatively unique to patients with acute myelomonocytic leukemia (Fig. 32-20). Leukemia cutis most commonly occurs concomitant with or following the diagnosis of leukemia. The skin may also be a site of relapse of leukemia after chemotherapy, especially in patients who present with leukemia cutis. Uncommonly, leukemia cutis may be identified while the bone marrow and peripheral blood are normal. These patients are classified as “aleukemic leukemia cutis,” as they have normal bone marrow evaluations and no circulating blasts. These cases are often misdiagnosed as cutaneous lymphomas and undertreated. They eventually relapse, with full-blown leukemia. The key to the diagnosis is a Leder stain, which will identify the atypical cells as myeloid. Systemic involvement occurs within 3 weeks
to 20 months (average 6 months). Leukemia cutis is a poor prognostic finding in patients with leukemia, with 90% of such patients having extramedullary involvement and 40% having meningeal infiltration. The term congenital leukemia applies to cases appearing within the first 4–6 weeks of life. Leukemia cutis occurs in 25–30% of such cases, the vast majority being congenital mye logenous leukemia. The typical morphology is multiple, red or plum-colored nodules. In about 10% of cases of congenital leukemia cutis (or 3% of all cases of congenital leukemia), the skin involvement occurs while the bone marrow and periph eral blood are normal. Systemic involvement is virtually always identified in 5–16 weeks. Unlike in other forms of leukemia, in congenital leukemia, cutaneous infiltration does not worsen prognosis. Congenital leukaemia cutis has been complicated by disseminated linear calcinosis cutis. Earlyonset aleukemic leukemia cutis can occasionally undergo spontaneous regression. One report involved a child with mastocytosis, who also developed a leukemia clone with a t(5; 17)(q35; q12), nucleophosmin (NPM)-retinoic acid receptor-α (RARA) fusion gene.
Granulocytic sarcoma (chloroma) Granulocytic sarcomas are rare tumors of immature granulo cytes. They occur in about 3% of patients with myelogenous leukemia. Granulocytic sarcoma is seen in four settings: in patients with known AML; in patients with CML or MDS as a sign of an impending blast crisis; in undiagnosed patients as the first sign of AML; or after BMT as the initial sign of relapse. Most lesions occur in the soft tissues, periosteum, or bone. Skin lesions represent 20–50% of reported cases. They may be solitary or multiple. They appear as red, mahogany, or violaceous firm nodules with a predilection for the face, scalp, or trunk. The name chloroma comes from the green color of fresh lesions, which can be enhanced by rubbing with alcohol; this is caused by the presence of myeloperoxidase. This appear ance is variable, so the preferred term is now granulocytic sarcoma. The diagnosis is not difficult if the diagnosis of leukemia has been established. Such patients are treated with appropriate chemotherapy. However, if the skin lesion is the initial mani festation of leukemia, and the blood and bone marrow are normal, the lesion may be misdiagnosed as a large-cell lym phoma. The treatment of such patients is controversial, but most go on to develop AML within months, so chemotherapy is often given. 737
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Hairy cell leukemia Skin involvement is rare in hairy cell leukemia, and violaceous papules and nodules, which are the characteristic morphology of other forms of leukemia cutis, are extremely rare in hairy cell leukemia. Rather, a diffuse erythematous, nonpruritic eruption occurs, often in the setting of a systemic mycobacte rial infection or a drug reaction. This may progress to erythroderma or a severe blistering eruption. Stopping the offending medication usually leads to resolution of the eruption. This is especially common in patients treated with 2-chlorodeoxyadenosine and allopurinol. The former treat ment alone does not lead to these severe skin reactions, sug gesting that the allopurinol is the cause. Patients with hairy cell leukemia also develop lesions of pustular vasculitis of the dorsal hands, a neutrophilic dermatitis closely related to bullous Sweet syndrome. This is sometimes termed a “vasculitis” in the oncology literature.
Nonspecific conditions associated with leukemia (leukemids) Leukemia and its treatment are associated with a series of conditions that may also be seen in patients without leukemia, but which are seen frequently enough in leukemic patients to be recognized as a complication of that condition or its treatment. When a dermatologist or dermatopathologist is consulted to evaluate a patient with leukemia and skin lesions, the differ ential diagnosis usually includes four groups of conditions: drug reactions, leukemia cutis, an infectious complication, and a reactive condition. Drug reactions include all forms of reac tions, but are most commonly erythema multiforme, morbil liform reactions, or acral erythema. Infections may present in many ways but are usually purpuric papules, pustules, or plaques, if they are caused by bacteria or fungi. Ulceration is typical. Herpes simplex and herpes zoster should be consid ered in all erosive, ulcerative, or vesicular lesions. The reactive conditions include a group of neutrophilic dermatoses with considerable clinical overlap. These include Sweet syndrome, pyoderma gangrenosum, neutrophilic hidradenitis, and leuko cytoclastic vasculitis. Transient acantholytic dermatosis and eosinophilic reactions resembling insect bites may occur, most commonly in patients with CLL. In CLL a pruritic and unre mitting exfoliative erythroderma is a unique feature. A granu lomatous rosacea-like leukemid and cutaneous reactive angiomatosis have also been described in patients with leukemia. Evaluation of these patients must be complete, and exten sive diagnostic tests and empiric treatment are often pursued until the diagnosis is established. In the acute setting, a clinical diagnosis is made based on morphology. Possible infectious complications are covered by appropriate antibiotics, espe cially if the patient is febrile or the diagnosis of a herpesvirus infection is made. A skin biopsy is often diagnostic. For herpes infections, a direct fluorescent antibody test should be done, as the results are virus-specific and rapid, so appropriate treat ment can be given quickly. Once the diagnostic tests return, the therapy is tailored to the appropriate condition. Except for herpes infections, a skin biopsy is often required. If infection is considered, a portion of the biopsy should be sent for culture. Angulo J, et al: Leukemia cutis presenting as localized cutaneous hyperpigmentation. J Cutan Pathol 2008 Jul; 35(7):662–665. Cho-Vega JH, et al: Leukemia cutis. Am J Clin Pathol 2008 Jan; 129(1):130–142. Cibull TL, et al: Myeloid leukemia cutis: a histologic and immunohistochemical review. J Cutan Pathol 2008 Feb; 35(2):180–185.
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D’Orazio JA, et al: Spontaneous resolution of a single lesion of myeloid leukemia cutis in an infant: case report and discussion. Pediatr Hematol Oncol 2008 Jun; 25(5):457–468. Hattori T, et al: Leukemia cutis in a patient with acute monocytic leukemia presenting as unique facial erythema. J Dermatol 2008 Oct; 35(10):671–674. Hejmadi RK, et al: Cutaneous presentation of aleukemic monoblastic leukemia cutis—a case report and review of literature with focus on immunohistochemistry. J Cutan Pathol 2008 Oct; 35(Suppl 1):46–49. Kanegane H, et al: Spontaneous regression of aleukemic leukemia cutis harboring a NPM/RARA fusion gene in an infant with cutaneous mastocytosis. Int J Hematol 2009 Jan; 89(1):86–90. Mariñas EA, et al: Cutaneous reactive angiomatosis associated with chronic lymphoid leukemia. Am J Dermatopathol 2008 Dec; 30(6):604–607. Remková A, et al: Acute vasculitis as a first manifestation of hairy cell leukemia. Eur J Intern Med 2007 May; 18(3):238–240. Skiljevic´ D, et al: Granulomatous rosacea-like leukemid in a patient with acute myeloid leukemia. Vojnosanit Pregl 2008 Jul; 65(7):565–568. Stern M, et al: Leukemia cutis preceding systemic relapse of acute myeloid leukemia. Int J Hematol 2008 Mar; 87(2):108–109. Weinel S, et al: Therapy-related leukaemia cutis: a review. Australas J Dermatol 2008 Nov; 49(4):187–190.
Cutaneous myelofibrosis Myelofibrosis is a chronic myeloproliferative disorder charac terized by a clonal proliferation of defective multipotential stem cells in the bone marrow. Overproduction and premature death of atypical megakaryocytes in the bone marrow produce excess amounts of platelet-derived growth factor, a potent stimulus for fibroblast proliferation and collagen production. Extramedullary hematopoiesis (EMH) is a hallmark of myelo fibrosis. Myelofibrosis may coexist with signs of mastocytosis. Blast cells and committed stem cells escape the marrow in large numbers, enter the circulation, and form tumors of the same atypical clone in other organs, especially the spleen, liver, and lymph node. EMH in the skin of neonates is usually caused by intrauterine viral infections. In adults, cutaneous EMH has rarely been reported, characteristically associated with myelofibrosis. Skin lesions are dermal and subcutaneous nodules. Histologically, the cutaneous lesions are composed of dermal and subcutaneous infiltrates of mature and imma ture myeloid cells, erythroid precursors (in only half of cases), and megakaryocytic cells (which may predominate). There is marked production of collagen fibers in the cutaneous lesions by the mechanism described above. Myelofibrosis must be distinguished from CML, since both have elevated white blood cell counts with immature myeloid forms, defective platelet production, and marrow fibrosis. Both may terminate in blast crisis, and myelofibrosis may rarely convert to CML. CML is associated with the Philadelphia chromosome, whereas chromosomal abnormalities occur in 40% of myelofibrosis cases on various chromosomes. Haniffa MA, et al: Cutaneous extramedullary hemopoiesis in chronic myeloproliferative and myelodysplastic disorders. J Am Acad Dermatol 2006 Aug; 55(2 Suppl):S28–31. Miyata T, et al: Cutaneous extramedullary hematopoiesis in a patient with idiopathic myelofibrosis. J Dermatol 2008 Jul; 35(7):456–461. Turchin I, et al: Unusual cutaneous findings of urticaria pigmentosa and telangiectasia macularis eruptiva perstans associated with marked myelofibrosis. Int J Dermatol 2006 Oct; 45(10):1215–1217.
Hypereosinophilic syndrome Idiopathic hypereosinophilic syndrome (HES) is defined as eosinophilia with more than 1500 eosinophils/mm3 for more than 6 months, with some evidence of parenchymal organ involvement; there must also be no apparent underlying disease to explain the hypereosinophilia and usually no
Dahabreh IJ, et al: Management of hypereosinophilic syndrome: a prospective study in the era of molecular genetics. Medicine (Baltimore) 2007 Nov; 86(6):344–354. Hayashi M, et al: Case of hypereosinophilic syndrome with cutaneous necrotizing vasculitis. J Dermatol 2008 Apr; 35(4):229–233. Leiferman KM, et al: Dermatologic manifestations of the hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007 Aug; 27(3):415–441. Sen T, et al: Hypereosinophilic syndrome with isolated Loeffler’s endocarditis: complete resolution with corticosteroids. J Postgrad Med 2008 Apr–Jun; 54(2):135–137. Taverna JA, et al: Infliximab as a therapy for idiopathic hypereosinophilic syndrome. Arch Dermatol 2007 Sep; 143(9):1110–1112.
Angioimmunoblastic lymphadenopathy with dysproteinemia (angioimmunoblastic T-cell lymphoma) Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is an uncommon lymphoproliferative disorder. Patients are middle-aged or elderly and present with fever (72%), weight loss (58%), hepatomegaly (60%), polyclonal hyperglob
ulinemia (65%), and generalized adenopathy (87%). Pruritus occurs in 44% and a rash in 46%. The skin eruption is usually morbilliform in character, resembling an exanthem or a drug reaction. Petechial, purpuric, nodular, ulcerative, and erythro dermic eruptions have also been reported, and may mimic infection. In about 30% of cases the eruption is associated with the ingestion of a medication. The eruptions usually resolve with oral steroids, misleading the clinician into believing that the eruption was benign. Reversible myelofibrosis has been described. Recent evidence suggests that the neoplastic cells are derived from germinal center T-helper cells, as they express genes unique to this population, including programmed death-1 (PD-1) and CXCL13. Histopathologically, there is a patchy and perivascular dermal infiltrate of various types of lymphoid cells, plasma cells, histiocytes (enough to rarely give a “granulomatous” appearance), and eosinophils. The lymphoid cells are usually helper T cells (CD4+). Some portion of the lymphoid cells is atypical in most cases, suggesting the diagnosis. Blood vessels are increased and the endothelial cells are prominent, often cuboidal. Unfortunately, these changes may not be adequate to confirm the diagnosis. However, clonal T-cell gene re arrangement is found in three-quarters of these skin lesions and is the same as the clone in the lymph node. Immuno phenotyping of the skin lesions does not give a consistent pattern. At times, the skin lesions will show leukocytoclastic vasculitis on biopsy. Lymph node biopsy is usually required to confirm the diagnosis and exclude progression to lymphoma. AILD appears to develop in a stepwise fashion. Initially, there is an immune response to an unknown antigen. This immune reaction persists, leading to oligoclonal T-cell prolif eration. Monoclonal evolution may occur, eventuating in lym phoma (angioimmunoblastic lymphoma [AILD-L]). These are usually T-cell lymphomas, but B-cell lymphomas can also occur. In the case of AILD-L, skin lesions may contain the neoplastic cells (secondary lymphoma cutis). In up to 50% of cases, multiple unrelated neoplastic cell clones have been iden tified. Clones identified in the skin may be different from clones found in lymph node. Trisomy 3 or 5, or an extra X chromosome may be found. AILD is an aggressive disease, with mortality ranging from 48% to 72% in various series (average survival time is 11–60 months). The cause of death is usually infection. Epstein–Barr virus and HHV 6 and 8 have been implicated in AILD. Treatment of AILD has included systemic steroids, metho trexate plus prednisone, combination chemotherapy, fludara bine, 2-chlorodeoxyadenosine, IFN-α, and cyclosporine. Early treatment with systemic steroids during an oligoclonal or pre lymphomatous stage may induce a long-lasting remission. Asymptomatic patients may not be treated initially but must be watched very closely. More aggressive chemotherapy achieves better remission. None the less, recurrence rates are high, and average survival is between 1 and 3 years.
Sinus histiocytosis with massive lymphadenopathy
evidence of vasculitis. Ninety percent of patients reported have been men, mostly between the ages of 20 and 50. Childhood cases are rare. Presenting symptoms include fever (12%), cough (24%), fatigue, malaise, muscle pains, and skin eruptions. Two pathogenic variants of HES have been defined: m-HES (myeloproliferative HES) and l-HES (lymphocytic HES). M-HES patients are overwhelmingly males, and anemia, thrombocytopenia, elevated serum B12 levels, mucosal ulcera tions, splenomegaly, and endomyocardial fibrosis are the clini cal features. Isolated Loeffler’s endocarditis has been reported as a presenting sign. Eosinophil clonality and interstitial dele tion on 4q12 result in fusions of FIP1qL1 and PDGFRa genes, forming an F/P fusion protein displaying constitutive activity, are pathogenically related to m-HES cases. Increased mast cells and elevated tryptase levels with myeloid precursors in peripheral blood and myelofibrosis may be found, suggesting that mast cells may be pathogenically related to this form of HES. Leukemia may develop in patients with m-HES. L-HES has been associated with circulating T-cell clones of CD4+ phenotype, which secrete Th2 cytokines, especially IL-5. Females and males are equally affected by l-HES and cutane ous manifestations are observed in virtually all patients. Skin manifestations include urticaria, angioedema, pruritus, eczema, and erythroderma. Splinter hemorrhages and necrotic skin lesions are seen in some HES patients as well. Endomyocardial fibrosis is uncommon, but pulmonary and digestive symptoms are common. Some cases of l-HES are clinically identical to Gleich syndrome or episodic angioedema and hypereosinophilia. Over time some patients with l-HES will develop lymphoma. Treatment is determined by classifying cases appropriately as m-HES or l-HES. M-HES patients may be treated with cor ticosteroids, hydroxyurea, IFN-α, and chemotherapeutic agents. Imatinib mesylate (Gleevac, 100 mg/day or less) can be highly effective for m-HES patients with the F/P mutation, as imatinib inhibits the phosphorylation of the F/P protein and leads to apoptosis of cells producing this protein. This has rapidly become first-choice treatment for this subset of patients. Response may be dramatic, with eosinophil levels improving, and skin and gastrointestinal manifestations clearing in days. For l-HES patients, systemic glucocorticoids, and perhaps IFN-α with glucocorticoids, can be used and are usually effec tive. Monoclonal anti-IL-5 antibody, cyclosporine A, anti-IL2R-α, infliximab, and CTLA-4-Ig may be treatment options. If lymphoma supervenes, intense chemotherapy and allogenic stem cell transplantation can be considered.
Matsui K, et al: Angioimmunoblastic T cell lymphoma associated with reversible myelofibrosis. Intern Med 2008; 47(21):1921–1924. Shah ZH, et al: Monoclonality and oligoclonality of T cell receptor beta gene in angioimmunoblastic T cell lymphoma. J Clin Pathol 2009 Feb; 62(2):177–181. Yu H, et al: Germinal-center T-helper-cell markers PD-1 and CXCL13 are both expressed by neoplastic cells in angioimmunoblastic T-cell lymphoma. Am J Clin Pathol 2009 Jan; 131(1):33–41.
Sinus histiocytosis with massive lymphadenopathy (Rosai–Dorfman disease) Sinus histiocytosis with massive lymphadenopathy (SHML), or Rosai–Dorfman disease, usually appears in patients in the first or second decade of life as a febrile illness accompanied 739
Ohnishi A, et al: Cutaneous Rosai–Dorfman disease. J Dermatol 2008 Sep; 35(9):604–605.
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Polycythemia vera (erythremia)
Fig. 32-21 Rosai–Dorfman disease. (Courtesy of Ellen Kim, MD)
by massive cervical (and commonly other) lymphadenopathy, polyclonal hyperglobulinemia, leukocytosis, anemia, and an elevated sedimentation rate. Males and black persons are espe cially susceptible. Extranodal involvement occurs in 40% of cases, with skin being the most common site. Ten percent of patients with SHML have skin lesions and 3% of patients have disease detectable only in the skin. The terms cutaneous sinus histiocytosis or cutaneous Rosai–Dorfman disease have been applied to these cases. Skin lesions consist of isolated or dis seminated yellow–brown papules, pustules, or nodules (Fig. 32-21), or macular erythema. Large annular lesions, resem bling granuloma annulare, may occur. Most patients with cutaneous Rosai–Dorfman are older (40–60 years). Histologically, there is a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. Nodular and diffuse infiltration of the dermis by large, foamy histiocytes is present. A very important diagnostic feature is the finding of intact lymphocytes (and less commonly, plasma cells) in the cyto plasm of the histiocytic cells. This is called emperipolesis. Foamy histiocytes may be seen in dermal lymphatics. The cutaneous histology in some cases may be very nonspecific (except for the finding of emperipolesis), and only on evalua tion of lymph node or other organ involvement does the diag nosis become clear. Immunohistochemistry and electron microscopy may be very useful, as the infiltrating cells are positive for CD4, factor XIIIa, and S-100, but do not contain Birbeck granules. The cause of this condition is unknown, but numerous reports have identified HHV 6 in involved lymph nodes. The condition usually clears spontaneously, so no treatment is required. Numerous agents have been used therapeutically with variable success, but are only indicated if the condition puts the patient at risk for death or a significant complication (usually by compressing a vital organ). Treatments have included radiation, systemic corticosteroids, and thalidomide. Single and multiagent chemotherapy is met with mixed to poor response. To treat skin lesions, cryotherapy, topical ster oids, acitretin, and intralesional steroids may be tried. Kong YY, et al: Cutaneous Rosai–Dorfman disease: a clinical and histopathologic study of 25 cases in China. Am J Surg Pathol 2007 Mar; 31(3):341–350. Mebazaa A, et al: Extensive purely cutaneous Rosai–Dorfman disease responsive to acitretin. Int J Dermatol 2007 Nov; 46(11):1208–1210. Merola JF, et al: Cutaneous Rosai–Dorfman disease. Dermatol Online J 2008 May 15; 14(5):8.
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Polycythemia vera (PCV) is characterized by an absolute increase of circulating red blood cells, with a hematocrit level of 55–80%. Leukocyte and platelet counts are also increased. The skin changes are characteristic. There is a tendency for the skin to be red, especially on the face, neck, and acral areas. The mucous membranes are engorged and bluish. The phrase “red as a rose in summer and indigo blue in winter” has been ascribed to Osler in describing PCV. Telangiectases, bleeding gums, and epistaxis are frequently encountered. Cyanosis, purpura, petechiae, hemosiderosis, rosacea, and koilonychia may also be present. In 50% of patients with PCV, aquagenic pruritus occurs. In about two-thirds of patients, this is of limited severity and does not require treatment. The pruritus is typically triggered after a bath or shower, and the feeling induced may be itching, burning, or stinging. It usually lasts 30–60 min and is inde pendent of the water temperature. Pruritus unassociated with water exposure may also occur. There is a concurrent elevation of blood and skin histamine. Pruritus is present in about 20% of patients at presentation and develops in the remaining 30% over the course of their disease. Patients with pruritus have lower mean corpuscular volumes and higher leukocyte counts. Some have suggested that iron deficiency plays a role in PCVassociated pruritus, so a ferritin level and a trial of iron therapy may be indicated. Platelet counts are no different between PCV patients who itch and those who do not. The treatment of PCV-associated pruritus may be difficult. Initial therapy would include first- or second-generation H1 antihistamines. Hydroxyzine was reported as the most effec tive antihistamine by a group of PCV patients. H2 blockers can be added. Narrow-band UVB has been reported to be effective in 80% of patients. Topical therapy is of limited benefit, but paroxetine (Paxil), 20–60 mg/day, may be dramatically effec tive. Phlebotomy may be useful in patients with elevated hematocrits, and imatinib mesylate appears effective in many patients. Abdel-Naser MB, et al: Cutaneous mononuclear cells and eosinophils are significantly increased after warm water challenge in pruritic areas of polycythemia vera. J Cutan Pathol 2007 Dec; 34(12):924–929. Jones CM, et al: Phase II open label trial of imatinib in polycythemia rubra vera. Int J Hematol 2008 Dec; 88(5):489–494.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 32-1 Jessner’s lymphocytic infiltrate. Fig. 32-2 Mycosis fungoides, patch stage, with small and large patches. Fig. 32-3 Tumor-stage mycosis fungoides. Fig. 32-4 Pagetoid reticulosis. Fig. 32-5 Sézary syndrome. Fig. 32-6 Mucha–Habermann disease. Fig. 32-7 Lymphoma, B-cell. Fig. 32-8 Intravascular lymphoma. Fig. 32-9 Plasmacytoma in myeloma. Fig. 32-10 Malignant histiocytosis. Fig. 32-11 Rosai–Dorfman disease. (Courtesy of Ellen Korn, MD) Fig. 32-12 Mycosis fungoides, patch/plaque stage. Fig. 32-13 Mycosis fungoides, plaque stage. Fig. 32-14 Lymphomatoid papulosis.
Bonus images for this chapter can be found online at http://www.expertconsult.com
Diseases of the Skin Appendages
Diseases of the hair Normal human hairs can be classified according to cyclical phases of growth. Anagen hairs are growing hairs, catagen hairs are those undergoing transition from the growing to the resting stage, and telogen hairs are resting hairs, which remain in the follicles for variable lengths of time before they fall out (teloptosis). The lag period between loss of the telogen hair and growth of a new anagen hair has been referred to as kenogen. Anagen hairs grow for about 3 years (1000 days), with a range between 2 and 6 years. The follicular matrix cells grow, divide, and become keratinized to form growing hairs. As the matrix produces the hair shaft, it incorporates substances that may be useful in medical or forensic analysis. Catagen hairs are in a transitional phase, lasting 1 or 2 weeks, in which all growth activity ceases, with the eventual formation of the telogen “club” hair. Many apoptotic cells are present in the outer root sheath of the catagen hair as it involutes. Telogen club hairs are resting hairs, which continue in this state for 3–5 months (about 100 days) before they are released. Among human hairs plucked from a normal scalp, 85–90% are anagen hairs and 10–15% are telogen hairs. Catagen hairs normally comprise less than 1% of scalp hairs. It has been estimated that the scalp normally contains about 100 000 hairs, and the average number of hairs shed daily is 100–150. The hair growth rate of terminal hairs is about 0.37 mm/day. Contrary to popular belief, neither shaving nor menstruation has any effect on hair growth rate. The average uncut scalp hair length is estimated to be 25–100 cm, although exceptional hairs may be as long as 170 cm (70 inches). Human hair is also designated as lanugo, vellus, or terminal hair. Lanugo hair is the fine hair present on the body of the fetus. This is replaced by the vellus and terminal hairs. Vellus hairs are fine and usually light-colored, and have a narrow hair shaft thinner than the width of the inner root sheath. Terminal hairs are coarse, thick, and dark, except in blonds. Hair occurs on all skin surfaces except the palms, soles, labia minora, lips, nails, glans, and prepuce. Terminal hairs are commonly present on a man’s face, chest, and abdomen, but vellus hairs usually predominate on these sites in women. Causes of alopecia are generally divided into the broad categories of cicatricial and noncicatricial alopecia. The evaluation should take into account the patient’s age and ethnicity. Examination of hair shafts can establish a diagnosis of tricho dystrophy. Hair counts, hair pull, and hair pluck (trichogram) can establish the degree of hair shedding, the type of hair that is shed, and the anagen to telogen ratio. Biopsies can also the determine anagen to telogen ratio, and provide information regarding the potential for regrowth, as well as providing a diagnosis. Biopsies are particularly valuable in the evaluation of cicatricial alopecia. Often, a correct diagnosis hinges on a synthesis of clinical, histologic, serologic, and immunofluorescent data.
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Collado MS, et al: Recent advances in hair cell regeneration research. Curr Opin Otolaryngol Head Neck Surg 2008 Oct; 16(5):465–471. Harries MJ, et al: Management of primary cicatricial alopecias: options for treatment. Br J Dermatol 2008 Jul; 159(1):1–22. Piraccini BM, et al: Drug-induced hair disorders. Curr Drug Saf 2006 Aug; 1(3):301–305. Randall VA: Androgens and hair growth. Dermatol Ther 2008 Sep–Oct; 21(5):314–328. Shapiro J: Clinical practice. Hair loss in women. N Engl J Med 2007 Oct 18; 357(16):1620–1630. Somani N, et al: Cicatricial alopecia: classification and histopathology. Dermatol Ther 2008 Jul–Aug; 21(4):221–237. Unger W, et al: The surgical treatment of cicatricial alopecia. Dermatol Ther 2008 Jul–Aug; 21(4):295–311.
Noncicatricial alopecia Alopecia areata Clinical features Alopecia areata (in French, pelade) is characterized by rapid and complete loss of hair in one or more round or oval patches, usually on the scalp, bearded area, eyebrows, eyelashes, and less commonly, on other hairy areas of the body. Often the patches are from 1 to 5 cm in diameter. A few resting hairs may be found within the patches. Early in the course there may be sparing of gray hair, and white hairs are rarely affected. Sudden whitening of hair may represent widespread alopecia areata in a patient with salt and pepper hair. In about 10% of cases of alopecia areata, especially in long-standing cases with extensive involvement, the nails develop uniform pits that may form transverse or longitudinal lines. Trachyonychia, onychomadesis, and red or spotted lunulae occur, but less commonly. Dermoscopic examination typically demonstrates diffuse, round, or polycyclic perifollicular yellow dots. Complete loss of scalp hair is referred to as alopecia totalis, and complete loss of all hair as alopecia universalis. In most cases, hair loss is confined to the scalp and is patchy in distribution. Loss may occur confluently along the temporal and occipital scalp (ophiasis) (Fig. 33-1) or on the entire scalp except for this area (sisaipho). Rarely, alopecia areata may present in a diffuse pattern that may mimic pattern alopecia. Clues to the correct diagnosis include a history of periodic regrowth, nail pitting, and the presence of tapered fractures or exclamation point hairs (Fig. 33-2). Alopecia areata generally presents as an anagen effluvium, with an inflammatory insult to the hair matrix resulting in tapering of the hair shaft and in fracture of anagen hairs. As the hair miniaturizes or converts from anagen to telogen, the remaining lower portion of the hair rises above the level of the scalp, producing the exclamation point hair. Alopecia areata is associated with a higher incidence than usual of atopic dermatitis, Down syndrome, lichen planus, and autoimmune diseases, such as systemic lupus erythematosus
Diseases of the Skin Appendages
33
Fig. 33-1 Ophiasis. (Courtesy of Shyam Verma, MD)
type 1 cytokines, including interleukin (IL)-2, interferon (IFN)γ, and tumor necrosis factor (TNF)-α. The hair bulb normally represents an area of relative immune privilege during anagen, as evidenced by a very low level of expression of major histocompatibility complex (MHC) class Ia antigens. This immune privilege may prevent antigen recognition by autoreactive CD8+ T cells. Alopecia areata may be related to collapse of this immune privilege. IFN-γ-deficient mice are resistant to alopecia areata. Onset of disease after Epstein–Barr virus infectious mononucleosis has been reported. Neuropeptides modify immune reactivity and may have a role in the disease. Heredity also plays a part. Overall, nearly 25% of patients have a positive family history; there are reports of twins with alopecia areata. Patients with “early onset, severe, familial clustering alopecia areata” have a unique and highly significant association with the HLA antigens DR4, DR11, and DQ7. The “later onset, milder severity, better prognostic” subsets of patients have a lower frequency of familial disease and do not share these HLA antigens. Familial alopecia areata associated with hereditary thrombocytopenia related to mutations in genes on chromosome 17 has been described. R620W (c.1858C>T, a variant of the protein tyrosine phosphatase nonreceptor 22 gene [PTPN22]) is associated with a variety of autoimmune disorders, including alopecia areata. It is associated with early onset of disease, widespread hair loss, and a positive family history.
Histology
Fig. 33-2 Exclamation point hairs of alopecia areata.
(SLE), thyroiditis, diabetes mellitus, myasthenia gravis, and vitiligo. However, most cases of alopecia areata occur without associated disease, and routine screening for these disorders is of little value unless prompted by signs or symptoms. Migratory poliosis of the scalp may represent a forme fruste of alopecia areata. Patients with this disorder present with migrating circular patches of white hair, but never lose hair. The histology resembles alopecia areata.
Etiologic factors The preponderance of evidence supports an autoimmune etiology. Oligoclonal and autoreactive T lymphocytes are present in the peribulbar inflammatory infiltrate, and many patients respond to immune-modulating drugs. Affected alopecia areata scalp skin grafted on to nude mice with severe combined immunodeficiency demonstrates loss of infiltrating lymphocytes and hair growth. In this model, injecting T lymphocytes with scalp homogenate can reproduce the alopecia. Follicular melanocytes substitute for scalp homogenates to produce alopecia areata in this model, providing evidence that follicular melanocytes are the targets for activated T cells in this disease. This hypothesis is also supported by the observations that white hair is rarely affected and regrowing hair is often depigmented. In early alopecia areata, the perifollicular and intrafollicular inflammatory infiltrate is composed of activated CD4+ and CD8+ T cells, together with macrophages and Langerhans cells. The early phase of hair loss appears to be mediated by 742
In early disease there is a lymphoid infiltrate in the peribulbar area of anagen or early catagen follicles. Eosinophils may be present in the infiltrate, and lymphocyte-mediated damage to the bulb produces melanin pigment incontinence in the surrounding stroma. The hair structures enter an abnormal catagen phase, followed by telogen. During this phase, the presence of many catagen hairs and pigment casts within the follicular canal can cause histologic confusion with trichotillomania. In alopecia areata, the follicles eventually miniaturize, appearing as small dystrophic anagen hairs high in the dermis, often with a persistent lymphocytic peribulbar infiltrate. The presence of a peribulbar infiltrate helps to distinguish the miniaturized follicles of alopecia areata from those of androgenetic alopecia. Fibrous tract remnants beneath the miniaturized bulbs of alopecia areata may contain lymphoid cells, eosinophils, and melanin pigment. These findings are never present in trichotillomania or androgenetic alopecia. With time, the lymphocytes disappear, but focal eosinophils and pigment remain. Finally, only focal melanin pigment remains in the fibrous tract remnants. Hair fiber granulomas and scarring never occur. Every histologic feature of alopecia areata may be seen in syphilis. The presence of plasma cells is suggestive of syphilis, but plasma cells are also lacking in about one-third of syphilis biopsies. Plasma cells may be present in biopsies from any form of inflammatory alopecia if the biopsy is taken from the occipital scalp, as this site readily recruits plasma cells.
Differential diagnosis The sharply circumscribed patch of alopecia with exclamation point hairs at the periphery and the absence of scarring are indicative of alopecia areata. Tinea capitis, androgenetic alopecia, early lupus erythematosus, syphilis, congenital triangular alopecia, alopecia neoplastica, and trichotillomania should be kept in mind when alopecia areata is considered. A biopsy will generally help to distinguish alopecia areata from these other entities, except syphilis, which may be indistinguishable. In endemic areas of southwest Asia, Pheidole ants shear hair shafts during the night, resulting in overnight loss of clumps
Treatment The natural course of the hair loss is highly variable. Some patches will regrow in a few weeks without any treatment. Various treatments can induce growth, but the inherent risks and cost must be weighed against the benefit of earlier regrowth. In his series of 63 consecutive responders to a follow-up questionnaire, Arnold found that, after reassurance only, hair had regrown in all but four patients after 1 year and in all but one after 2 years. The great majority had recovered in 3 months after their only office visit. Therefore, anecdotal reports of success must be interpreted carefully in the light of the high rate of spontaneous recovery. Intralesional injections of corticosteroid suspensions are the treatment of choice for localized, cosmetically conspicuous patches, such as those occurring in the frontal hairline or involving an eyebrow. Injections of triamcinolone, 2–10 mg/mL, are typically given intradermally or in the superficial subcutaneous tissue. Large volumes and higher concentrations of triamcinolone present a greater risk of atrophy. Injection under significant pressure or with a smallbore syringe increases the likelihood of retinal artery embolization. High-strength topical steroids may be used as a safer first-line therapy, but are less reliable than injections. Several investigators have reported the use of pulsed oral corticosteroids in rapidly progressing or widespread disease. However, long-term treatment is frequently needed to maintain growth, and the attendant risks should be carefully weighed against the benefits. In a study of 66 patients aged 9–60 years, monthly methylprednisolone was administered at a dose of 500 mg/day during 3 days or 5 mg/kg twice a day over 3 days in children. More than 60% of patients with widespread patchy alopecia responded. Half of the patients with alopecia totalis had a good response, while a quarter of those with universal alopecia responded. Patients with ophiasic alopecia areata did not respond. Induction of contact sensitivity to squaric acid dibutyl ester, dinitrochlorobenzene, and diphencyprone can be useful in refractory cases. In mice, contact immunotherapy is associated with a decrease in cutaneous activated T cells, a reduction in intrafollicular CD8+ lymphocytes, and reduced expression of CD44v3+ and CD44v10+ cells. These results suggest that blockade of leukocyte trafficking and extravasation is an important mechanism of action. Topical or oral methoxsalen and ultraviolet A (PUVA) therapy is an option for refractory or widespread lesions. Short-contact topical anthralin 1% cream (applied for 15–20 min and then shampooed off) can be of benefit. Topical minoxidil may be combined with other treatments or utilized as a single agent. Preliminary results suggest methotrexate and sulfasalazine may be beneficial. Biologics have produced mixed, and largely disappointing, results, and alopecia areata has developed during biologic therapy for other conditions. The 308 nm xenon chloride excimer laser (300–2300 mJ/cm2/session) has been reported to produce regrowth after 11 and 12 sessions over a 9–11-week period. Periocular pigmentation is associated with use of travoprost for eyelash disease. Therapeutic results are mixed. Alopecia areata can cause tremendous psychological stress. Education about the disease process, cosmetically acceptable alternatives (especially information about wigs), and research into innovative therapies should all be made available to the patient. In addition to the information conveyed by the dermatologist, an excellent resource is the National Alopecia Areata Foundation (NAAF): E-mail:
[email protected], website: www.naaf.org.
Prognosis The tendency is for spontaneous recovery in patients who are postpubertal at onset. At first, the regrowing hairs are downy and light in color; later, they are replaced by stronger and darker hair with full growth. Predictors of a poor prognosis are the presence of atopic dermatitis, childhood onset, widespread involvement, ophiasis, duration of longer than 5 years, and onychodystrophy. Acute diffuse and total alopecia is a newly defined subtype of alopecia areata that occurs in young adults and has a good prognosis. Ahmed AM, et al: Familial alopecia areata and chronic thrombocytopenia. J Am Acad Dermatol 2008 May; 58(5 Suppl 1):S75–77. Avgerinou G, et al: Alopecia areata: topical immunotherapy treatment with diphencyprone. J Eur Acad Dermatol Venereol 2008 Mar; 22(3):320–323. Bakar O, et al: Is there a role for sulfasalazine in the treatment of alopecia areata? J Am Acad Dermatol 2007 Oct; 57(4):703–706. Betz RC, et al: The R620W polymorphism in PTPN22 confers general susceptibility for the development of alopecia areata. Br J Dermatol 2008 Feb; 158(2):389–391. Feletti F, et al: Periocular pigmentation associated with use of travoprost for the treatment of alopecia areata of the eyelashes. J Eur Acad Dermatol Venereol 2007 Mar; 21(3):421–423. Freyschmidt-Paul P, et al: Interferon-gamma-deficient mice are resistant to the development of alopecia areata. Br J Dermatol 2006 Sep; 155(3):515–521. Garcia Bartels N, et al: Development of alopecia areata universalis in a patient receiving adalimumab. Arch Dermatol 2006 Dec; 142(12):1654–1655. Hubiche T, et al: Poor long term outcome of severe alopecia areata in children treated with high dose pulse corticosteroid therapy. Br J Dermatol 2008 May; 158(5):1136–1137. Joly P: The use of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia totalis or universalis. J Am Acad Dermatol 2006 Oct; 55(4):632–636. Kolde G, et al: Successful treatment of alopecia areata with efalizumab. J Eur Acad Dermatol Venereol 2008 Dec; 22(12):1519–1520. Lew BL, et al: Acute diffuse and total alopecia: a new subtype of alopecia areata with a favorable prognosis. J Am Acad Dermatol 2009 Jan; 60(1):85–93. Manolache L, et al: Alopecia areata and relationship with stressful events in children. J Eur Acad Dermatol Venereol 2009 Jan; 23(1):107–109. McMichael AJ, et al: Alopecia in the United States: outpatient utilization and common prescribing patterns. J Am Acad Dermatol 2007 Aug; 57(2 Suppl):S49–51. Misery L, et al: Treatment of alopecia areata with sulfasalazine. J Eur Acad Dermatol Venereol 2007 Apr; 21(4):547–548. Price VH, et al: Subcutaneous efalizumab is not effective in the treatment of alopecia areata. J Am Acad Dermatol 2008 Mar; 58(3):395–402. Rodriguez TA, et al: Onset of alopecia areata after Epstein–Barr virus infectious mononucleosis. J Am Acad Dermatol 2008 Jul; 59(1):137–139. Tosti A, et al: Alopecia areata during treatment with biologic agents. Arch Dermatol 2006 Dec; 142(12):1653–1654. Tosti A, et al: The role of scalp dermoscopy in the diagnosis of alopecia areata incognita. J Am Acad Dermatol 2008 Jul; 59(1):64–67.
Diseases of the hair
of hair. The resulting round patches of hair loss closely mimic alopecia areata.
Telogen effluvium Telogen effluvium presents with excessive shedding of normal telogen club hairs. This excessive shedding of telogen hairs has several possible mechanisms. It most commonly occurs 3–5 months after the premature conversion of many anagen hairs to telogen hairs induced by surgery, parturition, fever, drugs, dieting, or traction. Local patches of early telogen conversion may be induced by papulosquamous diseases affecting the scalp. Alternatively, follicles may remain in prolonged anagen rather than normally cycling into telogen. This occurs during pregnancy. On delivery, many follicles are then released simultaneously into telogen, and shedding 743
Diseases of the Skin Appendages
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occurs 3–5 months later. Prolongation of telogen also occurs during pregnancy, and results in an initial wave of hair loss soon after delivery or heralding early termination of a pregnancy. Shortening of the anagen phase occurs in pattern (androgenetic) alopecia, and results in telogen effluvium. Normally, anagen lasts about 1000 days and telogen about 100 days. This results in a 10:1 ratio of anagen to telogen hairs in the scalp. With progression of pattern alopecia, anagen shortens, and the ratio of anagen to telogen hairs falls. A greater proportion of hairs is in telogen at any one time, resulting in a chronic increase in telogen shed. Administration of topical minoxidil may produce a telogen effluvium by premature termination of telogen necessary to initiate anagen in responding follicles. This causes early telogen release and a brief telogen effluvium. Whatever the cause of the telogen loss, the hair is lost “at the root.” Each hair will have a visible depigmented clubshaped bulb and will lack a sheath (Fig. 33-3). In most cases, loss is diffuse. Patients commonly have more than one mechanism for telogen hair loss. Patchy or diffuse telogen may be associated with papulosquamous diseases of the scalp. Perceptible thinning of the hair is more common in patients with pre-existing pattern alopecia. In patients with pattern alopecia, shortening of the hair cycle results in increased telogen shed. Superimposed papulosquamous disease, iron deficiency, or thyroid disease can result in even more telogen shed and accentuates the pattern loss. Trichodynia is a common symptom in patients with telogen effluvium, as it is in pattern hair loss. Trichodynia often coexists with signs of depression, obsessive personality disorder, and anxiety. Telogen shed may be estimated by the pull test: grasping 40 hairs firmly between thumb and forefinger, followed by a slow pull that causes minimal discomfort to the patient. A count of more than 4–6 club hairs is abnormal, but the result is influenced by recent shampooing (a count of 2–3 hairs being abnormal in a freshly shampooed scalp), combing, and the phase of telogen effluvium (whether it is resolving or entering a chronic phase). The clip test may also be useful; 25–30 hairs are cut just
Fig. 33-3 Anagen and telogen hair (anagen hair has a pigmented bulb and is surrounded by a gelatinous root sheath; telogen hair has a nonpigmented bulb and lacks a root sheath).
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above the scalp surface and mounted. Indeterminate and telogen hairs are short and of small diameter. Many hairs of this type may be present in telogen effluvium or pattern alopecia. Trichogram evaluation (50 hairs plucked with a Kelly clamp with rubber drains over the teeth) can also provide information on the anagen to telogen ratio. Age, sex, race, and genetic factors influence the normal average daily hair loss in an individual. A full head of hair numbers about 100 000; of these, approximately 100–150 are lost daily. In telogen effluvium, estimates of loss vary from 150 to more than 400. Patients may be instructed to collect and count the hair daily; however, they should make sure they collect all small hairs and those that come out in washing and in the bed, as well as those present on the comb or brush. When the pull test is positive, hair shed counts are not needed. An alternative is to collect all hairs lost during a 1 min combing session. For this technique, developed by Dr Jeffrey Miller, the patient combs for 1 min prior to shampooing on 3 consecutive days. The patient is instructed to comb from the vertex to the anterior hairline. The normal range of lost hairs with this technique is 10–15. Loss of more than 50 is common in telogen effluvium. Serial 1 min hair counts can be performed to monitor progress. Telogen effluvium is commonly related to protein or other nutrient deprivation (Fig. 33-4). Assessment of dietary habits and determination of iron saturation and ferritin are the simplest ways to determine nutritional status. Iron replacement is advisable if saturation or ferritin is low, but in one study iron replacement alone did not result in resolution of telogen effluvium. Iron may merely serve as a marker for overall nutritional status. Patients with evidence of deficiency should be given supplements to correct the identified deficiency and encouraged to eat a varied diet. Sources of blood loss, such as menstrual bleeding and gastrointestinal blood loss, should be investigated. Hypothyroidism, allergic contact dermatitis to hair dyes, and renal dialysis with secondary hypervitaminosis A may also be associated with telogen effluvium. Druginduced telogen effluvium has been noted with the use of aminosalicylic acid, amphetamines, bromocriptine, captopril, carbamazepine, cimetidine, coumarin, danazol, enalapril, etretinate, levodopa, lithium carbonate, metoprolol, metyrapone, pramipexole, propranolol, pyridostigmine, and trimethadione. Postnatal telogen effluvium of infants may occur between birth and the first 4 months of age. Usually, regrowth occurs by 6 months of age. Telogen counts by Kligman in six
Fig. 33-4 Telogen effluvium secondary to crash dieting.
Bedocs LA, et al: Adolescent hair loss. Curr Opin Pediatr 2008 Aug; 20(4):431–435. Katz KA, et al: Telogen effluvium associated with the dopamine agonist pramipexole in a 55-year-old woman with Parkinson’s disease. J Am Acad Dermatol 2006 Nov; 55(5 Suppl):S103–104. Millikan L: Hirsutism, postpartum telogen effluvium, and male pattern alopecia. J Cosmet Dermatol 2006 Mar; 5(1):81–86. Piraccini BM, et al: Drug-induced hair disorders. Curr Drug Saf 2006 Aug; 1(3):301–305. Ramos-e-Silva M, et al: Hair, nail, and pigment changes in major systemic disease. Clin Dermatol 2008 May–Jun; 26(3):296–305.
Anagen effluvium Anagen effluvium usually results from hair shaft fracture. It is frequently seen following the administration of cancer chemotherapeutic agents, such as the antimetabolites, alkylating agents, and mitotic inhibitors. These agents result in temporary shutdown of the hair matrix with resultant tapering of the shaft (Pohl–Pinkus constrictions). Trichograms reveal tapered fractures. Only anagen hairs are affected. The 10% of scalp hairs in telogen have no matrix and are unaffected. The loss tends to be diffuse but not complete. It may resemble pattern alopecia. Severe loss is frequently seen with doxorubicin, the nitrosureas, and cyclophosphamide. When high doses are given, loss of anagen hairs becomes most apparent clinically in 1–2 months. The hair shafts are abruptly narrowed at the time of maximum drug effect, and when the very thin portion reaches the surface, the hair shafts all break at about the same time. With cessation of drug therapy, the follicle resumes its normal activity within a few weeks; the process is entirely reversible. It is apparent that mitotic inhibition merely stops the reproduction of matrix cells but does not perma-
Diseases of the hair
infants varied from 64% to 87%. He also found a tendency for the alopecia to occur in the male-pattern distribution. Idiopathic chronic telogen effluvium has been described by Whiting in a group of 355 patients (346 women and 9 men) with diffuse generalized thinning of scalp hair. Most were 30–60 years old, and their hair loss started abruptly, with increased shedding and thinning. There was a fluctuating course and diffuse thinning of the hair all over the scalp, accompanied by bitemporal recession. He found high telogen counts on horizontal sections of scalp biopsies and considers these patients to have a chronic form of telogen effluvium. This chronic form may respond to 5% minoxidil solution. If a 4 mm punch biopsy is performed, 25–50 hairs are normally present for inspection in transverse (horizontal) sections. If more than 12–15% of terminal follicles are in telogen, this indicates a significant shift from anagen to telogen. Pattern (androgenetic alopecia) demonstrates miniaturization, variable hair shaft diameter, and an increased proportion of telogen hairs. Traction alopecia and trichotillosis (trichotillomania) result in an increased number of catagen and telogen hairs. Pigment casts, empty anagen follicles, trichomalacia, and catagen hairs help distinguish these entities from simple telogen effluvium. No specific therapy is required for most patients with telogen effluvium. In the majority of cases the hair loss will stop spontaneously within a few months and the hair will regrow. Druginduced telogen effluvium responds to discontinuation of the offending agent. The prognosis is good if a specific event can be pinpointed as a probable cause. Papulosquamous scalp disorders may precipitate telogen hair loss and should be addressed. Iron and thyroid status should be determined if the course is prolonged or if history or physical examination suggests an abnormality. Patients should be encouraged to eat a balanced diet. In a mouse model, sonic stress can produce catagen. This model may be useful in the study of agents for the treatment of telogen effluvium.
Fig. 33-5 Loose anagen hair with “rumpled sock” cuticle.
nently destroy the hair. A pressure cuff applied around the scalp during chemotherapy and scalp hypothermia have been reported to prevent such anagen arrest, but as the scalp may be a site of metastasis, it may be better not to spare the scalp from the effects of chemotherapy. Topical minoxidil has been shown to shorten the period of baldness by an average of 50 days. In addition to the cytotoxic chemotherapeutic agents, various agents, such as isoniazid INH, thallium, and boron may induce anagen effluvium. Anagen effluvium with tapered fractures also occurs in alopecia areata and syphilis. In these diseases, an inflammatory insult to the hair bulb results in Pohl–Pinkus constrictions and tapered fracture. Anagen loss may also occur at the root. Loose anagen syndrome, described by Price in 1989, is a disorder in which anagen hairs may be pulled from the scalp with little effort. It occurs mostly in blond girls and usually improves with age. The syndrome appears to be related to a defect in the hair cuticle. Instead of anchoring the hair firmly, the cuticle simply folds back like a rumpled sock (Fig. 33-5), allowing the hair shaft to be extracted. Woolly hair can be associated with loose anagen hair syndrome. A keratin mutation, E337K in K6HF, was identified in three of nine families studied. Colobomas have also been associated with loose anagen hair. Anagen hairs may be easily extracted from active areas of lupus erythematosus and lichen planopilaris. They commonly lack the root sheath that normally surrounds a plucked anagen hair (Fig. 33-6). Anagen effluvium has also been described in lesions of pemphigus. Trüeb RM: Chemotherapy-induced anagen effluvium: diffuse or patterned? Dermatology 2007; 215(1):1–2. Yun SJ, et al: Hair loss pattern due to chemotherapy-induced anagen effluvium: a cross-sectional observation. Dermatology 2007; 215(1):36–40.
Pattern alopecia (androgenetic alopecia) Male-pattern baldness Male-pattern alopecia or male-pattern androgenetic alopecia (common baldness) shows itself during the teens, twenties, or early thirties with gradual loss of hair, chiefly from the vertex and frontotemporal regions. The process may begin at any time after puberty, and the presence of “whisker” or kinky hair may be the first sign of impending male-pattern alopecia. The anterior hairline recedes on each side, in the 745
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Fig. 33-6 Stain for citrulline demonstrates the inner root sheath (red) surrounded by an outer root in a plucked anagen hair from a normal scalp.
Geheimratswinkeln (“professor angles”), so that the forehead becomes high. Eventually, the entire top of the scalp may become devoid of hair. Several patterns of this type of hair loss occur, but the most frequent is the biparietal recession with loss of hair on the vertex. The rate of hair loss varies among individuals. Sudden hair loss may occur in the twenties and then proceed relentlessly, though very slowly, for a number of years. The follicles produce finer and lighter hairs with each hair cycle until terminal hairs are eventually replaced by vellus hairs. During evolution of the process, hair shafts vary significantly in diameter. The parietal and occipital areas are usually spared permanently from this process of progressive miniaturization. Early-onset male-pattern alopecia is related to the androgen receptor gene. There is no doubt that inherited factors and the effect of androgens such as dihydrotestosterone on the hair follicle are important. Arguments for regarding the inheritance as polygenic include the high prevalence, gaussian curve of distribution in the population, increased risk with number of affected relatives, increased risk in relatives of severely affected women compared with mildly affected, and greater import of an affected mother than an affected father. The possibility that the early onset (before the age of 30) and later onset (after the age of 50) forms may be inherited separately by single genes is also hypothesized. Male-pattern alopecia is dependent on adequate androgen stimulation and appears to be related to the androgen receptor gene. Eunuchs do not develop baldness if they are castrated before or during adolescence. If they are given androgen therapy, baldness may develop. The 5-α reduction of testosterone is increased in the scalp of balding individuals, yielding increased dihydrotestosterone. Androgen-inducible transforming growth factor (TGF)-β1 derived from dermal papilla 746
cells appears to mediate hair growth suppression. In congenital 5-α-reductase deficiency, the type 2 isoenzyme is lacking and baldness does not occur. Pattern alopecia does occur in males with X-linked ichthyosis, indicating that steroid sulfatase is not critical for the production of alopecia. Progressive shortening of the anagen phase of hair growth is noted as the hair shaft diameter decreases, so hairs are not only narrowing, but are becoming shorter. A higher proportion of telogen hairs in the affected area results in greater telogen shed. There may also be an increase in the duration of the lag phase between telogen and anagen (the kenogen lag phase). Histologically, a decrease in anagen and increase in telogen follicles is present. Follicular miniaturization and variability in shaft diameter are noted. These features are particularly evident in transverse sections. Below the level of the miniaturized or telogen follicle, a vascular or fibromucinous fibrous tract remnant is present. These tracts appear numerous in cross-section. Many mast cells may be noted in the fibrous tract remnant, but inflammatory cells are absent. Sebaceous glands may be enlarged, and hair thinning may be associated with solar elastosis. Sparse lymphoid inflammation with spongiosis may be noted at the level of the follicular infundibulum. This may represent associated seborrheic folliculitis. A sparse lymphoid infiltrate may also be noted at the level of the hair bulge. Miniaturized human hair follicles grafted on to immuno deficient mice can quickly regenerate and grow as well as or better than terminal follicles from the same individual. This suggests that even advanced pattern alopecia may be reversible. Unfortunately, available pharmacologic interventions produce little effect in advanced pattern alopecia. Minoxidil, an oral hypotensive drug that causes hypertrichosis when given systemically, is available as topical solutions (Rogaine). Minoxidil promotes the survival of dermal papilla cells, prolongs anagen phase, and results in enlargement of shaft diameter. Clinically, apparent success is best in early cases (less than 10 years) of limited extent (bald area of less than 10 cm diameter on the vertex) in whom pretreatment hair density is above 20 hairs/cm2. Minoxidil is available without a prescription as a 2% or a 5% solution. With the 2% solution, 26% of men studied showed moderate to dense regrowth, while 33% showed minimal regrowth after 4 months. Studies show a 45% increase in hair weight with the 5% solution compared to the 2% solution. In those who respond, regrowth can occur as early as 2 months after the first application. Those who respond must continue to use minoxidil indefinitely to maintain a response. Finasteride, a type 2 5-α-reductase inhibitor, given as a 1 mg tablet daily, is effective in preventing further hair loss and in increasing the hair counts to the point of cosmetically appreciable results in men aged 18–41 with mild to moderate hair loss at the vertex, in the anterior midscalp, and in the frontal region. It has been shown to stop hair loss in up to 90% of men for at least 5 years. Approximately 65% of men demonstrate hair regrowth. As with monoxidil, continued use of the product is required to sustain benefits. Hair patterning on the temples is not improved. It has been shown to lower dihydrotestosterone in the scalp and the serum of treated patients. Hair growth will be evident only after 6 months or more on the drug. If no effect is seen after 12 months, further treatment is unlikely to be of benefit. In one study, regimens that included finasteride were more effective than minoxidil alone, and therapeutic efficacy was enhanced by combining the two drugs. Short-term side effects related to finasteride are infrequent; however, the need to take this medication indefinitely suggests that study of long-term side-effect profiles is critical. A prostate cancer prevention trial with a
Female-pattern alopecia (androgenetic alopecia in women) Women generally have diffuse hair loss throughout the apical scalp with the part wider anteriorly. There is typically sparing of the frontal hairline, although a subset of women exhibits a “male” pattern of temporal recession. Although maintenance of the frontal hairline is the rule in women, a progressive decrease in hair density from the vertex to the front of the scalp does occur. The midline part is an important clinical clue, revealing a “Christmas tree pattern” of hair loss with the part tapering from the anterior to posterior scalp. The BASP classification has been suggested as a single hair loss classification scheme for use in men and women. It is based on basic (BA) types representing the shape of the anterior hairline, and specific (SP) types representing the density of hair on distinct areas (frontal and vertex). This is important because patients of either sex may demonstrate male or female patterns of alopecia. Phototrichograms and measurement of shaft diameter can be used to assess female-pattern alopecia. The same basic changes—reduced hair density and diameter, and diminished anagen and increased telogen hair—occur in women as in men. Sebaceous gland hyperplasia may be present, but is less common than in men. Transverse histologic sections demonstrate variability in the size of hair follicles (anisotrichosis). The cause is now believed to be a genetic predisposition with an excessive response to androgens. Both women and men with pattern alopecia have higher levels of 5-α-reductase and androgen receptor in frontal hair follicles compared to the levels in occipital follicles. There is also evidence suggesting a hierarchy of androgen sensitivity within follicular units. Follicular miniaturization relates to unrepaired DNA damage and a reduced proliferation rate of matrix keratinocytes. Smoking may be an independent risk factor. Most women with pattern alopecia have normal menses and fertility. If other evidence of androgen excess is present, such as hirsutism, menstrual irregularities, or acne, or if the onset is sudden, evaluation as outlined for hirsutism (see below) should be performed. Men with spinal and bulbar muscular atrophy (Kennedy disease), an X-linked neurodegenerative disease caused by an expansion of a polymorphic tandem CAG repeat within the androgen receptor gene, have a decreased incidence of pattern alopecia. Topical minoxidil is of benefit. Although some data suggest that 5% minoxidil may be of greater benefit than 2% minoxidil, the evidence is mixed. Given the higher cost of 5% minoxidil, the 2% formulation may be the best choice for many women. Oral antiandrogens, including spironolactone and cyproterone acetate, have been used to treat androgenetic alopecia in women. In one study, cyproterone acetate was more effective than minoxidil when there were other signs of hyperandrogenism, hyperseborrhea, and menstrual abnormalities, and when the body mass index was high. When these other factors were absent, minoxidil was the more effective treatment.
Treatment with finasteride is of no benefit for most women, although the subset with temporal recession may show some benefit. Finasteride treatment is contraindicated in women who may become pregnant. Hair transplantation, wigs, or interwoven hair may give satisfactory cosmetic results. In a pilot study, topical melatonin appeared to prolong anagen phase and may prove to be of some benefit. In some women, telogen effluvium may produce worsening of pre-existing pattern alopecia. Reversible causes of telogen effluvium, such as seborrheic dermatitis, nutrient deficiency, and thyroid disease, should be addressed. Camacho FM, et al: Value of hormonal levels in patients with male androgenetic alopecia treated with finasteride: better response in patients under 26 years old. Br J Dermatol 2008 May; 158(5): 1121–1124. Carlson JA, et al: Female-patterned alopecia in teenage brothers with unusual histologic features. J Cutan Pathol 2006 Nov; 33(11):741–748. El-Domyati M, et al: Proliferation, DNA repair and apoptosis in androgenetic alopecia. J Eur Acad Dermatol Venereol 2009 Jan; 23(1):7–12. Hong JB, et al: A woman with iatrogenic androgenetic alopecia responding to finasteride. Br J Dermatol 2007 Apr; 156(4):754–755. Lee WS, et al: A new classification of pattern hair loss that is universal for men and women: basic and specific (BASP) classification. J Am Acad Dermatol 2007 Jul; 57(1):37–46. Olsen EA, et al: The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol 2006 Dec; 55(6):1014–1023. Rogers NE, et al: Medical treatments for male and female pattern hair loss. J Am Acad Dermatol 2008 Oct; 59(4):547–566. Sewell LD, et al: “Anisotrichosis”: a novel term to describe pattern alopecia. J Am Acad Dermatol 2007 May; 56(5):856. Sinclair R, et al: Men with Kennedy disease have a reduced risk of androgenetic alopecia. Br J Dermatol 2007 Aug; 157(2):290–294. Su LH, et al: Association of androgenetic alopecia with smoking and its prevalence among Asian men: a community-based survey. Arch Dermatol 2007 Nov; 143(11):1401–1406. Yazdabadi A, et al: The Ludwig pattern of androgenetic alopecia is due to a hierarchy of androgen sensitivity within follicular units that leads to selective miniaturization and a reduction in the number of terminal hairs per follicular unit. Br J Dermatol 2008 Dec; 159(6):1300–1302.
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different dosage form of the same drug showed a decrease in the incidence of cancer. However, those cancers that did occur in the treatment group had a higher average Gleason score. This could be because only lower-grade cancers were prevented. Dutasteride blocks both type 1 and type 2 5-α-reductase, and is effective in the treatment of male-pattern hair loss. Other treatments that show some promise in preliminary studies include fluridil (a topical antiandrogen that suppresses the human androgen receptor) and hormoneenriched topical cell culture medium. Hair transplantation using micrografts of hair follicles from the occipital area to the anterior scalp may satisfactorily recreate hairlines and give excellent cosmetic results.
Trichotillomania (trichotillosis) Trichotillomania is the compulsive practice of plucking hair from the scalp, brows or eyelashes. Typical areas are irregular patches of alopecia that contain hairs of varying length. The scalp has a rough texture, resulting from the short remnants of broken-off hairs. Trichotillomania is seen mostly in girls under the age of 10, but boys, or adults of either sex, may engage in the practice also. Some patients relate exquisite pain localized to a follicle that can only be relieved by plucking the hair. When speaking with a patient with characteristic areas of alopecia, it has been suggested that it be asked not if but rather how removal of the hair is done. If this fails to uncover a history of hair pulling, shaving a 3 cm2 area in the involved part of the scalp will result in hairs too short for plucking, and normal regrowth in the “skin window” within 3 weeks. Finally, a biopsy, especially if cut horizontally, may demonstrate empty anagen follicles, catagen hairs, pigment casts within the infundibulum, trichomalacia, and hemorrhage. Alopecia areata shares many of these histologic features, and care must be taken to search for the presence of peribulbar lymphocytes or inflammatory cells within the fibrous tract remnants. Trichotillomania is usually a manifestation of an obsessive– compulsive disorder, but may also be associated with depression or anxiety. It may be associated with compulsive swallowing of the plucked hairs (trichophagia), and may 747
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result in formation of a gastric bezoar. Behavior modification, psychotherapy, and appropriate psychopharmacologic medication (such as serotonin-reuptake inhibitors) may be helpful. Valproic acid, quetiapine and naltrexone have been reported as effective in some patients. Adewuya EC, et al: Trichotillomania: a case of response to valproic acid. J Child Adolesc Psychopharmacol 2008 Oct; 18(5):533–536. Crescente JA Jr, et al: Quetiapine for the treatment of trichotillomania. Rev Bras Psiquiatr 2008 Dec; 30(4):402. De Sousa A: An open-label pilot study of naltrexone in childhood-onset trichotillomania. J Child Adolesc Psychopharmacol 2008 Feb; 18(1):30–33.
Other forms of noncicatricial alopecia Alopecia syphilitica may have a typical moth-eaten appearance on the occipital scalp (Fig. 33-7), may show a generalized thinning of the hair, or may resemble alopecia areata. Other areas such as the eyebrows, eyelashes, and body hair may be involved. The alopecia may be the first sign of syphilis. Follicular mucinosis (alopecia mucinosa) most commonly occurs on the scalp or beard area and manifests as a boggy red plaque or hypopigmented patch with hair loss. Comedonelike lesions may exude mucin when expressed. Biopsy demonstrates deposition of mucin in the outer root sheath and sebaceous glands. The mucin stains as hyaluronic acid, rather than epithelial sialomucin. Primary cases (unassociated with underlying disease) usually occur as localized lesions of the head or neck. Young people are primarily affected. The secondary type is associated with mycosis fungoides-type cutaneous T-cell lymphoma or a chronic inflammatory skin disease. Lesions associated with mycosis fungoides are generally widespread and chronic, and occur in older patients. Vascular or neurologic alopecia, most often of the lower extremities, may be seen in diabetes mellitus or atherosclerosis. In meralgia paresthetica there may be alopecia of the anesthetic area of the outer thigh. Endocrinologic alopecia may occur in various endocrinologic disorders. In hypothyroidism the hair becomes coarse, dry, brittle, and sparse. The proportion of telogen hairs has been shown to be 3–7 times higher than the normal 10%. In hyperthyroidism the hair becomes extremely fine and sparse. Oral contraceptives have been implicated in some instances of
androgenetic alopecia. It develops in predisposed women who are usually taking androgenic progestogens. It is advisable to discontinue the androgen-dominant pill and substitute an estrogen-dominant oral contraceptive. Some women develop telogen effluvium 2–4 months after discontinuing anovulatory agents, which is analogous to postpartum alopecia. Congenital alopecia occurs either as total or partial loss of hair, or a lack of initial growth, accompanied usually by other ectodermal defects of the nails, teeth, and bone. The hair is light and sparse, and grows slowly. Congenital triangular alopecia (Fig. 33-8) and aplasia cutis congenita are examples of congenital localized absence of hair, while hidrotic ectodermal dysplasia is an example of a diffuse abnormality of hair associated with dental and nail changes. Lipedematous alopecia consists of thickening of the scalp that gives the impression of thick cotton batting. The hair may be normal or shortened and sparse. Biopsy shows an increase in thickness of the subcutaneous fat and variable lymphoid inflammation. This disease appears to affect black persons primarily. González-Guerra E, et al: Lipedematous alopecia: an uncommon clinicopathologic variant of nonscarring but permanent alopecia. Int J Dermatol 2008 Jun; 47(6):605–609.
Cicatricial alopecia Cicatricial alopecia appears as areas of hair loss with absence of follicular ostia (Fig. 33-9). Acute lesions may appear as erythematous plaques, perifollicular papules, keratotic follicular
Fig. 33-8 Triangular alopecia. (Courtesy of Brooke Army Medical Center Teaching File)
Fig. 33-7 Syphilitic alopecia. (Courtesy of Brooke Army Medical Center Teaching File)
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Fig. 33-9 Loss of follicular ostia in scarring alopecia.
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spines, or pustules. Deep inflammatory lesions may be boggy or may resemble noncicatricial areata clinically. The inflammatory nature of the lesion may only be evident on biopsy. Discoid lupus erythematosus, lichen planopilaris, sarcoidosis, and folliculitis decalvans are the most common inflammatory causes of cicatricial alopecia. Chronic bacterial and fungal infections may produce inflammatory alopecia that mimics primary scarring alopecia. For example, fungal folliculitis may mimic lupus erythematosus. Biopsy can confirm the diagnosis and provide prognostic information regarding the potential for new growth. A 4 mm punch biopsy will provide the pathologist with an adequate specimen. Smaller specimens are of limited value. The punch should be placed parallel to the direction of hair growth to avoid transecting follicles, and the punch should be advanced to the deep subcutaneous fat. The biopsy site will typically bleed profusely, but a 4 mm-wide strip of gel foam advanced into the defect will generally provide rapid hemostasis. Sutures are rarely necessary, and as the scar from a sutured biopsy site generally stretches back to the original dimensions of the biopsy, suturing provides little benefit to the patient. Where to biopsy, how many biopsies to obtain, and how to process the tissue depend on the suspected diagnosis and the preference of the pathologist. In all cases, a pathologist experienced in the interpretation of scalp biopsies is an advantage. The pathologist may prefer vertical or transverse (horizontal) sectioning of the specimen. Each has advantages. Every follicular unit in the specimen will be demonstrated in transverse sections. Vertical sections are superior for demonstrating changes in the surface epidermis, dermoepidermal junction, superficial dermis, and subcutaneous fat. In general, the features of androgenetic (pattern) alopecia, telogen effluvium, and trichotillomania are better demonstrated in transverse (horizontal) sections through the specimen. Alopecia areata and syphilitic alopecia are well demonstrated in transverse sections if serial step sections are obtained to demonstrate deeper planes of section or if the block is cut horizontally in a bread-loaf fashion prior to embedding. They are equally well demonstrated with serial vertical sections through the block. Lupus erythematosus and lichen planopilaris are more easily demonstrated in serial vertical sections. The diagnostic yield can be enhanced by pairing vertical and transverse sections. If two biopsies are done, one specimen can be bisected vertically for direct immunofluorescence (DIF) and hematoxylin and eosin (H&E) processing. It is most easily split by laying it on its side and bisecting it with a 15 blade pushed cleanly through the specimen in a single downward motion. Sawing at the specimen will not produce a satisfactory result. One-half of the bisected specimen is placed in formalin, and the other half in immunofluorescent media. The second specimen can be bisected for transverse sections in the clinic or left for the laboratory to bisect after processing. If it is to be bisected in the clinic, it should be placed on its side. The 15 blade should be pushed downward through the specimen in a single motion at the level of the mid-dermis. All pieces for vertical and transverse sections may be placed in a single bottle to be embedded in a single cassette. In many forms of cicatricial alopecia, a biopsy of an active inflammatory lesion will be most diagnostic. In lupus erythematosus, the biopsy must be from a lesion of several months’ duration in order to demonstrate hyperkeratosis, follicular plugging, basement membrane thickening (Fig. 33-10), and dermal mucin. Only biopsies from established lesions of lupus will demonstrate reliable immunofluorescence. When biopsies of the most active area of alopecia have failed to yield a definite diagnosis, a biopsy from a scarred area may provide additional information. Scars show loss of elastic tissue with the Verhoeff–van Gieson stain. The pattern of
Fig. 33-10 Basement membrane thickening in lupus erythematosus (periodic acid–Schiff [PAS] stain).
Fig. 33-11 Scarring alopecia (H&E stain).
elastic tissue loss is the “footprint” of the preceding inflammatory process (Figs 33-11 and 33-12). Lichen planopilaris and folliculitis decalvans both affect the infundibulum. Both result in wedge-shaped superficial dermal scars. Discoid lupus erythematosus results in scarring of both the follicular units and the intervening dermis. Morphea does not produce a scar, but rather hyalinization of collagen bundles with preservation of the elastic fibers. In idiopathic pseudopelade, the fibrous tract remnants are widened, but the elastic tissue sheath at the periphery of the fibrous tract is preserved. Most patients with cicatricial alopecia experience gradual progression of the alopecia, and the prolonged course of the disease may lead to inappropriate therapeutic complacency. The progressive destruction of hairs will result in ever-expanding areas of permanent alopecia. Therefore, cicatricial alopecia must be treated aggressively and early to avoid 749
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Fig. 33-12 Scarring alopecia (elastic stain). Normal elastic fibers (black) indicate the nonscarred portions of the dermis.
permanent disfigurement. Surgical revision of the hairless plaque is an option for stable end-stage alopecia, but unless the underlying disease is controlled, surgery may only lead to a flare of the underlying disease with progression of hair loss. Therapy may be forestalled by the inability to establish a definite diagnosis. To help guide therapy for patients who defy diagnosis, work groups of the North American Hair Research Society have proposed a classification scheme based on the type and pattern of inflammation. Some forms of destructive alopecia are lymphocyte-mediated, while some are suppurative processes. The type of infiltrate and the portion of the pilosebaceous unit affected can be used to guide therapy. This classification system may also allow patients to enroll in clinical trials, even in the absence of a definite diagnosis.
Lymphoid-mediated disorders Lupus erythematosus
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Chronic cutaneous lupus of the scalp (discoid lupus erythematosus [DLE]) is a common cause of cicatricial alopecia. In active disease, anagen hairs may be easily extracted from the involved area. Usually, erythema, atrophy, follicular plugging, and mottled hyperpigmentation and hypopigmentation are present. Patients with chronic cutaneous lupus of the scalp may or may not have accompanying SLE or skin lesions of DLE on other parts of the body. The external ear canal and concha should always be examined, as they are common sites for discoid lesions. Occasionally, alopecia occurs in a plaque of tumid lupus. Lupus panniculitis may occasionally result in alopecia in the absence of surface skin changes. SLE is often associated with discoid lesions of the scalp. Patients with SLE may also have short miniaturized “lupus hairs” on the anterior scalp. Biopsy of early lesions of DLE is often nondiagnostic. Patchy lymphoid inflammation and perifollicular mucinous fibrosis may be the only histologic findings. Focal vacuolar interface dermatitis may or may not be noted. Active established lesions, present for several months, have a higher diagnostic yield. Active established lesions usually demonstrate hyperkeratosis, follicular plugging, vacuolar interface dermatitis, basement membrane zone thickening, pigment incontinence, and dermal mucin. Perivascular and periadnexal lymphoid infiltrates are patchy and involve the eccrine coil and fibrous tract remnants. Fibrous tract involvement creates dense vertical columns of lymphocytes. The underlying subcutaneous tissue may demonstrate nodular lymphoplasmacytic infiltrates and fibrin or hyaline rings around necrotic fat. Hypertrophic lesions of chronic cutaneous lupus erythematosus often demonstrate lichenoid dermatitis. DIF may be nonspecific, but active established lesions typically demonstrate a “full house”
Fig. 33-13 Frontal fibrosing alopecia. (Courtesy of Don Adler DO)
(continuous granular deposition of IgG, IgA, IgM, and C3) at the dermoepidermal junction. When present, this pattern is particularly helpful in distinguishing lichenoid hypertrophic lupus erythematosus from lichen planopilaris. Burnt-out lesions of DLE demonstrate loss of elastic fibers throughout the dermis, which differs from the focal peri-infundibular wedge-shaped scars of lichen planopilaris. In systemic lupus, there may be follicular atrophy associated with pronounced dermal mucinosis. Chronic cutaneous lupus may respond to intralesional or potent topical corticosteroids, but systemic therapy is frequently required. Antimalarials, retinoids, dapsone, thalidomide, sulfasalazine, mycophenolate mofetil, and methotrexate have been used successfully. Topical tazarotene and topical calcineurin inhibitors are generally disappointing.
Lichen planopilaris Lichen planopilaris presents with perifollicular erythema and progressive scarring. Small follicular papules may be noted, or the lesion may resemble the ivory white irregular patches of pseudopelade. In some patients, typical polygonal flattopped papules are present on the wrists and ankles, and lacy white lesions are noted on the oral and genital mucosa. Widespread follicular papules may be present on the trunk or extremities. In most patients, however, only the scalp is involved. Frontal fibrosing alopecia appears to be a variant of lichen planopilaris. Most patients are older women with bandlike frontotemporal alopecia (Fig. 33-13). Graham Little– Piccardi–Lassueur syndrome includes cicatricial alopecia on the scalp, keratosis pilaris in the skin of the trunk and extremities, and noncicatricial hair loss in the pubis and axillae. It has been described in association with complete androgen insensitivity syndrome, a condition that also presents with noncicatricial alopecia in the axillary and pubic hair. Diagnostic biopsies demonstrate lichenoid interface dermatitis of the follicular unit and sometimes the intervening epidermis. The entire fibrous tract may be filled with cytoid bodies (Fig. 33-14). The changes commonly occur focally and may be best visualized with serial vertical sections. Perifollicular mucinous fibrosis is common and focal perifollicular lymphoid infiltrates tend to involve the infundibulum (the infiltrates of lupus erythematosus tend to involve the isthmus). DIF may be negative or may reveal cytoid bodies and shaggy linear fibrin at the dermoepidermal junction. Lichen planopilaris responds to oral and intralesional corticosteroids. Topical corticosteroids may be adequate in a few patients, but the activity of the disease waxes and wanes, and slow progression should not lead to therapeutic complacency. Oral retinoids can be effective. Alternative therapies
Diseases of the hair Fig. 33-15 Central centrifugal cicatricial alopecia.
Neutrophil-mediated disorders Folliculitis decalvans Fig. 33-14 Lichen planopilaris, note cytoid bodies completely fill the fibrous tract remnant.
include the other oral agents used to treat lupus; however, there are fewer data regarding their use in lichen planopilaris. As in lupus, topical tazarotene and topical macrolactams are generally disappointing. Biologics have been suggested as therapy, but onset of lichen planopilaris has been noted during etanercept therapy.
Hot comb alopecia and central centrifugal cicatricial alopecia Hot comb alopecia was reported in the late 1960s as a scarring alopecia seen in black women who straightened their hair with hot combs for cosmetic purposes. It develops characteristically on the crown and spreads peripherally to form a large oval area of partial hair loss. The hot petrolatum used with the iron was thought to cause thermal damage to the hair follicle. However, Sperling et al reported a similar-appearing scarring alopecia in both men and women who did not report the use of hot combs. Some authors now regard hot comb alopecia, central centrifugal cicatricial alopecia (CCCA), and idiopathic pseudopelade to be one entity or overlapping entities that can be indistinguishable. CCCA is seen most commonly in African American women, is slowly progressive, usually begins in the crown, and advances to the surrounding areas (Fig. 33-15). The term is often used as a broad category that includes cases once classified as hot comb alopecia and central elliptical pseudopelade in white women. Some patients will demonstrate crops of crusts at the periphery of the patches, a feature of folliculitis decalvans. Treatment of CCCA is difficult and often unsatisfactory. Discontinuation of chemical and heat processing, and reduction of traction are routinely recommended, but the effectiveness of these recommendations has yet to be substantiated. Cases with overlapping features of folliculitis decalvans may respond to long-term antibiotic therapy and topical corticosteroids. In such overlapping cases, the histology shows a lymphocytic infiltrate during the chronic stage, but periodic crops of pustules demonstrate a neutrophilic folliculitis.
Folliculitis decalvans presents with crops of pustules that result in cicatricial alopecia. Successive crops of pustules, crusts, or erosions lead to expansion of the alopecic patches. Staphylococci are sometimes cultured from the lesions, and some authors have suggested that folliculitis decalvans merely represents a chronic staphylococcal infection. It is more likely that follicular destruction is the result of an abnormal suppurative immune response. Staphylococci and other organisms probably play a role in inciting the response. The lesions often respond to long-term treatment with tetracycline. The improvement may reflect the antineutrophil effects of the drug or its antimicrobial effects. Many patients also respond to other forms of antistaphylococcal therapy, but the lesions generally recur after the antibiotic is discontinued. Chronic antibiotic treatment generally results in a continued response. Some sustained responses have been noted after combination therapy with rifampin and clindamycin. Rifampin alone has been used, but may promote the emergence of resistance. Selenium sulfide shampoo and topical corticosteroids may be useful as adjunctive therapy. Oral retinoids, oral and topical fusidic acid, and oral zinc sulphate have sometimes produced sustained responses. A variant of folliculitis decalvans occurs in African American patients who present with pseudofolliculitis of the beard, acne keloidalis nuchae, and scarring alopecia in the vertex and parietal scalp. The scalp demonstrates ingrown hairs, crops of pustules or crusts, and permanent scarring alopecia. While pseudofolliculitis barbae is generally accepted to be the result of ingrown hairs, the pathogenesis of acne keloidalis nuchae remains in question. Histologically, ingrown hairs are common in advanced lesions. Early lesions may not demonstrate the hair. Some patients merely develop small papules on the nape of the neck, while others develop pustules, crusts, and progressive alopecia. This latter group overlaps with folliculitis decalvans.
Acne necrotica Acne necrotica presents with discrete excoriated follicular papules in the scalp. Biopsy demonstrates an inflammatory crust and suppurative folliculitis. Usually there is no associated scarring alopecia, but occasional cases overlap with folliculitis decalvans.
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Fig. 33-16 Erosive pustular dermatitis.
Fig. 33-18 Tufted doll’s hairs, cicatricial alopecia.
infundibulum) occur physiologically on the scalp and legs. They are common in the occipital scalp. Recurrent staphylo coccal infection is more common in patients with many compound hairs and commonly leads to tufted folliculitis.
Other forms of permanent alopecia Pseudopelade of Brocq
Fig. 33-17 Dissecting cellulitis.
Erosive pustular dermatitis of the scalp This often presents as expanding eroded patches with moist granulation tissue (Fig. 33-16). The lesions often follow trauma or a surgical procedure and tend to be chronic and progressive. They respond best to class I topical corticosteroids.
Dissecting cellulitis (perifolliculitis capitis abscessens et suffodiens of Hoffman) This often coexists with acne conglobata and hidradenitis suppurativa. It may also occur with folliculitis decalvans. The lesions are deep, boggy, and suppurative (Fig. 33-17). They may respond to tetracyclines, retinoids, and intralesional corticosteroids.
Tufted folliculitis Tufted folliculitis presents with doll’s hair-like bundling of follicular units. It is seen in a wide range of scarring conditions, including chronic staphylococcal infection, chronic lupus erythematosus, lichen planopilaris, Graham Little syndrome, folliculitis decalvans (Fig. 33-18), acne keloidalis nuchae, immunobullous disorders, and dissecting cellulitis. Compound hairs (two or more hairs sharing a common 752
Also known as alopecia cicatrisata, this is a rare form of cicatricial alopecia in which destruction of the hair follicles produces multiple round, oval, or irregularly shaped, hairless, cicatricial patches of varying sizes. They are usually coin-sized and are white or slightly pink in color, with a smooth, shiny, marble-like or ivory, atrophic, “onion skin” surface. Interspersed in the patches may be a few spared follicles with hairs growing from them. A clinical inflammatory stage is completely absent. No pustules, crusts, or broken-off hairs are present. The onset is, as a rule, insidious, with one or two lesions appearing on the vertex. The condition affects females three times more commonly than males, and has a prolonged course. In advanced cases large irregular patches are formed by coalescence of some of the many small macules, a pattern referred to as “footprints in the snow.” The alopecia is permanent and the disease is slowly progressive. Histologically, the majority of patients with clinical lesions of pseudopelade demonstrate true scarring (indicated by loss of elastic tissue) in a wedge-shaped pattern in the superficial dermis. The pattern is similar to that seen in lichen planopilaris and suggests that many cases classified as pseudopelade represent an end stage of lichen planopilaris. A subset of patients, however, demonstrates no perifollicular or interfollicular scarring at all. This subset has been called idiopathic pseudopelade. It shows significant clinical overlap with CCCA. In these patients, the dermis is contracted into a thin band of dense collagenous tissue. Elastic fibers are intact and quite thick as a result of elastic recoil related to dermal contraction. Fibrous tract remnants are wide and hyalinized with an intact elastic sheath. Lymphoid and neutrophilic inflammation is absent, but loss of the inner and outer root sheaths with subsequent hair fiber granuloma formation is noted. Sebaceous glands are decreased or absent, as they are in most forms of permanent alopecia. DIF is negative. The end stage of many forms of cicatricial alopecia can resemble pseudopelade clinically, but, like lichen planopilaris, they demonstrate distinct patterns of elastic tissue loss in the dermis. Folliculitis decalvans is distinguished by periodic crops of pustules or crusts at the periphery of the alopecic patches. It produces superficial wedge-shaped scars similar to those of lichen planopilaris.
Diseases of the hair Fig. 33-19 Traction alopecia.
Fig. 33-20 Pressure alopecia with scalp demonstrating pressureinduced geometric pressure necrosis.
Topical and intralesional corticosteroids and long-term tetracycline in anti-inflammatory doses may be tried but are not often successful. The disease usually reaches an inactive end stage after many years.
Traction alopecia Traction alopecia occurs from prolonged tension on the hair, either from wearing the hair tightly braided or in a ponytail, pulling the hair to straighten it, rolling curlers too tightly, or from the habit of twisting the hairs with the fingers. Traction alopecia most commonly involves the periphery of the scalp, especially the temples and above the ears (Fig. 33-19).
Sarcoidosis Sarcoidosis of the scalp presents with diffuse or patchy hair loss. The involved scalp is often indurated and a raised peripheral border may be present. The lesions are often red–brown in color and may have an apple jelly appearance with diascopy. Biopsy reveals noncaseating granulomas. Treatment is as for other forms of sarcoidosis.
Pressure alopecia Pressure alopecia occurs in adults after prolonged pressure on the scalp during general anesthesia, with the head fixed in one position. It may also occur in chronically ill persons after prolonged bed rest in one position (Fig. 33-20), which causes persistent pressure on one part of the scalp. It probably arises because of pressure-induced ischemia.
Tumor alopecia Tumor alopecia refers to hair loss in the immediate vicinity of either benign or malignant tumors of the scalp. Syringomas, nerve sheath myxomas, and steatocystoma multiplex are benign tumors that may be limited to the scalp and cause alopecia. Alopecia neoplastica is the designation given to hair loss from metastatic tumors, most often from breast or renal carcinoma (Fig. 33-21).
Keratosis pilaris atrophicans Keratosis pilaris atropicans includes many forms of keratosis pilaris with cicatricial alopecia. Variants include keratosis pilaris atrophicans faciei, atrophoderma vermiculatum, keratosis follicularis spinulosa decalvans, and ichthyosis follicularis.
Fig. 33-21 Alopecia neoplastica.
Keratosis pilaris atrophicans faciei (ulerythema ophryogenes, keratosis pilaris rubra atrophicans faciei, folliculitis rubra, lichen pilare, or xerodermie pilaire symmétrique de la face) begins in infancy as follicular papules with perifollicular erythema. Initially, the lesions are restricted to the lateral eyebrows. With time, they spread to involve the cheeks and forehead. There may be associated keratosis pilaris on the extremities and buttocks. The condition may also be associated with an atopic diathesis, ectodermal dysplasia, or Noonan syndrome. Atrophoderma vermiculatum (acne vermoulanti, honeycomb atrophy, folliculitis ulerythema reticulata, ulerythema acneiforme, folliculitis ulerythematous reticulata, atrophodermia reticulata symmetrica faciei, atrophoderma reticulatum) presents with erythematous follicular papules on the cheeks in childhood. With time, the lesions develop into pit-like depressions (reticulate atrophy). Autosomal-dominant inheritance has been described. This condition generally spares the scalp and eyebrows. Keratosis follicularis spinulosa decalvans is a rare X-linked disorder described by Siemens in 1926. The gene has been mapped to Xp21.2–p22.2. It begins in infancy with keratosis pilaris localized on the face, and then evolves to more diffuse 753
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involvement. Progressive cicatricial alopecia occurs on the scalp, eyebrows, and sometimes eyelashes. The alopecia starts during childhood, and active disease may remit during the early teenage years. Corneal and conjunctival inflammation, corneal dystrophy, and blepharitis occur, and photophobia is usually a prominent finding. Ichthyosis follicularis also demonstrates extensive spiny follicular hyperkeratosis, permanent alopecia, and photophobia. Palmar plantar keratosis, nail deformities, atopy, and recurrent cheilitis have been described.
Atrichia with papular lesions Atrichia with papular lesions is a rare autosomal-recessive disorder with early onset of atrichia, followed by a papular eruption appearing within the first years of life. The condition has been linked to chromosome 8p21 and mutations have been detected in what is now referred to as the hairless gene. It is discussed in more detail in Chapter 27. Alzolibani AA, et al: Pseudopelade of Brocq. Dermatol Ther 2008 Jul–Aug; 21(4):257–263. Elston DM, et al: Vertical and transverse sections of alopecia biopsy specimens: combining the two to maximize diagnostic yield. J Am Acad Dermatol 1995; 32:454. Elston DM, et al: Elastic tissue in scars and alopecia. J Cutan Pathol 2000; 27:147. Elston DM, et al: A comparison of vertical versus transverse sections in the evaluation of alopecia biopsy specimens. J Am Acad Dermatol 2005; 53:267. Harries MJ, et al: Management of primary cicatricial alopecias: options for treatment. Br J Dermatol 2008 Jul; 159(1):1–22. Hordinsky M: Cicatricial alopecia: discoid lupus erythematosus. Dermatol Ther 2008 Jul–Aug; 21(4):245–248. Kang H, et al: Lichen planopilaris. Dermatol Ther 2008 Jul–Aug; 21(4):249–256. Otberg N, et al: Folliculitis decalvans. Dermatol Ther 2008 Jul–Aug; 21(4):238–244. Shapiro J: Cicatricial alopecias. Dermatol Ther 2008 Jul–Aug; 21(4):211. Somani N, et al: Cicatricial alopecia: classification and histopathology. Dermatol Ther 2008 Jul–Aug; 21(4):221–237. Review. Unger W, et al: The surgical treatment of cicatricial alopecia. Dermatol Ther 2008 Jul–Aug; 21(4):295–311. Whiting DA, et al: Central centrifugal cicatricial alopecia. Dermatol Ther 2008 Jul–Aug; 21(4):268–278.
Hair color Melanin in the hair follicles is produced in the cytoplasm of the melanocytes. Organelles involved include the endoplasmic reticulum, ribosomes, and Golgi apparatus. Melanocytes producing hair pigment are associated with the hair matrix, and melanogenesis occurs only during anagen. This cyclic melanin synthesis distinguishes follicular melanogenesis from the continuous melanogenesis of the epidermis. With age, cyclic melanocytic activity in the follicular unit declines. By 40 years of age most individuals show evidence of graying. Graying results primarily from a reduction in tyrosinase activity within hair bulb melanocytes. Defective migration of melanocytes from a diminishing reservoir in the outer root sheath may play a role. Physiologic graying may also be related to reactive oxygen species-mediated damage to nuclear and mitochondrial DNA in bulbar melanocytes. The melanocortin 1 receptor gene (MCR1) is closely related to red hair, freckling, and sun sensitivity. The pigment in black and dark brown hair is composed of eumelanin, whereas in blond and red hair it is pheomelanin. In black hair the melanocytes contain the densest melanosomes. Brown hair differs only by its smaller melanosomes. Light brown hair consists of a mixture of the melanosomes of 754
dark hair and the incomplete melanosomes of blond hair. Many of the melanosomes in blond hair develop only on the matrix fibers and not in the spaces between the fibers. Red hair shows incomplete melanin deposits on the matrix fibers to produce a blotchy-appearing melanosome. Pheomelanin is distinguished by its relatively high content of sulfur, which results from the addition of cysteine to dopaquinone along the biosynthetic pathway of melanin synthesis. In gray hair (canities), melanogenic activity is decreased as a result of fewer melanocytes and melanosomes, as well as a gradual loss of tyrosinase activity. Graying of the scalp hair is genetically determined and may start at any age. Usually, it begins at the temples and progresses with time. The beard usually follows, with the body hair graying last. Premature whitening of scalp hair is usually caused by vitiligo, sometimes without recognized, or actually without, lesions of glabrous skin. Early graying (before age 20 in white or before age 30 in black persons) is usually familial; however, it may occur in progeria, Rothmund–Thomson syndrome, Böök syndrome, and Werner syndrome. In poliosis, gray or white hair occurs in circumscribed patches. This may occur in Waardenburg syndrome and piebaldism, Tietz syndrome, Alezzandrini syndrome, neuro fibromatosis, and tuberous sclerosis. Poliosis is also found in association with regressing melanoma, vitiligo, and Vogt– Koyanagi syndrome, and may be seen in alopecia areata when the new hairs grow. Migratory poliosis without hair loss may represent a forme fruste of alopecia areata. Green hair has been traced to copper in the water of a swimming pool. This occurs only in blond or light hair, and may be treated with topical EDTA, penicillamine-containing shampoos, or 1.5% aqueous 1-hydroxyethyl diphosphonic acid. Tars and chrysarobin stain light-colored hair brown. Changes in hair color occur in various disorders. The hair is blond in phenylketonuria and homocystinuria. Light hair is also seen in oasthouse disease (familial methionine malabsorption), Menkes kinky hair syndrome, and albinism. In Griscelli and Chédiak–Higashi syndromes the hair has a silvery sheen. In kwashiorkor the hair assumes a red–blond color and may demonstrate periodic banding (flag sign, segmental heterochromia). Alternating light and dark bands may also occur in iron deficiency anemia and with courses of sunitinib. In vitamin B12 deficiency and with IFN therapy, whitening may occur. The disorder has been called canities segmentata sideropenica. It responds completely to iron supplementation. Triparanol is associated with hypopigmented hair. Minoxidil (by changing vellus to terminal hairs) causes darkening of hair; another hypotensive agent, diazoxide, gives the hair a reddish tint. Chloroquine therapy may cause hair whitening, usually in redheads and blonds, but not in brunettes. Pigmentation of the eyelashes and irides has been described with latanoprost. Xanthotrichia (yellow hair) has been noted with selenium sulfide and dihydroxyacetone. Many black patients with acquired immunodeficiency syndrome (AIDS) have experienced softening, straightening, lightening, and thinning of their hair. Patients with human immunodeficiency virus (HIV)-1 infection may also experience elongated eyelashes and telogen effluvium. Hartmann JT, et al: Sunitinib and periodic hair depigmentation due to temporary c-KIT inhibition. Arch Dermatol 2008 Nov; 144(11): 1525–1526. Prevost N, et al: Xanthotrichia (yellow hair) due to selenium sulfide and dihydroxyacetone. J Drugs Dermatol 2008 Jul; 7(7):689–691. Vaughn MR, et al: A comparison of hair colour measurement by digital image analysis with reflective spectrophotometry. Forensic Sci Int 2009 Jan 10; 183(1–3):97–101.
Hair structure defects Hair structure defects
Examination of hairs for structural defects is greatly facilitated by a method devised by Shelley: putting a piece of doublestick tape on a microscope slide and aligning 5 cm segments of hair in parallel on it. Dermoscopy can be useful in assessing hair morphology. Microscopic mounts of hairs are best examined under a dissecting microscope or polarized light. Goldcoating and scanning electron microscopy can also be done on hairs so mounted. Hairs from multiple body sites may need to be sampled. This has been documented in Netherton syndrome where scalp hair can be normal while eyebrow hair demonstrates the characteristic hair shaft defect. Boussofara L, et al: Netherton’s syndrome: the importance of eyebrow hair. Dermatol Online J 2007 Jul 13; 13(3):21. Cheng AS, et al: The genetics of hair shaft disorders. J Am Acad Dermatol 2008 Jul; 59(1):1–22. Whiting DA, et al: Office diagnosis of hair shaft defects. Semin Cutan Med Surg 2006 Mar; 25(1):24–34.
Hair casts (pseudonits) Hair casts represent remnants of the inner root sheath. They often occur in great numbers and may mimic nits in the scalp. While nits are firmly cemented to the hair shaft, hair casts slide freely along the shaft. Taeb et al reviewed 36 published cases and distinguished two groups: girls between 2 and 8 years of age with diffuse involvement and no scalp disease, and children and adults with psoriasis, lichen planus, seborrheic dermatitis, or trichotillomania. Keipert made a similar distinction, separating a large group of cases with some keratinizing disorder of the scalp and dark, oddly shaped masses of keratin adherent to or surrounding the hairs, which he called para keratotic hair casts; and lighter-colored tubular casts, 2–4 mm long, which he called peripilar hair casts. Taeb et al found 0.025% tretinoin lotion effective. False hair casts may occur as a result of hair spray or deodorant concretions. Immunoglobulin casts and cutaneous spicules have been noted in multiple myeloma. Miller JJ, et al: Hair casts and cutaneous spicules in multiple myeloma. Arch Dermatol 2006 Dec; 142(12):1665–1666.
Pili torti Also known as twisted hairs, pili torti is a malformation of hair characterized by twisting of the hair shaft on its own axis (Fig. 33-22). The hair shaft is segmentally thickened, and light and dark segments are seen. Scalp hair, eyebrows, and eyelashes may be affected. The hairs are brittle and easily broken. In the classic type, unassociated with other disorders, onset is usually in early childhood; by puberty, it has usually improved. Clinically, it may be associated with patchy alopecia and short, broken hairs. It usually follows a dominant inheritance pattern, though recessive and sporadic cases have been reported. Acquired cases have been described in young women with anorexia nervosa. Pili torti may be seen with associated abnormalities. The Björnstad syndrome consists of congenital deafness of the cochlear type, with pili torti. Both autosomal-dominant and autosomal-recessive inheritance patterns have been described. BCS1L mutations cause the Björnstad syndrome. The gene encodes an ATPase necessary for the assembly of complex III in mitochondria. BCS1L mutations also cause lethal conditions, including the complex III deficiency and the GRACILE syndrome, with severe multisystem and neurologic manifestations. Pili torti also may occur in citrullinemia (argininosuccinate synthetase deficiency), Menkes kinky hair syndrome, Bazex
Fig. 33-22 Pili torti.
follicular atrophoderma syndrome, ectodermal dysplasias, Crandall syndrome (pili torti, nerve deafness, hypogonadism), Netherton syndrome (along with bamboo hair), with isotretinoin and etretinate therapy, in anorexia nervosa, and in trichothiodystrophy. Laron syndrome is an autosomal-recessive disease with primary insulin-like growth factor 1 deficiency and primary growth hormone insensitivity. Affected children have sparse hair and frontal recession. Pili torti et canaliculi, tapered hair, and trichorrhexis nodosa have been noted. Hinson JT, et al: Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. N Engl J Med 2007 Feb 22; 356(8):809–819.
Menkes kinky hair syndrome Pili torti, and often monilethrix and trichorrhexis nodosa, are all common in the hairs in this sex-linked recessively inherited disorder. It has also been called steely hair disease, because the hair resembles steel wool. The characteristic ivory color of the hair appears between 1 and 5 months of age. Drowsiness, lethargy, convulsive seizures, severe neurologic deterioration, and periodic hypothermia ensue with death at an early age. Hairs become wiry, sparse, fragile, and twisted about their long axes. Osteoporosis, and dental and ocular abnormalities are common. The skin is pale and the face pudgy, and the upper lip has an exaggerated “Cupid’s bow” configuration. The occipital horn syndrome, primarily a connective tissue disorder, is a milder variant of Menkes syndrome. Patients have a deficiency of serum copper and copper-dependent 755
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enzymes, resulting from mutations in the ATP7A gene. The gene encodes a trans-Golgi membrane-bound copper transporting P-type ATPase. Loss of this protein activity blocks the export of dietary copper from the gastrointestinal tract and causes the copper deficiency. Low serum copper and ceruloplasmin are characteristic, but are not seen in all patients. They are particularly variable in the first weeks of life. Other tests helpful for screening include the ratio of catechols, such as dihydroxyphenylalanine to dihydroxyphenylglycol. High levels of the catechols DOPA, dihydrophenylacetic acid, and dopamine, and low levels of dihydroxyphenylglycol are characteristic. Studies of copper egress in cultured fibroblasts have also been used. Early detection allows for genetic counseling and the institution of copper histidine treatment, which is being studied and has shown promising results in some infants. Pamidronate treatment is associated with an increase in bone mineral density in children with Menkes disease. In zebra fish, antisense morpholino oligonucleotides directed against the splice-site junctions of two mutant calamity alleles were able to correct the molecular defect. This is a promising area for research. Bertini I, et al: Menkes disease. Cell Mol Life Sci 2008 Jan; 65(1):89–91. Madsen EC, et al: In vivo correction of a Menkes disease model using antisense oligonucleotides. Proc Natl Acad Sci U S A 2008 Mar 11; 105(10):3909–3914. Rudolph V, et al: Copper trafficking and extracellular superoxide dismutase activity: kinky hair, kinky vessels. Hypertension 2008 Nov; 52(5):811–812.
Uncombable hair syndrome First reported in 1973 by Dupré et al as cheveux incoiffables (undressable hairs) and by Stroud and Mehergan as spunglass hair, the microscopic abnormality of a triangular crosssectional appearance with a longitudinal groove gives the disease its other name, pili triangulati et canaliculi. Clinically, the defect is noted in the first few years of life as dry, blond, shiny hair that stands straight out from the scalp and cannot be combed (Fig. 33-23). On light microscopy it may appear quite normal when viewed lengthwise, but on horizontal sectioning and on scanning electron microscopy it shows the longitudinal grooves that make it abnormally rigid. These depressions are sometimes seen in unaffected persons, so that 50% of hairs need to be affected for the condition to be clinically detectable. Autosomal-dominant, autosomal-recessive, and sporadic forms have been described. Uncombable hair has been associ-
Fig. 33-23 Uncombable hair syndrome.
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ated with angel-shaped phalango-epiphyseal dysplasia. It has also been seen in combination with retinal dystrophy, juvenile cataract, and brachydactyly. It has also been reported in a patient who acquired the abnormality at age 39 after an episode of diffuse alopecia treated with spironolactone. Although there are usually no associated ectodermal defects, isolated cases have been reported in which uncombable hair is one component of several clustered findings. Until more experience is available in the literature, grouping of these cases into new syndromes is premature. Some patients have responded clinically to biotin, 0.3 mg orally three times a day. Some cases improve spontaneously in late childhood. Anderson HF, et al: Uncombable hair syndrome. Cutis 2008 Jul; 82(1):20, 31–32. Jarell AD, et al: Uncombable hair syndrome. Pediatr Dermatol 2007 Jul–Aug; 24(4):436–438. Schena D, et al: Uncombable hair syndrome, mental retardation, single palmar crease and arched palate in a patient with neurofibromatosis type I. Pediatr Dermatol 2007 Sep–Oct; 24(5):E73–E75.
Monilethrix Monilethrix, also known as beaded hairs, is a rare hereditary disease. It is characterized by dryness, fragility, and sparseness of the scalp hair (Fig. 33-24), with fusiform or spindle-shaped swellings of the hair shaft separated by narrow atrophic segments. The hair tends to break at the delicate internodes. There is an occasional rupture at the node and longitudinal fissuring of the shaft, which also involves the nodes. The disease is often associated with keratosis pilaris of the extensor surfaces, temples, and back of the neck. Hair on regions other than the scalp may be affected. Leukonychia may occur. Inheritance of monilethrix is an autosomaldominant trait. It has been described in association with Menkes syndrome. Mutations in desmoglein 4 are seen in monilethrix and in localized autosomal-recessive hypotrichosis, a disorder that shares clinical features with monilethrix but lacks the characteristic hair shaft changes. Several cases of monilethrix have been linked to the type II keratin gene cluster on chromosome 12q13. Causative heterozygous mutations of
Fig. 33-24 Monilethrix.
Trichorrhexis nodosa The affected hair shafts fracture easily and may have small white nodes arranged at irregular intervals. These nodes are the sites of fraying of the hair cortex. The splitting into strands produces a microscopic appearance suggestive of a pair of brooms stuck together end to end by their bristles. The hairs soon break at these nodes (Fig. 33-25). The number of these nodes along one hair shaft varies from one to several, depending on its length. These fractured hairs are found mostly on the scalp, often in just a small area or areas, but other sites such as the pubic area, axillae, and chest may be involved. Several categories or types of trichorrhexis nodosa have been described. Proximal trichorrhexis nodosa involves the proximal shafts of the hairs of black patients who traumatize their hair with styling or chemicals. The involved hairs break a few centimeters from the skin surface, resulting in patches of short hair. It appears to occur in genetically predisposed patients. Distal trichorrhexis nodosa affects primarily Asians and white patients; it occurs several inches from the scalp, and is associated with trichoptilosis, or longitudinal splitting, known as split ends. Acquired localized trichorrhexis nodosa is a common type in which the defect occurs in a localized area, a few centimeters across. A number of diseases accompany this type of trichorrhexis nodosa in which pruritus is a prominent symptom; scratching and rubbing may be the cause. Among such diseases are circumscribed neurodermatitis, contact dermatitis, and atopic dermatitis. The occurrence of trichorrhexis nodosa in some patients with argininosuccinicaciduria has suggested an etiologic connection. Trichorrhexis nodosa has been described in Menkes kinky hair syndrome, Netherton syndrome, hypothyroidism, ectodermal dysplasia, the syndrome of intractable infant diarrhea, and trichothiodystrophy. Trichoschisis, a clean transverse fracture across the hair shaft, is more commonly present in trichothiodystrophy. The curly hair that may result from isotretinoin therapy has been attributed to extensive trichorrhexis nodosa. Because trauma may induce this hair shaft
abnormality, the specificity of this finding in the above conditions may simply be fortuitous. Treatment is directed toward the avoidance of trauma to the hair.
Trichorrhexis invaginata Also known as bamboo hair, trichorrhexis invaginata is caused by intussusception of the hair shaft at the zone where keratinization begins. The invagination is caused by softness of the cortex in the keratogenous zone. The softness may be caused by inadequate conversion of –SH to S–S proteins in the cortex. The patient with bamboo hair will have nodose ball-andsocket deformities, with the socket forming the proximal and the ball part forming the distal portion of the node along the hair shaft. This type of hair is associated with Netherton syndrome. Occasionally, only the proximal half of the abnormality is seen; this has been called golf tee hairs. Trichorrhexis invaginata associated with congenital ichthyosiform erythroderma or ichthyosis linearis circumflexa constitutes Netherton syndrome. Atopic manifestations and high IgE levels are commonly present. The bamboo hairs may be present not only on the scalp but also on the eyebrows, eyelashes, and rarely in other hairy areas. Hair sparsity is noted all over the body. The bamboo hairs may become normal within a few years. Other reported findings include pili torti, trichorrhexis nodosa, moniliform hairs, urticaria, angioedema, growth retardation, recurrent infections, multiple epithelial neoplasms, and mental retardation. An autosomal-recessive mode of inheritance has been suggested, although reported cases involving women far outnumber men. Pathogenic mutations have been identified in serine protease inhibitor Kazaltype 5 (SPINK5) on chromosome 5q32, a gene encoding lymphoepithelial Kazal-type-related inhibitor (LEKTI), a serine protease inhibitor involved in skin barrier formation and immunity. PUVA has been reported to help the circumflex linear ichthyosis, while etretinate has been reported both to exacerbate and to improve skin findings. Menne et al reported the bamboo hair defect in very thin, probably vellus, hairs in a 7-year-old boy with short, thin, brittle scalp hairs and no eyebrows. They termed this a canestick deformity.
Hair structure defects
a highly conserved glutamic acid residue of the type II hair keratins hHb6 and hHb1 occur. Both hHb1 and hHb6 are largely coexpressed in cortical trichocytes of the hair shaft, confirming that monilethrix is a disease of the hair cortex. Improvement of the hair may occur during pregnancy, but after delivery the hair returns to its original state. Improvement may also occur with age and there may be seasonal improvement during the summer. Improvement with acitretin has been reported.
Pili annulati (ringed hair, spangled hair) Pili annulati is an unusual disease in which the hair seems banded by alternating segments of light and dark color when seen in reflected light. The light bands are caused by clusters of abnormal air-filled cavities, which scatter light, and re duplicated lamina densa in the region of the root bulb. Hair growth is normal in patients with pili annulati, although it is rarely associated with trichorrhexis nodosa-like breaks of the hair shaft. There are no other associated abnormalities of skin or other organ systems. It is inherited by autosomaldominant mode, begins in infancy, and requires no treatment, since the spangled appearance of the hair is not unattractive (Fig. 33-26). The condition has been reported to disappear following recovery from alopecia totalis.
Pili pseudoannulati
Fig. 33-25 Trichorrhexis nodosa.
This anomaly of human hair mimics pili annulati. The two differ in that the light bands in pili annulati are caused by internal effects, whereas the bright segments in pili pseudo annulati are caused by reflection and refraction of light by flattened, twisted surfaces of hair. This latter type is a variant of normal hair. 757
keratoderma, and heart disease. It is caused by a recessive deletion mutation in desmoplakin. Woolly hairs tend to unite into tight locks, whereas the hairs of black persons remain individual. The hair may not grow beyond a length of 12 cm, but may attain a normal appearance in adult life. In the familial group the eyebrows and hairs on the arms, legs, and pubic and axillary regions may be short and pale. There are no associated cutaneous or systemic diseases. A Dutch kindred has been described with premature loss of curly, brittle hair, premature loss of carious teeth, nail dystrophy, and acral keratoderma. It has been designated the curly hair-acral keratoderma-caries syndrome. The microscopic findings of woolly hair include a decreased diameter, an ovoid shape on cross-section, a pili torti-like twisting about a longitudinal axis, trichorrhexis nodosa, and pili annulati.
Diseases of the Skin Appendages
33
Plica neuropathica (felted hair) Fig. 33-26 Spangled hair of pili annulati.
Kinking hair Acquired progressive kinking of the hair, first described and named by Wise and Sulzberger in 1932, involves a structural abnormality of kinking and twisting of the hair shaft at irregular intervals. The main recognized variant of this disorder begins in men in their late teens or early twenties on the fronto temporal or vertex regions, and then progresses to both the parietal and frontal areas. Usually straight, light brown hair becomes curly, frizzy, and lusterless. When this occurs in the androgen-dependent areas of young men it is a precursor of male-pattern hair loss; usually these men have a strong family history of androgenetic alopecia. Treatment with topical minoxidil has not prevented development of hair thinning. “Whisker” hairs, the short dark hairs that grow anterior to the ears in young people who eventually develop androgenic alopecia, is felt to be a variant of acquired kinking of the hair. Acquired hair kinking has been described in other clinical situations. Some reports detail prepubertal patients or women, as well as men, in whom kinking develops in non-androgendependent areas. In these reports alopecia has not developed, and the curly, frizzy hair may remain present or revert to its previous condition. Widespread kinking of the hair may be induced by drugs, notably retinoids, and it may also occur in patients with AIDS.
Woolly hair Woolly hair is present at birth and is usually most severe during childhood, when it is often impossible to brush the hair. In adult life there is a variable amelioration in the condition. There is a clear distinction between the appearance of the affected and nonaffected members of a family. Both autosomaldominant and autosomal-recessive inheritance have been described. Woolly hair nevus has partial scalp involvement by woolly hair, which has a markedly reduced diameter. Naxos’ disease is an autosomal-recessive syndrome with arrhythmogenic right ventricular cardiomyopathy, diffuse nonepidermolytic palmoplantar keratoderma, and woolly hair. Hair abnormalities are a reliable marker for subsequent heart disease. The disease is caused by a mutation in the gene encoding plakoglobin. Carvajal syndrome is a familial cardiocutaneous syndrome consisting of woolly hair, palmoplantar 758
This is a curling, looping, intertwisting, and felting or matting of the hair in localized areas of the scalp. Predisposing factors include kinky hairs, changes in hair care, and a neurotic mental state. Plica polonica is an older name for this condition. Burkhart CG, et al: Trichorrhexis nodosa revisited. Skinmed 2007 Mar–Apr; 6(2):57–58. Clarke JT, et al: Acquired kinking of the hair caused by acitretin. J Drugs Dermatol 2007 Sep; 6(9):937–938. Fichtel JC, et al: Trichorrhexis nodosa secondary to arginino succinicaciduria. Pediatr Dermatol 2007 Jan–Feb; 24(1):25–27. Liu CI, et al: Rapid diagnosis of monilethrix using dermoscopy. Br J Dermatol 2008 Sep; 159(3):741–743. Rudnicka L, et al: Trichoscopy: a new method for diagnosing hair loss. J Drugs Dermatol 2008 Jul; 7(7):651–654. Schaffer JV, et al: Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions. J Invest Dermatol 2006 Jun; 126(6):1286–1291. Schweizer J: More than one gene involved in monilethrix: intracellular but also extracellular players. J Invest Dermatol 2006 Jun; 126(6):1216–1219. Schweizer J, et al: Hair follicle-specific keratins and their diseases. Exp Cell Res 2007 Jun 10; 313(10):2010–2020. Shimomura Y, et al: Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis. J Invest Dermatol 2006 Jun; 126(6):1281–1285. Zlotogorski A, et al: An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis. J Invest Dermatol 2006 Jun; 126(6):1292–1296.
Pseudofolliculitis barbae Pseudofolliculitis barbae are hairs that, after appearing at the surface, curve back and pierce the skin as ingrowing hairs. This results in inflammatory papules and pustules, which may scar (Fig. 33-27). In severe cases, large deforming keloids may result in the beard area. Pseudofolliculitis of the beard is seen in more than 50% of black men, who must sometimes give up shaving to alleviate the disorder. A single-nucleotide polymorphism, giving rise to a disruptive Ala12Thr substitution in the 1A α-helical segment of the companion layer-specific keratin K6hf appears to be partially responsible for the phenotype. White persons are uncommonly affected; however, it is more common in renal transplant recipients. Tenderness responds to mid-strength topical steroids. The use of clippers or chemical depilatories, glycolic acid lotion, and adjunctive antibiotic therapy may be helpful. Benzoyl peroxide 5%/clindamycin 1% gel has been shown to be effective in double-blind evaluation. Laser hair removal with the long-pulse Nd:YAG laser is
Hair structure defects A
Fig. 33-27 Pseudofolliculitis barbae.
suitable for a wide range of skin types. The diode laser has also been used. Lally A, et al: Hypertrophic pseudofolliculitis in white renal transplant recipients. Clin Exp Dermatol 2007 May; 32(3):268–271. Quarles FN, et al: Pseudofolliculitis barbae. Dermatol Ther 2007 May–Jun; 20(3):133–136. Schulze R, et al: Low-fluence 1,064-nm laser hair reduction for pseudofolliculitis barbae in skin types IV, V, and VI. Dermatol Surg 2009 Jan; 35(1):98–107.
Pili multigemini This rare malformation is characterized by the presence of bifurcated or multiple divided hair matrices and papillae, giving rise to the formation of multiple hair shafts within the individual follicles (Fig. 33-28). It sometimes follows lines of Blaschko. Mehregan et al reported a patient with cleidocranial dysostosis and extensive pili multigemini over the heavily bearded chin and cheek areas. There is no treatment.
B
Fig. 33-28 A, Pili multigemini of beard. B, Multiple hair shafts in single follicle.
Pili bifurcati In this disorder, bifurcation is found in short segments along the shafts of several hairs. Each branch of the bifurcation is covered with its own cuticle. It has been seen in association with the trisomy 8 mosaic syndrome. Pili bifurcati differs from pili multigemini in which a single follicular matrix produces two different-sized hair shafts with separate cuticles that do not fuse again. Trichoptilosis is characterized by split distal ends that are never surrounded by a complete cuticle. Lester L, et al: The prevalence of pili multigemini. Br J Dermatol 2007 Jun; 156(6):1362–1363.
Trichostasis spinulosa Trichostasis spinulosa is a common disorder of the hair follicles that clinically gives the impression of blackheads (Fig. 33-29), but the follicles are filled with funnel-shaped, horny plugs within which are bundles of vellus hairs (Fig. 33-30). The hairs are round at their proximal ends and shredded distally. The disease occurs primarily on the nose and forehead, but
Fig. 33-29 Trichostasis spinulosa.
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hair dryer, analogous to the popping of popcorn. All damp hair will develop bubbles of gas when exposed to high heat.
33 Diseases of the Skin Appendages
Hypertrichosis Hypertrichosis is an overgrowth of hair not localized to the androgen-dependent areas of the skin. Several forms exist. Many cases are induced by medications, including minoxidil, cyclosporine, and efalizumab. The excessive hair growth can be managed with bleaching, trimming, shaving, plucking, waxing, chemical depilatories, and electrosurgical epilation. Laser treatment with long-pulse Nd:YAG, diode, ruby, longand short-pulse alexandrite lasers, and intense pulsed light sources can be effective. Skin type must be considered when choosing a laser system. The greatest experience in dark skin types has been with the long-pulse Nd:YAG laser.
Localized acquired hypertrichosis
Fig. 33-30 Trichostasis spinulosa.
may also occur on the trunk and be accompanied by pruritus. Dermoscopy or microscopy can be used to establish the diagnosis. The condition may be more common in patients in renal failure. Trichostasis spinulosa results from retention of telogen hairs, which are derived from a single hair matrix. It is primarily caused by a hyperkeratosis of the follicular infundibulum, which leads to a partial obstruction of the follicular orifice and thus does not permit shedding of small telogen hairs. The plugs may be removed with hydroactive adhesive (Biore) pads. Keratolytics are also effective after using a wax depilatory. The pulsed diode laser has been used successfully, and application of 0.05% tretinoin solution, applied daily for 2 or 3 months, may also produce satisfactory results. Elston DM, et al: Treatment of trichostasis spinulosa with a hydroactive adhesive pad. Cutis 2000; 66:77. Janjua SA, et al: Trichostasis spinulosa: possible association with prolonged topical application of clobetasol propionate 0.05% cream. Int J Dermatol 2007 Sep; 46(9):982–985. Pozo L, et al: Dermoscopy of trichostasis spinulosa. Arch Dermatol 2008 Aug; 144(8):1088.
Intermittent hair-follicle dystrophy Birnbaum et al reported a disorder of the hair follicle leading to increased fragility of the shaft, with no identifiable biochemical disturbance. The prevalence of this disorder is unknown.
Bubble hair deformity Bubble hairs appear as areas of hair with altered texture. Fragility has been reported. The hairs may be curved or straight and stiff. Small, bubble-like defects are found within the hair shafts on light and electron microscopy. The condition is produced by overheating of wet hair with a malfunctioning 760
Eyelash trichomegaly can occur with erlotinib, latanoprost, and intentionally with bimatoprost. Dermal tumors, such as melanocytic nevi, smooth muscle hamartomas, meningiomas, or Becker nevi, may have excessive terminal hair growth. Repeated irritation, trauma, occlusion under a cast, eczematous states, topical steroid use, linear melorheostotic scleroderma, lymphedema associated with filariasis, the Crow–Fukase (POEMS) syndrome, and pretibial myxedema may be other situations in which there is a localized increase in hair growth. Porphyrias generally show a localized hypertrichosis over the malar area, such as in porphyria cutanea tarda or variegate porphyria; however, in the Gunther variety of erythropoietic porphyria it may be generalized or more diffuse in nature.
Localized congenital hypertrichosis Hypertrichosis cubiti (hairy elbows) consists of long vellus hair on the extensor surfaces of the distal third of the upper arm and the proximal third of the forearm bilaterally. It is a progressive, excessive growth of lanugo hairs that often begins in infancy; the hairs may reach a length of 10 cm. Later they become coarser, but regression has been observed during adolescence. There appear to be familial cases and a sporadic form. Short stature and some developmental abnormalities are present in some cases; however, there is no need for endocrine studies or other evaluation. The condition appears to be of cosmetic significance only. Other causes of localized congenital hypertrichosis include congenital nevocytic nevi, anterior cervical hypertrichosis, and simple nevoid hypertrichosis. Localized hypertrichosis may be a sign of underlying spinal dysraphism when it occurs over the sacral midline.
Generalized congenital hypertrichosis (congenital hypertrichosis lanuginosa) This rare type of excessive and generalized hairiness is a fully penetrant X-linked dominant trait. The entire body is covered with fine vellus hairs 2–10 cm long (Fig. 33-31). The scalp hair appears to be normal. Except for the palms and soles, all other areas are covered. Congenital hypertrichosis lanuginosa may be associated with dental anomalies and gingival fibromatosis. This type of hairiness has attracted considerable attention over the centuries. Hair removal by laser may be quite useful. Other cases of congenital generalized hypertrichosis may be secondary to drug ingestion by the mother. The fetal hydantoin syndrome is characterized by hypertrichosis, depressed nasal bridge, large lips, a wide mouth, and a short, webbed
Hirsutism Fig. 33-31 Hypertrichosis lanuginosa. (Courtesy of Brooke Army Medical Center Teaching File)
Fig. 33-33 Hirsutism.
with acromegalic features. Drugs associated with hypertrichosis include minoxidil, cyclosporine, diphenylhydantoin, diazoxide, streptomycin, penicillamine, corticosteroids, danazol, psoralens, hexachlorobenzene, PUVA, topical bimatoprost, topical steroids, and topical androgens. Márquez G, et al: A case of trichomegaly of the eyelashes and facial hypertrichosis induced by erlotinib (Tarceva). Int J Dermatol 2009 Jan; 48(1):97–98. Mendiratta V, et al: Hypertrichosis lanuginosa congenita. Pediatr Dermatol 2008 Jul–Aug; 25(4):483–484. Papadopoulos R, et al: Trichomegaly induced by erlotinib. Orbit 2008; 27(4):329–330. Rallis E, et al: Efalizumab-induced hypertrichosis. Br J Dermatol 2008 May; 158(5):1158–1159.
Hirsutism Fig. 33-32 Hypertrichosis lanuginosa associated with an internal malignancy (malignant down).
neck. The fetal alcohol syndrome includes hypertrichosis, a small face, capillary hemangiomas, and physical and mental retardation. A case of generalized hypertrichosis and multiple congenital defects was reported by Kaler et al in a baby born to a mother who used minoxidil throughout pregnancy. Fetal valproate syndrome is characterized by generalized hypertrichosis sparing the palms and soles, coarse facies, gum hypertrophy, hypotonia, club feet and club hands, and abnormal dermatoglyphics.
Generalized or patterned acquired hypertrichosis These cases include those caused by acquired hypertrichosis lanuginosa, those associated with various syndromes, and those secondary to drug intake. Acquired hypertrichosis lanuginosa (Fig. 33-32) is an ominous sign of internal malignancy. Syndromes associated with increased hair growth include lipoatrophic diabetes, stiff skin syndrome, Down syndrome, Rubenstein–Taybi syndrome, Laband syndrome, Cornelia de Lange syndrome, Hurler syndrome, leprechaunism, Winchester syndrome, the Schynzel–Giedier syndrome, and hypertrichosis
Clinical features Hirsutism is an excess of terminal hair growth in women in a pattern more typical of men. Androgen-dependent growth areas affected include the upper lip, cheeks (Fig. 33-33), chin, central chest, breasts, lower abdomen, and groin. This altered growth pattern of the hair may be associated with other signs of virilization, which include temporal balding, masculine habitus, deepening of the voice, clitoral hypertrophy, and amenorrhea. Acne is an additional sign of hyperandrogenism.
Pathogenesis When virilization accompanies hirsutism, especially when progression is rapid, a neoplastic cause is likely. In the absence of virilization, a neoplastic cause is extremely unlikely. Most medically significant hirsutism is related to the polycystic ovarian syndrome (PCOS, hyperinsulinemic hyperandrogenism with anovulation). In a study of 873 patients with medically significant hirsutism, PCOS was present in 82%. Idiopathic hirsutism was present in 4.7%, and 6.75% of the patients had elevated androgen levels and hirsutism with normal ovulation. Ethnic variation should be considered when evaluating hirsutism. Women of Southwest Asian, Eastern European and 761
Diseases of the Skin Appendages
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southern European heritage commonly have facial, abdominal, and thigh hair; whereas Asian and Indian women generally have little terminal hair growth in these areas. In women, androgen biosynthesis occurs in the adrenal and ovary. Testosterone and the androgen precursor androstenedione are secreted by the ovary. The adrenal contributions are preandrogens: dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione. They require peripheral conversion in the skin and liver to testosterone. Testosterone is converted to dihydrotestosterone, the androgen that promotes androgen-dependent hair growth, in the hair follicle by 5-α-reductase. Receptor molecules in the end organ are necessary for binding and hormone action at that level. Because testosterone is normally bound to carrier molecules in the plasma at a 99% level, and it is the unbound testosterone that is active, the levels of free testosterone correlate with clinical evidence of androgen excess. Hirsutism may result from excessive secretion of androgens from either the ovary or the adrenal gland. The excessive secretion may be from functional excesses or, rarely, from neoplastic processes. Ovarian causes include PCOS (Stein– Leventhal syndrome), and a variety of ovarian tumors, both benign and malignant. PCOS is defined by anovulation (fewer than nine periods a year or periods longer than 40 days apart) with clinical evidence of hyperandrogenism. Ovarian cysts are not required for the diagnosis, and laboratory and imaging studies are not required to establish the diagnosis. The pathogenesis of PCOS may relate to insulin resistance with resultant elevated insulin levels leading to ovarian overproduction of androgens. Prevalence rates of PCOS for black and white women in the US are 8.0% and 4.8%, respectively. Ovarian tumors include unilateral benign microadenomas, arrhenoblastomas. Leydig cell tumors, hilar cell tumors, granular/theca cell tumors, and luteomas are rare causes of hirsutism. In tumor-associated hirsutism, the onset is usually rapid, occurs with other signs of virilization, and begins between the ages of 20 and 40. Adrenal causes include congenital adrenal hyperplasia (CAH) and adrenal tumors, such as adrenal adenomas and carcinomas. The adrenogenital syndrome or CAH is an autosomal-dominant disorder that may result from deficiencies of the following enzymes: 21-hydroxylase (most common form), 11β-hydroxylase, or 3β-hydroxy steroid dehydrogenase. Onset is generally in childhood, with ambiguous genitalia, precocious growth, and virilism. Nonclassic (adult-onset) CAH may present with hirsutism. Pituitary causes include Cushing’s disease, acromegaly, and prolactin-secreting adenomas. Prolactin-secreting micro adenomas have a 20% incidence of hirsutism and acne. Prolactin elevations may be seen in patients with PCOS. Other conditions in which prolactin levels may be elevated and that may lead to hirsutism include hypothyroidism, phenothiazine intake, and hepatorenal failure. Other causes of hirsutism include the exogenous intake of androgens. End-organ hypersensitivity may be a mechanism in patients with a normal evaluation. Drugs such as minoxidil, diazoxide, corticosteroids, and phenytoin, which have been reported to cause hirsutism, generally cause hypertrichosis—a generalized increase in hair that is not limited to the androgensensitive areas.
Evaluation Most hirsutism is related to ethnic heritage or PCOS. 21-Hydroxylase-deficient nonclassic adrenal hyperplasia, the hyperandrogenic insulin-resistant acanthosis nigricans syndromes, and androgen-secreting tumors are relatively uncommon causes. A careful history and physical examination are 762
essential. The history should focus on onset and progression, virilization, menstrual and pregnancy history, and family/ racial background. Physical examination may reveal signs of Cushing’s disease, hypothyroidism, or acromegaly. Other signs to be evaluated are the distribution of muscle mass and body fat, clitoral dimensions, voice depth, and galactorrhea. Laboratory evaluation is controversial. In the authors’ opinion, testing is of value only when it affects management. If this is accepted, there is no mandatory hormonal testing for stable hirsutism in patients who have no signs of virilization. A diagnosis of PCOS does not require laboratory confirmation. Determination of serum lipids and testing for glucose intolerance may be the most important laboratory evaluations in patients with PCOS, as they have the greatest impact on management and long-term prognosis. When the history and physical examination suggest the possibility of a neoplasm, laboratory evaluation should include a total testosterone level. A dehydroepiandrosterone sulfate level is commonly performed if an adrenal cause is suspected. A 24 h urine cortisol test is the gold standard for the diagnosis of Cushing’s disease. Measurement of thyroid-stimulating hormone (TSH), growth hormone, and somatomedin C levels are indicated if the history and physical examination suggest hypothyroidism or acromegaly. Dexamethasone suppression tests are recommended by some authorities, but the results often do not affect management. A baseline 17-hydroxyprogesterone and adrenocorticotropic hormone (ACTH) stimulation test can screen for late-onset CAH, but steroid replacement has not been proved to result in better outcomes than empiric treatment with antiandrogens. Baseline 17-hydroxyprogesterone may be normal in some women with nonclassic 21-hydroxylase deficiency, and ACTH stimulation may result in overdiagnosis of the syndrome. An exaggerated 17-hydroxyprogesterone response to ACTH stimulation is common in PCOS at a pharmacologic dose (250 µg) but not at a physiologic dose (1 µg) of ACTH. An ovarian origin of hirsutism can be identified by a buserelin test in 30% of patients with hirsutism and by dexa methasone in 22% of patients, but data proving that buserelin challenge results in better outcomes are lacking. A prolactin level will screen for prolactin-secreting tumors, but will also lead to further expensive testing in many patients ultimately diagnosed with PCOS. A prolactin level should be obtained in any patient with galactorrhea, but is of limited value as a routine screening test for patients with hirsutism alone. If signs of acromegaly, Cushing’s disease, or virilization are present clinically, referral to an endocrinologist is recommended. The presence of major menstrual irregularities is also an indication for referral to an endocrinologist or gynecologist. Although 90% of women with hirsutism have an elevated testosterone level, elevations above 200 ng/dL and rapid onset or progressive virilization suggest serious underlying disease. A major elevation in the DHEA sulfate level (greater than 7000 ng/mL) suggests an adrenal neoplasm, and imaging of the adrenal gland is recommended. Many patients with lateonset CAH will have normal screening DHEA sulfate. Patients with prolactin levels above 20 ng/mL should likewise be referred for further evaluation with an MRI or CT scan. Polymorphisms in the gene coding for sex hormone-binding globulin have been identified in some families with hirsutism, but such testing does not affect management.
Treatment Various forms of mechanical, chemical, and laser epilation can be performed, as for hypertrichosis. Spironolactone with various oral contraceptives, cyproterone acetate plus ethinyl estradiol, gonadotropin-releasing hormone agonists such as
Abbas M, et al: The use of metformin as first line treatment in polycystic ovary syndrome. Ir Med J 2008 Feb; 101(2):51–53. Blume-Peytavi U, et al: Medical treatment of hirsutism. Dermatol Ther 2008 Sep–Oct; 21(5):329–339. Demirci C, et al: Congenital adrenal hyperplasia. Dermatol Ther 2008 Sep–Oct; 21(5):340–353. Dikensoy E, et al: The risk of hepatotoxicity during long-term and low-dose flutamide treatment in hirsutism. Arch Gynecol Obstet 2009 Mar; 279(3):321–327. Kircher C, et al: Acarbose for polycystic ovary syndrome. Ann Pharmacother 2008 Jun; 42(6):847–851. Lin-Su K, et al: Congenital adrenal hyperplasia in adolescents: diagnosis and management. Ann N Y Acad Sci 2008; 1135:95–98. Lujan ME, et al: Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies. J Obstet Gynaecol Can 2008 Aug; 30(8):671–679.
Minozzi M, et al: Treatment of hirsutism with myo-inositol: a prospective clinical study. Reprod Biomed Online 2008 Oct; 17(4):579–582. Norman RJ, et al: Polycystic ovary syndrome. Lancet 2007 Aug 25; 370(9588):685–697. Rosenfield RL: What every physician should know about polycystic ovary syndrome. Dermatol Ther 2008 Sep–Oct; 21(5):354–361. Somani N, et al: The clinical evaluation of hirsutism. Dermatol Ther 2008 Sep–Oct; 21(5):376–391. Wanitphakdeedecha R, et al: Physical means of treating unwanted hair. Dermatol Ther 2008 Sep–Oct; 21(5):392–401.
Trichomycosis axillaris Discrete nodules, 1–2 mm in size and attached firmly to the hair shafts of the axillary or pubic areas, characterize tricho mycosis. The color of the nodules may be yellow (Fig. 33-34), red, or black. Hyperhidrosis of the affected regions is usually present. A yellowish discoloration of the axillae is sometimes noted. Large numbers of Corynebacterium are present in the concretions. The disorder may coexist with erythrasma and pitted keratolysis. Treatment with topical antibiotic preparations, such as topical clindamycin or erythromycin, or naftifine, which has antibacterial properties, combined with any modality that will decrease the hyperhidrosis, is effective, but shaving is faster.
Associated hair follicle diseases
leuprolide and nafarelin, flutamide, finasteride, and topical eflornithine have been used successfully alone and in various combinations to treat hirsutism. The optimal combination and dosage remain to be determined. Finasteride at doses of 2.5–5 mg/day has been shown to decrease hair number and diameter in women with hirsutism. The combination of spironolactone, 100 mg/day, plus finasteride, 5 mg/day, has been shown to be superior to spironolactone, 100 mg/day, alone. An analysis of the current literature suggested that spironolactone alone, 100 mg/day, is superior to finasteride alone, 5 mg/day, and low-dose cyproterone acetate alone, 12.5 mg/day for the first 10 days of a cycle, in the treatment of hirsutism. As spironolactone is commonly used at a dose of 100 mg twice a day, further studies are needed comparing this higher dose with other modes of therapy. In a prospective, randomized study of Diane 35 (cyproterone acetate [CPA], 2 mg, and ethinyl estradiol, 35 µg), Diane 35 plus spironolactone, and spironolactone alone, all treatments were well tolerated. Combination therapy resulted in superior measured endocrine responses, but the authors concluded that spirono lactone alone was the most cost-effective treatment. The choice of an oral contraceptive (OC) is also controversial. Thirdgeneration OCs result in a significant increase in sex hormonebinding globulin and decrease in free testosterone, but both second- and third-generation OCs are clinically effective in treating hirsutism. When flutamide is used, initial treatment with 250 mg/day is followed by a long maintenance treatment period using 125 mg/day. Insulin sensitizers are being studied in the treatment of hirsutism, particularly PCOS. The best data to date are for metformin. Metformin therapy has been shown to control menstrual cycles and improve fertility in women with PCOS. It causes a decline in testosterone and insulin levels. Oligomenorrheic women with an increased luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio and lower testosterone levels respond best. Spironolactone, 50 mg/ day, was superior to metformin, 1000 mg/day, in the treatment of hirsutism and menstrual cycle frequency in a study of 82 adolescent and young women with PCOS. Doses of 200 mg/ day are commonly used to treat hirsutism. At this dose, menstrual irregularities induced by the drug are common, and it may be best used in combination with an OC pill. Yasmin, which contains the progestogen drospirenone, has been shown to provide good cycle control for women with PCOS, with an improvement in acne but not in other symptoms of the syndrome. Good correlation has been noted between an increase in ovulation frequency with clomiphene citrate and the chance of pregnancy in women with PCOS. Other options include acarbose, gonadotrophins, and laparoscopic ovarian drilling. Infertility is best managed by a specialist in this field. Empiric treatment with an antiandrogen may be as good as steroid replacement for the management of hirsutism in patients with nonclassic CAH.
Rho NK, et al: A corynebacterial triad: prevalence of erythrasma and trichomycosis axillaris in soldiers with pitted keratolysis. J Am Acad Dermatol 2008 Feb; 58(2 Suppl):S57–S58.
Associated hair follicle diseases Pityriasis amiantacea (tinea amiantacea) Thick, asbestos-like (amiantaceous), shiny scales on the scalp characterize pityriasis amiantacea. The silvery-white or dull
Fig. 33-34 Trichomycosis axillaris. (Courtesy of Anthony Slagel, MD)
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gray crusting may be localized or, less often, generalized over the entire scalp. The proximal parts of the hairs are matted together by the laminated crusts. There are no structural changes in the hair, but in some patches where the crusting is thick, there may be some purulent exudate under the crust and temporary alopecia such as occurs after some cases of furunculosis of the scalp. The cause is most often severe or untreated seborrheic dermatitis or psoriasis. In a prospective study of 85 patients, psoriasis was documented in 35% and processes suggesting seborrheic dermatitis or atopic dermatitis occurred in another 35%. Tinea capitis was the eventual diagnosis in 13%. Staphylococcus was found in 96.5%, compared with 15% of controls. The patient should shampoo daily or every other day with selenium sulfide suspension, or a tar- or steroidcontaining shampoo, for a couple of weeks. Prior application of peanut oil or a keratolytic a few hours before shampooing facilitates removal of the scales and crusts. With such debridement, followed by topical steroid solution in Caucasians or steroid ointment in African Americans, the secondary bacterial infection usually resolves without the need for oral antistaphylococcal therapy. Abdel-Hamid IA, et al: Pityriasis amiantacea: a clinical and etiopathologic study of 85 patients. Int J Dermatol 2003; 42:260. Gordon D, et al: Dermacase: tinea or pityriasis amiantacea. Can Fam Physician 2009; 55:165.
Folliculitis nares perforans Perforating folliculitis of the nose is characterized by small pustules near the tip of the inside of the nose. The lesion becomes crusted, and when the crust is removed it is found that the bulbous end of the affected vibrissa is embedded in the inspissated material. The affected hairs are typical of those occurring inside the nostril. Staphylococcus aureus may at times be cultured from the pustules. The hair should be removed and antibiotic ointment such as mupirocin applied. White SW, et al: Pseudofolliculitis vibrissae. Arch Dermatol 1981; 117:368.
Acquired perforating dermatosis Perforating folliculitis, Kyrle’s disease, and acquired perforating collagenosis are designations that have been supplanted by the more inclusive term acquired perforating dermatosis. The condition is not uncommon and is most often associated with renal failure or diabetes or both. Between 4% and 10% of dialysis patients develop umbilicated dome-shaped papules on the legs, or less often on the trunk, neck, arms, or scalp, with variable itchiness (Fig. 33-35). Early lesions may be pustular; late lesions resemble prurigo nodularis both clinically and histologically. There is a central hyperkeratotic cone that projects into the dermis, so that when it is removed, a pitlike depression remains. Usually the papules are discrete, but they may coalesce to form circinate plaques. Coalescing verrucous plaques are frequently seen, especially on the lower extremities. Koebner phenomenon may also be observed, in which case plaques or elevated verrucous streaks are formed. The latter are seen primarily in the antecubital and popliteal spaces. Atrophic scars are seen on involution of these lesions. Histologically, the epidermis becomes edematous, the granular layer disappears, and parakeratosis develops. Eventually, the epidermis becomes atrophic, with disruption of the sites over the papillae. Through these sites necrobiotic connective tissue, degenerating inflammatory cells, and collagen bundles are extruded into a cup-shaped epidermal depression. 764
Fig. 33-35 Acquired perforating disease in uremia. (Courtesy of Curt Samlaska, MD)
The condition is felt to be a response to trauma, usually scratching or rubbing in response to the pruritus of the associated renal failure or dry skin. Other predisposing conditions reported include HIV infection, sclerosing cholangitis or other liver diseases, hypothyroidism, hyperparathyroidism, Hodgkin disease, in areas of healed herpes zoster, and as a reaction to laser hair removal or TNF-α inhibitors. Ultraviolet treatment of either PUVA or UVB type helps the pruritus of renal disease and improves the perforating disorder. Hydration of the skin with a soaking tub bath in plain water, followed immediately (without drying) by triamcinolone ointment, is also useful. Topical retinoic acid (0.1% cream), allopurinol, doxycycline, isotretinoin, and etretinate have been effective in flattening lesions. HIV-infected patients may respond well to thalidomide. The disease may remit promptly after renal transplantation. Doshi SN, et al: Koebnerization of reactive perforating collagenosis induced by laser hair removal. Laser Surg Med 2003; 32:177. Gilaberte Y, et al: Perforating folliculitis associated with tumor necrosis factor-alpha inhibitors administered for rheumatoid arthritis. Br J Dermatol 2007; 156:368. Hoque SR, et al: Acquired reactive perforating collagenosis. Br J Dermatol 2006; 154:759. Iyoda M, et al: Acquired reactive perforating collagenosis in a nondiabetic hemodialysis patient. Am J Kidney Dis 2003; 42:E11. Mahajan S, et al: Perforating folliculitis with jaundice in an Indian male: a rare case with sclerosing cholangitis. Br J Dermatol 2004; 150:614. Ohe S, et al: Treatment of acquired perforating dermatosis with narrow band UVB. J Am Acad Dermatol 2004; 50:892. Rivard J, et al: Ultraviolet phototherapy for pruritus. Dermatol Ther 2005; 18:344. Saray Y, et al: Acquired perforating dermatosis. J Eur Acad Dermatol Venereol 2006; 20:679.
Reactive perforating collagenosis Reactive perforating collagenosis is an inherited condition characterized by pinhead-sized, skin-colored papules that grow to a diameter of 4–6 mm and develop a central area of umbilication in which keratinous material is lodged (Fig. 33-36). The discrete papules may be numerous and involve sites of frequent trauma such as the backs of the hands, forearms, elbows, and knees. The lesion reaches a maximum size of about 6 mm in 4 weeks and then regresses spontaneously in 6–8 weeks. It is believed that this is caused by a peculiar reaction of the skin to superficial trauma. Koebnerization is often observed. Young children are most frequently affected. Most reports
Ermertcan AT, et al: Erythromelanosis follicularis faciei et colli associated with keratosis pilaris in two brothers. Pediatr Dermatol 2006; 23:31. Sardana K, et al: An observational analysis of erythromelanosis follicularis faciei et colli. Clin Exp Dermatol 2008; 33:333.
Disseminate and recurrent infundibulofolliculitis Hitch and Lund described a disseminate follicular eruption on the torso of a black man that involved all the pilosebaceous structures. The lesions were irregularly shaped papules pierced by a hair. They likened the eruption to cutis anserina viewed through a magnifying glass. The eruption is mildly pruritic at times, and is chronic, with recurrent exacerbations. The papules are uniform, and 1 or 2 mm in diameter; they involve all the follicles in the affected areas, which are usually the upper trunk and neck, though the entire trunk and proximal extremities may be involved. Rarely, pustules may occur. Histologically, the infundibular portion of the follicles is chiefly affected, and the lesions are inflammatory rather than hyperkeratotic. Edema, lymphocytic and neutrophilic infiltration, and slight fibroblastic infiltration surround the affected follicles. Treatment with topical steroids, isotretinoin, or PUVA may be effective. Fig. 33-36 Reactive perforating collagenosis.
support an autosomal-recessive mode of inheritance; however, a family in which it appeared to be inherited by autosomal dominance has been reported. No specific treatment is indicated, since the lesions involute spontaneously. Tretinoin 0.1% cream may be effective. Ramesh V, et al: Familial reactive perforating collagenosis. J Eur Acad Dermatol Venereol 2007; 21:766.
Traumatic anserine folliculosis Traumatic anserine folliculosis is a curious gooseflesh-like follicular hyperkeratosis that may result from persistent pressure and lateral friction of one skin surface on another. Such friction is often caused by habitual pressure on the elbows, chin, jaw, or neck, often while watching television. Two-thirds of patients who develop this are atopic. Padilha-Gonalves A: Traumatic anserine folliculosis. J Dermatol 1979; 6:365.
Erythromelanosis follicularis faciei et colli Erythromelanosis follicularis faciei et colli is an erythematous pigmentary disease involving the follicles. A reddish-brown, sharply demarcated, symmetrical discoloration involves the preauricular and maxillary regions. At times the pigmentation may be blotchy. In addition, follicular papules and erythema are present. Under diascopic pressure the reddish-brown area, containing telangiectases, becomes pale and the light brown pigmentation becomes more apparent. Pityriasiform scaling and slight itching may occur. Keratosis pilaris on the arms and shoulders is frequently found. It preferentially affects Asian and Indian patients.
Disorders of the sweat glands
Histologically, a slight hyperkeratosis occurs, with epidermal hyperpigmentation and dilation of the upper dermal vessels. The hair follicles may be enlarged in the infundibular area and the sebaceous glands may be hypertrophic. A lymphocytic infiltration surrounds the adnexa.
Aroni K, et al: Disseminate and recurrent infundibulofolliculitis: response to isotretinoin. J Drugs Dermatol 2004; 3:434. Hinds GA, et al: A case of disseminate and recurrent infundibulo folliculitis responsive to treatment with topical steroids. Dermatol Online J 2008; 14:11.
Lichen spinulosus Lichen spinulosus (keratosis spinulosa) is chiefly a disease of children and is characterized by minute filiform horny spines, which protrude from follicular openings independent of any papules. The spines are discrete and grouped. The lesions appear in crops and are symmetrically distributed over the trunk, limbs, and buttocks (acne corne). There is a predilection for the neck, buttocks, abdominal wall, popliteal spaces, and the extensor surfaces of the arms. Little or no itching is present. Occasional cases of a generalized form in adults with HIV infection or alcoholism have been reported. Histologic evaluation shows simple inflammatory changes and follicular hyperkeratosis. The lesions may respond to keratolytics and emollients, such as salicylic acid, lactic acid, or urea gels or ointments. Tretinoin or tacalcitol creams are other alternatives. The lesions tend to involute at puberty. Foreman SB, et al: Lichen spinulosus. Arch Dermatol 2007; 143:122. Kim SH, et al: Successful treatment of lichen spinulosis with topical tacalcitol cream. Pediatr Dermatol 2010; (epub).
Disorders of the sweat glands Hyperhidrosis Hyperhidrosis, or excessive sweating, may be localized to one or several areas or it may be more generalized. True generalized hyperhidrosis is rare, and even hyperhidrosis caused by systemic diseases is usually accentuated in certain regions. 765
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Palmoplantar hyperhidrosis (emotional hyperhidrosis) This type of hyperhidrosis is usually localized to the palms, soles, and/or axillae, and may be worse during warm temperatures. Patients with palm and sole hyperhidrosis may also have axillary hyperhidrosis, but only 25% of patients with axillary hyperhidrosis have palmoplantar hyperhidrosis. The hands may be cold and show a dusky hue. The soggy keratin of the hyperhidrotic soles is frequently affected by pitted keratolysis and has a foul odor. Sweating may be intermittent; in these cases anxiety, stress, or fear may trigger it. When sweating is constant, usually emotion is not as important. This type of sweating can be autosomal-dominantly inherited. Its onset is in childhood for the palmar type and adolescence for axillary disease. It tends to improve with age. Sweating typically ceases during sleep.
Gustatory hyperhidrosis Certain individuals regularly experience excessive sweating of the forehead, scalp, upper lip, perioral region, or sternum a few moments after eating spicy foods, tomato sauce, chocolate, coffee, tea, or hot soups. Gustatory sweating may be idiopathic or caused by hyperactivity of the sympathetic nerves (Pancoast tumor or postoperatively), sensory neuropathy (diabetes mellitus or subsequent to zoster), parotitis or parotid abscess, and surgery or injury of the parotid gland (auriculotemporal syndrome of von Frey). Frey syndrome occurs in one-third or more of patients following parotid surgery. Fortunately, only 10% of affected patients require treatment.
Other localized forms of hyperhidrosis Localized sweating can occur over lesions of blue rubber bleb nevus, glomus tumors, and hemangiomas (sudoriferous hemangioma), and in POEMS syndrome, Gopalan syndrome, complex regional pain syndrome, as a result of spinal cord tumors (especially when unilateral palmar hyperhidrosis is the complaint), and pachydermoperiostosis.
Generalized hyperhidrosis Febrile diseases, vigorous exercise, or a hot, humid environment, such as a tropical milieu, may induce generalized hyperhidrosis. Hyperthyroidism, acromegaly, diabetes mellitus, pheochromocytoma, hypoglycemia, salicylism, substance abuse, lymphoma, carcinoid syndrome, pregnancy, and menopause may also produce generalized hyperhidrosis. Additional causes of hyperhidrosis include concussion, Parkinson’s disease, other disturbances of the sympathetic nervous system, and metastatic tumors producing a complete transection of the spinal cord. Drugs such as anticholinesterases, antidepressants of the selective serotonin-reuptake inhibitor or tricyclic types, antiglaucoma agents, bladder stimulants, opioids, and sialo gogs may cause hyperhidrosis.
Treatment The therapy of generalized hyperhidrosis is aimed at treating the underlying systemic disease. Virtually all cases of hyperhidrosis seen by dermatologists are of the palmoplantar or axillary types, and the treatments discussed below relate primarily to these conditions. Topical medication Topical aluminum chloride or aluminum chlorhydroxide are the most commonly used agents for hyperhidrosis. For the axillae, application of a 10–35% solution nightly to a very dry axilla (blown dry with a hair dryer) is usually very effective. To limit irritation, lower concentrations should be tried first. Also, it should be washed off in 6–8 h. Occlusion is usually not required. In palmar hyperhidrosis the application of aluminum chloride nightly in up to a 50% concentration, alone or occluded with plastic gloves, has pro766
duced good results for some patients. If topical treatment is effective when performed nightly, the frequency may be reduced to as little as once or twice a week with continued benefit. Iontophoresis Iontophoresis with plain tap water is an alternative for patients for whom topical treatments fail. It is frequently effective, using either a Drionic device or a Fischer unit. Treatments generally require 20–30 min sessions each day or twice a day. Once response has occurred, treatments may be used intermittently (as little as once every 2 weeks) for maintenance. Use of glycopyrrolate 0.01% and aluminum chloride 2% in the iontophoresis medium may hasten the response. A new dry-type iontophoresis has been described but is not readily available. Botulinum toxin Injection of botulinum A toxin into 4 cm2 areas on the palms, soles, or axillae dramatically reduces sweating at the treated areas to at least 25% and often to less than 10% of baseline rates. Dosages vary according to the type of botulinum toxin A and the site of treatment. Grunfeld et al offer a complete review of injection techniques and tips. Complications are rare but include some grip weakness when higher doses are used in the palms. This problem, the expense, and the painful injections limit its use in the palms and soles especially. The hypohidrosis continues for an average of 7 months, with some patients continuing to have substantial benefit at 16 months after one injection. Repeated injections generally do not lose efficacy and result in similar response and complication rates. This form of treatment should be offered to all patients who fail topical treatments before surgical modalities are considered. Frey syndrome remits for 1–1.5 years in nearly every patient treated. This treatment may be considered for other rare forms of localized hyperhidrosis. Myobloc (botulinum toxin B) is also effective, but with more limited duration of response. Internal medication The use of anticholinergic agents such as propantheline bromide, oxybutynin (available in an extended-release formulation which may result in lower efficacy), and glycopyrrolate may be helpful. The dosage of each is regulated by the patient’s tolerance and response. Often, sweating is suppressed just as anticholinergic side effects reach intolerable levels, and this approach has to be abandoned. Side effects of acetylcholine-blocking agents may also cause or aggravate such conditions as glaucoma and convulsions. The effects on sweating generally last 4–6 h, and many patients prefer to use the medication to ensure dryness for special occasions only, rather than as continuous treatment. Other agents reported to reduce localized hyperhidrosis include diltiazem and clonidine. Surgical treatment Axillary hyperhidrosis may be effectively controlled by excision of the most actively sweating portion of the axillary skin, followed by undercutting and subcutaneous resection of the sweat glands for 1–2 cm on each side of the elliptical excision. This procedure is virtually always effective. Alternatively, liposuction or surgical ultrasonic aspiration removal may be used. The most important preoperative consideration is the accurate mapping of the most active sweating areas of the axillae. The responsible eccrine glands are not necessarily located in the same areas as the axillary hair and are often in a reasonably limited area. Mapping may be performed with cobalt chloride or starch iodide. Upper thoracic sympathectomy has been found to be effective in excessive palmar sweating when all other measures have failed. Sympathetic denervation of the upper extremities is performed via endoscopy by reversibly clipping or performing resection of the fourth thoracic sympathetic ganglion. Acute surgical complications occur in less than 2% but include chronic pain, infection, pneumothorax, hemothorax, bleeding, pneumonia, and even death. Sweating of the hands is stopped
Anliker MD, et al: Tap water iontophoresis. Curr Probl Dermatol 2002; 30:48. Bajaj V, et al: Use of oral glycopyrronium bromide in hyperhidrosis. Br J Dermatol 2007; 157:118. Cheshire WP, et al: Disorders of sweating. Semin Neurol 2003; 23:399. Cheshire WP, et al: Drug-induced hyperhidrosis and hypohidrosis. Drug Saf 2008; 31:109. Cladellas E, et al: A medical alternative to the treatment of compensatory hyperhidrosis. Dermatol Ther 2008; 21:406. Cohen JL, et al: Diagnosis, impact, and management of focal hyperhidrosis. Facial Plast Surg Clin North Am 2007; 15:17. De Bree R, et al: Repeated botulinum toxin type A injections to treat patients with Frey syndrome. Arch Otolaryngol Head Neck Surg 2009; 135:287. Grunfeld A, et al: Botulinum toxin for hyperhidrosis. Am J Clin Dermatol 2009; 10:87. Hornberger J, et al: Recognition, diagnosis, and treatment of primary focal hyperhidrosis. J Am Acad Dermatol 2004; 51:274. Klein A: Complications with the use of botulinum toxin. Dermatol Clin 2004; 22:197. Krogstad AL, et al: Daily pattern of sweating and response to stress and exercise in patients with palmar hyperhidrosis. Br J Dermatol 2006; 154:1118. Liu Y, et al: Surgical treatment of primary palmar hyperhidrosis. Eur J Cardiothorac Surg 2009; 35:398. Mijnhout GS, et al: Oxybutynin. Neth J Med 2007; 65:356. Na GY, et al: Control of palmar hyperhidrosis with a new “dry-type” iontophoretic device. Dermatol Surg 2007; 33:57. Ojimba TA, et al: Drawbacks of endoscopic thoracic sympathectomy. Br J Surg 2004; 91:264. Reisfeld R, et al: Evidence-based review of the nonsurgical management of hyperhidrosis. Thorac Surg Clin 2008; 18:157. Seo SH, et al: Tumescent superficial liposuction with curettage for treatment of axillary hyperhidrosis. J Eur Acad Dermatol Venereol 2008; 22:30. Sugimura H, et al: Thoracoscopic sympathetic clipping for hyperhidrosis. J Thorac Cardiovasc Surg 2009; 137:1370. Talarico-Filho S, et al: A double-blind, randomized, comparative study of two type A botulinum toxins in the treatment of primary axillary hyperhidrosis. Dermatol Surg 2007; 33:S44. Vor Kamp T, et al: Hyperhidrosis. Surgeon 2010; 8:287. Walles T, et al: Long term efficiency of endoscopic thoracic sympathicotomy. Interact Cardiovasc Thorac Surg 2009; 8:54. Wolina U, et al: Tumescent suction curettage versus minimal skin resection with subcutaneous curettage of sweat glands in axillary hyperhidrosis. Dermatol Surg 2008; 34:709.
Anhidrosis (hypohidrosis) Anhidrosis is the absence of sweating. Hypohidrosis, or reduced sweating, is part of the spectrum of these disorders. Dysfunction in any step in the normal physiologic process of sweating can lead to decreased or absent sweating. It may be localized or generalized. Generalized anhidrosis occurs in anhidrotic ectodermal dysplasia, miliaria profunda (tropical asthenia), Sjögren syndrome, Fabry syndrome, hereditary sensory neuropathy (type IV) with anhidrosis, and in some patients with diabetic neuropathy, thyroid dysfunction, and multiple myeloma. A large number of drugs may cause hypohidrosis. These include anticholinergics, antidepressants of the tricyclic type, antiepileptics, antihistamines, anti hypertensives, antipsychotics, antiemetics, antivertigo drugs, bladder antispasmodics, gastric antisecretory drugs, muscle
relaxants, neuromuscular paralytics, and opioids. Anhidrosis may follow infections, be part of a neurodegenerative disorder, occur as a symptom related to toxin exposure, be a paraneoplastic phenomenon, or be secondary to autoimmune inflammation. Atopic dermatitis is frequently associated with reduced sweating and pruritus when sweating is triggered. Patients with psoriasis may have similar symptoms, but less frequently. Anhidrosis with pruritus is a rare syndrome of young adults. Severe itching occurs whenever they are stimulated to sweat. No sweat is delivered to the skin surface, but when the body temperature is raised by about 0.5°C, fine papules appear at each eccrine orifice. The associated pruritus is so severe that patients feel completely incapacitated and distracted. Cooling immediately resolves the symptoms. This may represent one form of tropical asthenia or a mild form of the autonomic neuropathies described below. The natural history is unknown, but spontaneous resolution may occur after several years. These patients are frequently misdiagnosed as having cholinergic urticaria. Segmental anhidrosis may be associated with tonic pupils (Holmes–Adie syndrome); this is called Ross syndrome. Patients have heat intolerance and segmental areas of anhidrosis on the trunk, arms, or legs. Loss of deep tendon reflexes in the arms, trunk, and legs is consistently seen. Compensatory segmental hyperhidrosis of functionally intact areas may occur. A selective degeneration of the cholinergic sudomotor neurons is the hypothesized abnormality. Autonomic neuropathies associated with antibodies to nicotinic acetylcholine receptors may cause a variety of symptoms related to dysfunction of systems controlled by autonomic nerves. There is a spectrum of abnormalities ranging from severe autonomic failure characterized by orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction, and sicca syndrome to isolated anhidrosis and heat intolerance. In this condition a biopsy may reveal an inflammatory infiltrate surrounding the eccrine glands, and some patients respond to pulse steroids or immunosuppressants. It may also spontaneously resolve. Anhidrosis localized to skin lesions occurs regularly over plaques of tuberculoid leprosy. This is also true of segmental vitiligo (but not generalized type), in the hypopigmented streaks of incontinentia pigmenti, in lesions of syringo lymphoid hyperplasia with alopecia and anhidrosis, and on the face and neck of patients with the rare Bazex syndrome consisting of follicular atrophoderma, basal cell carcinomas, and hypotrichosis, an X-linked dominant disorder.
Disorders of the sweat glands
completely. Only 60% of patients are satisfied, however, since compensatory and gustatory hyperhidrosis occurs in more than two-thirds of patients. This may be severe and as debilitating as the original problem. Topical glycopyrrolate may sometimes help alleviate compensatory hyperhidrosis, but it does not decrease with time. Horner syndrome may rarely result. Endoscopic thoracic sympathetic block at T4 is being evaluated as another alternative.
Cheshire WP, et al: Drug-induced hyperhidrosis and hypohidrosis. Drug Saf 2008; 31:109. Hagemann G, et al: Adie’s pupil in the Ross syndrome. N Engl J Med 2000; 355:e5. Nolano M, et al: Ross syndrome. Brain 2006; 129:2119. Ogino J, et al: Idiopathic acquired generalized anhidrosis due to occlusion of proximal coiled ducts. Br J Dermatol 2004; 150:589. Palm F, et al: Successful treatment of acquired idiopathic generalized anhidrosis. Neurology 2007; 68:532. Sandroni P, et al: Other autonomic neuropathies associated with ganglionic antibodies. Auton Neurosci 2009; 146:13. Sommer C, et al: Selective loss of cholinergic sudomotor fibers causes anhidrosis in Ross syndrome. Ann Neurol 2002; 52:247. Thami GP, et al: Acquired idiopathic generalized anhidrosis. Clin Exp Dermatol 2003; 28:262. Vernino S, et al: Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy. Auton Neurosci 2009; 146:3.
Bromhidrosis Also known as fetid sweat, osmidrosis and malodorous sweating, bromhidrosis is chiefly encountered in the axillae. Bacterial 767
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decomposition of apocrine sweat, producing fatty acids with distinctive offensive odors, is considered to be the cause. Often, patients who complain of offensive axillary sweat actually have no offensive odor; the complaint represents a delusion, paranoia, phobia, or a lesion of the central nervous system. Intranasal foreign body and chronic mycotic infection in the sinuses are additional causes. True bromhidrosis is usually not recognized by the patient. Fish odor syndrome should be considered in patients presenting with complaints of offensive odor. It is caused by excretion of trimethylamine (which smells like rotten fish) in the eccrine sweat, urine, saliva, and other secretions. This chemical is produced from carnitine and choline in the diet and is normally metabolized in the liver. An autosomaldominant defect in the ability to metabolize trimethylamine because of a defect in flavin-containing mono-oxygenase 3 is the cause of this syndrome. Dietary reduction of foods high in carnitine and choline is beneficial. Antibacterial soaps and many commercial deodorants are quite effective in controlling axillary malodor. Frequent bathing, changing of underclothes, shaving of the axillae, and topical application of aluminum chloride (Drysol) are all helpful measures. Surgical removal of the glands either by excision or tumescent liposuction is possible, as in axillary hyperhidrosis, but this is rarely indicated. Botulinum toxin A injections in the axilla have controlled body odor in this site as well in the pubic area. Plantar bromhidrosis is produced by bacterial action on eccrine sweat-macerated stratum corneum. Hyperhidrosis is the chief associated factor, and pitted keratolysis is often present. Careful washing with an antibacterial soap and the use of dusting powders on the feet are helpful in eliminating bromhidrosis. Use of topical antibiotics, such as clindamycin, may be beneficial. Previously described measures to control plantar hyperhidrosis should be instituted. Botulinum toxin A is likely to be effective. Arseculeratne G, et al: Trimethylaminuria (fish odor syndrome). Arch Dermatol 2007; 143:81. Heckman M, et al: Amelioration of body odor after intracutaneous axillary injection of botulinum toxin A. Arch Dermatol 2003; 139:57. Lee JB, et al: A case of foul genital odor treated with botulinum toxin A. Dermatol Surg 2004; 30:1233. Seo SH, et al: Tumescent superficial liposuction with curettage for treatment of axillary bromhidrosis. J Eur Acad Dermatol Venereol 2008; 22:30.
Chromhidrosis Chromhidrosis, or colored sweat, is an exceedingly rare functional disorder of the apocrine sweat glands, frequently localized to the face or axilla. It has been less often noted on the abdomen, chest, breasts, thighs, groin, genitalia, and lower eyelids. The colored sweat may be yellow (most common), blue, green, or black. The colored secretion appears in response to adrenergic stimuli, which cause myoepithelial contractions. Colored apocrine sweat fluoresces and is caused by lipofuscin. Treatment with botulinum toxin A or topical capsaicin has been reported to be effective. Eccrine chromhidrosis is caused by the coloring of the clear eccrine sweat by dyes, pigments, or metals on the skin surface. Examples are the blue–green sweat seen in copper workers and the “red sweat” seen in flight attendants from the red dye in the labels in life-vests. Brownish staining of the axillae and undershirt may occur in ochronosis. Bile secretion in eccrine sweat occurs in patients with liver failure and marked hyperbilirubinemia. Small, round, brown or deep-green macules occur on the palms and soles. 768
Gandhi V, et al: Apocrine chromhidrosis localized to the areola in an Indian female treated with topical capsaicin. Indian J Dermatol Venereol Leprol 2006; 72:382. Matarasso SL: Treatment of facial chromhidrosis with botulinum toxin type A. J Am Acad Dermatol 2005; 52:89. Polat M, et al: Apocrine chromhidrosis. Clin Exp Dermatol 2009; 39:e373.
Fox–Fordyce disease Fox–Fordyce disease is rare, occurring mostly in women during adolescence or soon afterward. It may occasionally be familial in nature. It is characterized by conical, flesh-colored or grayish, intensely pruritic, discrete follicular papules in areas where apocrine glands occur. The axillae and areolae are the primary sites of involvement, but the umbilicus, pubes, labia majora, and perineum may be affected. Apocrine sweating does not occur in affected areas, and hair density may be decreased. In some cases there is no itching. Ninety percent of cases occur in women between the ages of 13 and 35, but the disease may present postmenopausally or in males. Pregnancy invariably leads to improvement. Histologically, Fox–Fordyce disease is characterized by obstruction of the follicular ostia by orthokeratotic cells. An inflammatory infiltrate of lymphocytes surrounds the upper third of the hair follicles and upper dermal vessels. There is an associated spongiosis of the infundibulum at the site of entrance of the apocrine duct into the hair follicle. In one case, detached apoeccrine cells obstructed the duct. Foam cells have been noted to be a histologic marker, as many of the above findings are either nonspecific or difficult to demonstrate. Localized axillary xanthomatosis has been postulated to be either a variant of Fox–Fordyce disease or a type of verruciform xanthoma. No form of therapy is universally effective for Fox–Fordyce disease. Oral contraceptive pills, topical tretinoin or adapalene, topical pimecrolimus or weak corticosteroid creams, intra lesional steroids, topical clindamycin solution, benzoyl pero xide, isotretinoin, and UV phototherapy have all been effective in small numbers of patients. Excision or liposuction-assisted curettage may be successful in axillary sites. Chae KM, et al: Axillary Fox–Fordyce disease treated with liposuction-assisted curettage. Arch Dermatol 2002; 138:452. Bormate AB Jr, et al: Perifollicular xanthomatosis as a hallmark of axillary Fox–Fordyce disease. Arch Dermatol 2008; 144:1020. Ghislain P-D, et al: Itchy papules of the axillae. Arch Dermatol 2002; 138:259. Kamada A, et al: Apoeccrine sweat duct obstruction as a cause for Fox–Fordyce disease. J Am Acad Dermatol 2003; 48:453. Pock L, et al: Pimecrolimus is effective in Fox–Fordyce disease. Int J Dermatol 2006; 45:1134. Scroggins L, et al: Fox–Fordyce disease in daughter and father. Dermatology 2009; 218:176.
Granulosis rubra nasi Granulosis rubra nasi is a rare familial disease of children, occurring on the nose, cheeks, and chin. It is characterized by diffuse redness, persistent hyperhidrosis, and small dark red papules that disappear on diascopic pressure. The tip of the nose is red or violet. There may be a few small pustules. Hyperhidrosis precedes the erythema (Fig. 33-37). The tip of the nose is cold and is not infiltrated. The disease disappears spontaneously at puberty without leaving any traces. The cause is unknown. Histologically, blood vessels are dilated and there is an inflammatory infiltrate about the sweat ducts.
Recurrent palmoplantar hidradenitis
Fig. 33-37 Early granulosis rubra nasi.
Treatment is with local preparations for relief of the inflammation, and reassurance that with puberty there is usually involution of the process. Akhdari N: Granulosis rubra nasi. Int J Dermatol 2007; 46:396.
Hidradenitis Hidradenitis is a term used to describe diseases in which the histologic abnormality is primarily an inflammatory infiltrate around the eccrine glands. This group includes neutrophilic eccrine hidradenitis and idiopathic plantar hidradenitis (recurrent palmoplantar hidradenitis).
Neutrophilic eccrine hidradenitis Ninety percent of patients with neutrophilic eccrine hidradenitis (NEH) have a malignancy. It has been described primarily in patients with acute myelogenous leukemia (AML); however, other leukemias, lymphomas, and uncommonly solid tumors may be present. It usually begins about 10 days after the start of chemotherapy. While the majority of patients have been treated with cytarabine, it has not been uniformly linked to any chemotherapeutic agent and may occur in patients who have not been treated. Patients with AML in remission have been reported to develop NEH with associated sclerodermoid changes that herald a relapse of the leukemia. Granulocyte colony-stimulating factor (G-CSF), imatinib mesylate, zidovudine, acetaminophen, and various antibiotics have also been implicated as triggers for this neutrophilic dermatosis. The lesions are typically erythematous and edematous papules and plaques of the extremities, trunk, face (peri orbital), and palms (in decreasing frequency). Pigmentation, purpura, or pustules may be present within the papules and plaques. Fever and neutropenia are often present. Histologically, there is a dense neutrophilic infiltrate around and infiltrating eccrine glands. Necrosis of sweat glands may be present, with or without the inflammatory infiltrate. Syringosquamous metaplasia may occur. This finding can also occur in fibrosing alopecia, in burn scars, adjacent to various nonmelanoma skin cancers and ischemic and surgical ulcers, in alopecia mucinosa, and in ports of radiation therapy. The lesions may recur with repeated courses of chemotherapy, but many do not. Resolution over 1–4 weeks (average, 10 days) usually occurs. Nonsteroidal anti-inflammatory drugs or oral corticosteroids may hasten the healing. Prophylactic administration of dapsone prevented recurrence in one patient. Infectious neutrophilic hidradenitis may present as a recurrent, pruritic, papular eruption. Serratia, Enterobacter cloacae,
Recurrent palmoplantar hidradenitis is primarily a disorder of healthy children and young adults. Lesions are primarily painful, subcutaneous nodules on the plantar surface, resembling erythema nodosum. Rarely, palmar lesions also occur. In some children Pseudomonas infection may be the cause (pseudo monal hot foot, see Chapter 14). Children may present refusing to walk because of plantar pain. The condition is typically recurrent, and may be triggered by exposure to wet shoes or cold, damp weather. The use of oral and topical steroidal preparations may be beneficial.
Diseases of the nails
Nocardia, and Staphylococcus aureus have been implicated, and appropriate antibiotics for bacterial agents are curative. The diagnosis is confirmed by histologic evaluation and culture of affected tissue (surface cultures may not be adequate). Additionally, many HIV-infected patients have developed neutrophilic eccrine hidradenitis.
Antonovich DD, et al: Infectious eccrine hidradenitis caused by Nocardia. J Am Acad Dermatol 2004; 50:315. Crawford GH, et al: Erythematous facial plaques in a patient with leukaemia. Arch Dermatol 2003; 139:531. Rubinson R, et al: Palmoplantar eccrine hidradenitis: seven new cases. Pediatr Dermatol 2004; 21:466. Shih IH, et al: Childhood neutrophilic eccrine hidradenitis. J Am Acad Dermatol 2005; 52:963. Srivastava M, et al: Neutrophilic eccrine hidradenitis masquerading as facial cellulitis. J Am Acad Dermatol 2007; 56:693. Yasukawa K, et al: Neutrophilic eccrine hidradenitis with sclerodermoid change heralding the relapse of AML. Dermatology 2007; 215:261.
Diseases of the nails Several general references are available that review a wide spectrum of nail changes. Andre J, et al: Pigmented nail disorders. Dermatol Clin 2006; 24:329. Baran R, et al: Baran and Dawber’s Diseases of the Nails and Their Management. Oxford: Blackwell Science, 2008. Bodman MA: Nail dystrophies. Clin Podiatr Med Surg 2004; 21:663. DeBerker D: Childhood nail diseases. Dermatol Clin 2006; 24:355. Holzberg M: Common nail disorders. Dermatol Clin 2006; 24:349. Iorizzo M, et al: Nail cosmetics in nail disorders. J Cosmet Dermatol 2007; 6:53. Kovich OI, et al: Clinical pathologic correlations for diagnosis and treatment of nail disorders. Dermatol Ther 2007; 20:11. Nandedkar-Thomas MA, et al: An update on disorders of the nails. J Am Acad Dermatol 2005; 52:877. Piraccini BM, et al: Drug-induced nail diseases. Dermatol Clin 2006; 24:387. Rich P, Scher R: Atlas of Nail Diseases. New York: Pantheon, 2003. Scher R, Daniel CR (eds): Nails. Philadelphia: Elsevier, 2005. Tosti A, et al: The nail in systemic diseases. Dermatol Clin 2006; 24:341.
Nail-associated dermatoses Numerous dermatoses are associated with characteristic, sometimes specific, nail changes. Many are considered elsewhere.
Lichen planus of nails The reported incidence of nail involvement in lichen planus varies from less than 1% to 10%. Lichen planus of the nails may occur without skin changes, but 25% with nail disease will have lichen planus at other locations. Although it may occur at any age, most commonly it begins during the fifth or sixth decade of life. The nail plate may be markedly thinned, and at times distinct papules of lichen planus may involve the nailbed. Twenty-nail dystrophy (trachyonychia) may be the 769
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Fig. 33-39 Pitting caused by psoriasis. Scheinfeld NS: Trachyonychia: a case report and review of manifestations, associations, and treatments. Cutis 2003; 71:299. Tosti A, et al: Nail lichen planus in children: clinical features, response to treatment and long term follow-up. Arch Dermatol 2001; 137:1027.
Psoriatic nails
Fig. 33-38 Pterygium caused by lichen planus. (Courtesy of Lawrence Lieblich, MD)
sole manifestation of lichen planus. Other nail changes are irregular longitudinal grooving and ridging of the nail plate, thinning of the nail plate, pterygium formation (Fig. 33-38), shedding of the nail plate with atrophy of the nailbed, sub ungual keratosis, or even onychopapilloma, erythronychia (red streaks), subungual hyperpigmentation, and nail degloving. This latter sign is a newly described entity where there is partial or total shedding of the nail or the entire nail apparatus. The surrounding skin may also slough. This may be caused by trauma, ischemia and gangrene, or severe dermatologic disease such as toxic epidermal necrolysis or lichen planus. The histologic changes of lichen planus may be evident in any individual nail constituent or a combination of them. The one most frequently involved is the matrix. Treatment is mostly unsatisfactory. Intralesional injection of corticosteroids may be of help in some patients. Digital nerve blocks should be considered before infiltration of the matrix or nailbed. Topical corticosteroids under polyethylene occlusive dressings are usually inadequate. Clobetasol combined with tazarotene may be successful. Oral prednisone (0.5–1 mg/kg for 3 weeks) or oral retinoids in combination with topical steroids applied to the involved sites has been successful in some patients. Tosti et al reported that typical lichen planus of the nails in children responded to 0.5–1 mg/kg/month of intramuscular triamcinolone acetonide given for 3–6 months, until the proximal half of the nail was normalized. Disease recurred in only two patients during the follow-up period. While twenty-nail dystrophy was not treated, patients spontaneously improved; those with idiopathic atrophy of the nails were unchanged. (See Chapter 12 for additional therapeutic considerations.) Baran R, et al: Nail degloving, a polyetiologic condition with 3 main patterns. J Am Acad Dermatol 2008; 58:232. De Berker DA, et al: Localized longitudinal erythronychia. Arch Dermatol 2004; 140:1253. Okiyama N, et al: Squamous cell carcinoma arising from lichen planus of nail matrix and nail bed. J Am Acad Dermatol 2005; 53:908. Piraccini BM, et al: Nail lichen planus. Eur J Dermatol 2010; 20:489. Richert B, et al: Nail bed lichen planus associated with onychopapilloma. Br J Dermatol 2007; 156:107.
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Nail involvement in psoriasis is common, with reported incidences varying from 10% to 78%. Older patients, those with active exacerbations of disease, and those with psoriatic arthritis are more likely to express nail abnormalities. In the nail plate there may be pits (Fig. 33-39), or much less often, furrows or transverse depressions (Beau’s lines), crumbling nail plate, or leukonychia, with a rough or smooth surface. Splinter hemorrhages are found in the nailbed, with reddish discoloration of a part or all of the nailbed, and horny masses. In the hyponychium, subungual hyperkeratosis, oil spots, and a yellowish– green discoloration may occur in the area of onycholysis. Onychomycosis may be closely simulated. The severity of nail disease may correlate with the severity of skin and joint disease. Pustular psoriasis may produce onycholysis, with lakes of pus in the nailbed or in the perionychial areas. Rarely, anonychia may result. Other papulosquamous diseases may affect the nails like psoriasis, with the exception of nail pitting. Reiter’s disease, pityriasis rubra pilaris, Sézary syndrome, and acrokeratosis paraneoplastica produce as a rule hypertrophic nails with subungual hyperkeratosis. Psoriatic nail disease may be a solitary finding or be part of a widespread skin and nail involvement. The treatment options selected depend on the degree of cutaneous and nail involvement. (See Chapter 10 for additional information and therapeutic options.) Successful systemic treatment of psoriasis will usually also improve or clear the nail changes. Methotrexate, PUVA, cyclosporine, the biologics, or acitretin may be effective. All local therapies have limitations. Intralesional injection of triamcinolone acetonide suspension, 3–5 mg/mL, with a 30-gauge needle is frequently helpful. Digital nerve block facilitates adequate injection. Topical 5-fluorouracil (5-FU) applied to the proximal nailfold has been reported to be effective. It is best to avoid the free edge of the nail when applying 5-FU, as it may cause distal onycholysis. Topical cyclosporine and topical tazarotene 0.1% gel may also be helpful. Topical calcipotriol improves about 50% of patients with localized pustular psoriasis of the nails and may be used as a maintenance treatment after successful intervention with systemic retinoids. Cassell S, et al: Therapies for psoriatic nail disease. J Rheumatol 2006; 33:1452. De Berker D: Management of psoriatic nail disease. Semin Cutan Med Surg 2009; 28:39. Diluvio L, et al: Childhood nail psoriasis. Pediatr Dermatol 2007; 24:332. Jiaravuthisan MM, et al: Psoriasis of the nail. J Am Acad Dermatol 2007; 57:1.
Darier’s disease Longitudinal, subungual, red or white streaks, associated with distal wedge-shaped subungual keratoses, are the nail signs diagnostic for Darier–White disease. Keratotic papules on the dorsal portion of the nailfold may clinically resemble acrokeratosis verruciformis, but histologically have features of Darier’s disease. Other nail findings include splinter hemorrhages and leukonychia. All of these findings are less pronounced on the toenails. Baran R, et al: An effective surgical treatment for nail thickening in Darier’s disease. J Eur Acad Dermatol Venereol 2005; 19:689. De Berker DA, et al: Localized longitudinal erythronychia. Arch Dermatol 2004; 140:1253.
Clubbing Clubbing is divided into two types: idiopathic and acquired, or secondary. The changes occur not only in the nails but also in the terminal phalanges. The nails bulge and are curved in a convex arc in both transverse and longitudinal directions. The eponychium is thickened. The angle formed by the dorsal surface of the distal phalanx and the nail plate (Lovibond’s angle) is approximately 160°; however, with clubbing this angle is obliterated and becomes 180° or greater (Fig. 33-40). There is no diamond-shaped window when the dorsal surfaces of the corresponding finger of each hand are opposed (Schamroth’s sign). The soft tissues of the terminal phalanx are bulbous and of are mobile when pressure is applied over the matrix. Thickening of the nailbed is present and can be assessed reliably by a plain radiograph of the index finger. Idiopathic clubbing is either of the isolated dominantly inherited type or of the pachydermoperiostosis type with its associated findings. In the hereditary isolated type, a homozygous missense mutation in exon 6 of the human HPGD gene encoding NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been identified. Secondary (acquired) clubbing is usually a consequence of pulmonary, cardiac, thyroid, hepatic, or gastrointestinal disease. Around 36% of HIV patients has been documented to express clubbed nails. Typically, there is periostitis, with periosteal new bone formation in the phalanges, metacarpals, and distal ulna and radius. This is called hypertrophic osteoarthropathy and is responsible for the painful clubbing. It typically occurs in men with bronchogenic carcinoma. Unilateral or asymmetrical clubbing may also occur in Takayasu arteritis and sarcoidosis.
Myers KA, et al: The rational clinical examination. Does this patient have clubbing? JAMA 2001; 286:1972. Pallarés-Sanmartin A, et al: Validity and reliability of the Schamroth sign for the diagnosis of digital clubbing. JAMA 2010; 304:159. Spicknall KE, et al: Clubbing. J Am Acad Dermatol 2005; 52:1020. Tariq M, et al: Mutation in the HPGD gene encoding NAD+dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing. J Med Genet 2009; 46:14.
Shell nail syndrome Cornelius et al described a shell nail in association with bronchiectasis. The nail resembles a clubbed nail, but the nailbed is atrophic instead of being a bulbous proliferation of the soft tissue.
Diseases of the nails
Noiles K, et al: Nail psoriasis and biologics. J Cutan Med Surg 2009; 13:1. Piraccini BM, et al: Pustular psoriasis of the nails. Br J Dermatol 2001; 144:1000. Salomon J, et al: Psoriatic nails: a prospective clinical study. J Cutan Med Surg 2003; 7:317. Tosti A, et al: Evaluation of the efficacy of acitretin therapy for nail psoriasis. Arch Dermatol 2009; 145:269.
Cornelius CE: Shell nail syndrome. Arch Dermatol 1969; 100:118.
Koilonychia (spoon nails) Spoon nails are thin and concave, with the edges everted so that if a drop of water were placed on the nail, it would not run off (Fig. 33-41). Koilonychia may result from faulty iron metabolism and is one of the signs of Plummer–Vinson syndrome, as well as of hemochromatosis. Spoon nails have been observed in coronary disease, syphilis, polycythemia, and acanthosis nigricans. Familial forms are also known to occur. Other associations include psoriasis, lichen planus, Raynaud disease, scleroderma, acromegaly, hypothyroidism and hyperthyroidism, monilethrix, palmar hyperkeratoses, and steatocystoma multiplex. A significant number of cases are idiopathic. Manual trauma in combination with cold exposure may result in seasonal disease. Sherpas are Tibetan people living in the Nepalese Himalayas, who often serve as porters on mountainclimbing expeditions. Chronic cold exposure, in combination with hypoxemia, may contribute to the high frequency with which koilonychia is observed among them. Gao XH, et al: Familial koilonychia. Int J Dermatol 2001; 40:290. Kumar G, et al: Koilonychia, or spoon-shaped nails, is generally associated with iron-deficiency anemia. Ann Emerg Med 2007; 49:243.
Congenital onychodysplasia of the index fingers Congenital onychodysplasia of the index fingers is defined by the presence of the condition at birth, index finger involvement (unilateral or bilateral), variable distortion of the nail or lunula, and polyonychia, micronychia, anonychia, hemi onychogryphosis, or malalignment. It may also involve adjacent fingers, such as the middle fingers and thumbs. An underlying bone dysplasia may be present beneath the involved nail. Cases have occurred in an autosomal-dominant pattern; other proposed causes include in utero ischemia or exposure to teratogens.
Dever LL, et al: Digital clubbing in HIV-infected patients. AIDS Patient Care STDS 2009; 23:19. Moriera AL, et al: Clubbed fingers. Clin Anat 2008; 21:314.
Fig. 33-40 Clubbing. (Courtesy of Lawrence Lieblich, MD)
Fig. 33-41 Koilonychia.
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De Smet L: Congenital onychodysplasia of the index finger. Genet Couns 2000; 11:37. Prais D, et al: Prevalence and new phenotypic and radiologic findings in congenital onychodysplasia of the index finger. Pediatr Dermatol 1999; 16:201.
Trachyonychia The nails may become opalescent, thin, dull, fragile, and finely ridged longitudinally (and as a result, distally notched). When this involves all 20 nails, it is referred to as twenty-nail dystrophy. This latter presentation may be seen at any age from 1 1 2 years to adulthood, although it is most commonly diagnosed in children. It can be idiopathic or caused by alopecia areata, psoriasis, lichen planus, atopy, ichthyosis vulgaris, or other inflammatory dermatoses. Familial forms exist. In some cases spongiosis may be found on nail biopsy. Trachyonychia has also been reported associated with autoimmune processes such as selective IgA deficiency, vitiligo, sarcoidosis, and graft versus host disease. Unilateral involvement may occur in complex regional pain syndrome. Thus it is caused by a heterogenous group of inflammatory conditions. Tazarotene alone or in association with topical steroids may improve the condition. Childhood cases may resolve spontaneously; in one study 50% cleared within 6 years. Blanco FP, et al: Trachyonychia. J Drugs Dermatol 2006; 5:469. Grover C, et al: Longitudinal nail biopsy: utility in 20-nail dystrophy. Dermatol Surg 2003; 29:1125. Pucevich B, et al: Unilateral trachyonychia in a patient with reflex sympathetic dystrophy. J Am Acad Dermatol 2008; 58:320. Sakata S, et al: Follow up of 12 patients with trachyonychia. Australas J Dermatol 2006; 47:166. Scheinfeld NS: Trachyonychia: a case report and review of manifestations, associations, and treatments. Cutis 2003; 71:299. Soda R, et al: Treatment of trachyonychia with tazarotene. Clin Exp Dermatol 2005; 30:301.
Onychauxis In onychauxis the nails are thickened but without deformity (simple hypertrophy). Simple thickening of the nails may be the result of trauma, acromegaly, Darier’s disease, psoriasis, or pityriasis rubra pilaris. Some cases are hereditary. Treatment involves periodic partial or total debridement of the thickened nail plate by mechanical or chemical (40% urea paste) means. Matricectomy and nail ablation are options, as they are in onychogryphosis, congenital nail dystrophies, and chronic painful nails such as recalcitrant ingrown toenails or splits within the medial or lateral third of the nail. Baran R, et al: Matricectomy and nail ablation. Hand Clin 2002; 18:696. Singh G, et al: Nail changes and disorders among the elderly. Indian J Dermatol Venereol Leprol 2005; 71:386.
Onychogryphosis Hypertrophy may produce nails resembling claws or a ram’s horn. Onychogryphosis may be caused by trauma or peripheral vascular disorders but is most often caused by neglect (failure to cut the nails for very long periods). It is most commonly seen in the elderly. Some recommend avulsion of the nail plate with surgical destruction of the matrix with phenol or the CO2 laser, if the blood supply is good. Baran R, et al: Matricectomy and nail ablation. Hand Clin 2002; 18:696. Mohrenschlager M, et al: Onychogryphosis in elderly persons. Cutis 2001; 68:233.
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Onychophosis A common finding in the elderly, onychophosis is a localized or diffuse hyperkeratotic tissue that develops on the lateral or proximal nailfolds, within the space between the nailfolds and the nail plate. It may involve the subungual area, as a direct result of repeated minor trauma, and most frequently affects the first and fifth toes. The use of comfortable shoes should be encouraged. The areas involved should be debrided and treated with keratolytics. Emollients are also helpful. Singh G, et al: Nail changes and disorders among the elderly. Indian J Dermatol Venereol Leprol 2005; 71:386.
Anonychia Absence of nails, a rare anomaly, may be the result of a congenital ectodermal defect, ichthyosis, severe infection, severe allergic contact dermatitis, self-inflicted trauma, Raynaud phenomenon, lichen planus, epidermolysis bullosa, or severe exfoliative diseases. Permanent anonychia has been reported as a sequel of Stevens–Johnson syndrome. It may also be found in association with congenital developmental abnormalities, such as microcephaly, and wide-spaced teeth (autosomalrecessive inheritance), the autosomal-dominant Cooks syndrome (bilateral nail hypoplasia of digits 1–3, the absence of nails of digits 4 and 5 of the hands, total absence of all toenails, and absence or hypoplasia of the distal phalanges of the hands and feet), DOOR syndrome (deafness, onycho-osteodystrophy, mental retardation), and the glossopalatine syndrome (abnormal mouth, tongue being attached to the temporomandibular joint). It may also present as an autosomal-recessive disorder with anonychia as the solitary finding. It has been found to be caused by a mutation in the R-spondin 4 gene. R-spondins are secreted proteins that activate the Wnt/β-catenin signaling pathway. R-spondin 4 is exclusively expressed in the mesenchyme underlying the digit tip epithelium in embryonic mice. Al Hawsawi K, et al: Anonychia congenita totalis. Int J Dermatol 2002; 41:397. Bruchle NO, et al: RSPO4 is the major gene in autosomal-recessive anonychia and mutations cluster in the furin-like cysteine-rich domains of the Wnt signaling ligand R-spondin4. J Invest Dermatol 2008; 128:791. Ishii Y, et al: Mutations in R-spondin 4 underlie inherited anonychia. J Invest Dermatol 2008; 128:867. Ozdemir O, et al: Total anonychia congenita. Genet Couns 2004; 15:43. Pall A, et al: Twenty-nail anonychia due to lichen planus. J Dermatol 2004; 31:146.
Onychoatrophy Faulty underdevelopment of the nail may be congenital or acquired. The nail is thinned and small. Vascular disturbances, epidermolysis bullosa, lichen planus, Darier’s disease, multicentric reticulohistiocytosis, and Hansen’s disease may cause onychoatrophy. It is also seen in congenital syndromes such as Apert, Goltz, Turner, Ellis–van Creveld, nail–patella, dyskeratosis congenita, cartilage–hair hypoplasia, progeria, hypohidrotic ectodermal dysplasia, incontinentia pigmenti, popliteal web, trisomy 13 and trisomy 18, and as a side effect of etretinate therapy. Al Hawsawi K, et al: Anonychia congenita totalis. Int J Dermatol 2002; 41:397.
Onychomadesis Onychomadesis is a periodic idiopathic shedding of the nail beginning at its proximal end. The temporary arrest of the
Diseases of the nails Fig. 33-42 Beau’s lines.
Fig. 33-43 Half and half nails.
function of the nail matrix may cause onychomadesis. Neurologic disorders, peritoneal dialysis, cutaneous T-cell lymphoma, Kawasaki’s disease, pemphigus vulgaris, drug allergy, and keratosis punctata palmaris et plantaris have been reported causes. It may appear as a periodic finding in runners. Immobilization from casting for fractures may cause onychomadesis and pyogenic granuloma formation. Medications such as antineoplastic agents, azithromycin, and retinoids may cause onychomadesis also.
demarcation between the two halves (Fig. 33-43). Seventy-six percent of hemodialysis patients and 56% of renal transplant patients have at least one type of nail abnormality. Half and half nails are the most frequent, affecting 20% of hemodialysis patients. Absence of lunula, splinter hemorrhage, and half and half nails were significantly more common in hemodialysis patients, while leukonychia was significantly more common in transplant patients.
Bodman MA: Nail dystrophies. Clin Podiatr Med Surg 2004; 21:663. Mehra A, et al: Idiopathic familial onychomadesis. J Am Acad Dermatol 2000; 43:349. Patel NC, et al: Neonatal onychomadesis with candidiasis limited to affected nails. Pediatr Dermatol 2008; 25:641. Piraccini BM, et al: Drug-induced nail diseases. Dermatol Clin 2006; 24:387. Tosti A, et al: Onychomadesis and pyogenic granuloma following cast immobilization. Arch Dermatol 2001; 137:231.
Beau’s lines Beau’s lines are transverse furrows that begin in the matrix and progress distally as the nail grows (Fig. 33-42). They are ascribed to the temporary arrest of function of the nail matrix. Although usually found to be bilateral, unilateral Beau’s lines may occur. Various systemic and local traumatic factors may cause this. They may result from almost any systemic illness or major injury, such as a broken hip. Some specific associations are childbirth, measles, paronychia, acute febrile illnesses, high altitude exposure, and drug reaction. When the process is intermittent, the nail plate may resemble corduroy. Shelley “shoreline” nails appear to be a very severe expression of essentially the same transient growth arrest. They have been reported in all 20 nails of a newborn. Guhl G, et al: Beau’s lines and multiple periungual pyogenic granulomas after long stay in an intensive care unit. Pediatr Dermatol 2008; 25:278. Mortimer NJ, et al: Beau’s lines. N Engl J Med 2004; 351:1778. Piraccini BM, et al: Drug-induced nail diseases. Dermatol Clin 2006; 24:387.
Half and half nails Half and half nails show the proximal portion of the nail white and the distal half red, pink, or brown, with a sharp line of
Salem A, et al: Nail changes in chronic renal failure patients under haemodialysis. J Eur Acad Dermatol Venereol 2008; 22:1326. Saray Y, et al: Nail disorders in hemodialysis patients and renal transplant recipients: a case control study. J Am Acad Dermatol 2004; 50:197.
Muehrcke’s lines Muehrcke described narrow white transverse bands occurring in pairs as a sign of chronic hypoalbuminemia. The lines may resolve when serum albumin is raised to or near normal (Fig. 33-44). Unlike Mees’ lines, the disturbance appears to be in the nailbed, not in the nail plate. Similar lines have been reported in patients with normal albumin levels who are receiving chemotherapy. In a case of unilateral Muehrcke’s lines associated with trauma, it was suggested that edema effects this change by inducing microscopic separation of the normally tightly adherent nail from its bed. Alam M, et al: Muehrcke’s lines in a heart transplant recipient. J Am Acad Dermatol 2001; 44:316. Chen W, et al: Nail changes associated with chemotherapy in children. J Eur Acad Dermatol Venereol 2007; 21:186. Morrison-Bryant M, et al: Muehrcke’s lines. N Engl J Med 2007; 30:917.
Mees’ lines Mees described single or multiple white transverse bands in 1919 as a sign of inorganic arsenic poisoning. They have also been reported in thallium poisoning, septicemia, dissecting aortic aneurysm, parasitic infections, chemotherapy, and both acute and chronic renal failure. Chauhan S, et al: Mees’ lines. Lancet 2008; 372:1410. Hall AH: Chronic arsenic poisoning. Toxicol Lett 2002; 128:69. Lu CI, et al: Short-term thallium intoxication. Arch Dermatol 2007; 143:93. Uede K, et al: Skin manifestations in acute arsenic poisoning from the Wakayama curry-poisoning incident. Br J Dermatol 2003; 149:757.
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Fig. 33-46 Onychoschizia.
Onychorrhexis (brittle nails)
Fig. 33-44 Muehrke’s lines.
Brittleness with breakage of the nails may result from frequent soap and water exposure, nail polish remover, hypo thyroidism, anorexia or bulimia, or after oral retinoid therapy. It affects up to 20% of the population, women twice as often as men. Fragilitas unguium (nail fragility) is part of this process. In a series of 35 patients treated with biotin, 63% showed clinical improvement. The nail plate thickness in patients treated with biotin increases by 25%. Daily application of white petrolatum after soaking in water is also helpful. Uyttendaele H, et al: Brittle nails: pathogenesis and treatment. J Drugs Dermatol 2003; 2:48. Van de Kerkhof PC: Brittle nail syndrome. J Am Acad Dermatol 2005; 53:644.
Onychoschizia Splitting of the distal nail plate into layers at the free edge (Fig. 33-46) is a very common problem among women and represents a dyshesion of the layers of keratin, possibly as a result of dehydration. Longitudinal splits may also occur. Patients with biotinidase deficiency may manifest onychoschizia, along with total or partial alopecia and an eczematous or desquamating periorificial eruption. Hypotonia, seizures, and developmental delay in children and depression in adults are the most common systemic abnormalities. Lack of treatment may result in loss of hearing and vision. Nail polish should be discontinued; nail buffing can be substituted. Frequent application of emollients may be helpful. Biotin has also been shown to be effective in doses up to 2.5 mg/day, or 2–4 times that much in deficient patients. Fig. 33-45 Terry nails. Zhao G, et al: Clinical manifestations of acute thallium poisoning. Eur Neurol 2008; 60:292.
Terry nails In Terry nails the distal 1–2 mm of the nail shows a normal pink color (Fig. 33-45), while the entire nail plate or proximal end has a white appearance as a result of telangiectases in the nailbed. These changes have been noted in 25% of hospitalized patients, most commonly those with cirrhosis, chronic congestive heart failure, and adult-onset diabetes, and in very elderly patients. Blyumin M, et al: Terry nails. Cutis 2005; 76:172.
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Redondo-Mateo J, et al: Facial erythema and onychoschizia. Arch Dermatol 2005; 141:1457.
Stippled nails Small, pinpoint depressions in an otherwise normal nail characterize this type of nail change. This may be an early change seen in psoriasis. Stippled nails are also seen with some cases of alopecia areata, in early lichen planus, psoriatic or rheumatoid arthritis, chronic eczematous dermatitis, perforating granuloma annulare, and in some individuals with no apparent disease. The deeper, broader pits are more specific for psoriasis. The pitting in alopecia areata tends to be shallower and more regular, suggesting a “Scotch plaid” (tartan) pattern. Tosti A, et al: Prevalence of nail abnormalities in children with alopecia areata. Pediatr Dermatol 1994; 11:12.
Diseases of the nails Fig. 33-47 Racquet nails.
Fig. 33-48 Nail–patella syndrome. (Courtesy of Marshall Guill, MD)
Racquet nails (nail en raquette)
Hyperpigmentation of the pupillary margin of the iris (“Lester iris”) is a characteristic finding in about half the cases. Patients with nail–patella syndrome may exhibit glomerulonephritis with urinary findings of albuminuria, hematuria, and casts of all kinds, especially hyaline casts. They may be predisposed to developing hemolytic–uremic syndrome, edema, and hypertension. Sixty percent of patients have renal abnormalities, and 20% suffer from renal failure. It is an autosomaldominant trait localized to the distal long arm of chromosome 9. Limb and kidney defects seen in L1M-homeodomain protein Lmx1b mutant mice are similar to those present in patients with nail–patella syndrome. Mutations of the human LMX1B gene result in this syndrome.
In racquet nails, the end of the thumb is widened and flattened, the nail plate is flattened as well, and the distal phalanx is abnormally short (Fig. 33-47). Racquet nails occur on one or both thumbs and are apparently inherited as an autosomaldominant trait. Baran R, et al: Baran and Dawber’s Diseases of the Nails and Their Management. Oxford: Blackwell Scientific, 2008.
Chevron nail (herringbone nail) This entity appears to be a rare transient fingernail ridge pattern of children. The ridges arise from the proximal nailfold and converge in a V-shaped pattern toward a midpoint distally. Parry EJ: Chevron nail/herringbone nail. J Am Acad Dermatol 1999; 40:497. Zaiac MN, et al: Chevron nail. J Am Acad Dermatol 1998; 38:773.
Hapalonychia Softened nails result from a defect in the matrix that makes the nails thin and soft so that they can be easily bent. This type of nail change is attributed to malnutrition and debility. It may be associated with myxedema, rheumatoid arthritis, anorexia, bulimia, Hansen’s disease, Raynaud phenomenon, oral retinoid therapy, or radiodermatitis. Baran R, et al: Baran and Dawber’s Diseases of the Nails and Their Management. Oxford: Blackwell Scientific, 2008.
Platonychia The nail is abnormally flat and broad. It may be seen as part of an autosomal-dominant condition in which multiple nail abnormalities are present in many members of a large family. Hamm H, et al: Isolated congenital nail dysplasia: a new autosomal dominant condition. Arch Dermatol 2000; 136:1239.
Nail–patella syndrome (hereditary osteo-onychodysplasia, Fong syndrome) Nail–patella syndrome comprises numerous anomalies and is characterized by the absence or hypoplasia of the patella and congenital nail dystrophy. Triangular lunulae are characteristic (Fig. 33-48). Other bone features are thickened scapulae, hyperextensible joints, radial head abnormalities, and post erior iliac horns. The skin changes may also include webbing of the elbows. Eye changes such as cataracts, glaucoma, and heterochromia of the iris may also be present.
Bongers EM, et al: Nail–patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol 2002; 17:703. Dyer JA, et al: Multiple triangular lunula unguis. Mo Med 2007; 104:506. Granata A, et al: Nail–patella syndrome and renal involvement. Clin Nephrol 2008; 69:377. Lee BH, et al: Clinico-genetic study of nail–patella syndrome. J Korean Med Sci 2009; 24(Suppl):S82. Schulz-Butulis BA, et al: Nail–patella syndrome. J Am Acad Dermatol 2003; 49:1086.
Onychophagia Nail biting is a common compulsive behavior that may markedly shorten the nail bed, sometimes damages the matrix, and at times leads to pterygium formation. It is a difficult habit to cure. If there is strong motivation, habit reversal training with awareness training, competing response training, and social support may help. Psychopharmacologic intervention with medications, such as serotonin-reuptake inhibitors, and hypnosis are other options. Ravindran AV, et al: Obsessive–compulsive spectrum disorders. Can J Psychiatry 2009; 54:331. Tanaka OM, et al: Nailbiting, or onychophagia. Am J Orthod Dentofacial Orthop 2008; 134:305. Twohig MP, et al: Evaluating the efficacy of habit reversal: comparison with a placebo control. J Clin Psychiatry 2003; 64:40.
Onychotillomania Onychotillomania is a compulsive neurosis in which the patient picks constantly at the nails or tries to tear them off. Like onychophagia, this obsessive–compulsive disorder may be treated by biofeedback, cognitive–behavioral methods, hypnosis, or psychopharmacologic agents. Inglese M, et al: Onychotillomania. Cutis 2004; 73:171. Lin YC, et al: Onychotillomania, major depressive disorder and suicide. Clin Exp Dermatol 2006; 31:597. Shenefelt PH: Biofeedback, cognitive–behavioral methods and hypnosis in dermatology. Dermatol Ther 2003; 16:114.
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Onycholysis Onycholysis is a spontaneous separation of the nail plate, usually beginning at the free margin and progressing proximally. Rarely, the lateral borders may be involved, with spread confined to these. Less often, separation may begin proximal to the free edge, in an oval area 2–6 mm broad, with a yellowish-brown hue (“oil spot”). This is a lesion of psoriasis; ordinary distal onycholysis is also commonly due to psoriasis. The nail itself is smooth and firm with no inflammatory reaction. Underneath the nail a discoloration may occur from the accumulation of bacteria, most commonly Pseudomonas, or yeast, most commonly Candida. Color changes, such as green (a result of pyocyanin from Pseudomonas), black, or blue may be seen. One or more nails may be affected. Onycholysis is noted most commonly in women, probably secondary to traumatically induced separation. It is common in patients with hand dermatitis. Keratinization of the distal nailbed, chronic exposure to irritants, untreated dermatitis, and secondary infection with Candida albicans are potential reasons for the failure of the nail to reattach itself. Systemic causes are many: hyper- and hypothyroidism, pregnancy, porphyria, pellagra, and syphilis. Onycholysis has also been associated with atopic dermatitis, eczema, lichen planus, congenital abnormalities of the nails, trauma induced by clawing, pinching, stabbing (manicuring), and foreignbody implantation. It may be caused by mycotic, pyogenic, or viral (herpes) infections. Women should be checked for vaginal candidiasis, because that anatomic location may be the source of the infection opportunistically invading and aggravating onycholysis. Chemical causes may include the use of solvents, nail polish base coat, nail hardeners containing formalin derivatives, artificial fingernails, and allergic or irritant contact dermatitis from their use. Rarely, photo-onycholysis may occur during or soon after therapy with tetracycline derivatives, psoralens, fluoroquinolones, or chloramphenicol, and subsequent exposure to sunlight. Chemotherapeutic agents and systemic retinoids may induce onycholysis. On rare occasions it may be a sign of subungual exostoses, squamous cell carcinoma, or metastasis. Autosomal-dominant hereditary forms are also known. Trauma and chemical irritants should be completely avoided and the nailbed should be kept completely dry. The affected portion of the nail should be kept clipped away. Drying by exposing the nailbed in this way will rid the area of Pseudomonas and assist greatly in eliminating Candida. The combination of drying and topical steroids to minimize inflammation will often allow for reattachment of the nail and improvement or cure. Usually, this process takes 3–6 months or more to occur. Anoop TM, et al: Plummer’s nails. Onycholysis. N Z Med J 2008; 121:66. Baran R, et al: Photoonycholysis. Photodermatol Photoimmunol Photomed 2002; 18:202. Helsing P, et al: Onycholysis induced by nail hardener. Contact Dermatitis 2007; 57:280. Hogeling M, et al: Onycholysis associated with capecitabine in patients with breast cancer. J Cutan Med Surg 2008; 12:93. Piraccini BM, et al: Drug-induced nail diseases. Dermatol Clin 2006; 24:387.
Median nail dystrophy (dystrophia unguis mediana canaliformis, solenonychia) Median nail dystrophy consists of longitudinal splitting or canal formation in the midline of the nail. The split, which often resembles a fir tree, occurs at the cuticle and proceeds outward as the nail grows (Fig. 33-49). Trauma has been sus776
Fig. 33-49 Median nail dystrophy.
pected of being the chief cause. Repeated typing with the nail tip on personal digital assistants or Blackberry™-type devices has been reported to cause a median nail dystrophy. Some cases will resolve with avoidance of trauma; however, many will persist for years despite scrupulous care. The deformity may result from a papilloma or glomus tumor in the nail matrix, producing a structure like a tube (solenos) distal to it. Familial cases and an onset with isotretinoin therapy are other associations. Olszewska M, et al: The PDA nail. Am J Clin Dermatol 2009; 10:193. Sweeney SA, et al: Familial median canaliform nail dystrophy. Cutis 2005; 75:161.
Pterygium unguis Pterygium unguis forms as a result of scarring between the proximal nailfold and matrix. The classic causative example is lichen planus. It has been reported to occur as a result of sarcoidosis, porokeratosis of Mibelli, peripheral circulatory disturbances, and Hansen’s disease. Onychomatricoma may uncommonly simulate pterygium, but histologic examination will confirm the nature of this benign tumor. Kim DS, et al: Pterygium unguis formation in porokeratosis of Mibelli. Br J Dermatol 2007; 156:1384. Perrin C, et al: Onychomatricoma with dorsal pterygium. J Am Acad Dermatol 2008; 59:990. Richert BJ, et al: Pterygium of the nail. Cutis 2000; 66:343.
Pterygium inversum unguis Pterygium inversum unguis is characterized by adherence of the distal portion of the nailbed to the ventral surface of the nail plate (Fig. 33-50). The condition may be present at birth or acquired, and may cause pain with manipulation of small objects, typing, and close manicuring of the nail. It is a condition resulting from the extension of the zone of the nailbed that normally contributes to the formation of the nail plate. This eventually leads to a more ventral and distal extension of the hyponychium. The most common forms of pterygium inversum unguis are the acquired secondary forms caused by systemic connective tissue diseases, particularly progressive systemic sclerosis and SLE.
Onychocryptosis (unguis incarnatus, ingrown nail)
Fig. 33-50 Pterygium inversum unguis.
Fig. 33-51 Pincer nails. Paley K, et al: Pterygium inversum unguis secondary to acrylate allergy. J Am Acad Dermatol 2008; 52(2 Suppl):S53. Vadmal M, et al: Pterygium inversum unguis associated with stroke. J Am Acad Dermatol 2005; 53:501.
Hangnail Hangnail is an overextension of the eponychium (cuticle), which becomes split and peels away from the proximal or lateral nailfold. These lesions are painful and annoying, so that persistent cuticle biting frequently develops. Trimming these away with scissors is the best solution. The use of emollient creams to keep the cuticle soft is also recommended. Lee HJ, et al: Minor cutaneous features of atopic dermatitis in South Korea. Int J Dermatol 2000; 39:337.
Pincer nails Pincer nails, trumpet nails, or omega (from the shape of the Greek letter) nails are alternative terms for a common toenail disorder in which the lateral edges of the nail slowly approach one another, compressing the nailbed and underlying dermis (Fig. 33-51). It may less often occur in the fingernails and, surprisingly, is usually asymptomatic. Uncommonly, pain, recurrent or chronic infections, or even underlying osteomyelitis may complicate this condition. It may be an autosomaldominantly inherited condition, acquired after trauma, or associated with Kawasaki’s disease, renal disease, lupus erythematosus or use of β-blockers. Some treatment success has been obtained with the use of commercial plastic braces after flattening of the nail. Urea ointment under occlusion, various surgical approaches, or chemical matricectomy with phenol and surgical nailbed repair have also been reported to be effective.
Ingrown toenail is one of the most frequent nail complaints. It occurs chiefly on the great toes, where there is an excessive lateral nail growth into the nailfold, leading to this painful, inflammatory condition. The lateral margin of the nail acts as a foreign body and may cause exuberant granulation tissue. Unguis incarnatus may be caused by wearing improperly fitting shoes and by improper trimming of the nail at the lateral edges so that the anterior portion cuts into the flesh as it grows distally. Drugs such as isotretinoin, lamivudine, and indinavir may induce periungual granulation tissue mimicking onychocryptosis. In mild cases, soaking the foot in warm soapy water and insertion of a cotton pad, dental floss, or a flexible plastic tube beneath the distal corner of the offending nail may make surgery unnecessary. When surgical intervention is necessary, simple removal of the lateral portion of the nail plate can produce significant relief. Another simple operation involves removal of the overhanging lateral nailfold so that the nail does not cut into it. When healed, the nail edge resembles that of the thumb, and an excellent functional result occurs. The nail is not altered, since it is not touched. Partial or complete nail avulsion with ablation of the nail matrix will prevent recurrence. Ablation can be accomplished surgically, with phenol, 10% sodium hydroxide, or with a CO2 laser. When phenol is used, the proximal nailfold should be incised and reflected to avoid burning the nailfold. As an alternative, it can be left in place and injected with a cortico steroid to reduce the subsequent inflammation. Liquid nitrogen spray to the area of tissue and nail involved for a freeze time of 20–30 s has been successful in some patients, but may be painful and is reserved for patients in whom other surgical approaches are not appropriate.
Diseases of the nails
Bostanci S, et al: Pincer nail deformity. Int J Dermatol 2004; 43:316. Kim KD, et al: Nail plate separation and splint fixation: a new non-invasive treatment of pincer nails. J Am Acad Dermatol 2003; 48:791. Mutaf M, et al: A new surgical technique for the correction of pincer nail deformity. Ann Plast Surg 2007; 58:496. Pang HN, et al: Pincer nails complicated by distal phalangeal osteomyelitis. J Plast Reconstr Aesthet Surg 2009; 62:254.
Retronychia Retronychia is an unusual event associated with ingrowing of the nail plate into the proximal nail fold. It then induces a chronic paronychia. The cause in the few cases reported has been trauma, usually of the great toe. An incomplete shedding of the nail plate results in the new growing nail pushing the old partially detached nail plate up and backwards into the proximal nail fold. Avulsion is curative. Akasakal AB, et al: Decompression for the management of onychocryptosis. J Dermatolog Treat 2004; 15:108. Andreassi A, et al: Segmental phenolization for the treatment of ingrowing toenails. J Dermatolog Treat 2004; 15:179. Baumgartner M, et al: Retronychia. Dermatol Surg 2010; (epub). Dahdah MJ, et al: Retronychia. J Am Acad Dermatol 2008: 58:1051. Heidelbaugh JJ, et al: Management of the ingrown toenail. Am Fam Physician 2009; 79:303. Kim YJ, et al: Nail-splinting technique for ingrown nails. Dermatol Surg 2003; 29:745. Ozdemir E, et al: Chemical matricectomy with 10% sodium hydroxide for the treatment of ingrowing toenails. Dermatol Surg 2004; 30:26. Persichetti P, et al: Wedge excision of the nail fold in the treatment of ingrown toenail. Ann Plast Surg 2004; 52:617.
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Rounding C, et al: Surgical treatments for ingrowing nails. Cochrane Database Syst Rev 2005; (2):CD001541. Woo S-H, et al: Surgical pearl: nail edge separation with dental floss for ingrown toenails. J Am Acad Dermatol 2004; 50:939.
Nail discolorations Andre J, et al: Pigmented nail disorders. Dermatol Clin 2006; 24:329.
Leukonychia or white nails Four forms of white nail are recognized: leukonychia punctata, leukonychia striata, leukonychia partialis, and leukonychia totalis. The punctate (Fig. 33-52) variety is common in completely normal persons with otherwise normal nails. Leukonychia striata, transverse white parallel line, may be hereditary, of traumatic origin, or associated with systemic diseases such as HIV or Kawasaki’s, or with drugs such as those used in chemotherapy. Partial leukonychia may occur with tuberculosis, nephritis, complex regional pain syndrome, Hodgkin disease, chilblains, metastatic carcinoma, or Hansen’s disease, or be idiopathic. Leukonychia totalis may be hereditary and is of a simple autosomal-dominant type. It may also be associated with typhoid fever, Hansen’s disease, cirrhosis, ulcerative colitis, nail biting, use of emetine, complex regional pain syndrome, cytostatic agents, and trichinosis. Leukonychia may result from abnormal keratinization, with persistence of keratohyalin granules in the nail plate. A syndrome comprising leukonychia totalis, multiple sebaceous cysts, and renal calculi in several generations has been reported. Other reports have linked total leukonychia with deafness or with koilonychia; however, it is most often inherited as an isolated finding. Antonarakis ES: Acquired leukonychia totalis. N Engl J Med 2006; 355:e2. Beard R, et al: Leukonychia striata in Kawasaki disease. J Pediatr 2008; 152:889. De D, et al: Hereditary leukonychia totalis. Indian J Dermatol Venereol Leprol 2007; 73:355. De Carvalho VO, et al: Transverse leukonychia and AIDS. Arch Dis Child 2006; 91:326. Dunman I, et al: Unusual cases of acquired leukonychia totalis and partialis secondary to reflex sympathetic dystrophy. J Eur Acad Dermatol Venereol 2007; 21:1445.
Fig. 33-52 Leukonychia punctata.
778
Longitudinal erythronychia Longitudinal red bands in the nail plate that commence in the matrix and extend to the point of separation of the nail plate and nailbed may occur on multiple nails with inflammatory conditions such as lichen planus or Darier’s disease, or as an isolated finding. When only a localized single or bifid streak is present, this may signal a benign or malignant tumor of the matrix. The fingernails of middle-aged persons are most commonly affected, with the thumbnail being most frequently involved. There may be a distal keratosis seen, as with Darier, human papilloma virus (HPV) infection, or a squamous cell carcinoma. Excision of this distal keratosis, however, usually does not result in cure or diagnostic findings; biopsy of the affected matrix is necessary. Since this may lead to a scar with a permanent split of the nail plate, observation may be indicated. As in longitudinal melanonychia, if the band broadens over time, then an excisional biopsy is indicated, as this may be secondary to an amelanotic melanoma. Baran R, et al: Idiopathic polydactylous longitudinal erythronychia. Br J Dermatol 2006; 155:219. de Berker DAR, et al: Localized longitudinal erythronychia. Arch Dermatol 2004; 140:1253. Jellinek NJ: Longitudinal erythronychia. J Am Acad Dermatol 2010; (epub).
Melanonychia Black or brown pigmentation of the normal nail plate is termed melanonychia. It may be present as a normal finding on many digits in black patients, as a result of trauma, systemic disease, or medication, or as a postinflammatory event from such localized events as lichen planus or fixed drug reaction. Pigmentation of the nails may occur with acanthosis nigricans, Addison’s disease, Peutz–Jeghers syndrome, and vitamin B12 deficiency, after adrenalectomy for Cushing syndrome, as a part of Laugier–Hunziker syndrome (pigmentation of the nails associated with buccal and lip hyperpigmentation), with PUVA or ionizing radiation treatment, and as a drug-induced melanocyte activation with such medications as chemotherapy, antimalarials, minocycline, antivirals (zidovudine [Fig. 33-53] or lamivudine), or metals (gold, arsenic, thallium, or mercury). Drugs may induce both transverse and longitudinal bands, with multidrug chemotherapy causing the majority of the former. Friction may cause longitudinal pigmented bands in the toenails, and subungual hemorrhage or black nail caused
Fig. 33-53 Zidovudine-induced hyperpigmentation of the nail.
Fig. 33-54 Longitudinal melanonychia.
by Proteus mirabilis or Trichophyton rubrum may enter into the differential diagnosis of a dark nail. Longitudinal black or brown banding of the nails has been reported to occur in 77–96% of black persons and 11% of Asians. It is a rare finding in white children; however, it is not uncommon in white adults. In a series by Duhard, the prevalence of melanonychia was 12.6 in 100 in a white hospitalized population, and 1.4 in 100 in 4400 white clinic-based patients. The risk increased with age, the peak occurring between the ages of 56 and 65. When only one nail is affected by melanonychia striata (a single longitudinal band of brown or black color [Fig. 33-54]), a tumor of the nail matrix is the most important consideration. The location in the matrix can be inferred from the location of the pigment in the nail plate when viewed end-on. Dorsal nail-plate pigmentation results from a proximal matrix lesion. Ventral nail-plate pigmentation is the result of a lesion in the distal matrix. Tosti et al studied 100 white adult patients with a single band of longitudinal melanonychia of unknown cause. Biopsies revealed melanocytic hyperplasia in 65, nevi in 22, melanocytic activation in 8, and melanoma in 5. Whereas they were unable to ascertain any clear clinical criteria that would exclude melanoma, they recommended a biopsy of any adult with the appearance of a longitudinal band of pigment in only one nail without a clear relation to a definite cause. Other reasons to biopsy include a band that has a triangular shape (one that is wider at the proximal part compared with the distal part), a blurred lateral border of the band, a lack of homogeneity of the pigmentations (bands or lines of different color), or pigmentation of the periungual skin (Hutchinson’s sign). The latter is not pathognomonic, however, as Bowen’s disease may produce this appearance, and pigmentation of the nail matrix and proximal nailbed may reflect through the nailfold (pseudoHutchinson’s sign). Finally, dermoscopic features that suggest melanoma are a brown coloration of the background and the presence of irregular coloration, spacing, or thickness of longitudinal lines or disruption of their parallelism. Retracting the proximal nailfold to expose the origin of the streak at the
Nail discolorations
matrix allows selection of the best biopsy site. The recommended biopsy is one that includes the whole lesion; this may be accomplished by the tangential matrix excision, which may leave minimal scarring in some cases, or more certainly this is accomplished by longitudinal excision. Recommendations for prepubertal children, however, are different. Longitudinal melanonychia that appears in children is usually benign in nature, and it is recommended that since an ungual melanocytic band can appear at an age when other nevi appear, the majority can be followed. If the lesion is alarming in its appearance, especially if it is widening or darkening, sampling the whole lesion via tangential matrix or longitudinal excision is, however, necessary. Abimelec P: Tips and tricks in nail surgery. Semin Cutan Med Surg 2009; 28:55. Andre J, et al: Pigmented nail disorders. Dermatol Clin 2006; 24:329. Goettmann-Bonvallot S, et al: Longitudinal melanonychia in children. J Am Acad Dermatol 1999; 41:17. Izumi M, et al: Subungual melanoma. J Dermatol 2008; 35:695. Lambiase MC, et al: Bowen disease of the nail bed presenting as longitudinal melanonychia: detection of human papillomavirus type 56 DNA. Cutis 2003; 72:305. Ledbetter LS, et al: Melanonychia associated with PUVA therapy. J Am Acad Dermatol 2003; 48:S31. Piraccini BM, et al: Drug-induced nail diseases. Dermatol Clin 2006; 24:387. Richert B, et al: New tools in nail disorders. Semin Cutan Med Surg 2009; 28:44. Smith DF, et al: Longitudinal melanonychia. Arch Dermatol 2003; 139:1209. Tosti A, et al: Dealing with melanonychia. Semin Cutan Med Surg 2009; 28:49.
Green nails When onycholysis is present, a green discoloration may occur in the onycholytic area as a result of an infection with Pseudomonas aeruginosa (see Chapter 14). The color change may also occur as transverse green stripes. The stripes are ascribed to intermittent episodes of infection. Green nails may also result from copper in tap water. Hengge UR, et al: Green nails. N Engl J Med 2009; 360:1125.
Staining of the nail plate Nicotine, dyes (including hair dyes and nail polish), potassium permanganate, mercury compounds, hydroquinone, elemental iron, mepacrine, photographic developer, anthralin, chrysarobin, glutaraldehyde, or resorcin may cause nail-plate staining. This is only a partial list; a complete listing is given in the article by Jeanmougin et al. A helpful diagnostic maneuver to distinguish nail-plate staining from exogenous sources and nail-plate pigmentation from melanin or endogenous chemicals is to scrape the surface of the nail plate several times firmly with a glass slide or scalpel blade. Exogenous stains frequently scrape off completely if the agent has not penetrated the entire nail plate. If the stain follows the curvature of the lunulae, it is probably endogenous; if it follows the curvature of the proximal and lateral nailfolds, it is exogenous. Coulson IH: “Fade out” photochromonychia. Clin Exp Dermatol 1993; 18:87. Jeanmougin M, et al: Nail dyschromia. Int J Dermatol 1983; 22:279.
Red lunulae Dusky erythema confined to the lunulae has been reported in association with alopecia areata. Twenty percent of patients with SLE have been reported to have this abnormality. It may 779
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also be seen in patients on oral prednisone for severe rheumatoid arthritis or dermatomyositis, in cardiac failure, cirrhosis, lymphogranuloma venereum, psoriasis, vitiligo, chronic urticaria, lichen sclerosus et atrophicus, CO2 poisoning, chronic obstructive pulmonary disease, twenty-nail dystrophy, and reticulosarcoma. The cause may be vascular congestion. Cohen PR: Red lunulae: case report and literature review. J Am Acad Dermatol 1992; 26:292. Tunc SE, et al: Nail changes in connective tissue diseases. J Eur Acad Dermatol Venereol 2007; 21:497.
Spotted lunulae This distinctive change occurs with alopecia areata. Cohen PR: The lunula. J Am Acad Dermatol 1996; 34:943.
Purpura of the nail beds Purpura beneath the nails usually results from trauma. Causes of toe involvement include physical pressure on the toes, such as that seen in surfboarding caused by a windsurfer trying to maintain his/her balance, or exogenous pressure exerted from poorly fitting shoes. It may simulate a melanoma if the patient does not communicate the acuteness at onset. Adams BB: Dermatologic disorders of athletes. Sports Med 2002; 32:309.
Blue nails A blue discoloration of the lunulae is seen in argyria and cases of hepatolenticular degeneration (Wilson’s disease). The blue color in the latter is probably related to the changes in copper metabolism by the patient. It has also been reported in hemoglobin M disease and hereditary acrolabial telangiectases. Lunular blue color, as well as blue discoloration of the whole nailbed, occurs with some therapeutic agents, especially 5-FU, minocycline, imipramine, mepacrine and other antimalarials, hydroxyurea, phenolphthalein, and azidothymidine. Blue discoloration may also result from subungual hematoma, blue nevi, and melanotic whitlow. Blue nails are a normal variant finding in Black people. Dalle S, et al: A blue–gray subungual discoloration. Arch Dermatol 2007; 143:937. Glaser DA, et al: Blue nails and acquired immunodeficiency syndrome: not always associated with azidothymidine use. Cutis 1996; 57:243. Kalouche H, et al: Blue lunulae. Australas J Dermatol 2007; 48:182. Kim Y, et al: A case of generalized argyria after ingestion of colloidal silver solution. Am J Ind Med 2009; 52:246. Piraccini BM, et al: Drug-induced nail abnormalities. Am J Clin Dermatol 2003; 4:31.
Yellow nail syndrome The yellow nail syndrome is characterized by marked thickening and yellow to yellowish-green discoloration of the nails often associated with systemic disease, most commonly lymphedema and compromised respiration. The nails are typically overcurved both transversely and longitudinally, grow very slowly (less than 0.2 mm/week), are often subject to onycholysis, and lose both lunulae and cuticles (Fig. 33-55). Lymphedema, pleural effusions, chronic pulmonary infections, and chronic sinusitis most commonly precede the nail changes. Other less frequently associated conditions include autoimmune disorders, immunodeficiency states, the use of gold or d-penicillamine, and malignancies. In the latter cases, treatment of the underlying lymphoma or solid tissue tumor has resulted in improvement of the nail findings. Individual 780
Fig. 33-55 Yellow nail syndrome.
clinical responses have been seen with oral zinc or 800 IU/day of d-α-tocopherol alone or in combination with itraconazole. While approximately 30–50% of patients experience spontaneous improvement in the condition of their nails, fluconazole taken in combination with vitamin E cured or improved all 13 patients treated by Baran et al. Baran R, et al: Combination of fluconazole and alpha-tocopherol in the treatment of yellow nail syndrome. J Drugs Dermatol 2009; 8:276. Elmariah SB, et al: Yellow nail syndrome. Dermatol Online J 2008; 14:17. Hoque SR, et al: Yellow nail syndrome. Br J Dermatol 2007; 156:1230. Maldonado F, et al: Yellow nail syndrome. Chest 2008; 134:375. Tosti A, et al: Systemic itraconazole in the yellow nail syndrome. Br J Dermatol 2002; 146:1067.
Neoplasms of the nailbed Various benign and malignant neoplasms may occur in or overlying the nail matrix and in the nailbed. Signs heralding such neoplasms are paronychia, ingrown nail, onycholysis, pyogenic granuloma, nail-plate dystrophy, longitudinal erythronychia, bleeding, and discolorations. Symptoms of pain, itching, and throbbing may also occur with various neoplasms. Benign tumors of the nails include verruca, pyogenic granuloma, fibromas, nevus cell nevi, myxoid cysts, angiofibromas (Koenen tumors), onychopapillomas, and epidermoid cysts. Pyogenic granuloma-like lesions may occur during treatment with isotretinoin, lamivudine, indinavir, or the epidermal growth factor receptor inhibitor family of drugs. Glomangioma is readily recognized by exquisite tenderness in the nailbed. Enchondroma of the distal phalanx often presents as a paronychia. Subungual exostoses may also present as an inflammatory process, but more commonly resemble a verruca at the start. Most of these are on the great toe, and radiographic evaluation will aid in the diagnosis of these last two entities. Onychopapillomas are benign tumors of the nail bed which usually present as longitudinal erythronychia. Tender swelling of the distal finger with nail distortion and radiographic evidence of solitary lytic changes can be caused by intraosseous epidermoid cysts. Onychomatricoma is a benign tumor of the nail matrix. It presents as a yellow thickened plate growing out from under the proximal nailfold and then extending distally in a longitudinal band (Fig. 33-56). There is an increased transverse curvature of the nail and splinter hemorrhages often are seen in the proximal nail. Uncommonly, it can appear as a cutaneous horn emanating from the proximal nailfold, with dorsal
Neoplasms of the nailbed Fig. 33-58 Subungual melanoma. Fig. 33-56 Onychomatricoma.
Evaluation of these masses may be carried out by plain x-ray, looking for bone lysis or other changes. MRI by both T1-weighted spin-echo images and turbo spin-echo T2-weighted images may offer excellent diagnostic information about these tumors as well.
Fig. 33-57 Bowen’s disease.
pterygium formation. Biopsy at the matrix origin will permit diagnosis. Bowen’s disease and squamous cell carcinoma of the nailbed are uncommon. Radiographs may reveal lytic changes in the distal phalanx. Metastases are rare. Mohs surgery is the treatment of choice. When they occur on more than one digit, they are proven to be secondary to HPV infection. Bowen’s disease may be pigmental (Fig. 33-57). When keratoacanthoma occurs, there is often lysis of underlying bone, which fills in after excision of the tumor. Basal cell carcinoma may occur, but is uncommon in this location. Subungual melanoma (Fig. 33-58) is frequently diagnosed late in the course of growth, since it simulates onychomycosis or subungual hematoma, with which it is confused. Amelanotic melanoma may occur and may be mistaken for granuloma pyogenicum. Although melanoma is rare among Japanese, periungual and subungual melanoma is more frequently found in Japanese than in other ethnic populations. Discussion of melanoma in this location may be found in Chapter 30 and in the melanonychia section of this chapter. Onycholemmal carcinoma is a slowly growing malignant tumor of the nail bed epithelium. It is composed of small cysts filled with eosinophilic amorphous keratin. The cyst wall is lined with atypical keratinocytes. No granular layer is seen. Also solid nests and strands of atypical keratinocytes fill the dermis and may invade the bone. Mohs excision or even disarticulation of the digit may be necessary.
Afshar A, et al: A rare metastasis in the hand. J Hand Surg Am 2007; 32:393. Alessi E, et al: Onycholemmal carcinoma. Am J Dermatopathol 2004; 26:397. Choi JH, et al: Subungual keratoacanthoma. Skeletal Radiol 2007; 36:769. Criscione V, et al: Onychopapilloma presenting as longitudinal leukonychia. J Am Acad Dermatol 2010; 63:541. de Berker DAR, et al: Localized longitudinal erythronychia. Arch Dermatol 2004; 140:1253. Figus A, et al: Squamous cell carcinoma of the lateral nail fold. J Hand Surg Br 2006; 31:216. Guarneri C, et al: Solitary asymptomatic nodule of the great toe. Int J Dermatol 2005; 44:245. Hu JC, et al: Cutaneous side effects of epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2007; 56:317. Inaoki M, et al: Onycholemmal carcinoma. J Cutan Pathol 2006; 33:577. Izumi M, et al: Subungual melanoma. J Dermatol 2008; 35:695. Koc O, et al: Subungual glomus tumour. Australas Radiol 2007; 51 Spec No:B107. Koch A, et al: Polydactylous Bowen’s disease. J Eur Acad Dermatol Venereol 2003; 17:213. Orsini RC, et al: Basal cell carcinoma of the nail unit. Foot Ankle Int 2001; 222:675. Perrin C, et al: Onychomatricoma with dorsal pterygium. J Am Acad Dermatol 2008; 59:990. Samlaska CP, et al: Intraosseous epidermoid cysts. J Am Acad Dermatol 1992; 27:454. Song M, et al: Surgical treatment of subungual glomus tumor. Dermatol Surg 2009; 35:786. Suga H, et al: Subungual exostosis. Ann Plast Surg 2005; 55:272. Tosti A, et al: Dealing with melanonychia. Semin Cutan Med Surg 2009; 28:49. Turowski CB, et al: Human papillomavirus-associated squamous cell carcinoma of the nail bed in African-American patients. Int J Dermatol 2009; 48:117.
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Diseases of the Skin Appendages
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782
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 33-1 Alopecia areata. Fig. 33-2 Alopecia areata. Fig. 33-3 Migratory poliosis. Fig. 33-4 Loose anagen syndrome. Fig. 33-5 Male-pattern hair loss. Fig. 33-6 Trichotillosis. Fig. 33-7 Trichobezoar being extracted from the stomach of a patient with compulsive trichophagia. (Courtesy of Wilford Hall Air Force Medical Center Teaching File) Fig. 33-8 Lichen planopilaris.
Fig. 33-9 Dissecting cellulitis. Fig. 33-10 Menkes kinky hair syndrome. Fig. 33-11 Trichostasis spinulosa. (Courtesy of Richard Vinson, MD) Fig. 33-12 Sacral hair tuft. (Courtesy of Brooke Army Medical Center Teaching File) Fig. 33-13 Hirsutism. Fig. 33-14 Trichomycosis axillaris. (Courtesy of Anthony Slagel, MD) Fig. 33-15 Tinea amiantacea. Fig. 33-16 Acquired perforating disease in uremia. (Courtesy of Curt Samlaska, MD)
Fig. 33-17 Disseminated infundibulofolliculitis. Fig. 33-18 Axillary hyperhidrosis. Fig. 33-19 Fox–Fordyce disease. Fig. 33-20 Congenital onychodystrophy of the index finger. (Courtesy of James Fitzpatrick, MD) Fig. 33-21 Onychophagia. Fig. 33-22 Alopecia areata. Fig. 33-23 Trichostasis spinulosa. (Courtesy of Richard Vinson, MD)
Bonus images for this chapter can be found online at http://www.expertconsult.com
Disorders of the Mucous Membranes
Lesions on the mucous membranes may be more difficult to diagnose than lesions on the skin, and not merely because they are less easily and less often seen. There is less contrast of color and greater likelihood of alterations in the original appearance because of secondary factors, such as maceration from moisture, abrasion from food and teeth, and infection. Vesicles and bullae rapidly rupture to form grayish erosions, and the epithelium covering papules becomes a soggy lactescent membrane, easily rubbed off to form an erosion. Grouping and distribution are less distinctive in the mouth than on the skin, and not infrequently it is necessary to establish the diagnosis by observing the character of any associated cutaneous lesions or by noting subsequent developments. Abdollahi M, et al: Current opinion on drug-induced oral reactions. J Contemp Dent Prac 2008; 9:1. Greenberg M, et al (eds): Burket’s Oral Medicine. Hamilton: BC Decker, 2008. Huber MA: White oral lesions, actinic cheilitis and leukoplakia. Clin Dermatol 2010; 28:262. Prabhu SR, et al (eds): Textbook of Oral Diagnosis. Oxford: Oxford University Press, 2009. Rogers RS III (ed.): Diseases of the mucous membranes. Dermatologic Clinics 2003; 21:1.
Cheilitis Cheilitis exfoliativa The term cheilitis exfoliativa has been used to designate a primarily desquamative, mildly inflammatory condition of the lips, of unknown cause, and also a clinically similar reaction secondary to other disease states. The former is a persistently recurring lesion that produces scaling and sometimes crusting; it most often affects the upper lip. The recurrent exfoliation leaves a temporarily erythematous and tender surface. In the latter form, the lips are chronically inflamed and covered with crusts that from time to time tend to desquamate, leaving a glazed surface on which new crusts form. Fissures may be present, and there may be burning, tenderness, and some pain. The lower lip is more often involved, with the inflammation limited to the vermilion part. The cheilitis may be secondary to seborrheic dermatitis, atopic dermatitis, psoriasis, retinoid therapy, pyorrhea, long-term actinic exposure, or the habit of lip-licking (Fig. 34-1). Uncommonly, the initial or only manifestation of atopic dermatitis may be a chronic cheilitis. Irritating or allergenic substances in lipsticks, dentifrices, and mouthwashes may be causative factors. Dyes in lipsticks may photosensitize. Candidiasis may be present. Cheilitis may be part of the Plummer–Vinson syndrome or Sjögren syndrome. Cheilitis is not uncommon in patients with acquired immune deficiency syndrome (AIDS), and it is a known common complication of protease inhibitor therapy. These and other uncommon causes of cheilitis are discussed in more detail within the specific entities.
34
The only uniformly effective treatment is the elimination of causes when they can be found. Topical tacrolimus ointment, pimecrolimus cream, or low-strength corticosteroid ointments and creams are usually helpful. If the underlying etiology is determined, specific therapy may be instituted. When there are fissures, petrolatum or zinc oxide ointment may be useful. Connolley M, et al: Exfoliative cheilitis successfully treated with topical tacrolimus. Br J Dermatol 2004; 151:241. Garcia-Silva J, et al: Protease inhibitor-related paronychia, ingrown toenails, desquamative cheilitis and cutaneous xerosis. AIDS 2000; 14:1289. Leland L, et al: Exfoliative cheilitis managed with antidepressant medication. Dent Update 2004; 31:524. Mani SA, et al: Exfoliative cheilitis. J Can Dent Assoc 2007; 73:629.
Allergic contact cheilitis The vermilion border of the lips is much more likely to develop allergic contact sensitivity reactions than is the oral mucosa. Allergic cheilitis is characterized by dryness, fissuring, edema, crusting, and angular cheilitis. Over 90% of patients are women and over half of the reactions are due to lipsticks. While patch testing with standard allergens will reveal a relevant positive in approximately 25–30% of patients, about 1 in 5 will only react to their own product. It may result from use of topical medications, dentifrices and other dental preparations, anti chap agents, lipsticks, and sunscreen-containing lip balms; from contact with cosmetics, nail polish, rubber, and metals; or from eating foods such as mangoes. Fragrance and nickel are the most commonly identified individual sensitizers. Treatment includes discontinuation of exposure to the offending agent and administration of topical tacrolimus, pimecrolimus, or corticosteroid preparations. Chan EF, et al: Contact dermatitis to foods and spices. Am J Contact Dermat 1998; 9:71. Francalanci S, et al: Multicentre study of allergic contact cheilitis from toothpastes. Contact Dermatitis 2000; 43:216. Freeman S, et al: Cheilitis. Am J Contact Dermat 1999; 10:198. Jacob SE, et al: Allergic contact dermatitis to propolis and carnauba wax from lip balm and chewable vitamins in a child. Contact Dermatitis 2008; 58:242. Schena D, et al: Contact allergy in chronic eczematous lip dermatitis. Eur J Dermatol 2008; 18:688. Strauss RM, et al: Allergic contact cheilitis in the UK. Am J Contact Dermat 2003; 14:75. Zug KA, et al: Patch-testing North American lip dermatitis patients. Dermatitis 2008; 19:202.
Actinic cheilitis Actinic cheilitis is an inflammatory reaction of the lips to chronic excessive sunlight exposure over many years. The lower lip, which is usually the only one involved, becomes
Disorders of the Mucous Membranes
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Fig. 34-1 Cheilitis secondary to lip-licking.
Fig. 34-3 Cheilitis glandularis. (Courtesy of Shyam Verma, MD)
Cavalcante AS, et al: Actinic cheilitis. J Oral Maxillofac Surg 2008; 66:498. Dufresne RG Jr, et al: Dermabrasion for actinic cheilitis. Dermatol Surg 2008; 34:848. Kodama M, et al: Photodynamic therapy for the treatment of actinic cheilitis. Photodermatol Photoimmunol Photomed 2007, 23:209. Markopoulos A, et al: Actinic cheilitis. Oral Dis 2004; 10:212. Orenstein A, et al: A new modality in the treatment of actinic cheilitis using the Er:YAG laser. J Cosmet Laser Ther 2007; 9:23. Rossi R, et al: Photodynamic therapy. Dermatol Ther 2008; 21:412. Smith KJ, et al: Topical 5% imiquimod for the therapy of actinic cheilitis. J Am Acad Dermatol 2002; 47:497.
Cheilitis glandularis Fig. 34-2 Actinic cheilitis.
scaly, fissured, atrophic, and at times eroded and swollen; leukoplakia and even squamous cell carcinoma may develop (Fig. 34-2). Painful erosions may occur; actual ulceration is very rare unless carcinoma has developed. Hereditary polymorphous light eruption can resemble chronic actinic cheilitis, but it has no malignant potential. Avoiding sun exposure and the use of sunscreen containing lip pomades suffice to minimize further damage. A biopsy should be performed on any suspicious, thickened areas that persist; preferably, a shave technique should be used to avoid scarring. Cryosurgical treatment may be effective, particularly for localized lesions. In cases with diffuse involvement, application of topical 5-fluorouracil (5-FU), imiquimod, or photo dynamic therapy may be curative. Treatment with a CO2 or Er:YAG laser, dermabrasion, or electrodesiccation may be required for severe disease and provides excellent results. Long-term follow-up is necessary; one study of 43 patients showed that 15% of CO2-treated lesions developed squamous cell carcinoma over an average follow-up time of 29 months. Should treatment fail, vermilionectomy of the lower lip may be necessary. Excision of the exposed vermilion mucous membrane with advancement of the labial mucosa to the skin edge of the outer lip is effective, but this is performed less frequently since the advent of laser therapy. Refer to Chapter 29 for more information on actinic cheilitis. Castineiras I, et al: Actinic cheilitis. J Dermatolog Treat 2010; 21:49. Castineiras I, et al: Dermabrasion for actinic cheilitis. Dermatol Surg 2008; 34:848.
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Cheilitis glandularis is characterized by swelling and eversion of the lower lip, patulous openings of the ducts of the mucous glands, cysts, and general enlargement of the lips (Fig. 34-3). Mucus exudes freely to form a gluey film that dries over the lips and causes them to stick together during the night. When the lip is palpated between the thumb and index finger, the enlarged mucous glands feel like pebbles beneath the surface. The lower lip is the site of predilection. In general, two types are recognized: cheilitis glandularis simplex and cheilitis glandularis apostematosa. (Apostematosa means “with abscess formation.”) The latter type probably stems from the simplex form by the development of infection. Cheilitis glandularis is a chronic inflammatory reaction that is due to an exuberant response to chronic irritation, or to atopic, factitious, or actinic damage. On biopsy, there is a moderate histiocytic, lymphocytic, and plasmacytic infiltration in and around the glands. Some believe it to be a disorder of ductal ectasia. Cheilitis glandularis has been reported to eventuate in squamous cell carcinoma, but these cases may be attributed to chronic sun exposure, which frequently precedes cheilitis glandularis. Treatment depends on the nature of the antecedent irritation; in most cases, treatment as described for actinic cheilitis is appropriate. Surgical debulking may be necessary. Intralesional triamcinolone may be beneficial in some cases, as may the combination of minocycline and tacrolimus ointment. Bovenschen JH: Novel treatment for cheilitis glandularis. Acta Derm Venereol 2009; 89:99. Nico MM, et al: Cheilitis glandularis. J Am Acad Dermatol 2010; 62:233. Stoopler ET, et al: Cheilitis glandularis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 95:312. Verma S: Cheilitis glandularis. Br J Dermatol 2003; 148:362.
Angular cheilitis is synonymous with perlèche. Fissures radiate downward and outward from the labial commissures. It is an intertriginous dermatitis caused by excessive wetness or dryness. It is often complicated by secondary infection with Candida albicans or Staphylococcus aureus. The disease usually occurs in elderly people who wear dentures, but it may develop simply from an overhanging of the upper lip and cheek, and recession and atrophy of the alveolar ridges in old age. Measuring the facial dimensions with a ruler and tongue blade will help with objective assessment of the importance of decreased vertical facial dimension in the development of perlèche. If the distance from the base of the nose to the lower edge of the mandible is greater than or equal to 6 mm less than the distance from the center of the pupil to the parting line of the lips, the vertical dimension is decreased. In these circumstances, drooling is usually a factor. In children, angular cheilitis occurs commonly in thumb suckers, gum chewers, and lollipop eaters. Other inciting factors include riboflavin deficiency, anorexia nervosa, Down syndrome, intraoral candidiasis, especially in patients with diabetes, AIDS, chronic mucocutaneous candidiasis, Sjögren syndrome, orthodontic treatment, drug-induced xerostomia, and atopic dermatitis. Opening the “bite” by improving denture fit, capping teeth, replacing lost teeth, or increasing denture height, combined with topical use of nystatin and iodochlorhydroxyquin in hydrocortisone ointment, is usually effective when the condition is associated with anatomically predisposing factors. Stubborn cases typically respond to a slightly stronger cor ticosteroid, such as desonide, in combination with a topical anticandidal agent. Injection of collagen or insertion of Softform implants to obliterate the angular creases may be beneficial. Therapy for underlying diseases should be maximized. If S. aureus is present, mupirocin ointment may be needed. Excision of the region, followed by a rotating flap graft, is another therapeutic option, but surgery should be reserved for resistant cases. Adedigba MA, et al: Patterns of oral manifestations of HIV/AIDS among 225 Nigerian patients. Oral Dis 2008; 14:341. Cross DL, et al: Angular cheilitis occurring during orthodontic treatment. J Orthod 2008; 35:229. Lu DP: Prosthodontic management of angular cheilitis and persistent drooling. Compend Contin Educ Dent 2007; 28:572. Sharon V, et al: Oral candidiasis and angular cheilitis. Dermatol Ther 2010; 23:230. Soy M, et al: Cutaneous findings in patients with primary Sjögren’s syndrome. Clin Rheumatol 2007; 26:1350. Strumia R: Dermatologic signs in patients with eating disorders. Am J Clin Dermatol 2005; 6:165.
Fig. 34-4 Fixed drug eruption.
of the same disease. Plasmoacanthoma is a verrucous tumor with a plasma cell infiltrate involving the oral mucosa, particularly along the angles. Other locations may occur, such as the perianal, periumbilical, or inguinal areas and toe webs. C. albicans has been found within the tissue, suggesting that it may be implicated as a cause of this disease. Excision, destruction, anticandidal preparations, and intralesional steroids are all options for treatment. Farrier JN, et al: Plasma cell cheilitis. Br J Oral Maxillofac Surg 2008; 46:679. Rocha N, et al: Plasma cell cheilitis. J Eur Acad Dermatol Venereol 2004; 18:96. Senol M, et al: Intertriginous plasmacytosis with plasmoacanthoma. Int J Dermatol 2008; 47:265. Tseng JT, et al: Plasma cell cheilitis. Clin Exp Dermatol 2009; 34:174.
Drug-induced ulcer of the lip Painful or tender, well-defined ulcerations without induration on the lower lip may heal after withdrawal of oral medications. The causative drugs may be phenylbutazone, chlorpromazine, phenobarbital, methyldopa, or thiazide diuretics. Solar exposure appears to be a predisposing causative influence; in some cases this reaction may represent a fixed drug photoeruption. On rare occasions, fixed drug eruptions may also involve the lip; usually the culprit is naproxen, one of the oxicams, or trimethoprim–sulfamethoxazole (Fig. 34-4). Ozkaya-Bayazit E: Specific site involvement with fixed drug eruptions. J Am Acad Dermatol 2003; 49:1003. Pemberton MN, et al: Fixed drug eruption to oxybutynin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 106:e19.
Plasma cell cheilitis
Other forms of cheilitis
This is also referred to as plasma cell orificial mucositis or, when the gingival is the site of involvement, plasma cell gingivitis. It is characterized by a sharply outlined, infiltrated, dark red plaque with a lacquer-like glazing of the surface of the involved area. This lesion has the same microscopic features as Zoon balanitis plasmacellularis. There is plasma cell infiltration in a bandlike pattern. Plasma cell cheilitis is not a response that is specific for any stimulus but rather represents a reaction pattern to any one of a variety of stimuli. Successful therapies include application of topical tacrolimus ointment or clobetasol propionate ointment twice a day.
Several diseases discussed elsewhere may affect the lips, including lichen planus, lupus erythematosus, atopic dermatitis, and psoriasis. A high percentage of patients with Down syndrome have cheilitis of one or both lips. Lip-biting may be a factor.
Plasmoacanthoma Plasma cell cheilitis and plasmoacanthoma have been reported in the same patient and are believed to represent a spectrum
Oral and cutaneous Crohn’s disease
Angular cheilitis
Oral and cutaneous Crohn’s disease Crohn’s disease is a chronic granulomatous disease of any part or parts of the bowel, to which the names terminal ileitis, regional enteritis, and granulomatous colitis have also been given. Patients with Crohn’s disease may develop inflammatory hyperplasia of the oral mucosa, with metallic dysgeusia and gingival bleeding. Reported typical changes include diffuse oral swelling, focal mucosal hypertrophy and fissuring (cobble-stoning), persistent ulceration, polypoid 785
Disorders of the Mucous Membranes
34
lesions, indurated fissuring of the lower lip, angular cheilitis, granulomatous cheilitis, or pyostomatitis vegetans. Oral involvement occurs in 10–20% of cases of Crohn’s disease, and 90% have granulomas on biopsy. Males with early-onset disease are most often affected. Concomitant involvement of the anal and esophageal mucosa is common. Many cases of Crohn’s disease with other cutaneous manifestations have been reported, notably pyoderma gangrenosum (more closely associated with ulcerative colitis) and erythema nodosum, polyarteritis nodosa, pellagra, pernicious anemia, an acrodermatitis-like eruption, urticaria, and necrotizing vasculitis. Direct extension to perianal skin may occur. Metastatic Crohn’s disease denotes noncaseating granulomatous skin lesions in patients with Crohn’s disease. In the absence of bowel involvement, the diagnosis cannot be made. Genital swelling or condyloma-like lesions, leg ulceration, pyogenic granuloma-like lesions of the retroauricular skin, or erythematous nodules, plaques, or ulcers in other locations are the morphologic appearances seen. Treatment of the gastrointestinal manifestations with sulf asalazine, metronidazole, systemic corticosteroids, infliximab, or immunosuppressive medications such as cyclosporine, azathioprine, mycophenolate mofetil, and methotrexate can improve the cutaneous findings. Several delivery systems use only the active ingredient of sulfasalazine, mesalamine. These include Asacol, Pentasa, Rowasa, and olsalazine, and they may be useful in treating the skin involvement of Crohn’s disease. A mouthwash containing triamcinolone acetonide, tetracycline, and lidocaine may provide symptomatic and objective improvement. Cutaneous ulcerated granulomas and erythematous plaques caused by Crohn’s disease may respond to high-potency topical corticosteroids or tacrolimus ointment. Curettage and zinc by mouth have resulted in healing in several reported patients. Dietary manipulation is another measure that can be helpful in select individuals. The course is often prolonged over several years. Emanuel PO, et al: Metastatic Crohn’s disease. J Cutan Pathol 2008; 35:457. Ephgrave K: Extra-intestinal manifestations of Crohn’s disease. Surg Clin North Am 2007; 87:673. Farhi D, et al: Significance of erythema nodosum and pyoderma gangrenosum in inflammatory bowel diseases. Medicine (Baltimore) 2008; 87:281. Harty S, et al: A prospective study of the oral manifestations of Crohn’s disease. Clin Gastroenterol Hepatol 2005; 3:866. Komatsuda A, et al: Cutaneous polyarteritis nodosa in a patient with Crohn’s disease. Mod Rheumatol 2008; 18:639. Mignogna MD, et al: Oral Crohn’s disease. Am J Gastroenterol 2008; 103:2954. Ojha J, et al: Gingival involvement in Crohn’s disease. J Am Dent Assoc 2007; 138:1574. Paradisi A, et al: Cutaneous Crohn disease mimicking anal condylomata in a child. J Am Acad Dermatol 2010; 63:165. Yuksel I, et al: Mucocutaneous manifestations of inflammatory bowel disease. Inflamm Bowel Dis 2009; 15:546.
Pyostomatitis vegetans Pyostomatitis vegetans, an inflammatory stomatitis, is most often seen in association with ulcerative colitis but may also occur in other inflammatory bowel diseases, such as Crohn’s disease. Edema and erythema with deep folding of the buccal mucosa characterize it, together with pustules, small vegetating projections, erosions, ulcers, and fibrinopurulent exudates (Fig. 34-5). Eroded pustules fuse into shallow ulcers, resulting in characteristic “snail-track” ulcers. It has also been associated with sclerosing cholangitis. Several cases have been reported without any underlying systemic disorder. 786
Fig. 34-5 Pyostomatitis vegetans. (Courtesy of Charles Casima, MD)
Histologically, there are dense aggregates of neutrophils and eosinophils. At times, crusted erythematous papulopustules that coalesce into asymmetrical annular plaques may occur with or after the oral lesions. These associated skin lesions favor the axilla, groin, and scalp, and are termed pyodermatitis vegetans. Topical corticosteroids or tacrolimus ointment may be effective; systemic steroids or infliximab, however, are usually necessary. Gonzalez-Moles MA, et al: Pyostomatitis vegetans. J Eur Acad Dermatol Venereol 2008; 22:252. Ko HC, et al: Two cases of pyodermatitis-pyostomatitis vegetans. J Dermatol 2009; 36:293. Lourenco SV, et al: Oral manifestations of inflammatory bowel disease. J Eur Acad Dermatol Venereol 2010; 24:204. Wechaniak AE, et al: Treatment of pyostomatitis vegetans with topical tacrolimus. J Am Acad Dermatol 2005; 52:722. Yasuda M, et al: Pyodermatitis-pyostomatitis vegetans associated with ulcerative colitis. Dermatology 2008; 217:146.
Cheilitis granulomatosa Cheilitis granulomatosa is characterized by a sudden onset and progressive course, terminating in chronic enlargement of the lips. Usually, the upper lip becomes swollen first; several months may elapse before the lower lip becomes swollen. Usually only enlargement is present, without ulceration, fissuring, or scaling. The swelling remains permanently. It may be a part of the Melkersson–Rosenthal syndrome when associated with facial paralysis and plicated tongue. The cause is unknown. Histologically, it is characterized by an inflammatory reaction of lymphocytes, histiocytes, and plasma cells, and by tuberculoid granulomas consisting of epithelioid and Langerhans giant cells. In the differential diagnosis, solid edema, angioedema, cheilitis glandularis, sarcoidosis, oral Crohn’s disease, infectious granulomas, contact allergy and Ascher syndrome must be considered. This may be the presenting sign in a patient who will develop Crohn’s disease or sarcoidosis at a later time. Treatment with intralesional injections of corticosteroids is sometimes successful. In the firmly established case, surgical repair of the involved lip through a mucosal approach and, in some cases, concomitant intralesional steroid treatment give best results. Other anecdotally effective medications include tetracyclines, roxithromycin, hydroxychloroquine, clofazimine, and sulfasalazine. Cernik C, et al: Asymptomatic, edematous upper lip in a 39-year-old woman. Arch Dermatol 2009; 145:77. Chiu CS, et al: Cheilitis granulomatosa associated with allergic contact dermatitis to betel quid. Contact Dermatitis 2008; 58:246.
Melkersson–Rosenthal syndrome Melkersson in 1928 and Rosenthal in 1930 described a triad consisting of recurring facial paralysis or paresis, soft nonpitting edema of the lips, and scrotal tongue. Attacks usually start during adolescence, with permanent or transitory paralysis of one or both facial nerves, repeated migraines, and recurring edema of the upper lip, cheeks, and occasionally the lower lip and circumoral tissues. Swelling of the skin and mucous membranes of the face and mouth is the dominant finding and most important diagnostic feature (Fig. 34-6). In order of frequency, the swelling occurs first on the upper lip, then the lower lip, and then other regions. Chronic eyelid swelling may occur. Extrafacial swellings appear on the dorsal aspect of the hands and feet, and in the lumbar region. The pharynx and respiratory tract may be involved, with thickening of the mucous membrane. The relapsing condition produces an overgrowth of connective tissue, edema, and atrophy of the muscle fibers, with permanent deformities of the lips, cheeks, and tongue. The cause is unknown. The association at times with megacolon, otosclerosis, and craniopharyngioma supports the theory of a neurotrophic origin. It may be familial. Histopathologic evaluation shows a tuberculoid type of granuloma with lymphedema and a banal perivascular infiltrate. In the differential diagnosis, a number of diseases characterized by edema of the lips must be considered. Ascher syndrome consists of swelling of the lips with edema of the eyelids (blepharochalasis) and is inherited. Melkersson– Rosenthal syndrome must also be differentiated from the acute swellings produced by angioedema, trauma, and infections of all sorts. Lymphangioma, hemangioma, neurofibroma, and sarcoidosis are some of the diseases to be considered on a clinical basis. Melkersson–Rosenthal syndrome is frequently seen in an incomplete form, and other granulomatous diseases may present as swellings of the lips or oral–facial tissues. It is worthwhile considering these as a group called orofacial granulomatosis so that various underlying disease states or etiologic factors will not be missed when evaluating such patients. Oral Crohn’s disease, patients who will develop typical
Crohn’s or sarcoidosis in the future, cheilitis granulomatosa, sarcoidosis, granulomatous infiltrates associated with tooth infections, and patients with food or contact allergic reactions should all be considered. There is no satisfactory treatment, although intralesional injections of corticosteroids may be beneficial. Decompression of the facial nerve may be indicated in those patients with recurrent attacks of facial palsy. Surgery alone or combined with intralesional steroid injections may be more successful than either alone. Odontogenic infection has been reported to initiate this condition and antibiotic therapy for this may lead to remission. Clofazimine, thalidomide, and prednisone combined with minocycline or tetracycline have been reported to improve individual patients.
Stomatitis nicotina
Lopez-Urbano MJ, et al: Granulomatous cheilitis. J Investig Allergol Clin Immunol 2009; 19:68. Praessler J, et al: Persistent non-tender swelling of the upper lip. Am J Clin Dermatol 2007; 8:251. Ratzinger G, et al: Cheilitis granulomatosa and Melkersson–Rosenthal syndrome. J Eur Acad Dermatol Venereol 2007; 21:1065.
Kakimoto C, et al: Melkersson–Rosenthal syndrome. Otolaryngol Head Neck Surg 2008; 138:246. Kondratiev S, et al: Melkersson-Rosenthal syndrome presenting as chronic eyelid swelling. Ophthalmic Surg Lasers Imaging 2010; 9:1. Kruse-Losler B, et al: Surgical treatment of persistent macrocheilia in patients with Melkersson–Rosenthal syndrome and cheilitis granulomatosa. Arch Dermatol 2005; 141:1085. Mignogna MD, et al: The multiform and variable patterns of onset of orofacial granulomatosis. J Oral Pathol Med 2003; 32:200.
Fordyce’s disease (Fordyce spots) Fordyce spots are ectopically located sebaceous glands, clinically characterized by minute orange or yellowish pinheadsized macules or papules in the mucosa of the lips, cheeks, and, less often, the gums. Similar lesions may occur on the areola, glans penis, and labia minora. Prominent lip involvement may result in a lipstick-like mark left on the rim of a glass mug after consuming a hot beverage (Meffert’s sign). Involvement of the labial mucosa with pseudoxanthoma elasticum may simulate Fordyce spots. Because the anomaly is asymptomatic and inconsequential, treatment should be undertaken only if there is a significant cosmetic problem. The CO2 laser, electrodesiccation and curettage, bichloracetic acid, photodynamic therapy, and isotretinoin are therapeutic options. Chen PL, et al: Fordyce spots of the lip responding to electrodesiccation and curettage. Dermatol Surg 2008; 34:960. Elston DM, et al: Fordyce spots. Cutis 2001; 68:24, 49. Ocampo-Candiani J, et al: Treatment of Fordyce spots with CO2 laser. Dermatol Surg 2003; 29:869.
Stomatitis nicotina Also known as smoker’s keratosis and smoker’s patches, stomatitis nicotina is characterized by distinct umbilicated papules on the palate. The ostia of the mucous ducts appear as red pinpoints surrounded by milky white, slightly umbilicated asymptomatic papules. The intervening mucosa becomes white and thick and has a tendency to desquamate in places, leaving raw, beefy-red areas. Ulceration and the formation of aphthous ulcers may occur. This condition is attributed to heavy smoking in middleaged men, although it has also been reported in nonsmokers who habitually drink hot beverages. Heat may be the causative event. Indeed, the most severe cases are associated with the type of tobacco use that produces intense heat—pipe and reverse smoking. Treatment consists of abstaining from the use of tobacco or ingestion of hot liquids.
Fig. 34-6 Melkersson–Rosenthal syndrome. (Courtesy of Curt Samlaska, MD)
Mirbod SM, et al: Tobacco-associated lesions of the oral cavity. J Can Dent Assoc 2000; 66:252. Taybos G: Oral changes associated with tobacco use. Am J Med Sci 2003; 326:179.
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Torus palatinus Torus palatinus is a bony protuberance in the midline of the hard palate, marking the point of junction of the two halves of the palate. It is asymptomatic. Exostoses also commonly occur in the floor of the mouth, involving the inner surface of the mandible. Piera-Navarro N, et al: Clinical evaluation of hard tissue proliferations of the mouth. Med Oral 2002; 7:97. Tran KT, et al: Torus palatinus. N Engl J Med 2007; 356:1759.
Fissured tongue Also known as furrowed tongue, scrotal tongue, or lingua plicata, fissured tongue is a congenital and sometimes familial condition in which the tongue is generally larger than normal and there are plicate superficial or deep grooves, usually arranged so that there is a longitudinal furrow along the median raphe, reminiscent of scrotal rugae (Fig. 34-7). Fissured tongue is seen in Melkersson–Rosenthal syndrome and in many patients with Down syndrome. Individual case reports have been seen in association with pachyonychia congenita, pemphigus vegetans, and Cowden syndrome. Geographic tongue occurs together with fissured tongue in 50% of patients, and both are more commonly present in psoriasis patients than nonpsoriatics. The condition gives rise to no difficulty, and treatment is not necessary, except that the deep furrows should be kept clean by use of mouthwashes. Herpetic geometric glossitis may mimic fissured tongue, but is painful, affects predominately immunocompromised individuals, and is centered on the back of the dorsal tongue. Byrd JA, et al: Glossitis and other tongue disorders. Dermatol Clin 2003; 21:123. Mirowski GW, et al: Herpetic geometric glossitis in an immunocompetent patient with pneumonia. J Am Acad Dermatol 2009; 61:139. Zargari O: The prevalence and significance of fissured tongue and geographic tongue in psoriatic patients. Clin Exp Dermatol 2006; 31:192.
Fig. 34-7 Fissured tongue.
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Geographic tongue Geographic tongue is also known as lingua geographica, transitory benign plaques of the tongue, glossitis areata exfoliativa, and benign migratory glossitis. In some patients it is a manifestation of atopy, and in others, of psoriasis. However, in most it is an isolated finding. The dorsal surface of the tongue is the site usually affected. Geographic tongue begins with a small depression on the lateral border or the tip of the tongue, smoother and redder than the rest of the surface. This spreads peripherally, with the formation of sharply circumscribed ringed or gyrate red patches, each with a narrow yellowish-white border, making the tongue resemble a map. The appearance changes from day to day; patches may disappear in one place and manifest themselves in others. The disease is characterized by periods of exacerbation and quiescence. The lesion may remain unchanged in the same site for long periods. The condition is frequently unrecognized because it produces no symptoms except for the occasional complaint of glossodynia. There are two clinical variants of geographic tongue. In one type, discrete, annular “bald” patches of glistening, erythematous mucosa with absent or atrophic filiform papillae are noted. Another type shows prominent circinate or annular white raised lines that vary in width up to 2 mm. The clinical appearance and histopathologic findings of the tongue lesions in pustular psoriasis, reactive arthritis (Reiter syndrome), and geographic tongue are identical; when the tongue lesions occur with psoriasis or reactive arthritis, the name annulus migrans has been suggested for this entity (Fig. 34-8). It has been reported as being acquired in patients with AIDS or as a result of lithium therapy. Histologically, the main features are marked transepidermal neutrophil migration with the formation of spongiform pustules in the epidermis and an upper dermal mononuclear infiltrate. Although treatment is not usually necessary, a 0.1% solution of tretinoin solution (Retin-A) applied topically has produced clearing within 4–6 days. Byrd JA, et al: Glossitis and other tongue disorders. Dermatol Clin 2003; 21:123. Miloglu O, et al: The prevalence and risk factors associated with benign migratory glossitis lesions in 7619 Turkish dental outpatients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; 107:e29. Shulman JD, et al: Prevalence and risk factors associated with geographic tongue among US adults. Oral Dis 2006; 12:381. Zargari O: The prevalence and significance of fissured tongue and geographic tongue in psoriatic patients. Clin Exp Dermatol 2006; 31:192.
Fig. 34-8 Annulus migrans.
Eruptive lingual papillitis Fig. 34-9 Black hairy tongue.
Black hairy tongue Black or brown hairy tongue occurs on the dorsum of the tongue anterior to the circumvallate papillae, where black, yellowish, or brown patches form, consisting of hairlike intertwining filaments several millimeters long (Fig. 34-9). The “hairs” result from a benign hyperplasia of the filiform papillae of the anterior two-thirds of the tongue, resulting in retention of long conical filaments of orthokeratotic and parakeratotic cells. It occurs far more frequently in men than in women. Black hairy tongue may be associated with several conditions that may be predisposing factors in its causation: smoking, use of oral antibiotics, psychotropic drugs, and presence of Candida on the surface of the tongue. This lesion may be differentiated both clinically and histologically from oral hairy leukoplakia, which is seen in human immunodeficiency syndrome (HIV)-infected patients. Hairy leukoplakia is usually seen on the lateral surface of the tongue at first in corrugated patches, then with time as solid white plaques that are adherent. Microscopic examination reveals acanthosis, parakeratosis, irregular projections of keratin, and vacuolated keratinocytes with Epstein–Barr virus present within them. A toothbrush may be used to scrub off the projections, either alone, with 1–2% hydrogen peroxide, or after application of Retin-A gel, 40% aqueous solution of urea, or papain (meat tenderizer). Such predisposing local factors as smoking, antibiotics, and oxidizing agents should be eliminated, if possible, and scrupulous oral hygiene should be maintained. Korber A, et al: Black hairy tongue. N Engl J Med 2006; 354:67. Pigatto PD, et al: Black hairy tongue associated with long-term oral erythromycin use. J Eur Acad Dermatol Venereol 2008; 22:1269. Taybos G: Oral changes associated with tobacco use. Am J Med Sci 2003; 326:179.
Smooth tongue Also known as bald tongue or atrophic glossitis, the smooth glossy tongue is often painful and results from atrophy of the filiform and eventually the fungiform papillae (Fig. 34-10). When present with vitamin B12 deficiency, it has been termed Moeller or Hunter glossitis. It begins with the tip and lateral surfaces of the tongue becoming intensely red, well-defined irregular patches in which the filiform papillae are absent or thinned and the fungiform papillae are swollen. The disease is chronic and the patches are painful and sensitive so that eating may be difficult and taste impaired. With time, the entire tongue becomes smooth and a leukoplakia may result. Treatment of pernicious anemia with vitamin B12 therapy will
Fig. 34-10 Smooth tongue in Plummer–Vinson syndrome.
result in improvements in the appearance and sensitivity of the tongue. Atrophic glossitis is also a distinctive sign of pellagra; it results from a deficiency of niacin or its precursor, tryptophan. The sides and tip of the tongue are erythematous and edematous, with imprints of the teeth. Eventually, the entire tongue assumes a beefy-red appearance. Small ulcers appear, and all the mucous membranes of the mouth may be involved. Later, the papillae become atrophied to produce a smooth, glazed tongue, as seen in pernicious anemia. Burning or pain in the ulcers may be present. Increased salivary flow early in the disease may lead to drooling and angular cheilitis. In malabsorption syndrome, riboflavin deficiency, anorexia nervosa, alcoholism, and sprue, similar changes may be noted. Vitamin B complex is curative. Patients with iron-deficiency anemia, alone or when combined with esophageal webs (Plummer–Vinson syndrome), folic acid deficiency, syphilis, amyloidosis, celiac disease, Sjögren syndrome, and Riley–Day syndrome, may all manifest smooth tongue. Candidiasis may result in tongue pain and a partial or total atrophic appearance, along with a red or magenta color, on the dorsum of the tongue. In such cases, anticandidal therapy results in rapid improvement. Atmatzidis K, et al: Plummer–Vinson syndrome. Dis Esophagus 2003; 16:154. Byrd JA, et al: Glossitis and other tongue disorders. Dermatol Clin 2003; 21:123. Lee HJ, et al: A smooth, shiny tongue. N Engl J Med 2009; 360:e8. Lehman JS, et al: Atrophic glossitis from vitamin B12 deficiency. J Periodontol 2006; 77:2090. Terai H, et al: Atrophic tongue associated with Candida. J Oral Pathol Med 2005; 34:397.
Eruptive lingual papillitis Lacour and Perrin first described this acute, self-limiting inflammatory stomatitis in 1997. It affects children of both sexes equally, with a mean age of onset of 3 1 2 years. It has a seasonal distribution, with the majority of cases occurring in the spring. Fever (40%), difficulties in feeding (100%), and intense salivation (60%) are common symptoms. The tongue 789
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Fig. 34-11 Eruptive lingual papillitis.
examination reveals inflammatory hypertrophy of the fungiform papillae on the tip and dorsolateral sites (Fig. 34-11). Additional signs include submandibular or cervical adenopathy (40%) and angular cheilitis (10%). Associated skin eruptions have not been described. Spontaneous involution occurs in a mean of 7 days with a range of 2–15 days. Recurrence is noted in 13%. It is felt to be the result of a viral infection, and the 50% transmission among family members further supports this theory. Brfannon RB, et al: Transient lingual papillitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 96:187. Lacour JP, et al: Eruptive familial lingual papillitis. Pediatr Dermatol 1997; 14:13. Roux O, et al: Eruptive lingual papillitis with household transmission. Br J Dermatol 2004; 150:299.
Median rhomboid glossitis Median rhomboid glossitis is characterized by a shiny oval or diamond-shaped elevation, invariably situated on the dorsum in the midline immediately in front of the circumvallate papillae (Fig. 34-12). The surface is abnormally red and smooth. In some instances, a few pale yellow papules surmount the elevation. On palpation the lesion feels slightly firm, but it usually causes no symptoms. It persists indefinitely, with little or no increase in size. There is no relationship to cancer. One report noted its presence a patient with pachyonychia congenita. It may result from abnormal fusion of the posterior portion of the tongue, but it is nearly always chronically infected with Candida. If there is palatal inflammation above the inflamed part of the tongue, AIDS should be suspected and an HIV test obtained. Histologically, the changes are those of a simple, chronic inflammation with fibrosis, and usually with fungal hyphae in the parakeratin layer. Treatment with oral antifungals, such as itraconazole, may lead to improvement. Bae GY, et al: A case of median rhomboid glossitis. J Dermatol 2003; 30:423. Karen JK, et al: Pachyonychia congenita associated with median rhomboid glossitis. Dermatol Online J 2007; 13:21. McCullough MJ, et al: Oral candidosis and the therapeutic use of antifungal agents in dentistry. Aust Dent J 2005; 50(4 Suppl 2):S36. Nelson BL, et al: Median rhomboid glossitis. Ear Nose Throat J 2007; 86:600.
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Fig. 34-12 Median rhomboid glossitis.
Eosinophilic ulcer of the oral mucosa Eosinophilic ulcer occurs most commonly on the tongue, but may occur anywhere in the oral mucosa. It is characterized by an ulcer with indurated and elevated borders that is usually covered by a pseudomembrane. It develops rapidly, most commonly on the posterior aspect of the tongue, and spontaneously resolves in a few weeks. A traumatic cause has been postulated for this benign, self-limited disorder. The histopathologic findings show a predominantly eosinophilic infiltrate in company with some histiocytes and neutrophils. In some multifocal, recurrent cases, CD30+ cells have been reported. These patients may have the oral counterpart of primary cutaneous CD30+ lymphoproliferative disease, or may simply be a simulator of this disorder. HIV-infected patients may develop ulcerations of the oral mucosa, resulting from a variety of infectious agents, such as herpes simplex virus (HSV), candidiasis, and histoplasmosis. However, 5 of the 16 patients they reported had no evidence of infection and simply showed eosinophilic infiltrates below the ulcer. Ada S, et al: Eosinophilic ulcer of the tongue. Australas J Dermatol 2007; 48:248. Segura S, et al: Eosinophilic ulcer of the oral mucosa. Br J Dermatol 2006; 155:460. Segura S, et al: Eosinophilic ulcer of the oral mucosa. Oral Dis 2008; 14:287.
Caviar tongue William Bean gave the picturesque name caviar tongue to the purplish venous ectasias so commonly found on the undersurface of the tongue after the age of 50. They are attributed to elastic tissue deterioration with aging and may be associated with Fordyce angiokeratomas of the scrotum. Phleboliths or thrombophlebitis may occasionally complicate this condition. Kocsard E, et al: The histopathology of caviar tongue. Dermatologica 1970; 140:318.
Cutaneous sinus of dental origin (dental sinus) In dental (or odontogenous) sinus, chronic periapical infection about a tooth produces a burrowing, practically asymptomatic,
Neoplasms Fig. 34-13 Odontogenic sinus.
Fig. 34-14 Oral hairy leukoplakia of HIV.
occasionally palpable, cordlike sinus tract that eventually appears beneath the surface of the gum, palate, or periorificial skin. It forms a fistulous opening with an inflamed red nodule at the orifice. It may appear anywhere from the inner ocular canthus to the neck but is most often seen on the chin or along the jawline (Fig. 34-13). Bilateral involvement has been reported. Dental radiography is diagnostic. Pyogenic granuloma, actinomycosis, squamous cell carcinoma, osteomyelitis of the mandible, congenital fistulas, the deep mycoses, bisphosphonate-related osteonecrosis of the jaw, and foreign body reactions must be considered in the differential diagnosis. Treatment requires the removal of the offending tooth or root canal therapy of the periapical abscess.
may arise on the anus and genitalia. Leukoplakia is found chiefly in men over the age of 40. Biopsy of these white lesions may reveal orthokeratosis or parakeratosis with minimal inflammation, or there may be evidence of varying degrees of dysplasia. There is a benign form that is usually a response to chronic irritation and that has very little chance of conversion into the precancerous dysplastic form. Premalignant leukoplakia, with atypical cells histologically, is present in only about 10–20% of leukoplakia. Unfortunately, it is not possible to predict clinically which lesions will be worrisome histologically, except that if ulceration, red areas, or erosions are scattered throughout, the lesion is most likely precancerous. Therefore, biopsy is indicated. When the lesion occurs on the lip, leukoplakia is closely related to chronic actinic cheilitis, which consists of a circumscribed or diffuse keratosis, almost invariably on the lower lip. It is preceded by an abnormal dryness of the lip and may be caused by smoking (especially pipe smoking) or chronic sun exposure. This type of leukoplakia is distinguished from squamous cell carcinoma of the lip by the absence of infiltration, from lichen planus and psoriasis of the lips and mouth by the absence of lesions elsewhere, and from lupus erythematosus by the absence of telangiectases. Biopsy is necessary, however, to differentiate these conditions fully. Intraoral leukoplakia appears to progress to squamous cell carcinoma in not more than 1% per year. In time, an extensive, thick, white pellicle may cover the tongue or oral mucosa. In old lesions the epithelium may be desquamated and there may be fissures or ulcerations. Such changes are associated with more or less hyperemia and tenderness, and with a tendency to bleed after slight trauma. If transformation to carcinoma occurs, it generally follows a 1 to 20-year lag time, with the exception that immunosuppressed transplant patients may have a rapid course of transformation. Oral hairy leukoplakia is a term used to describe white, corrugated plaques that occur primarily on the sides of the tongue of patients with AIDS (Fig. 34-14). This is a virally induced lesion, discussed in Chapter 19, which has a characteristic histology. Leukoplakia of the vulva usually occurs in obese women after menopause as grayish white, thickened, pruritic patches that may become fissured and edematous from constant rubbing and scratching. Secondary infection with edema, tenderness, and pain may occur. It is differentiated from lichen planus by the absence of discrete, rectangular, or annular flat papules of violaceous hue in the mucosa outside the thickened patches, about the anus, on the buccal mucosa, or on the skin. Leukoplakia of the vulva is most frequently confused with lichen sclerosus et atrophicus and other vulval atrophies. On
Barrowman RA, et al: Cutaneous sinus tracts of dental origin. Med J Aust 2007; 186:264. Mittal N, et al: Management of extra oral sinus cases. J Endod 2004; 30:541. Pasternak-Junior B, et al: Diagnosis and treatment of odontogenic cutaneous sinus tracts of endodontic origin. Int Endod J 2009; 42:271. Soares JA, et al: Conservative treatment of patients with periapical lesions associated with extraoral sinus tracts. Aust Endod J 2007; 33:131. Truong SV, et al: Bisphosphonate-related osteonecrosis of the jaw presenting as a cutaneous dental sinus track. J Am Acad Dermatol 2010; 62:672.
Neoplasms Many tumors may involve the oral cavity. Most are discussed elsewhere in this book, and several are uncommon entities that affect specialized oral structures, such as the many subtypes of benign and malignant proliferations that occur in the major and minor salivary glands. These will not be covered further here, and only a few selected neoplasms will be presented.
Leukoplakia Clinical features Leukoplakia presents as a whitish thickening of the epithelium of the mucous membranes, occurring as lactescent superficial patches of various shapes and sizes that may coalesce to form diffuse sheets. The surface is generally glistening and opalescent, often reticulated, and may even be somewhat pigmented. The white pellicle is adherent to the underlying mucosa and attempts to remove it forcibly cause bleeding. At times it is a thick, rough, elevated plaque. The lips, gums, cheeks, and edges of the tongue are the most common sites, but the lesion
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the penis, though leukoplakia may occur, a similar precancerous process called erythroplasia (of Queyrat) is usually seen instead.
Etiology Numerous factors are involved in the cause of leukoplakia. It may develop as a result of tobacco smoking, use of smokeless tobacco, areca, qat, or betel nut chewing, reverse smoking, alcohol, poorly fitting dentures, sharp and chipped teeth, or improper oral hygiene. Extensive involvement of the lips and oral cavity with leukoplakia may exist for years without any indication of carcinoma. On the other hand, small, inflamed patches may be the site of a rapidly growing tumor, which, with relatively insignificant local infiltration, may involve the cervical lymphatics. Carcinoma in leukoplakia usually begins as a localized induration, often about a fissure, or as a warty excrescence or a small ulcer. There is a 6–10% transformation rate of intraoral leukoplakia into squamous cell carcinoma. Predictors of a higher risk of squamous cell carcinoma development include older age, female sex, nonsmokers, large size, presence on the lateral or ventral tongue, floor of the mouth, or retromolar/soft palate complex, erythroleukoplakia, and a nonhomogeneous morphology. The degree of epithelial atypia may be considered in staging the risk of developing malignancy. Aneuploid leukoplakia has a high rate of transformation into aggressive squamous cell carcinoma, and the cancers derived from it are more likely to be lethal.
Treatment It must be remembered that cancer develops frequently on histologically dysplastic leukoplakia, so that its complete removal should be the goal in each case—first by conservative measures, then by surgery or destruction, if necessary. The use of tobacco should be stopped, and proper dental care obtained. Fulguration, simple excision, cryotherapy, and CO2 laser ablation are effective methods of treatment. Medical therapies that have been the subject of randomized clinical trials may lead to temporary resolution of the lesions, but relapses and adverse effects are common and there is no evidence that they prevent the transformation to malignancy.
Leukoplakia with tylosis and esophageal carcinoma Leukoplakia associated with tylosis and esophageal carcinoma is extremely rare but may occur.
Epidermization of the lip Relatively smooth leukokeratosis of the lower vermilion, blending evenly into the skin surface distally and having a steep, sharp, irregular proximal margin, may easily be mistaken clinically for precancerous leukoplakia. Histologically, it shows only hyperkeratosis, without parakeratosis or cellular atypia. A shallow shave excision suffices to cure it and to rule out precancerous leukoplakia; no fulguration is required.
Erythroplakia The term erythroplakia is applied to leukoplakia that has lost (or has not developed) the thick keratin layer that makes leukoplakia white; it is the usual pattern in mucocutaneous junctions. A focal red patch with no apparent cause should be suspected of being precancerous when found on the floor of the mouth, soft palate, or buccal mucosa, or under the tongue (Fig. 34-15). Histologically, there is cellular atypia, pleomorphism, hyperchromatism, and increased mitotic figures. 792
Fig. 34-15 Erythroplakia.
Carcinoma in situ or invasive carcinoma is found in 90% of lesions.
Oral florid papillomatosis Oral florid papillomatosis is a confluent papillomatosis covering the mucous membranes of the oral cavity. The distinctive picture is that of a white mass resembling a cauliflower, covering the tongue and extending on to the other portions of the mucous membranes, including the oropharynx, larynx, and trachea. Usually there is no lymphadenopathy. The course of the disease is progressive. Many lesions eventuate in squamous cell carcinoma, whereas others continue for many years, the patient dying of some intercurrent disease. Oral florid papillomatosis should be regarded as a verrucous carcinoma, which has been defined as a distinctive, slowly growing, fungating tumor representing a well-differentiated squamous cell carcinoma in which metastases occur very late or not at all. The histologic features are those of papillomatosis, acanthosis, and varying degrees of dysplasia of the epithelium, without disruption of the basement membrane. It is reasonable to expect the eventual development of epidermoid carcinoma in most patients. Esophageal involvement and keratotic papules of the extremities may occur. In the differential diagnosis, leukoplakia, proliferative verrucous leukoplakia, candidiasis, acanthosis nigricans, and condyloma acuminatum should be considered. The recommended treatment is surgical excision; however, it is often followed by recurrence and spread. Recombinant interferon-α 2a in combination with a CO2 laser has also been used.
Proliferative verrucous leukoplakia Proliferative verrucous leukoplakia is a slowly progressive condition that begins as multifocal sites of hyperplasia of the oral mucous membranes and proceeds to thicken and enlarge until squamous cell carcinoma results (Fig. 34-16). Women outnumber men 4:1. Initially flat, usually white patches are present, but the lesions relentlessly become warty, exophytic masses. The patches may involve the lips and chin. Seventy percent develop squamous cell carcinoma (most frequently of the palate and gingiva), with 40% of the total dying of proliferative verrucous leukoplakia-associated carcinoma. It has been irregularly associated with human papillomavirus (HPV)-16 infection, and risk factors for squamous cell carcinoma of the oral cavity are usually not present. Treatment is difficult because of the multifocal nature of the lesions. Aggressive early surgical therapy is best. Many patients develop recurrence after only a short interval. Laser treatment
Neoplasms Fig. 34-16 Proliferative verrucous leukoplakia, three sites of SCC: lip and twice in the palate.
Fig. 34-18 Acquired dyskeratotic leukoplakia.
disease is often discovered late, after it has metastasized to the cervical lymph nodes. Exfoliative cytology is a practical and accurate aid to oral cancer screening.
Fig. 34-17 Oral squamous cell carcinoma.
or photodynamic therapy should be considered primary options.
Squamous cell carcinoma Squamous cell carcinoma is the most common oral malignancy, comprising 2–3% of all new cancers. With nearly 30 000 yearly cases in the US, it is the tenth most common malignancy. It occurs primarily in older men. The most frequent sites are the lower lip, tongue, soft palate, and floor of the mouth (Fig. 34-17). Squamous cell carcinoma of the lip develops from actinic damage, with 95% of the cases involving the lower lip. Intraoral lesions frequently develop from leukoplakia or erythroplakia, at sites of frequent irritation, or from long-standing mucosal inflammatory disease such as ulcerative lichen planus. About 20% of oral squamous cell cancers have an associated focus of leukoplakia; these tend to be diagnosed at a less advanced stage than those where no associated leukoplakia exists. Verrucous carcinomas occur in the oral mucosa as they do on the skin. Tobacco-smoking, the use of smokeless tobacco, areca, qat, or betel nut-chewing, and reverse smoking are risk factors for the development of intraoral squamous cell carcinoma. Alcohol has not been shown to be an independent risk factor. They may also complicate xeroderma pigmentosa (the tip of the tongue), dyskeratosis congenita, dystrophic epidermolysis bullosa, erosive lichen planus, and oral submucous fibrosis. Unfortunately, the survival rate has remained at 50% for many years because
Bagan J, et al: Proliferative verrucous leukoplakia. Oral Dis 2010; 16:328. Brennan M, et al: Management of oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103(Suppl):S19.e1. Cabay RJ, et al: Proliferative verrucous leukoplakia and its progression to oral carcinoma. J Oral Pathol Med 2007; 36:255. Casiglia J, Woo SB: A comprehensive review of oral cancer. Gen Dent 2001; 49:72. El-Wajeh YA, et al: Qat and its health effects. Br Dent J 2009; 206:17. Greer RO: Pathology of malignant and premalignant epithelial lesions. Otolaryngol Clin North Am 2006; 39:249. Haya-Fernandez MC, et al: The prevalence of oral leukoplakia in 138 patients with oral squamous cell carcinoma. Oral Dis 2004; 10:346. Hernandez G, et al: Rapid progression from oral leukoplakia to carcinoma in an immunosuppressed liver transplant recipient. Oral Oncol 2003; 39:87. Ishii J, et al: Management of oral leukoplakia by laser surgery. J Clin Laser Med Surg 2004; 22:27. Jacob BJ, et al: Betel quid without tobacco as a risk factor for oral precancers. Oral Oncol 2004; 40:697. Kademani D: Oral cancer. Mayo Clin Proc 2007; 82:878. Lodi G, et al: Interventions for treating oral leukoplakias. Cochrane Database Syst Rev 2006; 4:CD001829. Lodi G, et al: Management of potentially malignant disorders. J Oral Pathol Med 2008; 37:63. Napier SS, et al: Natural history of potentially malignant oral lesions and conditions. J Oral Pathol Med 2008; 37:1. Reichart PA, et al: Oral erythroplakia. Oral Oncol 2005; 41:551. Rhodus NL: Oral cancer. Dent Clin North Am 2005; 49:143. Scheifele C, et al: The sensitivity and specificity of the OralCDx technique: evaluation of 103 cases. Oral Oncol 2004; 40:824. Schwartz RA: Verrucous carcinoma of the skin and mucosa. J Am Acad Dermatol 1995; 32:1. Sciubba JJ: Oral Cancer. Am J Clin Dermatol 2001; 2:239. Sudbo J, et al: The influence of resection and aneuploidy on mortality in oral leukoplakia. N Engl J Med 2004; 350:1405. Thoma G, et al: Risk factors for multiple oral premalignant lesions. Int J Cancer 2003; 107:285. Trivedy CR, et al: The oral health consequences of chewing areca nut. Addict Biol 2002; 7:115. van der Hem PS, et al: The results of CO2 laser surgery in patients with oral leukoplakia: a 25 year follow up. Oral Oncol 2005; 41:31.
Acquired dyskeratotic leukoplakia James and Lupton reported a patient with acquired dyskeratotic leukoplakia, which manifested as distinctive white plaques on the palate, gingivae, and lips (Fig. 34-18). There were similar lesions of the genitalia of the patient. Histologically, 793
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there was a unique finding of clusters of dyskeratotic cells in the prickle-cell layer in all affected sites. Aggressive laser treatment was followed by recurrence. Use of etretinate afforded some improvement, but the condition continues unabated after 20 years. James WD, et al: Acquired dyskeratotic leukoplakia. Arch Dermatol 1988; 124:117.
White sponge nevus The mouth, vagina, or rectum may be the site of this spongy, white overgrowth of the mucous membrane, with acanthosis, vacuolated prickle cells, and acidophilic condensations in the cytoplasm of keratinocytes, which have been shown by electron microscopy to be aggregated tonofilaments. The buccal mucosa is the most common site of involvement. There are no extramucosal lesions. Progression of the disorder generally stops at puberty. The disease is inherited as an autosomal-dominant disorder. A mutation in the mucosal keratin pair K4 and K13 has been identified as the inherited defect. HPV-16 DNA has been identified in some patients, the significance of which remains to be determined. Antibiotics, particularly tetracycline, may give significant improvement. A 0.25% aqueous preparation of tetracycline as a mouth rinse, 5 mL swished in the mouth for 1 min twice daily, has been successful. López Jornet P: White sponge nevus. Pediatr Dermatol 2008; 25:116. Nishizawa A, et al: A de novo missense mutation in the keratin 13 gene in oral white sponge naevus. Br J Dermatol 2008; 159:974. Otobe IF, et al: White sponge naevus. Clin Exp Dermatol 2007; 32:749. Zhang JM, et al: Two new mutations in the keratin 4 gene causing oral white sponge nevus in Chinese family. Oral Dis 2009; 15:100.
Melanocytic oral lesions A wide variety of melanocytic lesions appear on the mucous membranes. Nevi of the oral mucosa in general are very uncommon. Among the melanocytic nevi of the cellular type, the intramucosal type is the most frequent, with the compound nevus next and the junction nevus occurring only rarely. Ephelis, lentigo, blue nevus, and labial melanotic macules are other types of focal hyperpigmentation. Ephelides darken on sun exposure and are usually limited to the lower lip. The blue nevus has dendritic cells in the submucosa. Lentigines show acanthosis of rete ridges on biopsy. Oral melanotic macules are solitary, sharply demarcated, flat, pigmented lesions that occur chiefly in young women, do not change on sun exposure, and show only acanthosis and basallayer melanin on biopsy. Oral melanoacanthoma is a simultaneous proliferation of keratinocytes and melanocytes. It is most commonly observed in young black patients (average age, 23) on the buccal mucosa. It seems to be a reactive process, usually following trauma and resolving spontaneously in 40% of patients. Melanoma occurs uncommonly, mostly in older patients. It is recognized by being larger than the usual benign pigmented lesion and more irregular in shape, with a tendency to ulcerate and bleed. A peripheral areola of erythema and satellite pigmented spots may be present. There is a striking predilection for palatal (or, less often, gingival) involvement. The overall prognosis is poor (less than 5% survival at 5 years) because the lesions are usually deeply invasive by the time they are discovered. Whereas oral nevi are uncommon, biopsy of solitary pigmented oral lesions is indicated when the clinical diagnosis is uncertain. Biopsy of a pigmented tumor will occasionally reveal a squamous cell carcinoma. Buchner A, et al: Relative frequency of solitary melanocytic lesions of the oral mucosa. J Oral Pathol Med 2004; 33:550.
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Carlos-Bregni R, et al: Oral melanoacanthoma and oral melanotic macule. Med Oral Pathol Oral Cir Bucal 2007; 12:E374. Femiano F, et al: Oral malignant melanoma. J Oral Pathol Med 2008; 37:383. Gaeta GM, et al: Oral pigmented lesions. Clin Dermatol 2002; 20:286. Gondivkar SM, et al: Primary oral melanoma. Quintessence Int 2009; 40:41. Lisboa Castro J, et al: Pigmented oral squamous cell carcinoma. Int J Surg Pathol 2009; 17:153. Medina JE, et al: Current management of mucosal melanoma of the head and neck. J Surg Oncol 2003; 83:116. Meleti M, et al: Oral pigmented lesions of the oral mucosa and perioral tissues. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105:606. Ojha J, et al: Intraoral cellular blue nevus. Cutis 2007; 80:189.
Melanosis Pigmentation of the oral cavity tends to occur most frequently in black persons. In other races, the darker the skin, the more mucosal pigmentation may be expected. Oral melanosis may occur with Albright syndrome, Peutz–Jeghers syndrome, Carney complex, Laugier–Hunziker disease, and Addison’s disease, or rarely, as an idiopathic process with no associated disease. James et al reported a patient with inflammatory acquired oral hyperpigmentation that first occurred at age 30 with numerous distinct pigmented macules, similar to those seen in Peutz–Jeghers syndrome. However, the condition progressed rapidly to a diffuse oral hyperpigmentation (Fig. 34-19). This appeared to be caused by an undefined inflammation, and slow partial resolution occurred after several years of observation. In the differential diagnosis of oral hyperpigmentation, these other entities should be included. The amalgam tattoo is a focal, brownish-blue macule incurred from fragments of dental silver or amalgam being implanted into the gums (Fig. 34-20).
Fig. 34-19 Oral melanosis.
Fig. 34-20 Amalgam tattoo.
Abdollahi M, et al: A review of drug-induced oral reactions. J Contemp Dent Pract 2003; 15:10. James WD, et al: Inflammatory acquired oral hyperpigmentation. J Am Acad Dermatol 1987; 16:220. Laporta VN, et al: Minocycline-associated intra-oral soft-tissue pigmentation. J Clin Periodontol 2005; 32:119. Meleti M, et al: Oral pigmented lesions of the oral mucosa and perioral tissues. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105:606.
Osseous choristoma of the tongue Osseous choristoma of the tongue presents as a nodule on the dorsum of the tongue containing mature lamellar bone without osteoblastic or osteoclastic activity. This does not recur after simple excision. Naik VR, et al: Choristoma of the base of the tongue. Indian J Pathol Microbiol 2009; 52:86.
Peripheral ameloblastoma This is a neoplasm of the gingivae, which appears most often on the lower jaw. The mean age at onset is the early fifties and men outnumber women. It presents as a growing pink to red sessile or pedunculated mass. Excision is followed by recurrence in 19% of the cases, but the lesion is benign. Basal cell carcinoma can be simulated histologically. Curran AE, et al: Peripheral desmoplastic ameloblastoma. J Oral Maxillofac Surg 2008; 66:820. Vanoven BJ, et al: Peripheral ameloblastoma of the maxilla. Am J Otolaryngol 2008; 29:357.
Trumpeter’s wart Trumpeter’s wart is a firm, fibrous, hyperkeratotic, pseudoepitheliomatous nodule on the upper lip of a trumpet player. A similar callus may grow on the lower lip of trombone players. Gambichler T, et al: Skin conditions in instrumental musicians. Contact Dermatitis 2008; 58:217.
Epulis The term epulis means any benign lesion situated on the gingiva. The majority of these are reactive processes that display varying degrees of fibrosis, inflammation, and vascular proliferation on biopsy. Giant cell epulis (peripheral giant cell granuloma) is a solitary, bluish-red, 10–20 mm tumor occurring on the gingiva between or about deciduous bicuspids and incisors. Lesions may be induced by dental implants. Similar lesions may occur in the autosomal-dominantly inherited syndrome, cherubism. Histologically, they resemble giant cell tumor of the tendon sheath.
involving the gingiva. It may also occur on the buccal mucosa, lips, tongue, or palate. It is a red to reddish-purple, soft, nodular mass that bleeds easily and grows rapidly, but is usually not painful. When it develops during pregnancy, it is called pregnancy tumor or granuloma gravidarum. Surgical excision, pulsed dye or Nd:YAG lasers, and cryosurgery offer effective methods of treatment. Gordon-Nunez MA, et al: Oral pyogenic granuloma. J Oral Maxillofac Surg 2010; 68:2185. Jafarzadeh H: Oral pyogenic granuloma. J Oral Sci 2006; 48:167.
Mucocele
Heavy-metal poisoning may also induce such lesions. Bismuth, lead, and cis-platinum may produce a pigmented line along the gums near their margin. A multitude of medications will cause pigmentation. Amodiaquine, chloroquine, oral contraceptives, phenothiazines, phenolphthalein, quinacrine, quinidine, thallium, tobacco, and zidovudine are among the most common of these.
Granuloma fissuratum Granuloma fissuratum is a circumscribed, firm, whitish, fissured, fibrous granuloma occurring in the labioalveolar fold. The lesion is discoid, smooth, and slightly raised, about 1 cm in diameter. The growth is folded like a bent coin, so that the fissure in the bend is continuous on both sides with the labioalveolar sulcus. Symptoms are slight. It is an inflammatory fibrous hyperplasia that usually results from chronic irritation caused by poorly fitting dentures. In the dental literature it is called epulis fissuratum, particularly when there is a deep cleft traversing the lesion. Treatment is by surgical extirpation, CO2 laser ablation, or electrodesiccation after biopsy. Bhattacharyya I: Epulis fissuratum. Todays FDA 2008; 20:15.
Angina bullosa haemorrhagica The sudden appearance of one or more blood blisters of the oral mucosa characterizes this entity. There is no associated skin or systemic disease. The blisters may be recurrent, occur most often in the soft palate, and usually present in middleaged or elderly patients. No treatment is necessary. Sera D, et al: Angina bullosa haemorrhagica. Eur J Dermatol 2010; 20:509. Yip HK: Angina bullosa haemorrhagica. Gen Dent 2004; 52:162.
Mucocele The term mucocele refers to a lesion that occurs as a result of trauma or obstruction of the minor salivary ducts. The most common type is the mucous extravasation phenomenon, which is usually seen inside the lower lip because it is caused by trauma from biting (Fig. 34-21). The inside of the upper lip and buccal mucosa are uncommonly involved. It presents as a soft, rounded, translucent projection; it commonly has a bluish tint. The lesion varies from 2 to 10 mm in diameter. It is painless, fluctuant, and tense. Incision of it, or sometimes merely compression, releases sticky, straw-colored fluid (or bluish fluid if hemorrhage has occurred into it). Usually, the
Salum FG: Pyogenic granuloma, peripheral giant cell granuloma and peripheral ossifying fibroma. Minerva Stomatol 2008; 57:227. Scarano A, et al: Peripheral giant cell granuloma associated with a dental implant. Minerva Stomatol 2008; 57:529.
Pyogenic granuloma Pyogenic granuloma is an exuberant overgrowth of granulation tissue, frequently occurring in the oral cavity, most often
Fig. 34-21 Mucocele.
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lesions are solitary; however, multiple superficial mucoceles have been reported to occur with graft versus host disease and lichenoid inflammation. In these cases topical steroids may help prevent recurrences. The cause is rupture of the mucous duct, with extravasation of sialomucin into the submucosa to produce cystic spaces with inflammation. Granulation tissue formation is followed by fibrosis. Excisional biopsy will document the diagnosis and eliminate the problem. Cryotherapy and laser ablation have also been reported to be successful. There are true mucous retention cysts where there is true obstruction of the duct leading to an epithelial-lined cavity. They are seen more in the posterior portions of the oral mucosa. A ranula (from Rana, the frog genus) is a mucocele of the floor of the mouth. Two other cysts that may be present in the mouth are the parotid duct cyst, which occurs in musicians who use wind instruments (the cyst develops opposite the upper second molar on the buccal mucosa), and the dermoid cyst, which may occur on the floor of the mouth, especially in the sublingual area. Balasubramaniam R, et al: Superficial mucoceles in chronic graft-versushost disease. Gen Dent 2009; 57:82. Nico MM, et al: Mucocele in pediatric patients. Pediatr Dermatol 2008; 25:308. Silva A Jr, et al: Superficial mucocele of the labial mucosa. Gen Dent 2004; 52:424.
Acute necrotizing ulcerative gingivostomatitis (trench mouth, Vincent’s disease) Acute necrotizing ulcerative gingivitis (ANUG) is characterized by a rapid onset of characteristic punched-out ulcerations appearing on the interdental papillae and marginal gingivae. A dirty white pseudomembrane may cover the ulcerations. The lesions may spread rapidly and involve the buccal mucosa, lips, and tongue, as well as the tonsils, pharynx, and entire respiratory tract. The slightest pressure causes pain and bleeding. There is a characteristic foul, fetid odor that is always present. ANUG may lead to loss of attachment of the gingiva and alveolar bone (necrotizing ulcerative periodontitis). Trench mouth begins in a nidus of necrotic tissue, which provides an anaerobic environment for the infection by fuso spirochetal organisms (Bacteroides fusiformis) in association with Borrelia vincentii and other organisms. Poor dental hygiene, smoking, poor nutrition, ingestion of methylenedioxymethamphetamine (ecstasy), and immunosuppression are predisposing factors. It may be seen as a component of the oral infections and inflammatory lesions that occur in immunocompromised HIV-infected patients. Acute herpetic gingivostomatitis, primary HSV infection, may be confused with ANUG. Young children are susceptible to this severe febrile stomatitis with lymphadenitis. It is not primarily gingival in location and does not cause necrosis of the interdental papillae. Noma is a form of fusospirillary gangrenous stomatitis occurring in children with low resistance and poor nutrition. The onset is often triggered by measles. At the onset there is ulceration of the buccal mucosa; this rapidly assumes a gangrenous character and extends to involve the skin and bones, with resultant necrosis. It may end in the patient’s death. Treatment consists of thorough dental hygienic measures under the supervision of a dentist. Penicillin with debridement is the treatment of choice. Use of a 3% hydrogen peroxide mouthwash is also helpful. Brazier WJ, et al: Ecstasy related periodontitis and mucosal ulceration. Br Dent J 2003; 194:197.
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Buchanan JA, et al: Necrotizing stomatitis in the developed world. Clin Exp Dermatol 2006; 31:372. Euwonwu CO, et al: Noma (cancrum oris). Lancet 2006; 368:147. Feller L, et al: Necrotizing periodontal diseases in HIV-seropositive subjects. J Int Acad Periodontol 2008; 10:10. Golayan MO: The epidemiology, etiology, and pathophysiology of acute necrotizing ulcerative gingivitis associated with malnutrition. J Contemp Dent Pract 2004; 5:28. Salama C: Fusospirochetosis causing necrotic oral ulcers in patients with HIV infection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004; 98:321.
Acatalasemia Acatalasemia (Takahara’s disease) is a rare disease in which the enzyme catalase is deficient in the liver, muscles, bone marrow, erythrocytes, and skin. There are several forms. The absence of catalase leads to progressive gangrene of the mouth, with recurrent ulcerations resulting from increased susceptibility to infection by anaerobic organisms. Nearly 60% of affected individuals develop alveolar ulcerations, beginning in childhood. The mild type of the disease is characterized by rapidly recurring ulcers. In the moderate type, alveolar gangrene develops, with atrophy and recession of the alveolar bone, so that the teeth fall out spontaneously. In the severe type, widespread destruction of the jaw occurs. After puberty, all lesions heal, even in individuals who have the severe type. There is no gross difference in appearance between the blood of an acatalasic patient and that of a normal individual, but when hydrogen peroxide is added to a sample of blood, acatalasic blood immediately turns blackish-brown and the peroxide does not foam. Normal blood remains bright and causes the peroxide to foam exuberantly because of the presence of erythrocyte catalase. Acatalasia is a rare peroxisomal disorder and is inherited as an autosomal-recessive trait. Treatment consists of extraction of the diseased teeth and the use of antibiotics to control the harmful effects of the offending bacteria. Ogata M: Acatalasemia. Hum Genet 1991; 86:331. Perner H, et al: Acatalasemia—Takahara’s disease. Hautarzt 1999; 50:590.
Cyclic neutropenia Cyclic, or periodic, neutropenia is characterized by a decrease of circulating neutrophils and dermatologic manifestations. At regular intervals (21 days), neutropenia and mouth ulcerations develop, usually accompanied by fever, malaise, and arthralgia. Ulcerations of the lips, tongue, palate, gums, and buccal mucosa may be extensive. The ulcers are irregularly outlined and are covered by a grayish-white necrotic slough. The anterior teeth may show a grayish-brown discoloration. Premature alveolar bone loss and periodontitis occur. In addition, opportunistic cutaneous infections, such as abscesses, furuncles, noma, pyomyositis, and cellulitis, may develop during the neutropenic stage. Urticaria and erythema multiforme have been reported. There is a cyclic depression of neutrophils occurring at intervals of 12–30 days (average, 21 days) and lasting 5–8 days. The neutrophils in the peripheral blood regularly fall to low levels or completely disappear. Some cases have been associated with agammaglobulinemia. The cause of cyclic neutropenia is a germline mutation of the gene encoding neutrophil elastase (ELANE). This is thought to produce apoptosis of bone marrow progenitor cells. Both the autosomal-dominant disease and sporadic cases have this abnormality. Severe congenital neutropenia is caused by a mutation in the same gene but at a
Femiano F: Oral aphthous-like lesions, PFAPA syndrome. J Oral Pathol Med 2008; 37:319. Jacobs Z, et al: Periodic fever syndromes. Curr Allergy Asthma Rep 2010; (epub). Kanazawa N, et al: Autoinflammatory syndromes with a dermatological perspective. J Dermatol 2007; 34:601. Scully C, et al: Recurrent oral ulceration. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 106:845. Shiohara M, et al: Ela2 mutations and clinical manifestations in familial congenital neutropenia. J Pediatr Hematol Oncol 2009; 31:319.
Recurrent intraoral herpes simplex infection Recurrent intraoral infection with HSV is characterized by numerous small, discrete vesicles occurring in one or a few clusters. The site of involvement is a key feature in suspecting the diagnosis. The keratinized or masticatory mucosa (the palate, gingiva, and tongue) is affected. The grouped vesicles rupture rapidly to form punctate erosions with a red base. Smears from the base prepared with Wright stain will show giant multinucleated epithelial cells. Immunofluorescent tests and viral cultures are also confirmatory. The differential diagnosis of this uncommon manifestation of HSV includes oral herpes zoster, herpangina, and oral aphthosis. The latter two involve nonattached mucosa, whereas recurrent HSV involves mucosa fixed to bone. Differentiation from zoster is made on clinical grounds or by culture and immunofluorescent testing. Chronic progressive ulcerative and nodular intraoral herpes are seen occasionally in HIV-infected patients, or those with leukemia or neutropenia (Fig. 34-22). Mucosal toxicity to chemotherapy may be mimicked. Solitary painful erosions of the tongue or attached mucosa should be tested for HSV in such patients. Additionally, herpetic geometric glossitis, linear longitudinal, cross-hatched, or branching fissures of the dorsal tongue, usually along the central area, may occur. This may be quite painful and limit oral intake. While it usually affects only immunocompromised patients, at least one immunocompetent patient has been affected.
Fig. 34-22 Chronic herpes in a patient on cancer chemotherapy.
Recurrent aphthous stomatitis (canker sores, aphthosis)
different site. The latter condition predisposes to the development of myelodysplasia and acute myelogenous leukemia, while cyclic neutropenia does not. In the differential diagnosis are other periodic fever syndromes, including periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome, Mediterranean fever, Hibernian fever and hyperimmunoglobulin D syndrome, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome. All share a predisposition to the development of aphthous-like oral ulcerations. PFAPA syndrome is defined clinically and is characterized by 4 days of high fevers (over 40°C) that recur at regular intervals every 2–8 weeks, separated by wellbeing between episodes. Associated with fevers are aphthous stomatitis (70%), pharyngitis (72%), and cervical adenitis (88%). The disease is not familial, begins before 5 years of age, and responds to small doses of prednisone for 1–2 days. Tonsillectomy has been reported to cure it. Use of recombinant human granulocyte colony-stimulating factor (G-CSF) has been successful in the treatment of cyclic neutropenia patients. If the potential side effects limit use of this therapy, cyclosporine has been reported to be effective also. Administering antibiotics during infections seems to expedite recovery. Careful attention to oral hygiene, including plaque control, helps improve mouth lesions and reduces the risk of infections. Death may occur from pneumonia, sepsis, gangrenous pyoderma, or granulocytopenia.
Fig. 34-23 Aphthous stomatitis.
Arduino PG, et al: Herpes simplex virus type 1 infection. J Oral Pathol Med 2008; 37:107. Bruce AJ, et al: Acute oral ulcers. Dermatol Clin 2003; 21:1. Mirowski GW, et al: Herpetic geometric glossitis in an immuno competent patient with pneumonia. J Am Acad Dermatol 2009: 61:139. Woo SB, et al: Management of recurrent oral herpes simplex infections. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103(Suppl): S12.e1.
Recurrent aphthous stomatitis (canker sores, aphthosis) Clinical features Aphthous stomatitis is a painful, recurrent disease of the oral mucous membrane. It begins as small, red, discrete, or grouped papules, which in a few hours become necrotizing ulcerations. They are small, round, shallow, white ulcers (aphthae), generally surrounded by a ring of hyperemia (Fig. 34-23). As a rule, they are tender; they may become so painful that they interfere with speech and mastication. They are mostly about 5 mm in diameter but may vary in size from 3 to 10 mm. When larger, they are called major aphthae. A third subcategory, herpetiform aphthae, consists of small 1–3 mm lesions grouped into a coalescing larger plaque, which may take 1–4 weeks to resolve. Usually, 1–5 lesions occur per attack; however, they may occur in any number. They are located in decreasing frequency on the buccal and labial mucosa, edges of the tongue, buccal and lingual sulci, and soft palate. There is a marked predilection for the nonkeratinized mucosa (any not bound to underlying periosteum). This and the fact that they 797
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are rarely confluent, even when they occur as small crops of 1 or 2 mm lesions (herpetiform aphthae), help to distinguish them from the uncommon recurrent intraoral HSV infection. Aphthae may also occur on the vagina, vulva, penis, anus, and even the conjunctiva. When they involve the oral and genital mucosa and are nearly always present in numbers greater than or equal to three, the term complex aphthosis is applied. The lesions tend to involute in 1–2 weeks, but recurrences are common. These recurrences may be induced by trauma, such as self-biting, toothbrush injury, and dental procedures, spicy foods, citrus, fresh pineapple, walnuts, allergy, emotional stress, or hormonal changes in women, such as in menstruation, pregnancy, menarche, and menopause. A familial predisposition has also been described as familial epidemic aphthosis. Recurrent aphthous stomatitis is the most common lesion of the oral mucosa, affecting from 10% to 20% of the population. It starts commonly in the second or third decade and patients may experience recurrent bouts of lesions several times yearly for many decades. When present in neonates or young children, autoinflammatory syndromes should be considered. In PFAPA syndrome, the high fevers and associated findings occur with striking periodicity every 4 weeks, last 4–6 days, and resolve only to recur the following month. The children are otherwise well. One or two doses of prednisone (2 mg/kg) abort the attack and tonsillectomy may cure it. Aphthous oral ulcerations may also be seen in familial Mediterranean fever, TRAPS, hyperimmunoglobulinemia D and periodic fever, PAPA syndrome, and the newly defined deficiency of the interleukin-1-receptor antagonist (DIRA) syndrome. Ulcerations such as these may also be the presenting sign in Behçet syndrome, HIV infection, malabsorption syndromes, gluten-sensitive enteropathy, pernicious anemia, cyclic neutropenia, neutropenia, ulcerative colitis, and Crohn’s disease. History, physical examination, complete blood count, and long-term follow-up documenting the recurrent course in the absence of other symptoms will secure the diagnosis. Some patients have aphthosis associated with low folate, B12 or iron levels, so testing should include evaluation of these.
Etiologic factors Although individual patients often suspect that one of the factors mentioned above is responsible for precipitating their recurrence, infectious or immunologic causation is favored by investigators. The true cause is unknown. Histologically, the lesion consists of a lymphocytic inflammatory infiltration with occasional plasma cells and eosino phils, which suggests delayed hypersensitivity.
Diagnosis Aphthous stomatitis must be differentiated from mucous patches of early syphilis, candidiasis, Vincent angina, the avitaminoses (particularly pellagra and scurvy), erythema multiforme, pemphigus, cicatricial pemphigoid, lichen planus, primary HSV infection of the mouth, recurrent labial herpes, and recurrent intraoral HSV infection.
Treatment No permanent cure is available. Several topical agents will lessen the pain. A mixture of equal parts of elixir of Benadryl and Maalox, held in the mouth for 5 min before meals, is soothing. Kaolin may also be added to the mixture. Lidocaine (Xylocaine Viscous) 2% solution, keeping 1 teaspoonful in the 798
mouth for several minutes, is helpful in allaying pain. Another useful topical anesthetic is dyclonine hydrochloride (Dyclone) 0.5% applied to the lesions. A large number of reasonably effective over-the-counter remedies are also available. Triggers, such as spicy foods, citrus, walnuts, pineapple, and other irritating substances should be avoided. One may use other measures to shorten the course and induce healing of lesions. A mixture of equal parts of fluocinonide ointment and Orabase, applied to the ulcers three or four times a day, is effective in aiding the healing of existing ulcers; however, it does not prevent new ulcers. Some patients object to the thick, sticky texture of Orabase and prefer fluocinonide gel. Clobetasol ointment can also be very effective. Intralesional steroids and short 3- or 4-day courses of oral steroids may help, particularly for indolent or large lesions. Nonsteroidal alternatives include 5 mL of an oral suspension containing 250 mg of tetracycline; this is held in the mouth for 2 min and then swallowed. This is done four times daily for 1 week. Amlexanox 5% oral paste (Aphthasol) is a useful topical therapy both to induce healing and to relieve pain. Sucralfate suspension, alone or compounded with a topical steroid, may be useful, as has been described in peptic ulcer disease and the ulcerations of Behçet’s disease. To try to prevent new lesions, known triggers for the individual patient should be avoided as much as possible. Colchicine at 0.6 mg per day for 1 week, then increasing to 1.2 or even 1.8 mg per day, is recommended. If this is ineffective or gastrointestinal or other side effects limit dosage, dapsone may be added to colchicine or substituted for it. It is given in steadily increasing doses of 25 mg for 3 days, then 50 mg for 3 days, then 75 mg for 3 days, then 100 mg for 7 days. If the blood count is normal, no side effects are present, and the disease is not controlled, further increases to 125 or even 150 mg may be given. Thalidomide is another effective alternative, but caution regarding teratogenicity and neurotoxicity is necessary if this is to be considered. One method is thalidomide, 300 mg/day to start, 200 mg/day after 10 days, and 100 mg/day after 2 months. Relapses are treated with 100 mg/day for 12 days. Several investigators have reported finding low folate, iron, or B12 levels in about 20% of aphthosis patients investigated, but others do not see this with such high frequency. Still, it is worth investigating, as correction of the abnormality clears or improves the condition in most cases where an abnormality exists. Two studies document improvement with cyanocobalamin, even of those without abnormalities. Aksentijevich I, et al: An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 2009; 360:2467. Berlucchi M, et al: Update on treatment of Marshall’s syndrome (PFAPA syndrome). Ann Otol Rhinol Laryngol 2003; 112:365. Bruce AJ, et al: Acute oral ulcers. Dermatol Clin 2003; 21:1. Femiano F, et al: Guidelines for diagnosis and management of aphthous stomatitis. Pediatr Infect Dis J 2007; 26:728. Glucan E, et al: Cyanocobalamin may be beneficial in the treatment of recurrent aphthous stomatitis even when vitamin B12 levels are normal. Am J Med Sci 2008; 336:379. Hello M, et al: Use of thalidomide for severe recurrant aphthous stomatitis. Medicine (Baltimore) 2010; 89:176. Lynde CB, et al: Successful treatment of complex aphthosis with colchicine and dapsone. Arch Dermatol 2009; 145:273. Sampaio IC, et al: Two siblings with PFAPA syndrome. Pediatr Infect Dis 2009; 28:254. Scully C, et al: Oral mucosal disease: recurrent aphthous stomatitis. Br J Oral Maxillofac Surg 2008; 46:198. Scully C, et al: Auto-inflammatory syndromes and oral health. Oral Dis 2008; 14:690. Shetty C, et al: Current role of thalidomide in HIV-positive patients with recurrent aphthous ulcerations. Gen Dent 2007; 55:537. Zunt SL: Recurrent aphthous stomatitis. Dermatol Clin 2003; 21:33.
Behçet syndrome Fig. 34-24 Major aphthae.
Major aphthous ulcer (periadenitis mucosa necrotica recurrens) In Sutton’s disease, a major aphthous ulcer begins as a small shotlike nodule on the inner lip, buccal mucosa, or tongue, which breaks down into a painful, sharply circumscribed ulcer with a deeply punched-out and depressed crater. It may at times begin in the faucial pillars or oropharynx (Fig. 34-24). It may persist for 2–12 weeks before healing with a soft, pliable scar. There are seldom more than 1–3 lesions present at one time. However, remissions tend to be short, and new lesions may appear before old ones have quite healed. The term major aphthous ulcers has supplanted the unwieldy Latin name for this disease. The cause is unknown, but evidence favors an immunologic or infectious etiology. These painful lesions are frequently present in HIV-infected patients who may experience similar lesions in the esophagus, rectum, anus, and genitals. Treatment is difficult, and the general measures discussed under recurrent aphthae should be employed. Intralesional or systemic steroids in short courses, which may be effective, are often given. If recurrences are such that systemic steroids are prescribed for more than two or three short courses per year, alternative oral medications such as colchicine, dapsone, or thalidomide may be tried. Boldo A: Major recurrent aphthous ulceration. Conn Med 2008; 72:271. Chung JY, et al: Recurrent scarring ulcers of the oral mucosa. Arch Dermatol 1997; 133:1162. Shetty C, et al: Current role of thalidomide in HIV-positive patients with recurrent aphthous ulcerations. Gen Dent 2007; 55:537.
Behçet syndrome (oculo-oral-genital syndrome) Clinical features Behçet syndrome consists of recurrent oral aphthous ulcerations that recur at least three times in one 12-month period in the presence of any two of the following: recurrent genital ulceration, retinal vasculitis or anterior or posterior uveitis, cutaneous lesions (erythema nodosum; pseudofolliculitis or papulopustular lesions; or acneiform nodules in postadolescent patients who are not receiving corticosteroid treatment), or a positive pathergy test. Oral lesions occur on the lips, tongue, buccal mucosa, soft and hard palate, tonsils, and even in the pharynx and nasal cavity. The lesions are single or multiple, 2–10 mm or larger in diameter, and sharply circumscribed, with a dirty grayish
Fig. 34-25 Behçet disease.
base and a surrounding bright red halo. Other patients show deep ulcerations that leave scars resembling those caused by Sutton major aphthous ulcers. The lesions are so painful that eating may be difficult. A foul mouth odor is in most cases markedly noticeable. Genital lesions occur in men on the scrotum (Fig. 34-25) and penis or in the urethra, and in women, on the vulva, cervix, or vagina; they may be found in both sexes on the genitocrural fold, anus, or perineum, or in the rectum. These ulcerations are similar to those seen in the mouth. In addition, macules, papules, and folliculitis may develop on the scrotum. Lesions in women may lead to deep destruction of the vulva. Swellings of the regional nodes and fever may accompany oral and genital attacks. The ocular lesions start with intense periorbital pain and photophobia. Retinal vasculitis is the most classic eye sign and the chief cause of blindness. Conjunctivitis may be an early accompaniment of uveitis, and hypopyon a late one. Iridocyclitis is frequently seen. Both eyes are eventually involved. Untreated disease leads to blindness from optic atrophy, glaucoma, or cataracts. Neurologic manifestations are mostly in the central nervous system and resemble most closely those of multiple sclerosis. Remissions and exacerbations are the rule. Thrombophlebitis occurs with some frequency. Thrombosis of the superior vena cava may also occur. Arthralgia is most often present in the form of polyarthritis. Unfortunately, the international criteria include nonspecific common cutaneous lesions (pseudofolliculitis, papulopustular or acneiform lesions). Demonstration of either leukocytoclastic vasculitis or a neutrophilic vascular reaction on histologic examination of a lesion would make the cutaneous criteria more specific. There is a relatively high prevalence of Behçet’s disease in the Far East and Mediterranean countries, whereas in the US and Western Europe it is much less common. In large series of patients from areas of high prevalence, men with an age of onset in the thirties predominate. They tend to have a worse prognosis than women. Mangelsdorf et al reported on 25 patients seen in a university dermatology referral practice in the US; 22 of their patients were young women with a high frequency of mucocutaneous lesions and a low prevalence of ocular involvement. This may reflect referral bias or could indicate that the disease is less severe in the US. On histologic examination, the early lesions show a leukocytoclastic vasculitis. There is perivascular infiltration, which is chiefly lymphocytic in older lesions, with endothelial proliferation that obliterates the lumen. The cause of Behçet’s disease 799
Disorders of the Mucous Membranes
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has been postulated to have an infectious, immunologic, and/ or genetic basis but the evidence is still inconclusive for any of these.
Diagnosis Usually the disease starts with one oral ulceration, followed by others. It may take years before additional lesions develop. Therefore, the diagnosis requires two classic signs in addition to oral ulcerations. In women anal and genital lesions predominate, often with subsequent involvement of the eyes. Behçet’s disease must be differentiated from herpetic or aphthous stomatitis, pemphigus, oral cancer, and Stevens–Johnson syndrome (erythema multiforme). A skin puncture or pathergy test may be used to investigate patients further; however, it is not reliable in that it may be negative in otherwise welldocumented cases. It is done by injecting 0.1 mL of normal saline solution into the skin or by simply pricking the skin with a sterile needle. A pustule appears at the site within 24 h. If results are negative, the test should be repeated at 2–5 points before results are accepted. Pathergy has been observed in patients with Behçet’s disease, pyoderma gangrenosum, Sweet syndrome, and bowel-associated dermatosis–arthritis syndrome.
Treatment Usually, the ulcerations heal spontaneously. Mild mouthwashes and toothpastes and restricted use of the toothbrush should be prescribed when there are oral lesions. With regard to treating the symptoms and healing of the aphthae, local treatments as described for aphthae may be used. Sucralfate suspension has been studied in Behçet oral and genital ulcers, and was found to decrease pain and healing time. On the whole, the therapeutic problem of aphthosis is not the healing of the individual lesions but the prevention of new attacks. For that purpose, several options exist, none of which is optimal. Colchicine, 0.6 mg twice a day, may be started for 2 weeks. In the absence of response and gastrointestinal side effects, the dose may be increased to three times a day. Although this may not totally alleviate the mucocutaneous lesions, it may decrease their recurrence rate by 50% or more. Dapsone may be substi-
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tuted or added to this for improvement of response. The usual therapeutic final dose is 100 mg/day. Thalidomide has been found to be effective in many patients. One dosing method is thalidomide, 200 mg twice a day for 5 days, and 100 mg twice a day for 15–60 days. It has no effect on iridocyclitis. Of course, long-term treatment will commonly be complicated by neurotoxicity and the teratogenicity of this medication is well known. Methotrexate, in a weekly oral dose of 7.5 to 20 mg, should be reserved for severe refractory cases, as should more aggressive systemic treatments such as systemic corticosteroids, azathioprine, chlorambucil, cyclosporine, interferon-α, tumor necrosis factor antagonists, and cyclophosphamide. The long-term outlook is for intermittent recurrent flares that may be life-long. Blindness, neurologic impairment, and vascular thromboses are potential serious complications. Almonznino G, et al: Infliximab for the treatment of resistant oral ulcers in Behçet’s disease. Clin Exp Rheumatol 2007; 25:S99. Alpsoy E, et al: Mucocutaneous lesions of Behçet’s disease. Yonsei Med J 2007; 48:573. Calamia KT, et al: Behçet’s disease. Curr Rheumatol Rep 2008; 10:349. Calamia KT, et al: Epidemiology and clinical characteristics of Behçet’s disease in the US. Arthritis Rheum 2009; 61:600. Evereklioglu C: Managing the symptoms of Behçet’s disease. Expert Opin Pharmacother 2004; 5:317. Lin P, et al: Behçet’s disease. J Clin Rheumatol 2006; 12:282. Mangelsdorf HC, et al: Behçet’s disease. J Am Acad Dermatol 1996; 34:745. Mendes D, et al: Behçet’s disease—a contemporary review. J Autoimmun 2009; 32:178. Oh SH, et al: Comparison of the clinical features of recurrent aphthous stomatitis and Behçet’s disease. Clin Expt Dermatol 2009; 34:e208. Rogers RS 3rd: Pseudo-Behçet’s disease. Dermatol Clin 2003; 21:49. Uzun S, et al: The clinical course of Behçet’s disease in pregnancy. J Dermatol 2003; 30:499. Yurdakul S, et al: Behçet syndrome. Curr Opin Rheumatol 2004; 16:38.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. 34-1 Benign oral leukoplakia. Fig. 34-2 Torus palatinus.
Bonus images for this chapter can be found online at http://www.expertconsult.com
Cutaneous Vascular Diseases
Raynaud phenomenon and Raynaud’s disease Raynaud phenomenon occurs in the presence of an associated disease, usually collagen vascular disease, and often systemic sclerosis/scleroderma. This is also called secondary Raynaud’s phenomenon. Raynaud’s disease (or primary Raynaud’s disease) occurs in the absence of such disease. In a series of 165 patients with Raynaud, 51 had primary disease (Raynaud’s disease). A defined connective tissue disease was present in about one-third of the remaining patients, but 54 had undefined connective tissue disease (35 with positive antinuclear antibody [ANA] titer). In another study of 142 patients with idiopathic Raynaud phenomenon followed for more than 10 years, 14% progressed to a definite connective tissue disease. The initial presence of ANAs, thickening of fingers, older age at onset, and female sex were predictors of connective tissue disease. In a larger study of 586 patients with Raynaud, followed by sequential nailfold capillary microscopy and auto antibody determinations, these two investigations were able, in 80% of cases, to identify the 12.6% of patients who went on to develop systemic sclerosis. The absence of nailfold capillaroscopic findings is also predictive of primary Raynaud’s disease (no associated systemic disease). Laser Doppler perfusion imaging may enhance the evaluation of vascular damage from Raynaud’s. Technetium digital blood flow scintigraphy may aid in the early diagnosis of Raynaud’s of either the primary or the secondary type. Many of the studies on pathogenesis and therapy in Raynaud are conducted on patients with systemic sclerosis/scleroderma, so it may not be possible to translate these findings to patients with Raynaud’s disease. However, it appears that cold exposure is a major trigger of vasospasm in all Raynaud’s patients. There appears to be an exaggerated sympathetic response to cold. This may be due to both excessive vasoconstrictor tone and a weak systemic vasodilatation process, centrally mediated at least in part. The abnormal sympathetic response may also explain why some patients say that “stress” triggers Raynaud attacks. High homocysteine levels have been detected in patients with both primary and secondary Raynaud’s disease. Patients with systemic sclerosis and Raynaud’s phenomenon have elevated levels of endothelin (ET-1), and this correlated with both nailfold capillaroscopic findings and more advanced disease.
Raynaud phenomenon Raynaud phenomenon is produced by an intermittent constriction of the small digital arteries and arterioles. The digits have sequential pallor, cyanosis, and rubor. The involved parts are affected in paroxysms by the attacks of ischemia, which cause them to become pale, cold to the touch, and numb. The phenomenon is more frequently observed in cold weather. When exposed to cold, the digits become white
35
(ischemic), then blue (cyanotic), and finally red (hyperemic). In time, the parts may fail to regain their normal circulation between attacks and become persistently cyanotic and painful. If this phenomenon persists over a long period, punctate superficial necrosis of the fingertips develops (Fig. 35-1); later, even gangrene may occur. Raynaud phenomenon occurs most frequently in young to middle-aged women. It occurs with scleroderma, dermato myositis, lupus erythematosus, mixed connective tissue disease (MCTD), Sjögren syndrome, rheumatoid arthritis, and paroxysmal hemoglobinuria. Scleroderma was the underlying diagnosis in more than half of patients in one series. Occlusive arterial diseases, such as embolism, thromboangiitis obliterans, arteriosclerosis obliterans, and large-vessel vasculitis (Takayasu’s disease), may be present. In addition, various diseases of the nervous system, including cervical rib, scalenus anticus syndrome, and complex regional pain syndrome (reflex sympathetic dystrophy), may produce the disorder. Physical trauma, such as hand-transmitted vibration as occurs with pneumatic hammer operation, can induce a syndrome identical to Raynaud’s and has been termed “vibration white finger” or “hand–arm vibration syndrome”. Pianists and typists may also develop this phenomenon. Raynaud’s is a well-recognized complication following cold injury, especially frostbite. Pharmacological agents, such as bleomycin, ergot, β-blockers (including eyedrops), cyclosporine, interferon (IFN)-α and β, vinyl polychloride exposure, and cocaine, may also be the cause. The clumping of red blood cells is believed to be responsible for the induction of Raynaud phenomenon, with high titers of circulating cold agglutinins. It may occur in cryoglobulinemia and polycythemia vera. Patients with cancer may develop Raynaud’s as a paraneoplastic phenomenon. Endocrine disorders, such as acromegaly, pheochromocytoma, carcinoid, and hypothyroidism, may present with or be associated with Raynaud’s. Raynaud’s of the nipple is a variant of Raynaud’s that is difficult to diagnose. It presents with severe pain during lactation, and must be distinguished from nipple candidiasis and eczema. Patients report the onset of symptoms during pregnancy, and when asked, will say that the symptoms are triggered by cold and accompanied by biphasic or triphasic color changes of the nipple. Nifedipine can be highly effective in this condition and is safe for use during lactation, since little is found in the breast milk. Simple tests and physical examination will generally distinguish between Raynaud’s disease and Raynaud phenomenon. Sclerodactyly, digital pitted scars, puffy fingers with telangiectases, positive ANA, subcutaneous calcifications, basilar lung fibrosis, and changes on nailfold capillary microscopy (avascular “skip” areas with irregularly dilated capillary loops) are signs of connective tissue disease. An anticentromere antibody is an indicator of CREST (Calcinosis, Raynaud’s syndrome, Esophageal dysmotility, Sclerodactyly, Telangiectasia) syndrome. Measuring rewarming after cold exposure can distinguish hand–arm vibration syndrome
Cutaneous Vascular Diseases
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Fig. 35-1 Raynaud phenomenon with fingertip necrosis.
(HAVS) from Raynaud’s. HAVS patients will all rewarm their hand temperature by >2.2°C in the first 30 seconds, and will rewarm their hand temperature by 5°C in the same time period as normal persons (less than 5 min 30 sec); in Raynaud’s patients, rewarming averages 7 min and is always longer than 5 min 30 sec.
Raynaud’s disease (primary Raynaud’s disease) Raynaud’s disease is a primary disorder of cold sensitivity primarily seen in young women. The intermittent attacks of pallor, cyanosis, hyperemia, and numbness of the fingers are identical to those in Raynaud phenomenon. The disease is usually bilateral, and gangrene occurs in less than 1% of cases. The diagnosis requires the absence of the diseases enumerated under Raynaud phenomenon. Although some suggest that Raynaud’s disease should be present for 2 years before being classified as a primary process, it may take as long as 11 years for some systemic disorders to manifest. Overall, fewer than half of patients presenting with Raynaud symptoms will prove to have a connective tissue disease. The prognosis is good for primary Raynaud’s disease.
Treatment
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Treatments have often been studied only in patients with Raynaud’s phenomenon and digital ulceration, so not all treatments can be assumed to be effective in primary Raynaud’s disease or Raynaud’s secondary to other causes. If an underlying cause if found, treatment of that associated condition will often lead to improvement of the Raynaud’s. In both primary and secondary Raynaud’s, exposure to cold should be avoided. This includes avoidance of exposure to cold not only of the extremities but also of other parts of the body, since vaso spasm may be induced by reduction of core body temperature. Warm gloves should be worn whenever possible. Residence in a warm climate is helpful. Trauma to the fingertips should be avoided. Smoking is absolutely contraindicated. An attack of Raynaud’s may be broken at times by swinging the affected arm in a wide circle from the shoulder—the “windmill” maneuver. The use of standard nitroglycerin paste has had minimal efficacy and can produce systemic side effects. A new form of topical nitroglycerin, known as MQX-503, has been reported to improve Raynaud’s while having the same side effects as placebo. Alternative treatments, including ginkgo and other herbal medications, have limited efficacy when compared to the standard treatments below, and cannot be recommended for patients with significantly symptomatic disease.
Calcium channel-blockers are the first-line therapy used in Raynaud’s due to their efficacy and low side-effect profile. Prolonged-release amlodopine or nifedipine is usually recommended. Two-thirds of treated patients will respond favorably. The phosphodiesterase inhibitor sildenafil has been effective in both reducing the frequency of Raynaud’s episodes and in healing digital ulcers. It has become the secondline agent of choice. Tadalafil has not been compared to sildenafil, but has not been effective in secondary Raynaud’s in scleroderma, and substitution of tadalafil for sildenafil for cost savings may not be appropriate in the treatment of Raynaud’s. An angiotensin II-receptor type I antagonist (losartan) or selective serotonin-reuptake inhibitors (fluoxetine or venlafaxine) may be useful in refractory cases. Quinapril is not effective, suggesting that not all angiotensin-converting enzyme (ACE) inhibitors are effective in Raynaud’s. Intravenous biweekly N-acetylcysteine has been effective in reducing the number of attacks and was relatively side effectfree. The use of statins (specifically atorvastatin) in patients with Raynaud’s due to systemic sclerosis/scleroderma was associated with a reduction in Raynaud’s-associated symptoms. This may be through the vasoprotective actions of statins, since statin administration was associated with reduction of circulating markers of vascular injury, which are commonly elevated in scleroderma patients. Bosentan, an endothelin receptor (ETA and ETB) antagonist, significantly reduces the frequency of Raynaud’s attacks and reduces new digital ulcers. Iloprost, a prostaglandin analog, has substantial efficacy in scleroderma-associated Raynaud’s and digital ulceration, when given intravenously but not orally. Oral cisaprost has minimal or no efficacy. Treprostinil and epoprostenol have preliminary data supporting their benefit. In cases that are refractory to the medical treatments outlined above, surgical modalities can be considered. If single digits are involved, botulinum toxin injections in the palm around each involved neurovascular bundle may lead to dramatic and, at times, immediate pain reduction. Ulcerations of the affected digits heal following the injections. The duration of response is often months to years, and can be repeated with similar efficacy. Local digital sympathectomy can be effective, and avoids amputation of chronically ulcerated digits. Cervical sympathectomy and endoscopic thoracic sympathectomy may give initial relief, but Raynaud’s symptoms often recur after 1 year to 18 months. However, despite the return of the Raynaud’s symptoms, digital ulceration is markedly reduced. Compensatory hyperhidrosis is a common complication of thoracic sympathectomy. Allen D, et al: Paraneoplastic Raynaud’s phenomenon in a breast cancer survivor. Rheumatol Int 2009 Jun 11 (Epub ahead of print). Anderson JE, et al: Raynaud’s phenomenon of the nipple: a treatable cause of painful breastfeeding. Pediatrics 2004; 113:e360. Batthish M: Raynaud’s phenomenon as a presenting feature of hypothyroidism in an 11-year-old girl. J Rheumatol 2009; 36:203. Blagojevic J, Matucci-Cerinic M: Are statins useful for treating vascular involvement in systemic sclerosis? Nat Clin Pract Rheumatol 2009; 5:70. Bovenzi M: A longitudinal study of vibration white finger, cold response of digital arteries, and measure of daily vibration exposure. Int Arch Occup Environ Health 2009 Sep 4 (Epub ahead of print). Brueckner CS, et al: Effect of sildenafil on digital ulcers in systemic sclerosis—analysis from a single centre pilot study. Ann Rheum Dis 2009 Nov 8 (Epub ahead of print). Choi WS, et al: To compare the efficacy and safety of nifedipine sustained release with Ginkgo biloba extract to treat patients with primary Raynaud’s phenomenon in South Korea: Korean Raynaud study (KOARA study). Clin Rheumatol 2009; 28:553. Chung L, et al: MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud’s phenomenon. Arthritis Rheum 2009; 60:870. De Angelis R, et al: Raynaud’s phenomenon: clinical spectrum of 118 patients. Clin Rheumatol 2003; 22:279.
Schiopu E, et al: Randomized placebo-controlled crossover trial of tadalafil in Raynaud’s phenomenon secondary to systemic sclerosis. J Rheumatol 2009; 36:2264. Sulli A, et al: Raynaud’s phenomenon and plasma endothelin: correlations with capillaroscopic patterns in systemic sclerosis. J Rheumatol 2009; 36:1235. Sunderkotter C, et al: Comparison of patients with and without digital ulcers in systemic sclerosis: detection of possible risk factors. Br J Dermatol 2009; 160:835. Wasserman A, Brahn E: Systemic sclerosis: bilateral improvement of Raynaud’s phenomenon with unilateral digital sympathectomy. Semin Arthritis Rheum 2009 Oct 29 (Epub ahead of print). Wu YJ, et al: Vascular response of Raynaud’s phenomenon to nifedipine or herbal medication (duhuo-tisheng tang with danggui-sini tang): a preliminary study. Chang Gung Med J 2008; 31:492. Ziegler S, et al: Long-term outcome of primary Raynaud’s phenomenon and its conversion to connective tissue disease: a 12-year retrospective patient analysis. Scand J Rheumatol 2003; 32:343.
Erythromelalgia
Delgado S, et al: Bacterial analysis of breast milk: a tool to differentiate Raynaud’s phenomenon from infectious mastitis during lactation. Curr Microbiol 2009; 59:59. Dorafshar AH, et al: Reoperative digital sympathectomy in refractory Raynaud’s phenomenon. Plast Reconstr Surg 2009; 123:36e. Fregene A, et al: Botulinum toxin type A: a treatment option for digital ischemia in patients with Raynaud’s phenomenon. J Hand Surg Am 2009; 34:446. Friedman EA, et al: The effects of tadalafil on cold-induced vasoconstriction in patients with Raynaud’s phenomenon. Clin Pharmacol Ther 2007; 81:503. Funauchi M, et al: Effects of bosentan on the skin lesions: an observational study from a single center in Japan. Rheumatol Int 2009; 29:769. Gargh K, et al: A retrospective clinical analysis of pharmacological modalities used for symptomatic relief of Raynaud’s phenomenon in children treated in a UK paediatric rheumatology centre. Rheumatology (Oxford) 2009 Oct 1 (Epub ahead of print). Gayraud M: Raynaud’s phenomenon. Joint Bone Spine 2007; 74:e1. Gliddon AE, et al: Prevention of vascular damage in scleroderma and autoimmune Raynaud’s phenomenon: a multi-center, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum 2007; 56:3837. Herrick AL: A local approach to Raynaud phenomenon. Nat Rev Rheumatol 2009; 5:246. Heymann WR: Sildenafil for the treatment of Raynaud’s phenomenon. J Am Acad Dermatol 2006 Sep; 55:501. Khan MI, et al: Efficacy of cervicothoracic sympathectomy versus conservative management in patients suffering from incapacitating Raynaud’s syndrome after frost bite. J Ayub Med Coll Abbottabad 2008; 20:21. Koenig M, et al: Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis. Arthritis Rheum 2008; 58:3902. Kuwana M, et al: Long-term beneficial effects of statins on vascular manifestations in patients with systemic sclerosis. Mod Rheumatol 2009; 19:530. Kwon SR, et al: Diagnosis of Raynaud’s phenomenon by (99m) Tc-hydroxymethylene diphosphonate digital blood flow scintigraphy after one-hand chilling. J Rheumatol 2009; 36:1663. Lambova SN, Muller-Ladner U: The role of capillaroscopy in differentiation of primary and secondary Raynaud’s phenomenon in rheumatic diseases: a review of the literature and two case reports. Rheumatol Int 2009; 29:1263. Lazzerini PE, et al: Homocysteine and Raynaud’s phenomenon: a review. Autoimmun Rev 2009 Aug 15 (Epub ahead of print). Malenfant D, et al: The efficacy of complementary and alternative medicine in the treatment of Raynaud’s phenomenon: a literature review and meta-analysis. Rheumatology (Oxford) 2009; 48:791. Mariotti A, et al: Finger thermoregulatory model assessing functional impairment in Raynaud’s phenomenon. Ann Biomed Eng 2009 Sep 4 (Epub ahead of print). Mondelli M, et al: Sympathetic skin response in primary Raynaud’s phenomenon. Clin Auton Res 2009; 19:355. Morino C, et al: Raynaud’s phenomenon of the nipples: an elusive diagnosis. J Hum Lact 2007; 23:191. Nagy Z, et al: Nailfold digital capillaroscopy in 447 patients with connective tissue disease and Raynaud’s disease. J Eur Acad Dermatol Venereol 2004; 18:62. Neumeister MW, et al: Botox therapy for ischemic digits. Plast Reconstr Surg 2009; 124:191. Pope J, et al: Iloprost and cisaprost for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2000; (2):CD000953. Rosato E, et al: Laser Doppler perfusion imaging is useful in the study of Raynaud’s phenomenon and improves the capillaroscopic diagnosis. J Rheumatol 2009; 36:2257. Rosato E, et al: The treatment with N-acetylcysteine of Raynaud’s phenomenon and ischemic ulcers therapy in sclerodermic patients: a prospective observational study of 50 patients. Clin Rheumatol 2009; 28:1379. Salem KM, et al: Analysis of rewarming curves in Raynaud’s phenomenon of various aetiologies. J Hand Surg Eur Vol 2009; 34:621.
Erythromelalgia Also called erythermalgia and acromelalgia, erythromelalgia is a not uncommon condition. The population-based incidence is 1.3 per 100 000 per year: 2.0 per 100 000 in women and 0.6 per 100 000 in men per year. Erythromelalgia is an easily recognized clinical syndrome characterized by paroxysmal vasodilation affecting the feet, with burning, localized pain, redness, and high skin temperature. Infrequently, the hands (Fig. 35-2), face, and ears may be involved. The burning paroxysms may last from a few minutes to several days, and are usually triggered by an increase in environmental temperature or exercise. The average patient has 1–2 attacks per week, but in some patients, the attacks are much more frequent. Often, relief can only be obtained by immersing the burning feet in ice water. Over 20% of patients will have evidence of cold injury, and more than 1% will suffer gangrene or undergo amputation. Quality of life is severely impacted by this condition. Erythromelalgia can be considered primary, secondary, and familial. For treatment purposes, secondary cases of erythro melalgia should be carefully divided into those associated with myeloproliferative diseases, often with elevated platelets, and others. Myeloproliferative diseases complicated by erythromelalgia include polycythemia vera, thrombotic thrombocytopenic purpura, and various forms of thrombocythemia. Administration of romiplostim, a thrombopoiesisstimulating protein, has resulted in erythromelalgia. Low-dose aspirin is effective therapy for erythromelalgia associated with platelet abnormalities. If this fails, other methods to reduce the platelet count should be considered.
Fig. 35-2 Erythromelalgia of the hands (normal hands lateral to the patient’s).
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Cutaneous Vascular Diseases
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Acquired erythromelalgia has been reported secondary to topical exposure to isopropyl alcohol and after mushroom poisoning with Clitocybe acromelalga and Clitocybe amoenolens. Medications that have induced erythromelalgia include calcium channel-blockers (both nifedipine and verapamil), ergot derivatives such as bromocriptine and pergolide, and cyclosporine. There may be a long period of treatment (years) with these agents before the appearance of the erythromelalgia. Stopping the offending medication usually leads to improvement of symptoms within weeks. In the vast majority of cases seen by dermatologists, erythro melalgia is probably a neurological disorder. It can be seen in various neurological conditions or diseases associated with neurological sequelae, such as peripheral neuropathy, myelitis, multiple sclerosis, autoimmune small-fiber axonopathy, or diabetes mellitus. Two patients with autoimmune disease and idiopathic thrombocytopenic purpura developed erythromelal gia and responded to intravenous immunoglobulin (IVIG) therapy. Erythromelalgia is sometimes associated with Raynaud phenomenon, both disorders of abnormal neurovascular function. In many cases, no associated neurological disease may be detected by routine neurological examination, but careful neurological testing will reveal evidence of a smallfiber neuropathy in the majority of such cases. Inherited, familial, or hereditary erythromelalgia usually has its onset in childhood or adolescence (early or late onset). Familial cases have an autosomal-dominant inheritance pattern. Familial erythromelalgia is now known to be an “inherited neuronal ion channelopathy.” The mutation is in the gene SCN9A, which encodes a peripheral sodium channel NaV1.7. This is a mainly peripheral sodium channel with robust expression in dorsal root ganglion neurons and sympathetic ganglion neurons, especially those with nociceptive function. This sodium channel acts as a “threshold” channel and sets the gain in nociceptors. Many mutations in the affected gene have been mapped. Gene mutations causing erythromelalgia occur in areas that affect the structure of the actual channel by substituting amino acids in this critical location. The mutations causing erythromelalgia are gain-offunction mutations. The amount of gain of function correlates with the age of onset of the disease, more significant mutations having earlier onset. The nature of the mutation also affects the binding of medications to the channel, so various mutations may have different responses to same medication, depending on whether that mutation allows the drug to bind to the channel. Other gain-of-function mutations in the SCN9A gene cause “paroxysmal extreme pain disorder” (formerly called familial rectal pain syndrome). This disorder has prominent autonomic manifestations that include skin flushing (sometimes with only half of the face turning red [harlequin color change]), syncope with bradycardia, and severe burning pain—most commonly rectal, ocular, or mandibular. One mutation in NaV1.7 produced a clinical syndrome with features of both erythromelalgia and paroxysmal extreme pain disorder. Autosomal-recessive nonsense mutations that cause loss of function of the NaV1.7 channel result in the inability to sense pain. These patients are otherwise neurologically normal. When severe, erythromelalgia is a life-altering disease, and aggressive management is warranted. Patients may benefit from referral to special clinics for pain management or pain rehabilitation. At times, simple measures such as immersion in cool water may stop pain crises. Biofeedback can be of benefit. In general, no more than 50% of patients with erythro melalgia of the neuropathic type will respond to any one medication, so the treatment must be tailored to each patient, and often combinations of agents are used. Topical amitriptyline 1% and ketamine 0.5% in a gel are safe topical options, and are especially reasonable for affected thin-skinned areas, such
as the face or ears, where penetration would be optimal. Oral amitriptyline, sertraline, nortriptyline, and venlafaxine have shown benefit in some multiple patients. Oral magnesium in extremely high doses (>1 g per day in liquid form) was beneficial in one patient. Mexiletine, carbamazepine, and the combination of carbamazepine and gabapentin are also reported to be effective in individual patients. Neurosurgical intervention has been used in the most severely affected, carefully selected cases that have failed medical management.
Red ear syndrome Red ear syndrome describes a rarely reported disorder characterized by relapsing attacks of redness and burning affecting both ears, but usually only one ear at a time. The attacks are more common in the winter and are precipitated by touching, movements, and exposure to warmth. Associated conditions include neural disorders of the trigeminal and glossopharyngeal nerves, migraines, and lupus erythematosus. It is unclear if red ear syndrome is a disease sui generis or is actually erythromelalgia of the ears. Treatment with oral and topical tricyclics has been beneficial. Red ear syndrome must be distinguished from the springtime variant of polymorphous light eruption seen in young males with cold exposure, relapsing polychondritis (the lobe is also involved in red ear syndrome), cellulitis, and borrelial lymphocytoma. Badeloe S, et al: Secondary erythromelalgia involving the ears probably preceding lupus erythematosus. Int J Dermatol 2007; 46:6. Berk DR, Eisen AZ: Erythromelalgia of the ears: an unusual variant and response to therapy. J Drugs Dermatol 2008; 7:285. Berlin AL, et al: Coexistence of erythromelalgia and Raynaud’s phenomenon. J Am Acad Dermatol 2004; 50:456. Brill TJ, et al: Red ear syndrome and auricular erythromelalgia: the same condition? Clin Exp Dermatol 2009 Jun 1 (Epub ahead of print). Buttaci CJ: Erythromelalgia: a case report and literature review. Pain Med 2006; 7:534. Catterall WA, et al: Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci 2008; 28:11768. Chan MK, et al: Erythromelalgia: an endothelial disorder responsive to sodium nitroprusside. Arch Dis Child 2002; 87:229. Cheng X, et al: Mutation l136V alters electrophysiological properties of the Na(v)1.7 channel in a family with onset of erythromelalgia in the second decade. Mol Pain 2008; 4:1. Choi JS, et al: Mexiletine-responsive erythromelalgia due to a new Nav1.7 mutation showing use-dependent current fall-off. Exp Neurol 2009; 21:383. Cohen JS: High-dose oral magnesium treatment of chronic, intractable erythromelalgia. Ann Pharmacother 2002; 36:255. Cohen JS: Transdermal therapy for erythromelalgia. Arch Dermatol 2006; 142:1508. Coppa LM, et al: Erythromelalgia precipitated by acral erythema in the setting of thrombocytopenia. J Am Acad Dermatol 2003; 48:973. David MD, et al: Thermoregulatory sweat testing in patients with erythromelalgia. Arch Dermatol 2006; 142:1583. Davis MD, et al: Erythromelalgia: vasculopathy, neuropathy, or both? A prospective study of vascular and neurophysiologic studies in erythromelalgia. Arch Dermatol 2003; 139:1337. DiCaudo DJ, et al: Alleviation of erythromelalgia with venlafaxine. Arch Dermatol 2004; 140:621. Drenth JP, et al: Primary erythermalgia as a sodium channelopathy: screening for SCN9A mutations: exclusion of a causal role of SCN10A and SCN11A. Arch Dermatol 2008; 144:320. Durosaro O, et al: Intervention for erythromelalgia, a chronic pain syndrome: comprehensive pain rehabilitation center, Mayo Clinic. Arch Dermatol 2008; 144:1578. Estacion M, et al: Nav1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J Neurosci 2008; 28:11079. Firmin D, et al: Treatment of familial erythromelalgia with venlafaxine. J Eur Acad Dermatol Venereol 2007; 21:836.
Livedo reticularis, livedo racemosa Livedo reticularis is the term used to describe a netlike, mottled or reticulated, pink or reddish-blue discoloration of the skin, mostly on the extremities, especially the legs. It is more prominent with exposure to cold, and may vanish with warming. It is commonly seen on the lower extremities in young children and women. The pathogenic basis is reduced blood flow through and lowered oxygen tension in the venous plexus of the skin. Cutis marmorata is another name for livedoid physio logic mottling of skin exposed to cold. For clinical purposes, it is best to separate livedo reticularis (a benign condition in most cases) from fixed livedo reticularis, better known as livedo racemosa. Livedo racemosa forms irregular networks, and broken circular segments that are fixed and do not vary appreciably with temperature changes (Fig. 35-3). The lesions are usually asymptomatic. If necrosis or purpura occurs over the livedoid areas, the terms necrotizing livedo and “retiform
Livedo reticularis, livedo racemosa
Fisher TZ, et al: A novel Nav1.7 mutation producing carbamazepineresponsive erythromelalgia. Ann Neurol 2009; 65:733. Han C, et al: Early- and late-onset inherited erythromelalgia: genotypephenotype correlation. Brain 2009; 132:1711. Iqbal J, et al: Experience with oral mexiletine in primary erythromelalgia in children. Ann Saudi Med 2009; 29:316. Jackson AL, Oates JA: A patient with adult erythermalgia: evidence suggesting an autoimmune etiology. Am J Med Sci 2008; 335:320. Kalgaard OM, et al: Prostacyclin reduces symptoms and sympathetic dysfunction in erythromelalgia in a double-blind randomized pilot study. Acta Derm Venereol 2003; 83:442. Kluger N, et al: Romiplostim-induced erythromelalgia in a patient with idiopathic thrombocytopenic purpura. Br J Dermatol 2009; 161:482. Lampert A, et al: A pore-blocking hydrophobic motif at the cytoplasmic aperture of the closed-state Nav1.7 channel is disrupted by the erythromelalgia-associated F1449V mutation. J Biol Chem 2008; 283:24118. Lampert A, et al: Erythromelalgia mutation L823R shifts activation and inactivation of threshold sodium channel Nav1.7 to hyperpolarized potentials. Biochem Biophy Res Commun 2009; 390:319. Michiels JJ, et al: Platelet-mediated erythromelalgic, cerebral, ocular and coronary microvascular ischemic and thrombotic manifestations in patients with essential thrombocythemia and polycythemia vera: a distinct aspirin-responsive and coumadin-resistant arterial thrombophilia. Platelets 2006; 17:528. Misery L, et al: Severe neurological complications of hereditary erythermalgia. J Eur Acad Dermatol Venereol 2007; 21:1446. Mork C, et al: The prostaglandin E1 analog misoprostol reduces symptoms and microvascular arteriovenous shunting in erythromelalgia—a double-blind, crossover, placebo-compared study. J Invest Dermatol 2004; 122:587. Nanayakkara PWB, et al: Verapamil-induced erythermalgia. Neth J Med 2007; 65:349. Natkunarajah J, et al: Treatment with carbamazepine and gabapentin of a patient with primary erythermalgia (erythromelalgia) identified to have a mutation in the SCN9A gene, encoding a voltage-gated sodium channel. Clin Exp Dermatol 2009 Jun 17 (Epub ahead of print). Paticoff J, et al: Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small-fiber axonopathy. Anesth Analg 2007; 104:438. Pipili C, Cholongitas E: Erythromelalgia in a diabetic patient managed with gabapentin. Diabetes Res Clin Pract 2008; 79:e15. Reed KB, Davis MDP: Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota. J Eur Acad Dermatol Venereol 2009; 23:13. Saviuc PF, et al: Erythromelalgia and mushroom poisoning. J Toxicol Clin Toxicol 2001; 39:403. Sheets PL, et al: A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity. J Physiol 2007; 581:1019. Thami GP, et al: Erythromelalgia induced by possible calcium channel blockade by cyclosporin. BMJ 2003; 326:910. Young FB: When adaptive processes go awry: gain-of-function in SCN9A. Clin Genet 2008; 73:34.
Fig. 35-3 Livedo racemosa.
purpura” respectively may be used. Livedo racemosa and livedo with purpura or necrosis are almost always associated with significant systemic disease that requires treatment. Unfortunately, the literature does not always accurately separate these entities, and patients may present with variable livedo (resembling livedo reticularis) and later develop more fixed lesions. In addition, some patients who have more variable livedo may have serious underlying disease that may require evaluation and treatment. These patients may not be easily identifiable initially on physical examination features alone. In this section, the term livedo will be used to describe this cutaneous finding and its association with other conditions. When livedo reticularis is seen, the clinician should consider the following categories of diseases as possibly causal: physiologic, hypercoagulable states (including myelodysplasias, cancer, and antiphospholipid and Sneddon syndromes), vasculitis (especially medium- and large-vessel), emboli, medications, and neurologic disorders. Drugs may cause livedo. Amantadine (Symmetrel) may be not uncommonly associated with livedo reticularis. Quinidine and quinine may be associated with a photosensitivity that is livedoid in appearance, but on biopsy an interface dermatitis will be present. Minocycline can cause livedo, and this is a marker for the development of an antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis in these patients. The medication must be stopped immediately. Other medications associated with livedo include gemcitabine, heparin (perhaps associated with heparin-induced antiplatelet antibodies), IFNβ, and bismuth. Neurological disorders can create livedo reticularis by altering innervation and consequently blood flow in the skin. Brain injury, multiple sclerosis, diabetes mellitus, poliomyelitis, and Parkinson’s disease are some examples. Many of the syndromes with fixed livedo (livedo racemosa) have important systemic implications. These conditions can be either primary thrombotic processes or vascular inflammatory processes. If the vessels of the skin are affected, are the vessels in other organs, specifically the central nervous system (CNS) and kidneys, at risk? Sneddon syndrome usually occurs in young to middle-aged women. They present with livedo, and then develop cerebrovascular infarcts. The prognosis is poor. 805
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Frequently, patients have antiphospholipid antibodies (up to 85%) and may have enough features to be diagnosed with systemic lupus erythematosus (SLE). They would be accurately diagnosed as having antiphospholipid antibody syndrome. Other connective tissue diseases, such as dermatomyositis, rheumatoid arthritis, and systemic sclerosis, may have antiphospholipid/anticardiolipin antibodies and hence feature livedo. For this reason, patients with SLE and livedo are apt to have more severe disease manifestations, such as renal disease, vasculitis, and anticardiolipin antibodies, even in the absence of fullblown Sneddon syndrome. Headache may be the presenting symptom in these patients, and the misdiagnosis of migraine may initially be entertained. Not all patients with Sneddon syndrome can be diagnosed as having antiphospholid antibody syndrome, however, and their optimal evaluation and management is unclear. Other significant disorders with livedo as a skin manifestation include thrombotic processes (hypercoagulable states, type I cryoglobulinemia), microangiopathic hemolytic anemias (thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and disseminated intravascular coagulopathy), medium- and large-vessel vasculitides, and septicemia. Moyamoya disease is a rare, chronic cerebrovascular occlusive condition characterized by progressive stenosis of the arteries in the circle of Willis. Patients present with ischemic strokes or cerebral hemorrhages. Both idiopathic moyamoya disease and disease connected with factor V Leiden mutation have been associated with livedo reticularis. Divry–van Bogaert syndrome, with livedo racemosa, seizures, and significant CNS disease, may be related to moyamoya or Sneddon syndrome. Oxalosis may lead to livedo reticularis from deposition of oxalate crystals in and around blood vessel walls. The characteristic crystals are seen on biopsy. Calciphylaxis, with calcium deposits in vessels and tissue, may cause livedo by a still unclear mechanism. Other possible causes of livedo include cryofibrinogenemia, Graves’ disease (associated with anticardiolipin antibodies), atrial myxoma, tuberculosis (perhaps as a complication of vascular inflammation—vascular-based tuberculid), and syphilis. Asherson RA, et al: Unusual manifestations of the antiphospholipid syndrome. Clin Rev Allergy Immunol 2003; 25:61. Gibbs MB, et al: Livedo reticularis: an update. J Am Acad Dermatol 2005; 52:1009. Kraemer M, et al: The spectrum of differential diagnosis in neurological patients with livedo reticularis and livedo racemosa. A literature review. J Neurol 2005; 252:1155. Miesbach W, et al: Recurrent life-threatening thromboembolism and catastrophic antiphospholipid syndrome in a patient despite sufficient oral anticoagulation. Clin Rheumatol 2004; 23:256. Richards KA, et al: Livedo reticularis in a child with moyamoya disease. Pediatr Dermatol 2003; 20:124. Shoenfeld Y, et al: Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol 2004; 31:1344. Sladden MJ, et al: Livedo reticularis induced by amantadine. Br J Dermatol 2003; 149:656. Tebbe B: Clinical course and prognosis of cutaneous lupus erythematosus. Clin Dermatol 2004; 22:121. Tektonidou MG, et al: Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: prevalence, clinical associations, and long-term outcome. Arthritis Rheum 2004; 50:2569. Tietjen GE, et al: Migraine is associated with livedo reticularis: a prospective study. Headache 2002; 42:263. Tietjen GE, et al: Livedo reticularis and migraine: a marker for stroke risk? Headache 2002; 42:352.
Cholesterol emboli Cholesterol emboli resulting from severe atherosclerotic disease, usually of the abdominal aorta, may cause unilateral 806
Fig. 35-4 Livedo reticularis secondary to cholesterol emboli.
or bilateral livedo of the lower extremities. The livedo may not be present with the patient supine, and may only be present when the legs are dependent. Patients frequently have concomitant cyanosis (blue toes), purpura, nodules, ulceration, or gangrene (Fig. 35-4). Pain often accompanies the skin lesions. Acute renal failure occurs in up to 75% and about one-third of patients will have characteristic skin lesions. An eosinophilia on complete blood count is present in 80% of cases. Older men with severe atherosclerotic disease are at greatest risk. They are often on anticoagulant therapy, and many have recently undergone vascular surgery or instrumentation. Slightly more than 1% of left heart catheterizations are complicated by cholesterol emboli. The differential diagnosis includes vasculitis, septic staphylococcal emboli resulting from endocarditis or an infected aneurysm, and periarteritis nodosa. Mortality is around 75% at 1 year. Deep biopsy with serial sections may demonstrate the characteristic cholesterol clefts within thrombi. Frozen section evaluation with polarized microscopy is particularly sensitive. Livedo reticularis of recent onset in an elderly person warrants consideration of this diagnosis. Fukumoto Y, et al: The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study. J Am Coll Cardiol 2003; 42:211. Hagiwara N, et al: Renal cholesterol embolism in patients with carotid stenosis: a severe and underdiagnosed complication following cerebrovascular procedures. J Neurol Sci 2004; 222:109.
Evaluation of the patient with possible cutaneous vascular disorders In the evaluation of patients who present with livedo, purpura, or ulceration, a broad differential diagnosis must be considered. Among the diseases considered should be primary pathology of the cutaneous vasculature. In general, these vascular disorders of the skin are divided into two main groups: vasculitis and vasculopathy. Vasculitis includes disorders in which the primary damage in the blood vessels occurs due to inflammatory cells infiltrating and damaging the vessel walls. As a consequence of inflammation within vessels, the clotting cascade is triggered and thrombosis may be seen adjacent to and in the late stages of healing vasculitic lesions. In vasculopathy, the primary process is thrombosis. This is usually due to a hypercoagulable state. Once thrombosis occurs, inflammatory cells enter the vessel and vessel wall in an attempt to re-establish local circulation. Thus late in the process of a primary thrombotic process, vascular inflammation is seen and can be misinterpreted as a “vasculitis.” Emboli can be considered thrombotic events and late lesions from embolic lesions may also be inflammatory and misleading histologically. All these processes—vasculitis, vasculopathy,
Livedoid vasculopathy Synonyms for livedoid vasculopathy include livedoid vasculitis, atrophie blanche, segmental hyalinizing vasculitis, livedo reticularis with summer/winter ulceration, and PURPLE (painful purpuric ulcers with reticular pattern of the lower extremities). The vasculopathy is characterized clinically by early focal, painful purpuric lesions of the lower extremities that frequently ulcerate and heal slowly (Fig. 35-5). The ulcers heal, with small, stellate and reticulated, white scars, referred to as atrophie blanche (Fig. 35-6). The ulcers may be ringed by telangiectasis and hemosiderin-induced hyperpigmentation. Livedo racemosa may be present on the affected extremity or be more widespread. About two-thirds to three-quarters of the patients are female; the mean age of onset is 45 years. The condition is bilateral in 80% of patients and ulceration occurs in 70%. Histologically, livedoid vasculopathy is characterized by hyaline thrombi within small and at times medium vessels in the dermis. Perivascular hemorrhage may be present. Leukocytoclastic vasculitis is not found, and the biopsies can be described as showing “intravascular thrombosis without inflammation.” Focal lymphocytic intravascular and perivascular inflammation may be seen, but this is considered second-
Fig. 35-5 Livedoid vasculopathy.
ary to the thrombotic process, rather than a primary and pathogenic component of the disease. By direct immunofluorescence, fibrin, C3, and IgM are often found in the vessel walls, but these are again considered secondary to the thrombosis. In biopsies of older lesions, recanalizing vessels may demonstrate endothelial proliferation. Biopsy of the atrophie blanche-like lesions may show lobular vascular proliferation, as observed in chronic stasis dermatitis. In about 15% of patients, an initial biopsy does not reveal diagnostic histology and a second biopsy is required. After two biopsies, diagnostic pathology is found in 98% of patients. The pathogenic etiology is considered to be a hypercoagulable state that results in spontaneous thrombosis of superficial skin vessels. The thrombosis results in low tissue oxygen tension, with local hypoxia and skin damage. However, the hypercoagulable state can be identified with current testing technology in only about 40% of patients. In livedoid vasculopathy, testing should include anticardiolopin antibody, lupus anticoagulant, factor V Leiden gene mutation (usually heterozygous), protein C, S, or antithrombin III heterozygous deficiency, prothrombin G20210A gene mutation, cryoproteins, and homocysteine level. The finding of methylene tetrahydrofolate reductase (MTHFR) deficiency with or without hyperhomocysteinemia has been reported in livedoid vasculopathy, but the pathogenic significance of this is unclear. Plasminogen activator inhibitor-1 (PAI-1) mutation with increased PAI-1 plasma levels has been found in some patients with livedoid vasculopathy. PAI-1 is an important inhibitor of fibrinolysis, and elevated levels are associated with an increased risk of thrombosis. Not surprisingly, underlying connective tissue disease, carcinomas, myeloma, lymphoma, venous insufficiency, deep venous thrombosis, and cerebrovascular accident have been seen in association with livedoid vasculopathy. These are all conditions associated with a prothrombotic state in some patients. Mononeuropathy multiplex has been reported in association with livedoid vasculopathy. There is a broad differential diagnosis for livedoid vasculopathy, since many conditions can cause livedo reticularis with ulceration of the lower extremity. The conditions that must be excluded include small-vessel vasculitis (especially
Livedoid vasculopathy
and emboli—alter cutaneous blood flow and can be accompanied by livedo. If vessels lose competence they may leak, creating purpura, and if vasculitis, vasculopathy, or emboli are severe enough or affect a large enough vessel, the viability of the overlying skin is compromised, and necrosis and ulceration may occur. Complicating this situation is the fact that patients may have both a vasculitis and a hypercoagulable state, resulting in biopsies that, at times, are pathogenically discordant. A patient with an inherited or acquired disorder of coagulation and a drug-induced cutaneous vasculitis would be a not uncommon example. The above discussion makes it clear that this area of differential diagnosis is a difficult one for even the most skilled dermatologist. Careful sampling of early lesions, with large and deep biopsies if necessary, may be required to find the “primary” vascular pathology. Since vasculitis may be a focal process, step sections may be required to find the diagnostic features. In addition, the diagnosis proposed must be interpreted in the context of other elements of the patient’s medical condition, such as medications, infections, underlying diseases, and involvement of other organ systems besides the skin.
Fig. 35-6 Atrophie blanche.
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that associated with hepatitis C virus and essential mixed cryoglobulinemia or a connective tissue disease), microscopic polyarteritis, polyarteritis nodosa (PAN) (both cutaneous and systemic), peripheral vascular disease, erythema induratum mimicking PAN, and hydroxyurea-associated leg ulceration. The treatment of livedoid vasculopathy is directed at treating the hypercoagulable state. About one-third of patients are smokers, and this should be stopped. Patients with venous insufficiency should be managed with elevation, compression, and bandaging as appropriate. These patients may improve with this local therapy alone. If venous insufficiency ulcerations with an atrophie blanche appearance are slow to heal, consideration for treatment with the livedoid vasculopathy therapeutic ladder should be considered. Agents demonstrated to be effective in livedoid vasculopathy (in order of their recommended use) include: low-dose aspirin, oral pent oxifylline, oral dipyridamole, folic acid and a B complex multi vitamin (in patients with MTHFR mutation and elevated homocysteine), danazol or stanazol (to increase endogenous antithrombotic proteins), heparin (low molecular weight or regular), and warfarin. Warfarin may be slightly superior to heparin. No treatment is universally beneficial in all patients, and treatment may need to be tailored to individual response and disease activity. In patients with connective tissue diseases (and antiphospholipid antibodies) hydroxychloroquine may be beneficial. In refractory cases, tissue plasminogen activator infusion, IVIG, and rituximab can be considered. Hyperbaric oxygen may accelerate ulcer healing. Other treatments that have been reported as effective include PUVA, niacin, iloprost, and ketanserin. Systemic immunosuppressives usually are of no benefit in cases with true livedoid vasculopathy. If there is a dramatic response to steroids, another diagnosis should be sought. Anavekar ND, Kelly R: Heterozygous prothrombin gene mutation associated with livedoid vasculopathy. Australas J Dermatol 2007; 48:120. Boyvat A, et al: Livedoid vasculopathy associated with heterozygous protein C deficiency. Br J Dermatol 2000; 143:840. Browning CE, Callen JP: Warfarin therapy for livedoid vasculopathy associated with cryofibrinogenemia and hyperhomocysteinemia. Arch Dermatol 2006; 142:75. Calamia KT, et al: Livedo (livedoid) vasculitis and the factor V Leiden mutation: additional evidence for abnormal coagulation. J Am Acad Dermatol 2002; 46:133. Callen JP: Livedoid vasculopathy: what it is and how the patient should be evaluated and treated. Arch Dermatol 2006; 142:1481. Cardoso R, et al: Livedoid vasculopathy and hypercoagulability in a patient with primary Sjögren’s syndrome. Int J Dermatol 2007; 46:431. Davis MD, Wysokinski WE: Ulcerations caused by livedoid vasculopathy associated with a prothrombotic state: response to warfarin. J Am Acad Dermatol 2008; 58:512. Deng A, et al: Livedoid vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity (4G/4G) treated successfully with tissue plasminogen activator. Arch Dermatol 2006; 142:1466. Frances C, Barete S: Difficult management of livedoid vasculopathy. Arch Dermatol 2004; 140:1011. Gotlib J, et al: Heterozygous prothrombin G20210A gene mutation in a patient with livedoid vasculitis. Arch Dermatol 2003; 139:1081. Hairston BR, et al: Treatment of livedoid vasculopathy with lowmolecular-weight heparin: report of 2 cases. Arch Dermatol 2003; 139:987. Hairston BR, et al: Livedoid vasculopathy. Arch Dermatol 2006; 142:1413. Irani-Hakime NA, et al: Livedoid vasculopathy associated with combined prothrombin G20210A and factor V (Leiden) heterozygosity and MTHFR C677T homozygosity. J Thromb Thrombolysis 2008; 26:31. Juan WH, et al: Livedoid vasculopathy: long-term follow-up results following hyperbaric oxygen therapy. Br J Dermatol 2006; 154:251. Kavala M, et al: A case of livedoid vasculopathy associated with factor V Leiden mutation: successful treatment with oral warfarin. J Dermatolog Treat 2008; 19:121.
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Magy N, et al: Livedoid vasculopathy with combined thrombophilia: efficacy of iloprost. Rev Med Interne 2002; 23:554. Meiss F, et al: Livedoid vasculopathy: the role of hyperhomocysteinemia and its simple therapeutic consequences. Eur J Dermatol 2006; 16:159. Mimouni D, et al: Cutaneous polyarteritis nodosa in patients presenting with atrophie blanche. Br J Dermatol 2003; 148:789. Ravat FE, et al: Response of livedoid vasculitis to intravenous immunoglobulin. Br J Dermatol 2002; 147:166. Toth C, et al: Mononeuropathy multiplex in association with livedoid vasculitis. Muscle Nerve 2003; 28:634. Tsai TF, et al: Polymorphisms of MTHFR gene associated with livedoid vasculopathy in Taiwanese population. J Dermatol Sci 2009; 54:214. Zeni P, et al: Successful use of rituximab in a patient with recalcitrant livedoid vasculopathy. Ann Rheum Dis 2008; 67:1055.
Calciphylaxis Calciphylaxis is an increasingly reported syndrome that is potentially fatal. It occurs most commonly in the setting of chronic renal failure, often with type 2 diabetes, and obesity. Women outnumber men 3 : 1 to 4 : 1. About 1–4% of patients on hemodialysis and 4% of patients on peritoneal dialysis develop calciphylaxis. About half of calciphylaxis patients are diabetic and more than half have a body mass index (BMI) of >30. Every gain in the BMI of 1 point over 30 increases the risk for calciphylaxis by 10%. Calciphylaxis occurs on the background of extensive calcification of the media of mediumsized and small arterioles. Parathyroid hormone (PTH) levels are often abnormal (either high or low), and calciphylaxis may also be seen in the setting of primary hyperparathyroidism, as well as secondary hyperparathyroidism of renal failure. Tumors may also produce PTH-related proteins and be associated with calciphylaxis. In about 20% of calciphylaxis patients, the Ca X PO4 product will be greater than 70, a sensitive but not specific marker for calciphylaxis. The arteriolar calcification is a chronic process due to many metabolic factors and signaling molecules that cause vascular smooth-muscle cells to transform to an osteogenic phenotype. Thus the vascular calcification in calciphylaxis and most cases of calcific uremic arteriolopathy is due to local deposition of calcium in the blood vessels by the vascular smooth muscles cells. It is not metastatic or dystrophic calcification. Liver disease and systemic corticosteroid therapy increase the risk for development of calciphylaxis by 2–3-fold. Calciphylaxis begins as fixed livedo reticularis (livedo racemosa). Areas within the livedo become increasingly violaceous and eventually purpuric, bullous, and necrotic. Subcutaneous nodules may herald the onset of the livedo and be associated with it. Affected tissue in calciphylaxis has reduced tissue oxygenation. Lesions affect the legs below the knees in 90% of cases. More proximal lesions, and lesions of the fatty areas of the thighs, buttocks, and abdomen occur in about two-thirds of cases. Severe pain is a cardinal feature of calciphylaxis, often requiring narcotic analgesia for control. Ischemic myopathy may occur in severe cases, and muscle pain may precede the appearance of the skin lesions. Necrotic skin lesions are very resistant to healing and infection of open wounds with septicemia is a common cause of death. The 1-year survival of all calciphylaxis patients is about 40%, and only 10% in patients with both proximal and distal disease. An optimum biopsy to confirm the diagnosis of calciphylaxis should be adjacent to the necrotic area where there is erythema or early purpura. Ideally, it should be deep and large enough to identify diagnostic features. This may require an incisional rather than a simple punch biopsy. Since vascular calcification is common in all patients with chronic renal failure, this alone cannot confirm the diagnosis. In addition,
Al-Absi AI, et al: Case report: medial arterial calcification mimicking temporal arteritis. Am J Kidney Dis 2004; 44:e73. Asobie N, et al: Calciphylaxis in a diabetic patient provoked by warfarin therapy. Clin Exp Dermatol 2008; 33:342. Funabiki M, et al: Sudden onset of calciphylaxis: painful violaceous livedo in a patient with peritoneal dialysis. Clin Exp Dermatol 2009; 34:622. Guldbakke KK, Khachemoune A: Calciphylaxis. Int J Dermatol 2007; 46:231. Hackett BC, et al: Calciphylaxis in a patient with normal renal function: response to treatment with sodium thiosulfate. Clin Exp Dermatol 2009; 34:39. Hanafusa T, et al: Intractable wounds caused by calcific uremic arteriolopathy treated with bisphosphonates. J Am Acad Dermatol 2007; 57:1021. Hayden MR, et al: Vascular ossification—calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis—calcific uremic arteriolopathy: the emerging role of sodium thiosulfate. Cardiovasc Diabetol 2005; 4:4. Hussein MR, et al: Calciphylaxis cutis: a case report and review of literature. Exp Mol Pathol 2009; 86:134. Kalajian AH, et al: Calciphylaxis with normal renal and parathyroid function: not as rare as previously believed. Arch Dermatol 2009; 145:451.
Kyritsis I, et al: Combination of sodium thiosulphate cinacalcet, and paricalcitol in the treatment of calciphylaxis with hyperparathyroidism. Int J Artif Organs 2008; 31:742. Li JZ, Huen W: Images in clinical medicine. Calciphylaxis with arterial calcification. N Engl J Med 2007; 357:1326. Mwipatayi BP, et al: Calciphylaxis: emerging concept in vascular patients. Eur J Dermatol 2007; 17:73. Nigwekar SU, et al: Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol 2008; 3:1139. Ohta A, et al: Penile necrosis by calciphylaxis in a diabetic patient with chronic renal failure. Intern Med 2007; 46:985. Pallure V, et al: Cinacalcet as first-line treatment for calciphylaxis. Acta Derm Venereol 2008; 88:62. Schliep S, et al: Successful treatment of calciphylaxis with pamidronate. Eur J Dermatol 2008; 18:554. Weenig RH, et al: Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol 2007; 56:569. Woods M, et al: Penile calciphylaxis. J Am Acad Dermatol 2006; 54:736.
Purpura
there should be evidence of tissue damage (necrosis), extravascular calcification, and thrombosis in the arterioles of the dermis and subcutaneous tissue. The pathogenesis of calciphylaxis is still being elucidated. In most cases, it occurs on the background of extensive calcification of arterioles of the skin. The calcification triggers intimal proliferation and narrows the arterioles. Gradually or rather suddenly, the patient will develop areas of livedo and necrosis. This heralds the onset of vascular thrombosis. The mechanism that triggers this thrombotic phase of calciphylaxis and the appearance of the skin lesions is unclear. Some of these may be prothrombotic states, such as female gender, warfarin administration, trauma, the presence of cancer, edema, and anatomic location. The skin overlying fatty areas, such as the medial thighs, abdomen, and breasts of women, is particularly susceptible to thrombotic diseases such as diffuse dermal angiomatosis and warfarin and heparin necrosis. This may be caused by low blood flow or the reduced circulation due to tethering and kinking of vessels due to gravity. In some patients, low protein C levels are identified. Human immunodeficiency virus (HIV) infection and cryofibrinogenemia have also been associated. A useful model to consider pathogenically is that calciphylaxis is analogous to atherosclerotic myocardial disease. There is a gradual and progressive abnormality of the vasculature, with narrowing of the vessel lumen (by plaque in the case of atherosclerosis and by intimal calcification in the case of calciphylaxis). The acute symptomatology is triggered by thrombosis of the narrowed vessel, leading to occlusion of the vessel and downstream anoxia and necrosis. As in atherosclerotic disease, treatment for calciphylaxis should be directed at early prevention of intimal calcification. Unlike atherosclerosis, however, it is unclear how to prevent intimal calcification in the setting of renal disease. Penile calciphylaxis is a particularly painful variant. The glans penis develops a deep necrotic ischemic ulceration. The risk factors are diabetes and renal failure. Penectomy is often required for pain management. One case resembled temporal arteritis. Much of the treatment for calciphylaxis is directed at altering abnormal calcium metabolism. Low calcium dialysis, oral phosphate binders, cinacalcet, bisphosphonates, and intra venous sodium thiosulfate have all been used with some success. Once the ulcerations are present, gentle debridement is associated with healing and increased survival. Painful ulcers may also respond to hyperbaric oxygen therapy. Parathyroidectomy is best reserved for cases refractory to the above regimens and a marked elevation of PTH.
Marshall–White syndrome and Bier spots The marbled mottling produced in the forearm and hand by occluding the brachial artery with a tight sphygmomanometer cuff is characterized initially, and chiefly, by pale macules 1–2 cm in diameter. These were described by Bier in 1898 and are known as Bier spots. Wilkin re-examined this phenomenon with laser Doppler velocimetry and concluded that the red spots on the hand are caused by relative vasodilation, with vasoconstriction in the pale areas. Wilkin JK, et al: Bier’s spots reconsidered: a tale of two spots, with speculation on a humerus vein. J Am Acad Dermatol 1986; 14:411.
Purpura Purpura is the term used to describe extravasation of blood into the skin or a mucous membrane. It presents as distinctive brownish-red or purplish macules a few millimeters to many centimeters in diameter. Several terms are used to describe various clinical manifestations of purpura. Petechiae are superficial, pinhead-sized (90 mmHg 9. elevated BUN/creatinine 10. arteriographic abnormality. Separating systemic PAN from microscopic polyangiitis (MPA) can be difficult, and the skin manifestations clinically and histologically are of no benefit in this regard. PAN is 2–4 times more common in men than in women and the mean age of presentation is 45–50 years. A cutaneous vasculitis identical to PAN has been seen in intravenous drug abusers (see below) and in association with SLE, inflammatory bowel disease, hairy cell leukemia, familial Mediterranean fever, and Cogan syndrome (nonsyphilitic interstitial keratitis and vestibulo-auditory symptoms). Infectious associations include hepatitis B, hepatitis C, and antecedent streptococcal infections. Vascular-based tuberculids (erythema induratum, nodular tuberculid) may have histology identical to PAN. The proportion of PAN cases associated with HBV is currently about 5–7% of cases overall, but this percentage is falling with HBV immunization. The identification of associated hepatitis virus infection has therapeutic and prognostic implications. The skin is involved in up to 50% of patients with the systemic form of PAN, with wide-ranging findings. The most striking and diagnostic lesions (15% of patients) are 5–10 mm subcutaneous nodules occurring singly or in groups, distributed along the course of the blood vessels, above which the skin is normal or slightly erythematous (macular arteritis). These nodules are often painful and may pulsate and, in time, ulcerate (Fig. 35-24). Common sites are the lower extremities, especially below the knee. Ecchymoses and peripheral gangrene of the fingers and toes may also be present. Livedo reticularis in combination with subcutaneous nodules strongly suggests the diagnosis of PAN. Palpable purpura with histologic features of cutaneous LCV may be seen in PAN in 20% of patients. Urticaria is present in 6% of cases of PAN. HBVassociated PAN is associated with cutaneous findings in only 30% of cases.
Fig. 35-24 Polyarteritis nodosa with multiple leg ulcerations.
Classic systemic PAN may involve the vessels throughout the entire body. It has a particular predilection for the skin, peripheral nerves, gastrointestinal tract, and kidneys. Hypertension (due to renal involvement in 80%), tachycardia, fever, edema, and weight loss (>70%) are cardinal signs of the disease. Arthralgia/arthritis (up to 75%), myocardial and intestinal infarctions, and peripheral neuritis (75%) are also seen. Mononeuritis multiplex, most often manifested as foot drop, is a hallmark of PAN. Involvement of the meningeal, vertebral, and carotid arteries may lead to hemiplegia and convulsions. The lungs and spleen are rarely involved. Aneurysms develop, which may result in multiorgan infarcts. A Five Factor Score (FFS) has been validated, with 1 point each for proteinuria, renal insufficiency, gastrointestinal tract involvement, CNS involvement, and cardiomyopathy. The 5-year survival for patients with FFS scores of 0, 1, and >2 are 88%, 75%, and 54% respectively. Prior to the use of systemic immunosuppressives, the mortality for systemic PAN exceeded 90%. A leukocytosis of as high as 40 000/mm3 may occur, with neutrophilia to 80%; thrombocytosis, progressive normocytic anemia, and an elevated sedimentation rate and C-reactive protein (CRP) may also be found. Hepatitis B and C studies should be performed. Urinary abnormalities, such as protein uria, hematuria, and casts, are present in 70% of patients. The prevalence of ANCA positivity is related to how one diagnoses PAN as opposed to MPA. ANCAs are more commonly found in MPA than in PAN, and in both diseases p-ANCA is the predominant type. HBV-associated PAN is rarely, if ever, ANCA-positive. The histology is that of an inflammatory necrotizing and obliterative panarteritis that attacks the small and mediumsized arteries. Focal vasculitis forms nodose swellings that become necrotic, producing aneurysms and rupture of the vessels. Hemorrhage, hematoma, and ecchymosis may result. Obliteration of the lumen may occur, with ischemic necrosis of surrounding tissue. Characteristically, the arteries are affected at their branching points. The mainstay of diagnosis is the presence of these histologic features and the constellation of clinical findings. The preferable site for biopsy is an accessible area such as skin, muscle, or testis. If these are not involved, angiography may detect 829
35
aneurysmal dilations as small as 1 cm wide in the renal, hepatic, or other visceral vessels.
Cutaneous Vascular Diseases
Treatment Untreated classic PAN can be fatal, death usually being due to renal failure or cardiovascular or gastrointestinal complications. Death generally occurs early in the course of the disease. Patients with HBV- or HCV-associated PAN should be given IFN and other antiviral treatments as their initial therapy. For PAN not associated with HBV or HCV, treatment with corticosteroids and cytotoxic agents has increased the 5-year survival rate to more than 75%. Corticosteroids in the range of 1 mg/kg/day are given initially. Once the disease remits, the dose should be reduced. After an average of 3–6 months, with the patient in remission, the steroids are slowly tapered to discontinuation. Cyclophosphamide is given with steroids or sometimes as a single agent. Initially, 2 mg/kg/day as a single dose is recommended. Twice this amount may be required for severely ill patients. The oral dose is then adjusted to maintain the white blood cell count between 3000 and 3500/mm3 and the neutrophil count above 1500 cells/mm3. When the disease has been quiescent for at least 1 year, the cyclophosphamide may be tapered and stopped. On average, 18–24 months of therapy are required. Pulsed intravenous cyclophosphamide is associated with a lower incidence of toxicity, especially the longterm risk of malignancy. Plasma exchange may be used for acute crises or treatment failures with corticosteroids and cyclophosphamide. Ulcerations in PAN can be very painful due to the associated neuropathy. They should be managed like nonhealing leg ulcers.
Cutaneous polyarteritis nodosa About 10% of patients present with PAN localized to the skin and with limited systemic involvement. Neuropathy occurs in 20%. Subcutaneous nodules (80%), livedo (70%), and ulceration (44%) are the characteristic cutaneous features that should lead to suspicion of cutaneous PAN. Atrophie blanche-like lesions around the ankles may be the sole cutaneous manifestation of cutaneous PAN. Plaques on the trunk and proximal extremities expanding slowly and centrifugally are another manifestation. At the periphery of the plaques is a ring of 1–2 cm subcutaneous nodules. Cutaneous PAN has a better prognosis and will require less aggressive therapy, patients rarely suffering the systemic renal, gastrointestinal, and cardiovascular complications of systemic PAN. This form of PAN is the most common childhood pattern of PAN. Whether there are two clear subsets of patients, cutaneous and systemic PAN, or rather a spectrum of disease is controversial. Patients with “cutaneous” PAN must be followed carefully and regularly evaluated to exclude the development of systemic involvement, which may appear as long as two decades after the initial diagnosis. The diagnosis of cutaneous PAN is made by biopsy of a subcutaneous nodule. An excisional biopsy is recommended, as the vasculitis is focal. The affected arteriole is at the junction of the dermis and subcutaneous tissue or in the subcutaneous fat. Adjacent to the affected vessel there is an inflammatory panniculitis, and inadequate evaluation of the biopsy or too small a sample may lead to the erroneous diagnosis of a panniculitis. Also distal to the affected arteriole, thrombosis usually occurs. If the biopsy is inadequate in depth or size, this bland thrombosis without inflammation is seen and the erroneous diagnosis of a “vasculopathy” will be made. Cutaneous PAN has been associated with HBV surface antigenemia, HCV infection, Crohn’s disease, Takayasu arteritis, relapsing polychondritis, streptococcal infections, tuberculosis, and medica830
tions (minocycline). Typically, the only laboratory abnormality is an elevated erythrocyte sedimentation rate (ESR) or CRP. In some cases, a p-ANCA may be present. Most patients respond well to aspirin, NSAIDs, prednisone, pentoxifylline, sulfapyridine, or methotrexate, alone or in some combination. In childhood cutaneous PAN, since streptococcal infection is common, penicillin treatment may be used. In refractory cases, IVIG may be used. Asano Y, et al: High-dose intravenous immunoglobulin infusion in polyarteritis nodosa: report on one case and review of the literature. Clin Rheumatol 2006; 25:396. Bauzá A, et al: Cutaneous polyarteritis nodosa. Br J Dermatol 2002; 146:694. Chan PT, et al: Inflammatory plaque with peripheral nodules: a new specific finding of cutaneous polyarteritis nodosa. J Am Acad Dermatol 2009; 60:320. Diaz-Perez JL, et al: Cutaneous polyarteritis nodosa. Semin Cutan Med Surg 2007; 26:77. Fathalla BM, et al: Cutaneous polyarteritis nodosa in children. J Am Acad Dermatol 2005; 53:724. Fein H, et al: Cutaneous arteritis presenting with hyperpigmented macules: macular arteritis. J Am Acad Dermatol 2003; 49:519. Fortin PR, et al: Prognostic factors in systemic necrotizing vasculitis of the polyarteritis nodosa group: a review of 45 cases. J Rheumatol 1995; 22:78. Guillevin L, et al: Prognostic factors in polyarteritis nodosa and Churg–Strauss syndrome: a prospective study in 342 patients. Medicine (Baltimore) 1996; 75:17. Guillevin L, et al: Short-term corticosteroids then lamivudine and plasma exchanges to treat hepatitis B virus-related polyarteritis nodosa. Arthritis Rheum 2004; 51:482. Komatsuda A, et al: Cutaneous polyarteritis nodosa in a patient with Crohn’s disease. Mod Rheumatol 2008; 18:639. Kumar L, et al: Benign cutaneous polyarteritis nodosa in children below 10 years of age: a clinical experience. Ann Rheum Dis 1995; 54:134. Matsumura Y, et al: A case of cutaneous polyarteritis nodosa associated with ulcerative colitis. Br J Dermatol 2000; 142:561. Mimouni D, et al: Cutaneous polyarteritis nodosa in patients presenting with atrophie blanche. Br J Dermatol 2003; 148:789. Pak H, et al: Purpuric nodules and macules on the extremities of a young woman: cutaneous polyarteritis nodosa. Arch Dermatol 1998; 134:232. Pennoyer JW, et al: Ulcer associated with polyarteritis nodosa treated with bioengineered human skin equivalent (Apligraf). J Am Acad Dermatol 2002; 46:145. Rogalski C, Sticherling M: Panarteritis cutanea benigna—an entity limited to the skin or cutaneous presentation of a systemic necrotizing vasculitis? Report of seven cases and review of the literature. Int J Dermatol 2007; 46:817. Schaffer JV, et al: Perinuclear antineutrophilic cytoplasmic antibodypositive cutaneous polyarteritis nodosa associated with minocycline therapy for acne vulgaris. J Am Acad Dermatol 2001; 44:198. Segelmark M, Selga D: The challenge of managing patients with polyarteritis nodosa. Curr Opin Rheumatol 2007; 19:33. Sheth AP, et al: Cutaneous polyarteritis nodosa of childhood. J Am Acad Dermatol 1994; 31:561. Siberry GK, et al: Cutaneous polyarteritis nodosa. Arch Dermatol 1994; 130:884. Soufir N, et al: Hepatitis C virus infection in cutaneous polyarteritis nodosa. Arch Dermatol 1999; 135:1001.
ANCA-positive small-vessel vasculitides Antineutrophil cytoplasmic antibodies (ANCAs) have become an important laboratory finding used in the diagnosis and, in some cases, the prognosis of systemic vasculitis. ANCAs occur in three patterns: cytoplasmic (c-ANCA); perinuclear (p-ANCA); and atypical ANCA. c-ANCA is associated with antibodies directed against proteinase 3 (PR3). Antibodies against myeloperoxidase result in the p-ANCA pattern, but antibodies against other antigens may also give this pattern. Atypical ANCAs are not directed against myeloperoxidase or
Microscopic polyangiitis With the advent of ANCA serologies and clarification of the features of microscopic polyangiitis (MPA), this diagnosis is becoming increasingly more common. There is a north–south gradient in incidence, with southern European countries having 3–4 times as many cases. Most patients with MPA have systemic symptoms, such as fever, weight loss, myalgias, and arthralgias, which can present with an acute flu-like illness or can evolve for months to years before a more explosive phase of their disease. These cases have been termed “slowly progressive MPA.” Most patients with MPA will have or develop segmental necrotizing and crescentic glomerulonephritis (80–90%), with pulmonary involvement in 25–65% of cases. Pulmonary capillaritis, which can be complicated by hemorrhage, occurs in 12–29% of MPA patients. The skin is involved in 44% of cases of MPA. Purpura as papules, macules, or ecchymoses (retiform purpura) is present in 26% of cases and cutaneous ulceration may result. Urticarial lesions occur in 1% of cases. Patients with MPA may present with skin lesions as their initial clinical findings. Livedo is seen in two-thirds of such patients. Skin biopsies of macules, papules, petechiae, or sites adjacent to ecchymoses may reveal a necrotizing LCV in the reticular dermis. Palisading and neutrophilic granulomatous dermatitis was found on a skin biopsy of the elbow of an MPA patient. Vasculitic neuropathy is common (58%) and eye disease may occur. Eosinophilia and asthma are not seen. ANCAs are positive in 70% of cases, p-ANCA more frequently than c-ANCA. MPA is separated from PAN by the presence of glomerulonephritis, pulmonary symptoms, and the absence of hypertension and microaneurysms. ANCAs are less frequently positive in PAN.
MPA is managed like other forms of ANCA-SVV, with systemic corticosteroids and often cytotoxic agents from the disease onset. If the disease is localized, sulfamethoxazole/ trimethoprim with corticosteroids may be considered. In generalized but non-organ-threatening disease, methotrexate may be added to the corticosteroids. Cyclophosphamide is usually used in the early induction phase of treatment (6–12 months) as monthly pulses (as opposed to daily treatment). Lowertoxicity immunosuppressives (methotrexate, azathioprine, mycophenolate mofetil) may be used as maintenance or in milder cases. IVIG and anti-TNF agents (infliximab) may be considered in refractory cases. Relapses are frequent; the 5-year survival is about 75% and 7-year survival is 62%. Bosch X, et al: Treatment of antineutrophil cytoplasmic antibodyassociated vasculitis: a systematic review. JAMA 2007; 298:655. Greenfield JR, et al: ANCA-positive vasculitis induced by thioridazine: confirmed by rechallenge. Br J Dermatol 2002; 147:1265. Guilleven L, et al: Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999; 42:421. Irvine AD, et al: Microscopic polyangiitis. Arch Dermatol 1997; 133:474. Jacobs-Kosmin D, et al: Pantoprazole and perinuclear antineutrophil cytoplasmic antibody-associated vasculitis. J Rheumatol 2006; 33:629. Kawakami T, et al: Cutaneous manifestations in patients with microscopic polyangiitis: two case reports and a minireview. Acta Derm Venereol 2006; 86:144. Kawakami T, et al: Clinical and histopathologic features of 8 patients with microscopic polyangiitis including two with a slowly progressive clinical course. J Am Acad Dermatol 2007; 57:840. Kluger N, et al: Comparison of cutaneous manifestations in systemic polyarteritis nodosa and microscopic polyangiitis. Br J Dermatol 2008; 159:615. Maejima H, et al: Microscopic polyangiitis presenting urticarial erythema and Henoch–Schönlein purpura: two case reports. J Dermatol 2004; 31:655. Niiyama S, et al: Dermatological manifestations associated with microscopic polyangiitis. Rheumatol Int 2008; 28:593. Penas PF, et al: Microscopic polyangiitis: a systemic vasculitis with a positive p-ANCA. Br J Dermatol 1996; 134:542. Watz H, et al: Bronchioloalveolar carcinoma of the lung associated with a highly positive pANCA-titer and clinical signs of microscopic polyangiitis. Pneumologie 2004; 58:493.
ANCA-positive small-vessel vasculitides
PR3. Most laboratories now perform specific tests to determine whether positive ANCAs are reactive against myeloperoxidase or PR3. Anti-PR3 antibodies are relatively specific for Wegener granulomatosis and microscopic polyangiitis. Antibodies against myeloperoxidase are less specific and can be found in microscopic polyangiitis, Churg–Strauss syndrome, and drug-induced vasculitis. Usually, either anti myeloperoxidase or anti-PR3 antibodies are found, but not both. If both patterns are found, drug-induced vasculitis should be suspected. ANCAs have been used to delineate a group of small-vessel vasculitides called “ANCA small-vessel vasculitides” or ANCA-SVV. These include microscopic polyangiitis, Wegener granulomatosis, and Churg–Strauss syndrome. These diseases have overlapping features, but characteristically demonstrate pulmonary hemorrhage and/or necrotizing glomerulonephritis (pulmonary–renal syndrome). Conversely, 60% of patients with the pulmonary–renal syndrome will have ANCA-SVV. With ANCA testing, ANCASVV can be diagnosed with 85% sensitivity and 98% specificity. While ANCAs are usually negative in Takayasu arteritis, giant-cell arteritis, Kawasaki’s disease, and Behçet disease, positive ANCAs can be found in cryoglobulinemia and other forms of skin-limited vasculitis, in 20% of patients with SLE, and in a higher percentage of patients with RA. ANCAs are used in the setting of vasculitis with systemic features or in situations where the clinical findings suggest ANCA-SVV. ANCA testing does not replace other tests or, more importantly, histologic confirmation of the presence of vasculitis. While the ANCA-SVVs are of unknown etiology, in multiple cases a solid tumor has been identified at the time of the diagnosis of the vasculitis, and Wegener granulomatosis and microscopic polyangiitis are the two most frequent forms of ANCA-positive vasculitis. Thrombophlebitis occurs in about 8% of persons with an ANCA-positive vasculitis.
Wegener granulomatosis Wegener granulomatosis is a syndrome consisting of necrotizing granulomas of the upper and lower respiratory tract, generalized necrotizing angiitis affecting the medium-sized blood vessels, and focal necrotizing glomerulitis. By far the most common initial manifestation, present in 90% of patients, is the occurrence of rhinorrhea, severe sinusitis, and nasal mucosal ulcerations, with one or several nodules in the nose, larynx, trachea, or bronchi. Fever, weight loss, and malaise occur in these patients, who are usually 40–50 years of age and more often male than female (1.3:1). Obstruction in the nose may also block the sinuses. The nodules in the nose frequently ulcerate and bleed. The parenchymal involvement of the lungs produces cough, dyspnea, and chest pain. Granulomas may occur in the ear and mouth, where the alveolar ridge becomes necrotic, and ulceration of the tongue and perforated ulcers of the palate develop. The combination of nasal and palatal involvement may lead to saddle-nose deformity. The “strawberry gums” appearance of hypertrophic gingivitis is characteristic, and biopsy from these lesions may be diagnostic (Fig. 35-25). Cutaneous findings occur in 45% of patients. Nodules may appear in crops, especially along the extensor surfaces of the extremities. The firm, slightly tender, flesh-colored or violaceous nodules may later ulcerate. These may be mistaken for ulcerating rheumatoid nodules. The necrotizing angiitis of the skin may present as a palpable purpura, petechial or 831
nasal carriage of Staphylococcus aureus, an accepted trigger of Wegener granulomatosis. In refractory cases, IVIG and antiTNF therapy (infliximab) may be used. Tacrolimus, 0.1 mg/ kg/day, was successful in treating a pyoderma gangrenosumlike ulceration in a patient with Wegener granulomatosis.
Cutaneous Vascular Diseases
35
Fig. 35-25 Wegener granulomatosis, strawberry gingiva.
hemorrhagic pustular eruption, subcutaneous nodules, or ulcers. Livedo reticularis is rare in Wegener granulomatosis. Patients may present with pyoderma gangrenosum-like lesions and several patients have been reported presenting with features of temporal arteritis. The condition previously described as “malignant pyoderma” is now felt to represent Wegener granulomatosis. Limited forms involving the upper respiratory tract without renal involvement may also occur and have a better prognosis. Cutaneous findings can be associated with limited disease. Focal necrotizing glomerulitis occurs in 85% of patients. It may be fulminant from the outset or may become more severe as the disease progresses. Renal failure was the most frequent cause of death before cyclophosphamide treatment. Other organs frequently involved include the joints (arthralgia in two-thirds); eyes (conjunctivitis, episcleritis, and proptosis) in 58%; and CNS and cardiac involvement in 22% and 12% of patients, respectively. Histologically, the cutaneous lesions may demonstrate an LCV, with or without granulomatous inflammation. Granulomatous vasculitis may be seen. Palisaded granulomas with multinucleated giant cells and a central core of neutrophils and debris are a characteristic finding. Often, if the lesions are ulcerated, they are nonspecific histologically. Biopsy of another affected organ may be required to confirm the diagnosis. The early detection of Wegener granulomatosis has improved with the availability of ANCA testing, as 75– 80% of patients are c-ANCA (anti-PR3)-positive. Untreated Wegener granulomatosis has a mean survival time of 5 months and a 90% mortality over 2 years. Cyclophosphamide therapy has dramatically changed the prognosis. Treatment recommendations are cyclophosphamide, 2 mg/kg/day, and prednisone, 1 mg/kg/day, followed by tapering of the prednisone to an alternate-day regimen. Complete remission is achieved in up to 93% of patients and lasts an average of 4 years for still living patients. In more limited disease, patients may respond to methotrexate alone or methotrexate in combination with prednisone. After initial induction therapy and a remission, methotrexate, azathioprine, leflunomide, or mycophenolate mofetil may be used instead of cyclophosphamide. Treatment should be continued for at least 1 year. Trimethoprim–sulfamethoxazole may decrease the relapse rate and can be considered for long-term treatment of patients with limited upper respiratory tract involvement in remission in combination with conventional immunosuppressive protocols. The benefit of long-term sulfamethoxazole/trimethoprim is due to its reduction of 832
Bartolucci P, et al: Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology 2002; 41:1126. De Groot K, et al: Wegener’s granulomatosis: disease course, assessment of activity and extent and treatment. Lupus 1998; 7:285. Frances C, et al: Wegener’s granulomatosis. Arch Dermatol 1994; 130:861. Gürses L, et al: Wegener’s granulomatosis presenting as neutrophilic dermatosis: a case report. Br J Dermatol 2000; 143:207. Manchanda Y, et al: Strawberry gingiva: a distinctive sign in Wegener’s granulomatosis. J Am Acad Dermatol 2003; 49:335. Micali G, et al: Cephalic pyoderma gangrenosum (PG)-like lesions as a presenting sign of Wegener’s granulomatosis. Int J Dermatol 1994; 33:477. Nishino H, et al: Wegener’s granulomatosis associated with vasculitis of the temporal artery. Mayo Clin Proc 1993; 68:194. Rozin A: Infliximab efficiency in refractory Wegener’s granulomatosis. Rheumatology 2003; 42:1124. Wenzel J, et al: Successful treatment of recalcitrant Wegener’s granulomatosis of the skin with tacrolimus (Prograf). Br J Dermatol 2004; 151:927.
Churg–Strauss syndrome Churg–Strauss syndrome (CSS) occurs in three phases. The initial phase, often lasting many years, consists of allergic rhinitis, nasal polyps, and asthma. The average age of onset of the asthma is 35 years in CSS (as opposed to allergic asthma, which often presents in childhood). After 2 to 12 years, a debilitated asthmatic begins to experience attacks of fever and eosinophilia (20–90%), with pneumonia and gastroenteritis (second phase). After a few more months or years, but on average 3 years after the initial symptoms, a diffuse angiitis involves the lungs, heart, liver, spleen, kidneys, intestines, and pancreas. Mononeuritis multiplex is common. Triggers of this third phase have included vaccination, desensitization, leukotriene inhibitors, azithromycin, inhaled fluticasone, or rapid discontinuation of corticosteroids. Renal involvement is less common than in Wegener granulomatosis or microscopic polyangiitis. A fatal outcome is likely in most untreated patients, with congestive heart failure resulting from granulomatous inflammation of the myocardium being the most frequent cause of death. Increased rates of arterial and venous thrombosis are seen in CSS, perhaps related to the dense infiltrates of eosinophils. Cutaneous lesions are present in two-thirds of patients. Palpable purpura is seen in nearly 50% of patients. Subcutaneous nodules on the extensor surfaces of the extremities and on the scalp are seen in 30%. Firm, nontender papules may be present on the fingertips. These may resemble lesions seen with septic emboli or atrial myxoma, but show vasculitis on biopsy. Urticaria, solar urticaria, and livedo reticularis can occur in CSS. Plaques with the histologic features of eosinophilic cellulitis (Well syndrome) can be seen. Laboratory studies are significant for a peripheral eosino philia, which correlates with disease severity. ANCAs are frequently positive (55–70%), most commonly for antimyeloperoxidase (p-ANCA) and less frequently for anti-PR3 (c-ANCA), and tend to correlate with disease severity. Histologically, a small-vessel vasculitis is present that involves not only superficial venules, but also larger and deeper vessels. The tissue is often diffusely infiltrated with eosinophils, and granulomas may be present. Palisaded granulomas differ from those in Wegener granulomatosis in that
Abe R, et al: Disseminated subcutaneous nodules alone as manifestations of Churg–Strauss syndrome. Int J Dermatol 2008; 47:532. Abe-Matsuura Y, et al: Allergic granulomatosis (Churg–Strauss) associated with cutaneous manifestations. J Dermatol 1995; 22:46. Ames PR, et al: Eosinophilia and thrombophilia in Churg–Strauss syndrome: a clinical and pathogenetic overview. Clin Appl Thromb Hemost 2009 Oct 14 (Epub ahead of print). Assaf C, et al: Churg–Strauss syndrome: successful treatment with mycophenolate mofetil. Br J Dermatol 2004; 150:596. Black JG, et al: Montelukast-associated Churg–Strauss vasculitis: another associated report. Ann Allergy Asthma Immunol 2009; 102:351. Chen KR, et al: Granulomatous arteritis in cutaneous lesions of Churg–Strauss syndrome. J Cutan Pathol 2007; 34:330. Davis MDP, et al: Cutaneous manifestations of Churg–Strauss syndrome. J Am Acad Dermatol 1997; 37:199. Drage LA, et al: Evidence for pathogenic involvement of eosinophils and neutrophils in Churg–Strauss syndrome. J Am Acad Dermatol 2002; 47:209. Fisher K, et al: Cutaneous Churg–Strauss granuloma in a child. J Cutan Pathol 2009; 36:910. Govoni M, et al: Churg–Strauss syndrome and Wells syndrome: coincidence or pathogenetic association? A new case report. Clin Exp Rheumatol 2007; 25:S41. Jaworsky C: Leukotriene receptor antagonists and Churg–Strauss syndrome: an association with relevance to dermatopathology? J Cutan Pathol 2008; 35:611. Kranke B, et al: Macrolide-induced Churg–Strauss syndrome in a patient with atopy. Lancet 1997; 350:1551. Lee SC, et al: Wells syndrome associated with Churg–Strauss syndrome. J Am Acad Dermatol 2000; 43:556. Louthrenoo W, et al: Childhood Churg–Strauss syndrome. J Rheumatol 1999; 26:1387. Nepal M, Padma H: Fluticasone-associated cutaneous allergic granulomatous vasculitis: an underrecognized but important cause of drug-induced cutaneous Churg–Strauss syndrome. South Med J 2008; 101:761. Oh MJ, et al: Churg–Strauss syndrome: the clinical features and long-term follow-up of 17 patients. J Korean Med Sci 2006; 21:265. Shimauchi T, et al: Solar urticaria as a manifestation of Churg–Strauss syndrome. Clin Exp Dermatol 2007; 32:209. Tatsis E, et al: Interferon-alpha treatment of four patients with the Churg–Strauss syndrome. Ann Intern Med 1998; 129:370. Vanoli M, et al: A case of Churg–Strauss vasculitis after hepatitis B vaccination. Ann Rheum Dis 1998; 57:256.
Cocaine-associated vasculitis There are numerous reports of various forms of cutaneous vasculitis associated with the intravenous or intranasal use of cocaine. Skin lesions have included typical LCV, as well as larger-vessel vasculitis resembling PAN. Localized nasal lesions with vasculitis resembling Wegener granulomatosis have been observed in patients using inhaled cocaine. This has been termed “cocaine-induced pseudovasculitis” or “cocaineinduced midline destructive lesions” to try to distinguish it from true Wegener granulomatosis. In addition, patients using cocaine may develop more widespread cutaneous and sys-
temic vasculitis affecting kidneys, lungs, and testes. The cutaneous lesions resemble LCV, but ecchymotic lesions and skin necrosis were more prominent in these patients than in the typical LCV patient. Purpura and necrosis of the earlobe were especially common and characteristic. Agranulocytosis, not a typical feature of ANCA-positive vasculitis, was also found. These patients have an elevated c-ANCA (PR3-ANCA), similar to patients with true Wegener granulomatosis. However, the c-ANCA in patients with cocaine-induced vasculitis reacts with human neutrophil elastase (HNE-ANCA). Patients with Wegener granulomatosis and microscopic polyangiitis are negative for HNE-ANCA. Street cocaine is commonly contaminated with pharmaceutical agents. Surprisingly, levamisole has been found in the cocaine seized by law enforcement in up to 30% of cases in the US and 100% in Italy. Levamisole therapy is associated with ecchymotic purpura and necrosis, with a predilection for the ears. It also causes agranulocytosis and c-ANCA positivity. It is therefore unclear whether the vasculitic lesions seen in recreational cocaine users are due to the cocaine or to the levamisole excipient or both. In every patient presenting with a cutaneous or systemic vasculitis, a detailed history of recreational drug use must be obtained, and toxicology screening should be considered in any patient with vasculitis having the features outlined above, especially agranulocytosis or cutaneous necrosis, or failure to respond to appropriate therapy. In these patients, stopping of the drug may lead to a gradual improvement of the vasculitis, although initial immunosuppressive therapy may be required. Treatment to eradicate nasal S. aureus should be considered if there are prominent nasal findings.
Giant-cell arteritis/temporal arteritis
they generally lack multinucleated giant cells and the core contains eosinophils. In some patients, flame figures, similar to those in Well syndrome, are noted in the dermis. Corticosteroids alone may be used in patients with CSS and an FFS (see PAN above) of 0. Cyclophosphamide alone or in combination with corticosteroids should be used in cases of neuropathy, refractory glomerulonephritis, myocardial disease, severe gastrointestinal disease, and CNS involvement. Methotrexate and other immunosuppressives can be used as a steroid-sparing agent, especially to maintain a remission. IFN-α, mycophenolate mofetil, and the anti-TNF agents (in fliximab and etanercept) have also been used successfully in CSS.
Barbano G, et al: Disseminated autoimmune disease during levamisole treatment of nephrotic syndrome. Pediatr Nephrol 1999; 13:602. Fucci N: Unusual adulterants in cocaine seized on Italian clandestine market. Forensic Sci Int 2007; 172:e1. Kinzie E, et al: Levamisole found in patients using cocaine. Ann Emerg Med 2009; 53:546. Menni S, et al: Ear lobe bilateral necrosis by levamisole-induced occlusive vasculitis in a pediatric patient. Pediatr Dermatol 1997; 14:477. Neynaber S, et al: PR3-ANCA-positive necrotizing multi-organ vasculitis following cocaine abuse. Acta Derm Venereol 2008; 88:594. Rachapalli SM, Kiely PD: Cocaine-induced midline destructive lesions mimicking ENT-limited Wegener’s granulomatosis. Scand J Rheumatol 2008; 37:477. Rongioletti F, et al: Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol 1999; 140:948. Wiesner O, et al: Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis. Arthritis Rheum 2004; 50:2954. Zhu NY, et al: Agranulocytosis after consumption of cocaine adulterated with levamisole. Ann Intern Med 2009; 150:287.
Giant-cell arteritis/temporal arteritis Giant-cell arteritis is a systemic disease of people over the age of 50 years (mean age >70), favoring women (2:1). It is uncommon in African Americans and favors whites. Its best-known location is the temporal artery, where it is known as temporal arteritis, cranial arteritis, and Horton’s disease. It is characterized by a necrotizing arteritis with granulomas and giant cells, which produce unilateral headache and exquisite tenderness in the scalp over the temporal or occipital arteries in 50–75% of patients. Temporal headaches are characteristically constant, severe, and boring. Ear and parotid pain and masticationinduced jaw claudication may occur. Fever, anemia, and a high sedimentation rate (>50) are usually present. Proximal, 833
35 Cutaneous Vascular Diseases
Andonopoulos AP, et al: Experience with infliximab (anti-TNFα monoclonal antibody) as monotherapy for giant cell arteritis. Ann Rheum Dis 2003; 62:1116. Botella-Estrada R, et al: Magnetic resonance angiography in the diagnosis of a case of giant cell arteritis manifesting as scalp necrosis. Arch Dermatol 1999; 135:769. Carlson JA, Chen KR: Cutaneous vasculitis update: neutrophilic muscular vessel and eosinophilic, granulomatous, and lymphocytic vasculitis syndromes. Am J Dermatopathol 2007; 29:32. Hamidou MA, et al: Temporal arteritis associated with systemic necrotizing vasculitis. J Rheumatol 2003; 30:2165. Marcos O, et al: Tongue necrosis in a patient with temporal arteritis. J Oral Maxillofac Surg 1998; 56:1203. Tsianakas A, et al: Scalp necrosis in giant cell arteritis: case report and review of the relevance of this cutaneous sign of large-vessel vasculitis. J Am Acad Dermatol 2009; 61:701.
Fig. 35-26 Giant cell arteritis with scalp necrosis.
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symmetrical, and severe morning and even day-long stiffness, soreness, and pain occur in 50% of patients (associated polymyalgia rheumatica). It is rarely fatal. Blindness may develop and is the most feared complication of the disease. Many patients who develop visual loss have premonitory symptoms allowing for the diagnosis and intervention, which may prevent permanent visual loss. The cutaneous manifestations may be only inflammatory. The affected artery becomes evident as a hard, pulsating, tender, tortuous bulge under red or cyanotic skin. Another manifestation is necrosis of the scalp (Fig. 35-26). The lesions may first appear as ecchymoses. Later, they may become vesicular or bullous and are followed by gangrene. Urticaria, purpura, alopecia, tender nodules, prurigo-like nodules, and livedo reticularis may be seen. Lingual artery involvement may cause an accompanying red, sore, or gangrenous tongue. Nasal septal perforation may develop. Actinic granuloma may be associated. Actinic damage of the arterial elastic tissue of the temporal artery may be possible due to its superficial location. The elderly Caucasian is at greatest risk, and when lesions are biopsied, at times only the external half of the artery that received solar radiation is involved. Temporal arteritis may be an actinically induced disease. Polymyalgia rheumatica (PMR) has a significant clinical association with giant-cell arteritis. Prompt treatment may forestall serious disease. About 10% of central retinal artery occlusions are due to giant-cell arteritis. ESRs are elevated in more than 90% of patients with giant-cell arteritis. Temporal artery biopsy is generally diagnostic, provided that at least a 2 cm segment is provided. Even arteries that are normal to palpation may show diagnostic findings. Magnetic resonance angiography is a noninvasive diagnostic method that may aid in confirming the clinical suspicion and identify the best site to biopsy. Not all patients with arteritis of the temporal artery have giant cell arteritis, as temporal arteritis may be a manifestation or part of the systemic vasculitides such as PAN, Wegener granulomatosis, or microscopic polyarteritis. Pathogenically, the presence of TNF polymorphisms in patients with PMR and temporal arteritis suggests a genetic predisposition. Treatment is usually begun with prednisone, 60 mg/day, and continued for 1 month or until all reversible clinical and laboratory parameters (such as the ESR) have returned to normal. The disease is quite steroid-responsive and tapering to a dose of 7.5–10 mg/day is usually possible. Daily therapy seems to be important and is usually necessary for a minimum of 1–2 years. Most patients achieve complete remission that is often maintained after therapy is withdrawn. Anti-TNF agents may be used in refractory cases, but relapses occur when treatment is stopped, and corticosteroid therapy is usually required.
Takayasu arteritis Known also as aortic arch syndrome and pulseless disease, Takayasu arteritis is a thrombo-obliterative process of the great vessels stemming from the aortic arch, occurring generally in young women (female to male ratio, 9 : 1) in the second or third decade of life. It is more common in Japan, Southeast Asia, India, and South America. Radial and carotid pulses are typically obliterated. Most skin changes are due to the disturbed circulation. There may be loss of hair and atrophy of the skin and its appendages, with underlying muscle atrophy. Occasional patients with cutaneous necrotizing or granulomatous vasculitis of small vessels have been reported. Erythematous nodules with or without livedo, simulating erythema nodosum or erythema induratum, may rarely occur. Pyoderma gangrenosum-like ulcerations are well described in Japan. Pyoderma gangrenosum lesions precede the diagnosis of the arteritis by an average of 3 years. These lesions are more commonly generalized and in three-quarters of cases occur on the upper extremities. Treatment of Takayasu arteritis with prednisone, 1 mg/kg/ day tapered in 8–12 weeks to 20 mg/day or less, is recommended. Methotrexate may be used for its steroid-sparing effects. With active medical and surgical intervention, the aggressive course of this disease can be modified. The pyoderma gangrenosum-like lesions are also treated with systemic steroids, but azathioprine, cyclophosphamide, mycophenolate mofetil, cyclosporine, and tacrolimus have also been effective. Ohta Y, et al: Inflammatory diseases associated with Takayasu’s arteritis. Angiology 2003; 54:339. Pascual-Lopez M, et al: Takayasu’s disease with cutaneous involvement. Dermatology 2004; 208:10. Skaria AM, et al: Takayasu arteritis and cutaneous necrotizing vasculitis. Dermatology 2000; 200:139. Ujiie H, et al: Pyoderma gangrenosum associated with Takayasu’s arteritis. Clin Exp Dermatol 2004; 29:357.
Malignant atrophic papulosis Papulosis atrophicans maligna, also known as Degos’ disease, is a potentially fatal obliterative arteritis syndrome. Some affected patients have a long benign course with skin lesions only, while in others, death occurs within a few years. Degos’ disease occurs 2–3 times more frequently in men than in women, often presenting between the ages of 20 and 40. Familial kindreds are well reported. In patients with the more aggressive variant, survival averages 2–3 years after the disease has developed. Skin lesions are usually the first sign of the disease. Clinically, Degos’ disease is characterized by the presence of pale rose, rounded, edematous papules occurring mostly on the trunk. Similar lesions may occur on the bulbar conjunctiva and oral
Cebeci Z, et al: Degos’ disease. Ophthalmology 2009; 116:1415. Chung HY, et al: Degos’ disease: a rare condition simulating rheumatic diseases. Clin Rheumatol 2009; 28:861. Cuchillero RMO, et al: Benign cutaneous Degos’ disease. Clin Exp Dermatol 2003; 28:145. De Breucker S, et al: Inefficacy of intravenous immunoglobulins and infliximab in Degos’ disease. Acta Clin Belg 2008; 63:99. Dyrsen ME, et al: Parvovirus B19-associated catastrophic endothelialitis with a Degos-like presentation. J Cutan Pathol 2008; 35:20. Guhl G, et al: Wegener’s granulomatosis: a new entity in the growing differential diagnosis of Degos’ disease. Clin Exp Dermatol 2009; 34:e1. High WA, et al: Is Degos’ disease a clinical and histological end point rather than a specific disease? J Am Acad Dermatol 2004; 50:895. Hohwy T, et al: A fatal case of malignant atrophic papulosis (Degos’ disease) in a man with factor V Leiden mutation and lupus anticoagulant. Acta Derm Venereol 2006; 86:245. Kanekura T, et al: A case of malignant atrophic papulosis successfully treated with nicotine patches. Br J Dermatol 2003; 149:660. Katz SK, et al: Malignant atrophic papulosis (Degos’ disease) involving three generations of a family. J Am Acad Dermatol 1997; 37:480. Kim DW, et al: Degos’ disease (malignant atrophic papulosis) as a fatal cause of acute abdomen: report of a case. Surg Today 2008; 38:866. Liu CM, et al: Lesions resembling malignant atrophic papulosis in a patient with progressive systemic sclerosis. Cutis 2005; 75:101.
Moss C, et al: Degos disease: a new simulator of non-accidental injury. Dev Med Child Neurol 2009; 51:647. Powell J, et al: Benign familial Degos’ disease worsening during immunosuppression. Br J Dermatol 1999; 141:524. Requena L, et al: Degos’ disease in a patient with acquired immunodeficiency syndrome. J Am Acad Dermatol 1998; 38:852. Saglik E, et al: Malignant atrophic papulosis: endocardial involvement and positive anticardiolipin antibodies. J Eur Acad Dermatol Venereol 2006; 20:602. Scheinfeld N: Degos’ disease is probably a distinct entity: a review of clinical and laboratory evidence. J Am Acad Dermatol 2005; 52:375. Scheinfeld N: Malignant atrophic papulosis. Clin Exp Dermatol 2007; 32:483. Shahshahani MM, et al: A case of Degos disease with pleuropericardial fibrosis, jejunal perforation, hemiparesis, and widespread cutaneous lesions. Int J Dermatol 2008; 47:493. Tan WP, et al: Generalized red papules with gastrointestinal complications. Clin Exp Dermatol 2007; 32:615. Thomson KF, Highet AS: Penile ulceration in fatal malignant atrophic papulosis (Degos’ disease). Br J Dermatol 2000; 143:1320. Torrelo A, et al: Malignant atrophic papulosis in an infant. Br J Dermatol 2002; 146:916. Zhao WH, et al: A fatal case of malignant atrophic papulosis. Eur J Dermatol 2009; 19:193. Zhu KJ, et al: The use of intravenous immunoglobulin in cutaneous and recurrent perforating intestinal Degos disease (malignant atrophic papulosis). Br J Dermatol 2007; 157:206.
Thromboangiitis obliterans
mucosa. Palms, soles, and face are spared, but the penis may be involved. Over days to weeks, the lesions become umbilicated, with a central depression, which enlarges. The center becomes distinctively porcelain-white, while the periphery becomes livid red and telangiectatic. Central atrophy occurs eventually. The eruption proceeds by crops in which only a few new lesions appear at any one time. One patient was reported to develop panniculitis. Lesions characteristic of Degos’ disease may be seen in patients with lupus erythematosus, dermatomyositis, scleroderma, and Wegener granulomatosis. Systemically, ischemic infarcts involve the intestines, producing acute abdominal symptoms, which include epigastric pain, fever, and hematemesis. Death is usually due to fulminating peritonitis caused by multiple perforations of the intestine. Less commonly, death occurs from cerebral infarctions. Wedge-shaped necroses brought on by the occlusion of arterioles and small arteries account for the clinical lesions. Proliferation of the intima and thrombosis constitute the typical histologic picture. The thrombosing process is usually pauci-inflammatory, although neutrophils or lymphocytes may be found associated with the thrombosis. The overlying dermis, which is infarcted, contains abundant mucin, especially early in the lesion’s evolution. Adnexae are typically necrotic and the depressed central portion may be noted histologically. The etiology of this disease is unknown, but based on the infarctive nature of the lesions and the universal presence of arteriolar thrombosis, a hyperthrombotic state or endothelial abnormality is suggested. While most patients have not had abnormalities identified, abnormal platelet aggregation and abnormal coagulation have been identified in some cases. Antiphospholipid antibodies and anticardiolipin antibodies have been present in some patients, and a Leiden factor V mutation in one patient. Parvovirus B19 infection was associated with a fatal case in an adult. Administration of immunosuppressives has not been beneficial. IVIG has been of therapeutic benefit in one case, but failed in another. Ingestion of low-dose acetylsalicylic acid alone or in combination with dipyridamole (Persantine) has been effective in some patients. Heparin, as described by Degos, has been helpful, and should be considered if antiplatelet therapy is ineffective. Nicotine patches, 5 mg/day, were effective in one case. In severe crises, fibrinolytic therapy should be considered. The prognosis is guarded in patients with systemic involvement.
Thromboangiitis obliterans (Buerger’s disease) Thromboangiitis obliterans (TAO) is a nonatherosclerotic segmental occlusive disease affecting the arteries of multiple extremities. It is most often seen in men between the ages of 20 and 40 who smoke heavily. Smoking and, rarely, the use of smokeless tobacco are intimately tied to Buerger’s disease. Various diagnostic criteria have been proposed. They usually include: age younger than 45 (or 50); history of tobacco use; distal extremity involvement (infrapopliteal segmental arterial occlusion with sparing of the proximal vasculature); frequent distal upper extremity involvement (Raynaud or digital ulcers); consistent angiographic findings; superficial thrombo phlebitis; exclusion of autoimmune disease, diabetes mellitus, and hypercoagulable or embolic states. The vasomotor changes in early cases may be transitory or persistent; they produce blanching, cyanosis, burning, and tingling. Superficial thrombophlebitis in the leg and foot occurs in 38% of cases and 44% of patients may have Raynaud phenomenon. The color of the part may change when it is elevated or lowered below heart level, being red when dependent and white when elevated. Pain is a constant symptom, coming at first only after exercise and subsiding on resting. Instep and foot claudication is the classic complaint. Ultimately, the dorsalis pedis and posterior tibial pulses disappear, followed by others. In TAO, skin supplied by affected arterioles tends to break down, with central necrosis and ulceration, and eventual gangrene (Fig. 35-27). Gastrointestinal involvement has been reported. Exposure to cold may cause exacerbations, and more cases are identified in the winter than any other season. Arteriography should be carried out to investigate for central atherosclerotic disease, which may be operable, rather than the inoperable distal damage of Buerger’s disease. A characteristic tapering and occlusion of the major arteries with “corkscrew” collateral arteries is found in Buerger’s disease on angiography. A vasculo-occlusive syndrome similar to Buerger’s disease has been reported in cannabis smokers, but venous thrombophlebitis does not occur. The pathogenic mechanism of the vascular occlusion in Buerger’s disease is unknown. In one report G20210A prothrombin mutations, the majority homozygotic, were found, but these findings have not been reproduced.
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Arteriosclerosis obliterans
Cutaneous Vascular Diseases
35
Fig. 35-27 Buerger’s disease.
The most important therapeutic aspect is the cessation of smoking. Even one or two cigarettes/day, smokeless tobacco, or nicotine replacement may keep the disease active. Intravenous iloprost (a prostaglandin analog) may help the patient with critical limb ischemia get through an acute episode. Oral iloprost is ineffective. Sympathectomy can provide temporary relief. Autologous transplantation of bone marrow mononuclear cells into the calf muscle has benefited patients with TAO and other forms of limb ischemia. G-CSFmobilized peripheral blood mononuclear cells have had similar efficacy. In patients who stop smoking and do not have gangrene, major amputations are rare. In continued smokers, at least 43% will require amputations. Implantation of a spinal cord stimulator may be tried. Boda Z, et al: Stem cell therapy: a promising and prospective approach in the treatment of patients with severe Buerger’s disease. Clin Appl Thromb Hemos 2009; 15:552. Cazalets C, et al: Cannabis arteritis: four new cases. Rev Med Interne 2003; 24:127. De Vriese AS, et al: Autologous transplantation of bone marrow mononuclear cells for limb ischemia in a Caucasian population with atherosclerosis obliterans. J Intern Med 2008; 263:395. Espinoza LR: Buerger’s disease: thromboangiitis obliterans 100 years after the initial description. Am J Med Sci 2009; 337:285. Faizer R, Forbes TL: Buerger’s disease. J Vasc Surg 2007; 46:812. Kakihana A, et al: Improvement of cardiac function after granulocytecolony stimulating factor-mobilized peripheral blood mononuclear cell implantation in a patient with non-ischemic dilated cardiomyopathy associated with thromboangiitis obliterans. Intern Med 2009; 48:1003. Kobayashi M, et al: Ischemic intestinal involvement in a patient with Buerger’s disease: case report and literature review. J Vasc Surg 2003; 38:170. Laohapensang K, et al: Seasonal variation of Buerger’s disease in northern part of Thailand. Eur J Vasc Endovasc Surg 2004; 28:418. Malecki R, et al: Thromboangiitis obliterans in the 21st century—a new face of disease. Atherosclerosis 2009; 206:328. Manfredini R, et al: Thromboangiitis obliterans (Buerger’s disease) in a female mild smoker treated with spinal cord stimulation. Am J Med Sci 2004; 327:365. Matsushita M, et al: Buerger’s disease in a 19-year-old woman. J Vasc Surg 2003; 38:175. Olin JW: Thromboangiitis obliterans (Buerger’s disease). N Engl J Med 2000; 343:864.
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Arteriosclerosis obliterans is an occlusive arterial disease most prominently affecting the abdominal aorta, and the small and medium-sized arteries of the lower extremities. The symptoms are due to ischemia of the tissues. There is intermittent claudication manifested by pain, cramping, numbness, and fatigue in the muscles on exercise; these are relieved by rest. There may be “rest pain” at night when in bed. Also, sensitivity to cold, muscular weakness, stiffness of the joints, and paresthesia may be present. Sexual impotence is common and there is an increased frequency of coronary artery disease. Impaired to absent pulses (dorsalis pedis, posterior tibial, or popliteal arteries) may be found on physical examination, confirming the diagnosis. The feet, especially the toes, may be red and cold. Striking pallor of the feet on elevation and redness when dependent are compatible findings. Decreased to absent hair growth may be observed on the legs. Ulceration and gangrene may supervene. If present, they usually begin in the toes and are quite painful. Arteriography may be indicated as a preliminary to corrective surgery (arterial grafts). Occasionally, subclavian atherosclerosis may give rise to these signs in the distal upper extremity, producing painful nails and loss of digital skin. Diabetes mellitus, smoking, and hyperlipidemia are risk factors for the development of atherosclerosis. Claudication and diminished blood pressure in the affected extremity are findings that may lead to earlier diagnosis and thus to curative surgical intervention. Usually, bypass of the affected artery or sympathectomy, or both, are the preferred treatment. Balloon angioplasty or stent placement may also be effective. When critical limb ischemia is present, injection of stem cells into the calf muscle may be beneficial. Kerdel FA, et al: Subclavian occlusive disease presenting as a painful nail. J Am Acad Dermatol 1984; 10:523. Matsumoto K, et al: Insulin resistance and arteriosclerosis obliterans in patients with NIDDM. Diabetes Care 1997; 20:1738.
Diffuse dermal angiomatosis Diffuse dermal angiomatosis (DDA) is a not uncommon disorder that preferentially affects women. The most common location is the breast, especially the dependent portion. Affected women tend to have large, pendulous breasts, and are usually older than 45 years of age. Patients may have had a reduction mammoplasty (often decades before), and the disease tends to localize adjacent to the scar from that procedure. The clinical lesions may be reticulated groups of telangiectasias, ischemic (retiform) purpura, or ulceration, or some combination. The erythematous/telangiectatic plaques are slightly palpable but not usually indurated. The nipple and areola are spared. The affected patients often have multiple risk factors for a hypercoagulable state or premature atherosclerosis. These include a personal history of atherosclerotic cardiovascular disease, obesity, smoking, hypertension, mutations in the thrombolytic pathway (analogous to those seen in livedoid vasculopathy), and a strong family history for premature atherosclerotic disease-related cardiovascular events. The areas involved are very similar to those affected by other prothrombotic disorders such as warfarin necrosis and heparin necrosis—skin with overly abundant adipose tissue. The breast is most commonly affected, but the abdomen and medial thighs are also sites of predilection. Usually, only one site is affected, but if the breast is involved, the process can be bilateral. Surgical procedures on the affected area may lead to ulceration that is very painful and slow to heal. Because a surgical procedure triggered the ulceration, a mistaken diagnosis of pyoderma gangrenosum may be entertained.
McLaughlin ER, et al: Diffuse dermal angiomatosis of the breast: response to isotretinoin. J Am Acad Dermatol 2001; 45:462. Pichardo RO, et al: What is your diagnosis? Diffuse dermal angiomatosis secondary to anticardiolipin antibodies. Am J Dermatopathol 2002; 24:502. Quatresooz P, et al: Diffuse dermal angiomatosis: a previously undescribed pattern of immunoglobulin and complement deposits in two cases. Am J Dermatopathol 2006; 28:150. Villa MT, et al: The treatment of diffuse dermal angiomatosis of the breast with reduction mammaplasty. Arch Dermatol 2008; 144:693. Yang H, et al: Diffuse dermal angiomatosis of the breast. Arch Dermatol 2006; 142:343.
Mucocutaneous lymph node syndrome (Kawasaki’s disease) The typical presentation is an irritable, ill-appearing, febrile infant or child younger than 5 years old. Clinical findings (four of which, plus fever for 5 days, are diagnostic of Kawasaki syndrome) include a skin eruption; stomatitis (injected pharynx, strawberry tongue) and fissuring cheilitis; edema of the hands and feet; conjunctival injection; and cervical lymph adenitis. The skin eruption is polymorphous and may be macular, morbilliform, urticarial, scarlatiniform, erythema multiforme-like, pustular, or erythema marginatum-like. An early finding (within the first week) is the appearance of an erythematous, desquamating perianal eruption in about twothirds of patients. Periorbital edema has been reported. Fifteen to 20% of children with Kawasaki’s disease (KD) and fever will not have one or more of the other cardinal features. These cases are termed “incomplete KD.” These patients are still at risk for cardiac disease. Numerous cutaneous and systemic complications have been reported as accompanying or following KD. Pincer nail deformities may appear and resolve spontaneously. Intestinal pseudo-obstruction may occur. Facial nerve paralysis has been described, and a severe peripheral vasculitis with vasospasm, digital ischemia, and gangrene can occur. Numerous children have developed guttate or plaque psoriasis 10–20 days after the KD had begun. The presumed mechanism is the triggering of psoriasis by the superantigens associated with the acute illness. The acute illness evolves over 10–20 days. A week or two following the acute illness, the fingers and toes desquamate, starting around the nails (Fig. 35-28). Coronary artery aneu-
Fig. 35-28 Desquamation in Kawasaki’s disease.
Mucocutaneous lymph node syndrome
Histologically, a diffuse dermal proliferation of endothelial cells and bland blood vessels occupies much of the dermis. Atypical cells and atypical vascular shapes (as seen in angio sarcoma and Kaposi sarcoma) are not seen. The dermal cells stain for markers of endothelial cells The pathogenesis is felt to be local chronic ischemia, which may either lead to vascular proliferation (angiomatosis), or if acute and severe, may lead to retiform purpura or ulceration. The fatty areas are poorly oxygenated (worse in the obese patient), and the pendulous nature of the breasts may stretch or tether the vessels, further compromising the circulation. Inherited and acquired hypercoagulable risk factors (smoking, atherosclerosis, and so on) contribute to the pathogenesis. The treatment involves reversing the contributing factors. This includes stopping smoking, weight reduction, and antithrombotic medications such as low-dose aspirin, 81 mg per day, and pentoxifylline, 400 mg BID. Reduction mammoplasty may lead to resolution. Atherosclerosis of the arteries serving the affected area may be found, and vascular surgery to enhance circulation may lead to improvement. One patient has been successfully treated with isotretinoin. Isotretinoin has a fibrinolytic effect, which may be the mechanism by which it improved DDA in this one patient.
rysms occur in 20–25% of untreated children and 3–5% of treated children. This is the most common cause of acquired cardiac disease in young children. The cardiac involvement, which, in addition to aneurysms, can include decreased left ventricular function, arrhythmias, mitral regurgitation, and pericardial effusion, may lead to immediate cardiac complications, the major cause of morbidity and mortality. In addition, over time, those with aneurysms can develop coronary artery stenosis, and as a result acute cardiac events can occur in young adulthood.
Pathogenesis A viral or infectious pathogenesis is attractive for the following reasons: 1. Cases were rare before 1950. 2. KD affects children older than 3 months but younger than 8 years. 3. Seasonal peaks occur in the winter and spring. 4. Focal epidemics have been reported. 5. Oligoclonal IgA immune responses are found, suggesting a respiratory portal of entry of an infectious agent. There are increased superantigens in the stool of children with KD. A KD-like illness has been described with group A meningococcal septicemia. An infectious pathogenesis, therefore, remains the most plausible etiologic hypothesis. It has long been suspected that there is a genetic basis for KD. The disease is 10–20 times more common in persons from Northeast Asia (Japan and Korea), where rates of up to 1 per 150 children are reported. When these Asians move to the US, they still have this high rate of increased susceptibility. The risk of a sibling developing KD is increased tenfold. Children of parents who had KD in childhood have a twofold increased risk of developing KD. A recent genome-wide search of almost 1000 KD cases and family members found strong linkage to five genes, three of which form a single functional network. The central gene of this network is CAMK2D, which encodes a serine/threonine kinase expressed in cardiomyocytes and vascular endothelial cells. These genes are already known to be involved in cardiac and inflammatory pathways. The transcripts of these genes were also markedly suppressed during KD. The previously reported genetic associations for KD were not found in this study, including the ITPKC gene mutation. Coronary arterial disease occurs after day 10 of the illness (subacute phase), in combination with thrombocythemia (up to 1 million). This combination of an altered endovascular surface and too many platelets, plus abnormal blood flow in 837
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the coronary aneurysms, leads to thrombosis and occlusion of the vessels and the subsequent cardiac events.
Treatment IVIG is the cornerstone of therapy, given in a single dose of 2 g/kg infused over 10–12 h. Response to treatment is best if given during the first 5–6 days of the illness; however, children with persistent fever beyond this period may benefit from later treatment. Aspirin is used to reduce inflammation and platelet aggregation. The dose is 80–100 mg/kg/day in four divided doses. Once the child has been afebrile for 3–7 days, the aspirin dose is decreased to a single daily dose of 3–5 mg/kg. If the child remains febrile, a second 2 g/kg dose of IVIG should be given. A single dose of infliximab, 5 mg/kg, has been reported to be effective in refractory cases, but response, as with other treatments, is not universal. If there is no response to the second IVIG dose, systemic steroid therapy is commonly given. Angioplasty, thrombolytic therapy, or coronary artery bypass surgery may be required for patients with coronary disease. Ahn SY, et al: Treatment of intravenous immunoglobulin-resistant Kawasaki disease with methotrexate. Scand J Rheumatol 2005; 34:136. Ayusawa M, et al: Revision of diagnostic guidelines from Kawasaki disease (the 5th revised edition). Pediatr Int 2005; 47:232. Burgner D, et al: A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet 2009; 5:e1000319. Burns JC, Glodé MP: Kawasaki syndrome. Lancet 2004; 364:533. Burns JC, et al: Infliximab treatment for refractory Kawasaki syndrome. J Pediatr 2005; 146:662. Fretzayas A, et al: Meningococcal group A sepsis associated with rare manifestations and complicated by Kawasaki-like disease. Pediatr Emerg Care 2009; 25:190. Garty B, et al: Guttate psoriasis following Kawasaki disease. Pediatr Dermatol 2001; 18:507. Harnden A, et al: Kawasaki disease. BMJ 2009; 338:1133. Larralde M, et al: Kawasaki disease with facial nerve paralysis. Pediatr Dermatol 2003; 20:511. Miura M, et al: Coronary risk factors in Kawasaki disease treated with additional gammaglobulin. Arch Dis Child 2004; 89:776. Muta H, et al: Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan. J Pediatr 2004; 144:496. Pannaraj PS, et al: Failure to diagnose Kawasaki disease at the extremes of the pediatric age range. Pediatr Infect Dis J 2004; 23:789. Thapa R, et al: Neonatal Kawasaki disease with multiple coronary aneurysms and thrombocytopenia. Pediatr Dermatol 2007; 24:662. Yamauchi H, et al: Optimal time of surgical treatment for Kawasaki coronary artery disease. J Nippon Med Sch 2004; 71:279. Yoon SY, et al: Plaque type psoriasiform eruption following Kawasaki disease. Pediatr Dermatol 2007; 24:336.
Telangiectasia Telangiectasia are fine linear vessels coursing on the surface of the skin; the name given to them collectively is telangiectasia. Telangiectasia may occur in normal skin at any age, in both sexes, and anywhere on the skin and mucous membranes. Fine telangiectases may be seen on the alae nasi of most adults. They are prominent in areas of chronic actinic damage. In addition, persons long exposed to wind, cold, or heat are subject to telangiectasia. Calcium channel-blockers may lead to telangiectatic lesions in a generalized or photodistribution and contribute to the appearance of photoaging. Telangiectasias may also be found on the legs as a result of heredity, varicosities, pregnancy, and birth control pill use. Telangiectases can be found in conditions such as radio dermatitis, xeroderma pigmentosum, lupus erythematosus, scleroderma and the CREST syndrome, rosacea, pregnancy, 838
cirrhosis of the liver, AIDS, poikiloderma, basal cell carcinoma, necrobiosis lipoidica diabeticorum, lichen sclerosus et atrophicus, sarcoid, lupus vulgaris, keloid, adenoma sebaceum, Kaposiform hemangioendothelioma, angioma serpiginosum, angiokeratoma corporis diffusum, hereditary benign telangiectasia, Cockayne syndrome, ataxia-telangiectasia, and Bloom syndrome. Altered capillary patterns on the finger nailfolds (cuticular telangiectases) are indicative of collagen vascular disease, such as lupus erythematosus, scleroderma, or dermatomyositis. They may infrequently be present in rheumatoid arthritis. These disorders are reviewed in Chapter 8. Beaubien ER, et al: Kaposiform hemangioendothelioma. J Am Acad Dermatol 1998; 38:799. Cooper SM, Wojnaraowska F: Photo-damage in Northern European renal transplant recipients is associated with the use of calcium channel blockers. Clin Exp Dermatol 2003; 28:588. Grabczynska SA, Cowley N: Amlodipine-induced photosensitivity presenting as telangiectasia. Br J Dermatol 2000; 142:1255. Huh J, et al: Localized facial telangiectasias following frostbite injury. Cutis 1996; 57:97. Ioulios P, et al: The spectrum of cutaneous reactions associated with calcium antagonists: a review of the literature and the possible etiopathogenic mechanisms. Dermatol Online J 2003; 9:6. Kanekura T, et al: Lichen sclerosus et atrophicus with prominent telangiectasia. J Dermatol 1994; 21:447. Silvestre JF, et al: Photodistributed felodipine-induced facial telangiectasia. J Am Acad Dermatol 2001; 45:323.
Generalized essential telangiectasia Generalized essential telangiectasia (GET) is characterized by the appearance of telangiectasia over a large segment of the body without preceding or coexisting skin lesions. Lesions tend to appear first on the legs and progress caudad. Women are more commonly affected, with the condition starting between age 20 and 50. Characteristic features include: 1. widespread cutaneous distribution 2. progression or permanence of the lesions 3. accentuation in dependent areas and by dependent positioning 4. absence of coexisting epidermal or dermal changes, such as atrophy, purpura, depigmentation, or follicular involvement. The telangiectases may be distributed over the entire body or localized to some large area, such as the legs, arms, and trunk. They may be discrete or confluent. Distribution along the course of the cutaneous nerves may occur. Systemic symptoms are absent, although conjunctival telangiectasias can also be seen. GET is usually not believed to be associated with an increased risk of epistaxis, but gastrointestinal bleeding has been reported. Families with this disorder, inherited as an autosomal-dominant trait, have been reported. The cause of essential telangiectasia is unknown. Treatment is with vascular lasers, if required. Collagenous vasculopathy, a condition favoring middleaged males, is clinically similar to GET but histologically distinct. Histologically, markedly dilated subepidermal vessels are present. These blood vessels have thickened vascular walls and perivascular hyaline. Type IV collagen staining accentuates the superficial vessels. Ali MM, et al: Generalized essential telangiectasia with conjunctival involvement. Clin Exp Dermatol 2006; 31:781. Davis TL, et al: Collagenous vasculopathy: a report of three cases. J Cutan Pathol 2008; 35:967. Gambichler T, et al: Generalized essential telangiectasia successfully treated with high-energy, long-pulse, frequency-doubled Nd:YAG laser. Dermatol Surg 2001; 27:355.
Unilateral nevoid telangiectasia In unilateral nevoid telangiectasia (UNT), fine, thread-like telangiectases develop in a unilateral, sometimes dermatomal (or following the lines of Blaschko) distribution. Spider angiomas may also be present. The most common distribution is unilateral or bilateral involvement of the third and fourth cervical dermatomes. The condition is rare in men; in affected women, it starts in adulthood. The familial form (very rare) favors males, is autosomal-dominant, and appears postnatally. UNT is associated with conditions that have increased levels of estrogen: puberty, pregnancy, oral contraceptive use, HCV infection, and cirrhosis. Treatment with pulse dye laser can be effective. Dadlani C, et al: Unilateral nevoid telangiectasia. Dermatol Online J 2008; 14:3. Derrow AE, et al: Acquired unilateral nevoid telangiectasia in a 51-year-old female. Int J Dermatol 2008; 47:1331. Hynes LR, et al: Unilateral nevoid telangiectasia: occurrence in two patients with hepatitis C. J Am Acad Dermatol 1997; 36:819. Karakas M, et al: Unilateral nevoid telangiectasia. J Dermatol 2004; 31:109. Kreft B, et al: Unilateral nevoid telangiectasia syndrome. Dermatology 2004; 209:215. Sardana K, et al: Unilateral nevoid telangiectasia syndrome. J Dermatol 2001; 28:453. Sharma VK, Khandpur S: Unilateral nevoid telangiectasia—response to pulsed dye laser. Int J Dermatol 2006; 45:960. Taskapan O: Acquired unilateral nevoid telangiectasia syndrome (letter). J Am Acad Dermatol 1998; 39:138. Woollons A, et al: Unilateral naevoid telangiectasia syndrome in pregnancy. Clin Exp Dermatol 1996; 21:459.
Hereditary hemorrhagic telangiectasia (Osler’s disease) Also known as Osler–Weber–Rendu disease, hereditary hemorrhagic telangiectasia (HHT) is characterized by small tufts of dilated capillaries scattered over the mucous membranes and the skin. These slightly elevated lesions develop mostly on the lips, tongue, palate, nasal mucosa, ears, palms, fingertips, nailbeds, and soles. They may closely simulate the telangiectases of the CREST variant of scleroderma, which may be distinguished by the lack of other features of CREST syndrome and by anticentromere antibodies, which are not found in HHT. Diagnostic criteria have been proposed and include: 1. epistaxis—spontaneous, recurrent nosebleeds 2. telangiectases—multiple at characteristic sites (lips, oral cavity, fingers, nose) (Fig. 35-29) 3. visceral lesions—gastrointestinal bleeding, pulmonary, hepatic, cerebral, or spinal arteriovenous malformation (AVM) 4. family history—one affected first-degree relative. The presence of three of the four criteria indicates a definite diagnosis, while two of four indicate a possible diagnosis. There are at least three variants, HHT1 and HHT2, and a third associated with juvenile polyposis. Frequent nosebleeds and melena are experienced because of the telangiectasia in the nose and gastrointestinal tract. Epistaxis is the most frequent and persistent sign. Worsening epistaxis may herald high-output cardiac failure from AVMs. Pregnancy can also exacerbate HHT. Gastrointestinal bleeding is the presenting sign in up to 25% of cases; however, 40–50% develop gastrointestinal bleeding some time during the course of their disease. Chronic persistent anemia requiring iron and
Fig. 35-29 Hereditary hemorrhagic telangiectasia.
Hereditary hemorrhagic telangiectasia
Long D, Marshman G: Generalized essential telangiectasia. Australas J Dermatol 2004; 45:67.
blood transfusions is characteristic of severe cases. The spleen may be enlarged. Pulmonary and CNS AVMs may appear later in life. Liver failure can result from diffuse intrahepatic shunting—hepatic artery to vein, bypassing the liver parenchyma. Retinal arteriovenous aneurysms occur only rarely. Other sites of bleeding may be the kidney, spleen, bladder, liver, meninges, and brain. The risk of cerebral hemorrhage from cerebral AVMs, cerebral abscesses, and pulmonary hemorrhage from pulmonary AVMs is probably high enough that asymptomatic patients should be screened for the presence of cerebral and pulmonary AVMs. Because of the risk of cerebral abscess, some have advocated antibiotic prophylaxis for dental and contaminated skin procedures. The telangiectases tend to increase in number in middle age; however, the first appearance on the undersurface of the tongue and floor of the mouth is at puberty. Pulmonary or intracranial arteriovenous fistulas and bleeding in these areas may be a cause of death. HHT is inherited as an autosomal-dominant trait. The vascular abnormalities found in HHT consist of direct arterio venous connections without an intervening capillary bed. Affected patients have mutations in one of three genes, most commonly in two, endoglin (ENG) or ALK-1 (ACVRL1). They encode a homodimeric integral membrane glycoprotein, which is a transforming growth factor (TGF)-β receptor. HHT1 is associated with ENG mutations, and HHT2 with ACVRL1 mutations. HHT1 patients have a higher prevalence of pulmonary AVMs, while HHT2 patients tend to have a milder phenotype and later age of onset, but increased liver manifestations. Patients with HHT and juvenile polyposis have mutations in the MADH4 gene, a downstream effector of TGF-β signaling. TGF-β is a potent stimulator of vascular endothelial growth factor (VEGF) production. VEGF leads to disorganized and tortuous vessels, as seen in HHT. VEGF levels are increased in patients with HHT. Treatment is directed at controlling the specific complication, and identifying and treating AVMs before they become symptomatic. The tendency to epistaxis has been reduced by estrogen therapy and some recommend oral contraceptives for affected postpubertal females. Dermoplasty of the bleeding nasal septum may be performed by replacing the mucous membrane with skin from the thigh or buttock. Repeated laser treatments of the nasal and gastrointestinal mucosa are often required. Topical tranexamic acid has been used to control epistaxis. Bleeding episodes are treated supportively with iron and red blood cell transfusions. Interventional radiology with selective embolization can treat pulmonary and CNS AVMs and episodes of bleeding, avoiding invasive surgeries. In patients with liver failure or high-output heart failure due to liver AVMs, liver transplantation may be required. Blocking 839
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VEGF with thalidomide (or more effectively with lenalidomide) can reduce gastrointestinal bleeding and transfusion dependence. Bevacizumab, a monoclonal inhibitor of VEGF, has dramatically improved some severely ill HHT patients, reducing the size and flow of their hepatic AVMs, reversing heart and liver failure, and reducing transfusion requirement. Abdalla SA, et al: Visceral manifestations in hereditary haemorrhagic telangiectasia type 2. J Med Genet 2003; 40:494. Al-Saleh S, et al: Screening for pulmonary and cerebral arteriovenous malformations in children with hereditary haemorrhagic telangiectasia. Eur Respir J 2009; 34:875. Bose P, et al: Bevacizumab in hereditary hemorrhagic telangiectasia. N Engl J Med 2009; 360:2143. Bowcock SJ, Patrick HE: Lenalidomide to control gastrointestinal bleeding in hereditary haemorrhagic telangiectasia: potential implications for angiodysplasias? Br J Haematol 2009; 146:220. Faughnan ME, et al: International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. J Med Genet 2009 Jun 29 (Epub ahead of print). Fernandez-Fernandez FJ: Hereditary haemorrhagic telangiectasia: from symptomatic management to pathogenesis based treatment. Eur J Hum Genet 2009 Nov 4 (Epub ahead of print). Flieger D, et al: Dramatic improvement in hereditary hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab. Ann Hematol 2006; 85:631. Fuchizaki U, et al: Hereditary haemorrhagic telangiectasia (Rendu– Osler–Weber disease). Lancet 2003; 362:1490. Gallione CJ, et al: A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004; 363:852. Garcia-Tsao G, et al: Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2000; 343:931. Goussous T, et al: Hereditary hemorrhagic telangiectasia presenting as high output cardiac failure during pregnancy. Cardiol Res Pract 2009; 2009:437237. Haneen S, et al: Mutation analysis of “Endoglin” and “Activin receptorlike kinase” genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allelespecific PCR-technique. BMC Med Genet 2009; 10:53. Kanna B, Das B: Hemorrhagic pericardial effusion causing pericardial tamponade in hereditary hemorrhagic telangiectasia. Am J Med Sci 2004; 327:149. Khalid SK, et al: Worsening of nose bleeding heralds high cardiac output state in hereditary hemorrhagic telangiectasia. Am J Med 2009; 122:779.e1. Klepfish A, et al: Intranasal tranexamic acid treatment for severe epistaxis in hereditary hemorrhagic telangiectasia. Arch Intern Med 2001; 161:767. Lee JB, et al: The diagnostic quandary of hereditary haemorrhagic telangiectasia vs. CREST syndrome. Br J Dermatol 2001; 145:646. Mager JJ, Westermann CJJ: Value of capillary microscopy in the diagnosis of hereditary hemorrhagic telangiectasia. Arch Dermatol 2000; 136:732. Mei-Zahav M, et al: Symptomatic children with hereditary hemorrhagic telangiectasia: a pediatric center experience. Arch Pediatr Adolesc Med 2006; 160:596. Mitchell A, et al: Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transpl 2008; 14:210.
Leg ulcers Leg ulcers are a common medical condition, affecting 3–5% of the population over the age of 65. The cause of chronic leg ulceration is venous insufficiency alone in 45–60% of cases, arterial insufficiency in 10–20%, diabetes mellitus in 15–25%, or combinations in 10–15%. Smoking and obesity increase the risk for ulcer development and persistence, independent of the underlying cause. Defining the cause of the leg ulceration is important in treating the leg ulcer. The wound healing response is complex, involving intricate interactions between different cell types, structural proteins, 840
growth factors, and proteinases. Normal wound repair consists of three phases—inflammation, proliferation, and remodeling—that occur in a predictable sequence.
Venous diseases of the extremities Stasis dermatitis Stasis dermatitis presents as erythema and a yellowish or light-brown pigmentation of the lower third of the lower legs, especially in the area just superior to the medial malleolus. An associated eczematous dermatitis may occur. The dermatitis may be weepy or dry, scaling or lichenified; it is almost invariably hyperpigmented by melanin and hemosiderin. Varicose veins are usually present, though they need not be numerous or conspicuous. Stasis dermatitis is a cutaneous marker for venous insufficiency. The approach to management should be two-fold: relief of symptoms and treatment of the underlying venous insufficiency. Patients with pruritus and an eczematous component should be treated with emollients and topical corticosteroids. The daily use of elevation and support stockings is strongly recommended.
Venous insufficiency and obesity-associated mucinosis Localized areas of mucin deposition can be observed directly over the perforators on the lower extremity. These present as blushed, red–blue, partially compressible, agminated papules. On biopsy, deposits of dermal mucin against a background of the changes of venous insufficiency are seen. In the setting of morbid obesity and lower extremity edema, pretibial translucent papules can appear and merge into plaques. The plaques are composed of dermal mucin (hyaluronic acid). The diagnosis of “pretibial myxedema” is usually made, but thyroid functions are normal. With weight loss the lesions improve, suggesting that they were due to the lower extremity edema/ venous insufficiency of obesity.
Venous insufficiency ulceration Stasis dermatitis and venous ulceration result from increased pressure in the venous system of the lower leg. The most common cause is insufficiency of the valves in the deep venous system and lower perforating veins of the lower leg. With each contraction of the calf, blood should be pumped to the heart via this “muscle pump.” Intact valves in the lower leg are required to prevent this “pumped” blood from refluxing out through the perforators into the superficial system. Increased flow through the superficial system results in enlargement of the superficial venous plexus and the appearance of “varicose veins.” Increased pressure on the iliac veins from pregnancy or obesity, or simple inactivity may also result in the appearance of “venous insufficiency,” as well. The valvular insufficiency results in disorder in the venous and capillary circulation in the leg. Valve insufficiency may occur from prior thrombo phlebitis or congenital “weakness.” Prolonged standing without walking or contracting the calf muscles, sitting for long periods, anemia, zinc deficiency, and a defective fibrinolytic system may accelerate the process. If a history of thrombo phlebitis is present, an evaluation for a hypercoagulable state, such as a deficiency of Leiden factor V, should be considered. Edema and fibrosis develop in the skin over the medial aspect of the ankle and lower third of the shin (Fig. 35-30). Following minor trauma, a macular hemorrhage appears. This is the premonitory sign of an impending ulceration. Venous
Fig. 35-30 Stasis dermatitis, venous insufficiency.
Fig. 35-31 Venous leg ulcer.
ulcers usually occur on the lower medial aspect of the leg. They may appear on the background of stasis dermatitis with lipodermatosclerosis (Fig. 35-31). Venous ulcerations can be painful, but not as painful as pyoderma gangrenosum or arterial or embolic ulcerations. The ulcer tends to be round or oblong and has a characteristic yellow, fibrinous base. Multiple lesions may occur. In most cases, the diagnosis of a venous ulceration can be made on clinical grounds. If there is no clear history or physical findings of venous insufficiency, venous rheography can be performed. An ABI (ankle:brachial index, or ratio of blood pressure in the leg to the arm) should be performed, especially in cases where peripheral pulses are diminished and hair on
Venous diseases of the extremities
the lower legs is lost. This will identify coexistent arterial disease. More extensive vascular studies may be necessary to identify the presence and extent of arterial disease or focal venous valvular incompetence or congenital absence. In leg ulcers of the lower medial leg, even if cutaneous findings of venous insufficiency are absent, venous insufficiency will still be the most common cause of the ulcer. Lesions in atypical locations, those that do not respond appropriately to therapy, and those in which venous rheography is normal may require a biopsy to exclude other causes, including a cutaneous neoplasm. Additional workup may also be required to identify other, less common causes of leg ulcers, such as cholesterol emboli, atherosclerotic disease, diabetes mellitus, sickle cell disease, vasculitis, infection, and pyoderma gangrenosum. Despite extensive research and the marketing of many new products and devices for the treatment of leg ulcers, very little has changed in their management over the last decades. Treatment is primarily to improve venous return and reduce edema. Compression therapy is the mainstay of treatment. This involves the use of pressure wraps, such as Unna boots covered with Coban or elastic wraps. Elevation of the leg above the heart, for as much of the time as is possible (a minimum of 2 h twice a day), is also beneficial. Elastic support of the legs must be continued after the ulcer heals. Other causes of edema, such as cardiac failure, must be addressed. The avoidance of long, cramped sitting (in airplanes or vehicles) or prolonged standing is advisable. Diuretics are overused and not proven to be of benefit. If there is a central cause of fluid retention (cirrhosis, heart failure, renal failure), diuretics may be beneficial, but otherwise they are best avoided. Avoidance of trauma is important. Pentoxifylline, 400–800 mg three times a day, in addition to compression, is beneficial in healing refractory venous ulcerations. A cooperative patient and a patient physician are necessary in the long-term management of venous disease. Topical anti-infectives are usually not necessary (except metronidazole gel to prevent anaerobic overgrowth). There is a high risk of allergic contact dermatitis from other topical antibiotics. Oral antibiotics should only be used to treat associated invasive infection. A rim of erythema commonly surrounds an ulcer. Expanding erythema, an enlarging ulcer, or increasing pain or tenderness may be signs of infection. Surface cultures and Gram stains may demonstrate colonizing, but not pathogenic, bacteria. Biopsy for histology and tissue homogenate culture is the most effective way to demonstrate a true invasive pathogen. Many treatment options have been developed for chronic ulcers. Unfortunately, conclusive comparative studies between the various treatment alternatives are lacking. All are to be used in combination with compression treatment. Occlusive and semipermeable biosynthetic wound dressings can be very effective when combined with compression. They can speed healing, reduce pain, make dressing changes infrequent, and help debridement. If a hard eschar is present over the ulcer when first seen, a dressing will assist in its removal. Early in the treatment of an ulcer, a highly inflammatory and exudative phase occurs. This will often wash off the semipermeable dressing and may require the use of fenestrated dressings and even the application of absorbent padding over the dressing for the first few weeks. The patient will interpret this increased wound exudate, which is normal and indicates the conversion of a non-healing to a healing wound, as an infection. He/she should be appropriately educated before such dressings are applied. Dressings containing dilute acetic acid or silver may help reduce bacterial overgrowth in the wound, but fail to decrease the time to healing. However, metronidazole gel 0.75% instilled into the wound will help to reduce the amount of wound exudate (by eliminating anerobic bacteria) and remove the smell of the wound exudate. The smell of achronic
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leg ulcer may reduce the patient’s quality of life. Becaplermin (Regranex) is expensive, but promotes wound healing. Granulation tissue formation is enhanced. It may be useful in wounds that are unable to develop a granulation tissue base despite local care and conservative debridement. Weekly de bridement of the anesthetic dead fibrinous tissue can be useful in stimulating granulation tissue at the base of slow-to-heal venous ulcerations. Injection of granulocyte–macrophage colony-stimulating factor (GM-CSF) into the ulcer base may also stimulate refractory ulcers to heal. It is very expensive. Grafts and skin substitutes should be reserved for refractory ulcers that have failed conservative therapy. In more than 90% of cases, only simple but persistently applied measures are required. Enhanced compliance, longer elevation, and removal of leg edema are the first steps in attempting to heal refractory leg ulcers. If these are not optimized, expensive dressing and medications will not lead to healing. The role of vascular surgery or venous ablation in the healing of leg ulcers is controversial. Risk factors that predict failure to heal within 24 weeks of limb compression therapy include a large wound area, history of venous ligation or stripping, history of hip or knee replacement, ABI 90% repigmentation. Treatment should be limited to 4–6 months and the patient must be monitored for acne, atrophy, and telangiectasias. Topical pimecrolimus cream and tacrolimus ointment 0.1% have been particularly efficacious in treating facial vitiligo. In some series they have been as effective as superpotent topical steroids and avoid the complications of atrophy and acne induced by topical steroids. Patients who initiate treatment in the summer have a higher rate of response. Continual application may be required, as patients who discontinue treatment may suffer the appearance of new lesions. With topical therapies, new areas of vitiligo appear in untreated areas, suggesting there is no systemic effect. Topical pimecrolimus may enhance the efficacy of narrow-band UVB (NBUVB) in repigmenting facial, but not non-facial vitiligo. Topical calcipotriene and other vitamin D analogs have had variable results. Alone these agents lack efficacy. When they are used in combination with other treatments, some studies have demonstrated additive benefit and others no benefit. Therefore, these agents cannot be recommended. NBUVB twice weekly has become the preferred form of phototherapy to treat vitiligo. It avoids the need for prolonged eye protection and the occasional psoralen-induced nausea. About half of patients will achieve more than 75% repigmentation of the face, trunk, proximal arms, and legs. Hand and foot lesions repigment in less than 25% of patients. Children may have slightly higher response rates than adults. In patients with >20% BSA involvement, only about 5% will show complete repigmentation with phototherapy. Long courses of treatment may be required. PUVA therapy can also be used to treat vitiligo, but is less effective than NBUVB. Repigmentation from phototherapy may begin after 15–25 treatments; however, significant improvement may take as many as 100–200 treatments (6–24 months). On average, maximum improvement is seen after about 9 months of therapy. If follicular repigmentation has not appeared after 3 months, phototherapy treatments should be discontinued. Known photosensitivity, porphyria, and systemic lupus erythematosus are contraindications to phototherapy. Topical application of 8-methoxypsoralen at a concentration of 0.01–0.1%, followed by UVA exposure, may lead to repigmentation. Topical PUVA is used for focal or limited lesions. Inadvertent burns with blistering are frequent complications
Total depigmentation If more than 50–80% of the body surface area is affected by vitiligo, the patient can consider depigmentation. This form of treatment should be considered permanent and the goal is total depigmentation. Limited areas (such as those exposed daily) may be treated, but satellite and distant depigmentation may occur, so the action of the medication cannot be limited to the applied area. Monobenzone (monobenzyl ether of hydroquinone) 20% is applied twice a day for 3–6 months to residual pigmented areas. Up to 10 months may be required to complete the treatment. About 1 in 6 patients treated experiences acute dermatitis, usually confined to the still-pigmented areas, but this rarely limits treatment. Once the patient achieves a uniform depigmented appearance, he/she is very satisfied. Topical 20% 4-methoxyphenol cream (mequinol, monomethyl ether of hydroquinone) can also be used for depigmentation. The Q-switched laser selectively destroys melanocytes and can also achieve depigmentation. It can be combined with a topical depigmenting agent for added efficacy.
Chemical leukoderma (occupational vitiligo) Chemical leukoderma is an acquired, depigmented dermatosis caused by repeated exposure to chemicals. It is frequently misdiagnosed as vitiligo. Patients with vitiligo or a family history of vitiligo are at much greater risk of developing chemical leukoderma. The diagnostic criteria are:
1. acquired vitiligo-like depigmented lesions 2. history of repeated exposure to a specific chemical compound 3. patterned vitiligo-like macules conforming to site of exposure 4. confetti macules. The majority of cases are caused by exposure to aromatic or aliphatic derivatives of phenols and catechols, including paratertiary butylphenol (adhesive in shoes), amylphenol, butylcatechol, and alkyl phenols. However, sulfhydryls, mercurials, arsenics, cinnamic aldehyde, p-phenylenediamine, chloroquine, and azelaic acid have also been incriminated. Some of these compounds have a structure similar to tyrosine and may be converted by tyrosine-related protein-1 to compounds toxic to the melanocyte. This process is considered to be different from depigmentation following allergic contact dermatitis. The clinical pattern may be very similar to idiopathic vitiligo, but lesions tend to be concentrated in areas of repeated contact with the incriminated substance. The first recognized cases of occupational vitiligo occurred in individuals who worked in rubber garments or wore gloves that contained monobenzyl ether of hydroquinone. This compound may still contaminate some rubber products. Phenolic antiseptic detergents used in hospitals and in industrial cleaners have caused chemical leukoderma in janitorial and housekeeping employees. Adhesives and glues containing incriminated chemicals may be found in shoes, wristbands, adhesive tape, and rubber products used in brassieres, girdles, panties, or condoms. Self-sticking bindis (the cosmetic used by many Indian women on the forehead) have been reported to induce leukoderma from the adhesive material. Also, electrocardiograph electrodes may cause similar round hypopigmented spots at the site of contact. The most common location for chemical leukoderma is the face (40% of cases), followed by the hands and feet. The scalp is rarely affected. Hair dye (at the rim of the scalp but not on the scalp), deodorant (axilla), detergent, adhesives (face, bindis), rubber sandals (feet), black socks and shoes (feet), and rubber condoms (penis) are the exposures associated with lesions in various anatomic regions. Pruritus occurs in more than 20% of patients (a rare complaint in vitiligo patients). The clinical lesions are sharply marginated macules and patches, often with confetti or pea-sized macules seen at the periphery. This clinical pattern is atypical for idiopathic vitiligo and should suggest the diagnosis of chemical leukoderma. More than 25% of patients have lesions outside the area of contact with the incriminated chemical. In about 10% of patients, new vitiliginous lesions will continue to develop, even after exposure to the chemical is stopped. Treatment is avoidance and measures used for idiopathic vitiligo (see above). Chemical leukoderma in a person without vitiligo has a good prognosis, with repigmentation in up to 75% of cases. If a person with vitiligo develops a chemical leukoderma, repigmentation only occurs in 20% of cases. Histologically, the vitiliginous areas of a chemical leukoderma show an absence of melanocytes identical to lesions of true vitiligo.
Chemical leukoderma
during treatment in the US, even when the patient is treated by professionals. For this reason, topical PUVA has been very difficult for the patient to carry out at home. Topical PUVA, however, is widely used in India with success, suggesting that, in the right hands, this treatment can be effective. Excimer laser phototherapy can be as effective as NBUVB, and the response is more rapid. It can be used on limited areas, avoiding whole-body UV exposure. While 25% of treated patches repigment completely, treatment-resistant areas (elbows, knees, wrists, dorsal hands and feet) have only a 2% rate of at least 75% repigmentation. The addition of topical steroid treatment to excimer laser may enhance efficacy. In certain situations, the use of systemic immunosuppressives may be appropriate in the treatment of vitiligo. This is usually in the setting of very rapidly progressive disease, with the goal of reducing the total amount of pigment loss. Systemic corticosteroids are usually used and are tapered over several months. Twice weekly dexamethasone, at a dose of 10 mg, is one such regimen. Once the disease is arrested, the patient can be converted to phototherapy. The long-term use of systemic immunosuppressives is not recommended. They initially may control the disease, but with chronic use, unacceptable toxicity often develops. Surgical treatments can be applied to limited lesions if the above methods do not prove beneficial, but these are timeconsuming. They are recommended primarily in patients with treatment-resistant vitiligo. Patients must have stable disease (no new lesions, or expansion of lesions for 1 year). Surgical procedures are not effective in patients who exhibit Koebner phenomenon or have active vitiligo. Given its expense, surgical treatment should be reserved for exposed skin sites covering less than 2–3% of BSA. Minigrafting, transplantation of autologous epidermal cell suspension, and ultra thin epidermal grafts have all been used. UV phototherapy is often given following the surgical procedure. Systemic immunosuppressives, specifically high-dose corticosteroids, can arrest rapidly progressive vitiligo. However, they cannot be used long-term due to toxicity, so another form of therapy must be sought once the vitiligo has been arrested.
Akimoto S, et al: Multiple actinic keratoses and squamous cell carcinomas on the sun-exposed areas of widespread vitiligo. Br J Dermatol 2000; 142:824. Alajlan A, et al: Transfer of vitiligo after allogeneic bone marrow transplantation. J Am Acad Dermatol 2002; 46:606. Attili VR, Attili SK: Lichenoid inflammation in vitiligo—a clinical and histopathologic review of 210 cases. Int J Dermatol 2008; 47:663. Au WY, et al: Generalized vitiligo after lymphocyte infusion for relapsed leukaemia. Br J Dermatol 2001; 145:1015. Austin M: Fighting and living with vitiligo. J Am Acad Dermatol 2004; 51:S7.
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Basak PY, et al: The role of helper and regulatory T cells in the pathogenesis of vitiligo. J Am Acad Dermatol 2009; 60:256. Chen YF, et al: Treatment of vitiligo by transplantation of cultured pure melanocyte suspension: analysis of 120 cases. J Am Acad Dermatol 2004; 51:68. Cockayne SE, et al: Vitiligo treated with topical corticosteroids: children with head and neck involvement respond well. J Am Acad Dermatol 2002; 46:964. Esfandiarpour I, et al: The efficacy of pimecrolimus 1% cream plus narrow-band ultraviolet B in the treatment of vitiligo: a double-blind placebo-controlled clinical trial. J Dermatolog Treat 2009; 20:14. Falabella R, Barona MI: Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res 2009; 22:42. Fenton JS, et al: Vitiligo: nonsurgical treatment options and the evidence behind their use. J Drugs Dermatol 2008; 7:705. Gawkrodger DJ, et al: Guideline for the diagnosis and management of vitiligo. Br J Dermatol 2008; 159:1051. Ghosh S, Mukhopadhyay S: Chemical leucoderma: a clinico-aetiological study of 864 cases in the perspective of a developing country. Br J Dermatol 2009; 160:40. Godse KV: Comparison of two diluents of 1% methoxsalen in the treatment of vitiligo. Indian J Dermatol Venerol Leprol 2008; 74:298. Grimes PE: White patches and bruised souls: advances in the pathogenesis and treatment of vitiligo. J Am Acad Dermatol 2004; 51:S5. Grimes PE, et al: Topical tacrolimus therapy for vitiligo: therapeutic responses and skin messenger RNA expression of proinflammatory cytokines. J Am Acad Dermatol 2004; 51:52. Halder RM, Chappell JL: Vitiligo update. Semin Cutan Med Surg 2009; 28:86. Hartmann A, et al: Occlusive treatment enhances efficacy of tacrolimus 0.1% ointment in adult patients with vitiligo: results of a placebocontrolled 12-month prospective study. Acta Derm Venereol 2008; 88:474. Hexsel CL, et al: A clinical trial and molecular study of photoadaptation in vitiligo. Br J Dermatol 2009; 160:534. Hsu S: Camouflaging vitiligo with dihydroxyacetone. Dermatol Online J 2008; 14:23. Lepe V, et al: A double-blind randomized trial of 0.1% tacrolimus vs 0.05% clobetasol for the treatment of childhood vitiligo. Arch Dermatol 2003; 139:581. Linthorst Homan MW, et al: Impact of childhood vitiligo on adult life. Br J Dermatol 2008; 159:915. Martin-Garcia RF, et al: Chloroquine-induced, vitiligo-like depigmentation. J Am Acad Dermatol 2003; 48:981. Mulekar SV, et al: Treatment of vitiligo on difficult-to-treat sites using autologous noncultured cellular grafting. Dermatol Surg 2009; 35:66. Natta R, et al: Narrowband ultraviolet B radiation therapy for recalcitrant vitiligo in Asians. J Am Acad Dermatol 2003; 49:473. Nicolaidou E, et al: Narrowband ultraviolet B phototherapy and 308-nm excimer laser in the treatment of vitiligo: a review. J Am Acad Dermatol 2009; 60:470. Njoo MD, et al: Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy. J Am Acad Dermatol 2000; 42:245. Njoo MD, et al: Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and the Q-switched ruby laser. J Am Acad Dermatol 2000; 42:760. Nordlund JJ, et al: Dermatitis produced by applications of monobenzone in patients with active vitiligo. Arch Dermatol 1985; 121:1141. Olssom MJ: What are the needs for transplantation treatment in vitiligo, and how good is it? Arch Dermatol 2004; 140:1273. Passeron T, et al: Topical tacrolimus and the 308-nm excimer laser: a synergistic combination for the treatment of vitiligo. Arch Dermatol 2004; 140:1065. Radakovic-Fijan S, et al: Oral dexamethasone pulse treatment for vitiligo. J Am Acad Dermatol 2001; 44:814. Sassi F, et al: Randomized controlled trial comparing the effectiveness of 308-nm excimer laser alone or in combination with topical hydrocortisone 17-butyrate cream in the treatment of vitiligo of the face and neck. Br J Dermatol 2008; 159:1186. Silverberg NB, et al: Tacrolimus ointment promotes repigmentation of vitiligo in children: a review of 57 cases. J Am Acad Dermatol 2004; 51:760.
Suga Y, et al: Medical pearl: DHA application for camouflaging segmental vitiligo and piebald lesions. J Am Acad Dermatol 2002; 47:436. Taieb A, Picardo M: Clinical practice. Vitiligo. N Engl J Med 2009; 260:160. Tanioka M, Miyachi Y: Camouflaging vitiligo of the fingers. Arch Dermatol 2008; 144:809. Tanioka M, Miyachi Y: Camouflage for vitiligo. Dermatol Ther 2009; 22:90. Tazi-Ahnini R, et al: The autoimmune regulator gene (AIRE) is strongly associated with vitiligo. Br J Dermatol 2008; 159:591. van Geel N, et al: Double-blind placebo-controlled study of autologous transplanted epidermal cell suspensions for repigmenting vitiligo. Arch Dermatol 2004; 140:1203.
Vogt–Koyanagi–Harada syndrome Vogt–Koyanagi–Harada syndrome (VKHS) is a disease complex affecting the eyes, skin, auditory system, and central nervous system (CNS). It affects primarily pigmented races and is rare in white persons. It is more common in females, and affects all ages. The disease occurs in four phases. First is the prodromal phase or meningoencephalitic phase, with fever, malaise, headache, nausea, and vomiting. The CNS involvement can include meningismus, headaches, mental status changes, cerebrospinal fluid pleocytosis, tinnitus, and dysacusis. Recovery is usually complete. The second stage, the uveitic phase, is characterized by anterior and/or posterior uveitis and inflammation of many other parts of the eye. The third or convalescent phase begins 3 weeks to 3 months after the uveitis appears, usually as it begins to improve. This stage is characterized by frontal non-cicatricial alopecia, vitiligo, and poliosis of scalp, eyebrows, eyelashes, and hairs of the axillae. The skin lesions must begin after the ocular symptoms to be considered diagnostic. The fourth phase is one of recurrent attacks of uveitis. Most ocular complications occur as a result of this stage of the disease, and include permanent decreased visual acuity, cataracts, and glaucoma. VKHS is a cell-mediated autoimmune disease with the autoantigen(s) felt to be solely expressed in melanin-containing cells. The target antigens may be the tyrosinase family proteins, as immunization of mice with several of these proteins can induce a syndrome similar to VKHS. Supporting this hypothesis are the rare observations that vitiligo, erythroderma, interferon therapy for hepatitis C, and melanoma can all be associated with the appearance of VKHS. Aggressive immunosuppressive therapy with systemic steroids and immunomodulatory medications (cyclosporine, azathioprine, mycophenolate, tacrolimus, infliximab) may preserve ocular function and prevent ocular complications. Th17 CD4+ cells stimulated by high levels of interleukin (IL)-23 and secreting IL-17 are present in VKHS patients with active uveitis. IL-23 is important in the production and maintenance of auto immune diseases, and IL-17 is one of the most important effector cytokines in autoimmune diseases. At least four patients with psoriasis and VKHS have been reported. Aisenbrey S, et al: Vogt–Koyanagi–Harada syndrome associated with cutaneous malignant melanoma: an 11-year follow-up. Graefe’s Arch Clin Exp Ophthalmol 2003; 241:996. Andreoli CM, Foster CS: Vogt–Koyanagi–Harada disease. Int Ophthalmol Clin 2006; 46:111. Chi W, et al: IL-23 promotes CD4+ T cells to produce IL-17 in Vogt– Koyanagi–Harada disease. J Allergy Clin Immunol 2007; 119:1218. Kluger N, et al: Vogt–Koyanagi–Harada syndrome associated with psoriasis and autoimmune thyroid disease. Acta Derm Venerol 2008; 88:397. Liu X, et al: Inhibitory effect of cyclosporin A and corticosteroids on the production of IFN-gamma and IL-17 by T cells in Vogt–Koyanagi–Harada syndrome. Clin Immunol 2009; 131:333.
Alezzandrini syndrome Alezzandrini syndrome is a very rare condition characterized by a unilateral degenerative retinitis, followed after several months by ipsilateral vitiligo on the face and ipsilateral poliosis. Deafness may also be present. Hoffman MD, Dudley C: Suspected Alezzandrini’s syndrome in a diabetic patient with unilateral retinal detachment and ipsilateral vitiligo and poliosis. J Am Acad Dermatol 1992; 26:496.
Leukoderma Postinflammatory leukoderma may result from many inflammatory dermatoses, such as pityriasis rosea, psoriasis, herpes zoster, secondary syphilis, and morphea. Sarcoidosis, tinea versicolor, mycosis fungoides, scleroderma, and pityriasis lichenoides chronica may all present with hypopigmented lesions (only rarely are these actually depigmented), as may Hansen’s disease. Burns, scars, postdermabrasion, and intra lesional steroid injections with depigmentation are other examples of leukoderma. Friedman SJ, et al: Perilesional linear atrophy and hypopigmentation after intralesional corticosteroid therapy. J Am Acad Dermatol 1988; 19:537.
Oculocutaneous albinism Oculocutaneous albinism (OCA) is an autosomal-recessively inherited trait with reduction or absence of melanin in skin, hair, and eyes. Eye problems are frequently present, including moderate to severe impairment of visual acuity, nystagmus, strabismus, and photophobia. The cutaneous phenotype of the various forms of albinism is broad, but the ocular phenotype is reasonably constant in most forms. Genetic disorders of pigment cells can now be defined as caused by: 1. disruption of melanoblast migration to target tissues during development (Waardenburg syndrome and piebaldism) 2. disruption of melanin synthesis (oculocutaneous albinism) 3. disruption of melanosome formation (Chédiak–Higashi and Hermansky–Pudlak syndromes) 4. disruption of melanosome transport and melanin transfer to keratinocytes (Griscelli syndrome). The most serious sequelae of albinism are gross visual dis turbances and the increased risk for the development of skin cancer. A number of syndromes associated with albinism can also cause premature mortality due to impairment of the functioning of other involved organs and systems.
Disorders of melanin synthesis The four genetic forms of non-syndromal OCA are all caused by disruption of melanin synthesis and all autosomal-recessive disorders. Their prevalence varies widely around the world, but is estimated to be about 1 in 17 000. That means that about 1 in 70 persons carries a gene for OCA. Given the phenotypic overlap of the various forms of OCA, genetic testing is recommended to establish the diagnosis. Since both parents are obligate carriers and two-thirds of healthy siblings are at risk for being carriers, genetic counseling is recommended. Carriers are asymptomatic. All persons with OCA and their parents should be educated regarding aggressive sun protection with sunscreens, appropriate clothing, and sun avoidance. Vitamin D supplementation may be required. As adults, patients should be examined for skin lesions suspicious for melanoma and nonmelanoma skin cancer.
Oculocutaneous albinism
Niccoli L, et al: Efficacy of infliximab therapy in two patients with refractory Vogt–Koyanagi–Harada disease. Br J Ophthalmol 2009; 93:1553. Paredes I, et al: Immunomodulatory therapy for Vogt–Koyanagi–Harada patients as first-line therapy. Ocul Immunol Inflamm 2006; 14:87. Rao NA, et al: Vogt–Koyanagi–Harada disease diagnostic criteria. Int Ophthalmol 2007; 27:195. Rathinam SR, et al: Vogt–Koyanagi–Harada syndrome after cutaneous injury. Ophthalmology 1999; 106:635. Sylvestre DL, et al: Vogt–Koyanagi–Harada disease associated with interferon alpha-2b/ribavirin combination therapy. J Viral Hep 2003; 10:467. Tsuruta D, et al: Inflammatory vitiligo in Vogt–Koyanagi–Harada disease. J Am Acad Dermatol 2001; 44:129. Wong SS, et al: Vogt–Koyanagi–Harada disease: extensive vitiligo with prodromal generalized erythroderma. Dermatology 1999; 198:65.
Oculocutaneous albinism 1 OCA1 results from mutations in the tyrosinase gene and accounts for approximately 40% of OCA worldwide. It is the most severe form of albinism, and is the most common type of albinism in Japanese, non-Hispanic Caucasians, and a mixed race European population, with a prevalence of about 1 in 40 000. Affected patients are homozygous for the mutant gene or are compound heterozygotes for different mutations in the tyrosinase gene (TYR). OCA1 is divided into two forms: OCA1A and OCA1B. At birth these are indistinguishable. OCA1A is the most severe form, with complete absence of tyrosinase activity and complete absence of melanin in the skin and eyes. Visual acuity is decreased to 20/400. The hair, eyelashes, and eyebrows are white, and the skin is white and does not tan. Irises are light blue to pink and fully translucent. Amelanotic nevi may be present. In OCA1B, tyrosinase activity is greatly reduced but not absent. Affected patients may show an increase in skin, hair, and eye color beginning at age 1–3 years, and can tan. Iris color may also darken over time. OCA1B was originally called “yellow mutant” albinism. Temperature-sensitive OCA (OCA1-TS) is considered a variant of OCA1B; it results from mutations in the tyrosinase gene that produce an enzyme with limited activity below 35°C (95°F) and no activity above this temperature. Affected patients have white hair, skin, and eyes at birth. At puberty, dark hair develops in cooler acral areas. Visual acuity is not as severely affected in OCA1B.
Oculocutaneous albinism 2 OCA2 has a prevalence of 1 in 36 000 in white Europeans, but as much as 1 in 4000 in some parts of Africa. It is the most common form of OCA, accounting for approximately 50% of OCA worldwide. OCA2 was formerly called “tyrosinasepositive” albinism, or “brown OCA.” Inheritance is autosomalrecessive and results from mutations in the OCA2 gene, formerly known as the P gene. The OCA2 gene encodes an integral melanosomal protein that is important for normal biogenesis of melanosomes and for normal processing and transport of melanosomal proteins such as tyrosinase and tyrosinase-related protein 1 (TYRP1). The cutaneous phenotype of OCA2 patients is broad, ranging from nearly normal pigmentation to virtually no pigment. Newborns have pigmented hair. Nevi and ephelides are common. Pink irises are usually not seen. Visual defects are not as severe as in OCA1. Pigmentation increases with age and visual acuity improves from infancy to adolescence. Prader–Willi and Angelman syndromes are caused by deletions in the chromosomal region contiguous to and sometimes including the OCA2 gene. One percent of patients with these syndromes also have OCA2. 859
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Oculocutaneous albinism 3
Hermansky–Pudlak syndrome
OCA3 is caused by mutations in the TYRP1 gene. TRYP1 protein is an enzyme in the melanin biosynthesis pathway that oxidizes dihydroxyindole carboxylic acid (DHICA) monomers into melanin. Mutations in this enzyme result in delayed maturation and early degradation of tyrosine. This form of OCA has been most commonly found in African patients and was called “rufous” or red OCA. It has also been seen in a large Pakistani family and a Caucasian patient. Patients have red hair and reddish-brown skin. Visual abnormalities may not be detectable.
Hermansky–Pudlak syndrome (HPS) is an autosomal-recessive disorder consisting of oculocutaneous albinism, a hemorrhagic diathesis secondary to the absence of dense bodies in platelets, and accumulation of a ceroid-like material in the reticuloendothelial system, visceral organs, oral mucosa, and urine. Patients with this disorder have a history of easy bruisability, epistaxis, gingival bleeding, hemoptysis, and bleeding after various surgical procedures and childbirth. Major bleeding occurs in 40% of HPS patients. The hypopigmentation is due to impaired melanosome formation, trafficking, or transfer to keratinocytes. Currently, eight human genes (HPS1–8) have been identified, which, when independently mutated, lead to a clinical picture consistent with HPS. It is anticipated that more HPS genes will be identified in humans, since in mice there are at least 14 non-allelic genes that, when singly defective, give rise to HPS. While the HPS subtypes 1–8 all share the clinical signs and symptoms noted above, a few subtypes either lack some of or have additional unique features that serve to distinguish them from the other HPS subtypes. Seven of the eight genes causing HPS (not HPS2) are parts of distinct complexes that are called biogenesis of lysosome-related organelle complexes, or BLOCs. Mutations in any member of a BLOC tend to create a similar clinical phenotype. There are three known BLOCs, and mutations in most of the BLOC subunits cause a variant of HPS. The most common subtype is HPS1, which, together with HPS4, comprises 50% of the known worldwide cases of HPS. One in 21 Puerto Ricans has a mutation (usually a 16-base pair [bp] duplication) in the HPS1 gene. HPS accounts for 80% of albinos in Puerto Rico, and 1 in 1800 Puerto Ricans in the northwest region of the country has HPS. HPS1 and HPS4 are clinically very similar, since they together form the BLOC3 complex (Fig. 36-14). These are the two most severe forms of HPS. Skin pigmentation can vary from total lack to lighter hair and skin coloring than in other members of the family. Ocular changes similar to those of OCA can occur, including iris trans illumination, hypopigmented retina, visual impairment, horizontal nystagmus, and strabismus. Atypical nevi, acanthosis nigricans-like lesions in the axillae and neck, and trichomegaly also occur. Solar damage, as evidenced by solar lentigines, actinic keratoses, and nonmelanoma skin cancers, occurs in 80% of patients with the 16-bp duplication in HPS1. Interstitial pulmonary fibrosis, inflammatory bowel disease, renal failure, and cardiomyopathy are late complications, and can cause premature mortality between the ages of 20 and 50 years. Sixty percent of patients with HPS have pulmonary symptoms, starting at a mean age of 35 years. Pirfenidone, an antifibrotic
Oculocutaneous albinism 4 OCA4 is due to mutations in the MATP gene encoding a membrane-associated transporter protein, predicted to span the membrane 12 times and to function as a transporter. Patients are hypopigmented to a variable degree, and are phenotypically identical to patients with OCA2. Visual acuity is decreased and nystagmus is found in many but not all patients. This has also been reported in a Turkish patient, as well as German, Japanese, and Korean OCA patients.
Disorders of melanosome formation These are multisystem syndromes that are associated with albinism. These syndromes are caused by genes that function in intracellular organelle formation and movement in a variety of specialized cell types, such as melanocytes, neurons, immune cells, monocytes, platelets, and type II epithelial cells in lungs. The silver hair of some of these syndromes may demonstrate pigment clumping, allowing the diagnosis to be suspected.
Chédiak–Higashi syndrome Chédiak–Higashi syndrome (CHS) is a progressively degenerative, fatal disease characterized by partial oculocutaneous albinism (decreased skin, eye, and hair pigment), giant intracellular granules, pigment clumping in hair shafts, and a bleeding diathesis due to absent or reduced platelet-dense bodies. It presents in childhood, usually with life-threatening infections of the skin and lungs. Common pathogens are Staphylococcus aureus, streptococcus, Gram-negative organisms, Candida, and Aspergillus. Immunoglobulins, antibody production, and phagocytosis are normal, but neutropenia is common and leukocytes display impaired migration. Natural killer cells are decreased in function. The hair of these patients is blond and sparse. The ocular albinism is accompanied by nystagmus and photophobia. In darker-skinned races, affected patients are lighter-skinned than their parents and siblings, and may have speckled hyper- and hypopigmentation. CHS results from mutations in the SHS1 gene, the exact biological function of which is unknown. The gene must be important in lysosome and lysosome-related organelle trafficking or size regulation. Melanosomes are giant, and platelets, eosinophils, basophils, and monocytes have giant intracellular granules that are azurophilic. In 85% of cases a lymphohistiocytosis syndrome occurs, referred to as the “accelerated phase.” It is fatal and caused by the unfettered proliferation of lymphocytes creating a lymphoma-like situation with fever, anemia, neutropenia, hepatosplenomegaly, and lymphadenopathy. Liver function tests and serum ferritin may be elevated. Bone marrow transplantation (BMT) prior to the onset of this phase may be lifesaving, and also prevents the infections. Unfortunately, even with BMT, if CHS patients survive into adulthood they develop progressive neurological involvement. 860
Fig. 36-14 Hermansky–Pudlak syndrome, freckling of the “V” of the neck and a basal cell carcinoma in a Puerto Rican man.
Disorders of melanocyte transport Griscelli syndrome Griscelli syndrome (GS) is a rare autosomal-recessive disorder with mild skin and hair hypopigmentation, immunological impairment, lymphohistiocytosis, or defects in the central nervous system. Patients do not have a bleeding tendency. There are three forms of GS. GS1 is caused by mutations in the MYO5A gene encoding the actin-associated myosin Va motor protein. Patients have primary neurological dysfunction but no immunological disease. They have silver hair. GS1 and Elejalde syndrome are felt to be the same disease. GS2 is due to mutations in the RAB27A gene. Patients have silver hair, infections, and lymphohistiocytosis. Leukocytes infiltrating the brain can cause secondary neurological disease, but patients have no primary neural defects. GS3 is cause by mutations in Melanophilin and results only in cutaneous hypopigmentation. The three genes responsible for GS all form a protein complex essential for the capture and local movement of melanosomes in the actin-rich periphery of melanocytes. Al-Khenaizan S: Hyperpigmentation in Chédiak–Higashi syndrome. J Am Acad Dermatol 2003; 49(5 Suppl):S244. Emanuel PO, et al: Griscelli syndrome. Skinmed 2007; 6:147. Gronskov K, et al: Oculocutaneous albinism. Orphanet J Rare Dis 2007; 2:43. Huizing M, et al: Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. Annu Rev Genomics Hum Genet 2008; 9:359. Lazarchick J, et al: Chédiak–Higashi syndrome. Blood 2005; 10:4162. Tager AM, et al: Case records of the Massachusetts General Hospital. Case 32-2009: a 27-year-old man with progressive dyspnea. N Engl J Med 2009; 361:1585. Toro J, et al: Dermatologic manifestations of Hermansky–Pudlak syndrome in patients with and without a 16-base pair duplication in the HPS1 gene. Arch Dermatol 1999; 135:774. Wei A, et al: A comprehensive analysis reveals mutational spectra and common alleles in Chinese patients with oculocutaneous albinism. J Invest Dermatol 2009 Oct 29 (Epub ahead of print). Wei ML: Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res 2006; 19:19.
Waardenburg syndrome Four genotypic variants of Waardenburg syndrome exist, with overlapping phenotypic features; all are autosomal-dominant. Types 1 and 3 are caused by mutations in the PAX3 gene, encoding a transcription factor. Type 2 is caused by mutations in the MITF gene, also encoding a transcription factor, and type 4 is due to either a heterozygous mutation in the SOX10 gene (encoding a transcription factor), or homozygous mutations in the endothelin-3 (EDN3) or the endothelin B receptor (EDNR3) gene. These mutations impair the ability of melanoblasts to reach their final target sites (inner ear, eye, skin) during embryogenesis. Patients with this syndrome have features of piebaldism, with a white forelock, hypopigmentation, premature graying, and other characteristic findings including synophrys, congenital deafness, dystopia canthorum (broad nasal root), and ocular changes, including heterochromia iridis (Fig. 36-15). Types 1 and 3 are both characterized by dystopia canthorum; in type 1, white forelock and depigmented skin patches are more frequent; while in type 3, limb anomalies occur. In type 2, no dystopia canthorum is observed, but hearing loss and heterochromia iridis are more frequently found. Type 4 Waardenburg’s syndrome is identical to type 3, except that it is associated with Hirschprung disease.
Oculocutaneous albinism
agent, can slow the progression of pulmonary fibrosis in HPS1 patients with significant residual lung function (initial forced ventilatory capacity >50%). Lung transplantation can be considered. HPS2 is caused by a mutation in the gene (AP3B1) coding for the 3βA subunit of AP3, a molecule necessary for normal protein trafficking to the lysosome. HPS2 is notable for immunodeficiency and persistent neutropenia, with patients suffering recurrent bacterial infections of the upper respiratory system and middle ear, possibly due to the lack of antigen presentation by the CD1b molecule, since CD1b fails to gain access to the lysosome. Initially, patients may be misdiagnosed as having CHS due to pigment dilution and recurrent infections. However, the large intracellular granules of CHS are absent. Mild pulmonary fibrosis and a mild hearing defect can be associated with HPS2. HPS3, HPS5, and HPS6 have mild clinical findings, without reported pulmonary or gastrointestinal involvement. They are due to mutations in three proteins that make up BLOC2. HPS 7 and 8 are very rare and present with a phenotype of oculocutaneous albinism and a bleeding tendency due to platelet dysfunction. The HPS7 gene (DTNBP1) encodes dysbindin; the HPS8 gene is BLOC1S3.
Piebaldism Piebaldism is a rare, autosomal-dominant syndrome with variable phenotype, presenting at birth. The characteristic clinical features are a white forelock and patchy absence of skin pigment (Fig. 36-16). The depigmented lesions are static and characteristically occur on the anterior and posterior trunk, mid-upper arm to wrist, mid-thigh to mid-calf, and shins. A characteristic feature of piebaldism is the presence of hyperpigmented macules within the areas lacking pigmentation and also on normally pigmented skin. The depigmented lesions may repigment spontaneously, or especially after injury. The white forelock is a triangular or diamond-shaped midline white macule on the frontal scalp or forehead, and is the only
Fig. 36-15 Waardenburg syndrome with heterochromia iridis.
Disorders of melanoblast migration and survival These disorders cause “spotting,” i.e. patches of white hair and/or unpigmented skin.
Fig. 36-16 Piebaldism, vitiligo-like depigmentation.
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Disturbances of Pigmentation
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manifestation in 80–90% of patients. The medial portions of the eyebrows and eyelashes may be white. Histologically, melanocytes are completely absent in the white macules. Piebaldism is caused by mutations in the KIT gene (gene product kit proto-oncogene), encoding a cell surface receptor for the steel factor, an embryonic growth factor. The phenotypic differences between families are caused by different locations of mutations in the gene. A mild phenotype occurs in cases associated with mutations in the ligand-binding region, whereas more severe phenotypes occur from mutations in the tyrosine kinase region of the receptor. The white lesions may respond to camouflage cosmetics or surgical corrections (see discussion under vitiligo). Hirschprung disease and neurofibromatosis type I have rarely been associated with piebaldism.
Cross–McKusick–Breen syndrome Also known as Cross syndrome, oculocerebral hypopigmentation syndrome, or hypopigmentation and microphthalmia,
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this extremely rare disorder is characterized by white skin, blond hair with a yellow–gray metallic sheen, small eyes with cloudy corneas, jerky nystagmus, gingival fibromatosis, and severe mental and physical retardation. Spritz RA: Molecular basis of human piebaldism. J Invest Dermatol 1994; 103(Suppl):137. Thomas I, et al: Piebaldism: an update. Int J Dermatol 2004; 43:716.
Bonus images for this chapter can be found online at http://www.expertconsult.com Fig. Fig. Fig. Fig. Fig.
36-1 36-2 36-3 36-4 36-5
Dermatopathia pigmentosa reticularis. Vitiligo, characteristic periorificial location. Hemochromatosis. Idiopathic guttate hypomelanosis. Piebaldism, white forelock.
Dermatologic Surgery
Dermatology has always been a surgically oriented specialty. While procedures such as curettage, biopsy, destruction, and excision have been key components of the field, the practice has evolved to include a greater number and extent of surgical procedures. This progression can be attributed to a variety of factors. Dermatologists have a greater understanding of cutaneous pathology, which places them in a unique role to manage complex surgical procedures. In addition, outpatient dermatologic surgery has been shown to be cost-effective, safe, and efficacious, and to deliver a greater degree of patient convenience, particularly when compared to other fields. With this in mind, the American Board of Dermatology mandates certain surgical exposure and experience for all residents in dermatology residency programs. Furthermore, with the recent Accreditation Council for Graduate Medical Education (ACGME) accreditation of Procedural Dermatology fellowships, dermatologic surgery has become recognized as a mainstream medical option for patients. While the practice of dermatologic surgery can be the subject of entire textbooks, the following chapters provide a survey of procedures, indications, and appropriate management within the spectrum of the field.
Preparation for surgery A thorough and complete preoperative evaluation is required prior to performing any surgical procedure. A detailed medical history must be obtained, including information on drug allergies, current medications (including herbal or natural supplements), presence of a pacemaker or implantable cardioverter/ defibrillator, recently implanted prosthetics, history of prior wound infection or perioperative bleeding, and history of endocarditis, or cardiac valvular or congenital malformation.
Anticoagulants Much has been written regarding the role of antiplatelets and/ or anticoagulants and surgical bleeding. Dermatologists are frequently presented with the dilemma of whether to discontinue blood thinners in the setting of surgery. Data and multiple reviews have shown that continuous treatment with blood thinners perioperatively in patients undergoing Mohs and cutaneous surgery is not associated with an increase in surgical complications leading to significant morbidity. In contrast, discontinuation of these medications may increase the risk of catastrophic cerebral and cardiovascular complications. Kovich and Otley reported a series of thrombotic complications in a group of patients who had discontinued aspirin or warfarin prior to surgery; these included stroke, transient ischemic attack, myocardial infarction, pulmonary embolus, and death. Multiple authors feel that the potential adverse effects of discontinuing essential medical blood thinners far outweigh the potential side effects of surgical bleeding (i.e.
37
managing a postoperative hematoma). In fact, despite some surgeons’ claims to the contrary, several studies have demonstrated that blinded surgeons are unable to identify intra operatively which patients are taking anticoagulation medication based on the subjective amount of surgical oozing. As such, it is recommended that patients be maintained on all medically necessary blood thinners during cutaneous surgery. Patients taking aspirin for primary prevention may discontinue use 2 weeks prior to any surgical procedure. Herbal supplements are becoming increasingly popular with patients who are looking for a “natural” option to traditional medication. Patients may not readily volunteer the fact that they are taking these supplements, either because they do not characterize them as medication or out of fear that physicians will not be accepting of alternative treatments. Therefore, it is important to ask patients specifically if they are taking any supplements. Ginkgo, garlic, ginseng, ginger, and vitamin E may increase the risk of perioperative bleeding. As these herbal supplements are not medically necessary, patients should discontinue them for several weeks prior to undergoing dermatologic surgery. Ah-Weng A: Preoperative monitoring of warfarin in cutaneous surgery. Br J Dermatol 2003; 149:386–389. Dinehart SM, Henry L: Dietary supplements: altered coagulation and effects on bruising. Dermatol Surg 2005; 31:819–826. Dixon AJ, et al: Bleeding complications in skin cancer surgery are associated with warfarin but not aspirin therapy. Br J Surg 2007 Nov; 94(11):1356–1360. Hurst EA, et al: Bleeding complications in dermatologic surgery. Semin Cutan Med Surg 2007; 26:40–46. Kovich O, Otley CC: Thrombotic complications related to discontinuation of warfarin and aspirin therapy preoperatively for cutaneous operation. J Am Acad Dermatol 2003; 48:233–237. Lewis KG, Dufresne RG Jr: A meta-analysis of complications attributed to anticoagulation among patients following cutaneous surgery. Dermatol Surg 2008; 34:160–164. Otley CC: Perioperative evaluation and management in dermatologic surgery. J Am Acad Dermatol 2006 Jan; 54(1):119–127. Review. Syed S, et al: A prospective assessment of bleeding and international normalized ratio in warfarin-anticoagulated patients having cutaneous surgery. J Am Acad Dermatol 2004; 51:955–957. West SW, et al: Cutaneous surgeons cannot predict blood-thinner status by intraoperative visual inspection. Plast Reconstr Surg 2002; 110:98–103.
Antibiotic prophylaxis Dermatologists performing cutaneous surgery are often faced with the decision of whether to prescribe prophylactic antibiotics. The main issues surrounding antibiotic prophylaxis are prevention of surgical site infections and reduction of the risk of endocarditis or contamination of prosthetic devices in highrisk patients. While there is a trend in medicine towards evidence-based approaches, this is often overlooked by many dermatologists when it comes to antibiotic prophylaxis. While
Dermatologic Surgery
37
reducing infection is one objective in the use of antibiotics, dermatologists must take into consideration the risks of such treatment, including adverse drug reaction, serious drug reactions, drug interactions, development of resistant strains of bacteria, and increased cost.
Surgical site infection Determining the indications for antibiotic prophylaxis for surgical site infections requires an understanding of the various types of wound that the dermatologist may encounter. Wounds are categorized into four groups: 1. Clean wounds (class I) are created on normal skin using clean or sterile technique. Examples include excision of neoplasms, noninflamed cysts, biopsies, and most cases of Mohs surgery. The majority of dermatologic surgery falls into this category. The infection rate of these wounds is less than 5%. Of note, this incidence is based on general surgery cases, which are often of longer duration and a greater extent than most dermatologic procedures. This explains the lower actual infection rate in dermatologic surgery, which is in the 1–3% range. 2. Clean-contaminated wounds (class II) are created on contaminated skin or any mucosal or moist intertriginous surface, such as the oral cavity, upper respiratory tract, axilla, or perineum. The infection rate of these wounds is 10%. 3. Contaminated wounds (class III) involve visibly inflamed skin with/without nonpurulent discharge and have an infection rate of 20–30%. Examples included inflamed cysts or traumatic wounds. 4. Infected wounds (class IV) have contaminated foreign bodies, purulent discharge, or devitalized tissue. Examples included necrotic tumors, ruptured cysts, or active hidradenitis suppurativa. These wounds have an infection rate of 40%. Clean (class I) wounds, which constitute the vast majority of dermatologic surgery procedures, do not require antibiotic prophylaxis. Although antibiotic prophylaxis in clean-contaminated (class II) wounds is not a clear issue, most cases do not require routine antibiotics. It is preferable to treat infections should they arise (as they are not a common occurrence, even in class II wounds), rather than expose all patients to antibiotics and the increased rate of drug-related adverse events. The exception to this would be those surgery cases that violate mucosal membranes (i.e. oral, nasal, or anogenital mucosa), and patients with heavily colonized skin (i.e. atopic dermatitis or infected skin), as well as those patients in whom a wound infection would result in significant morbidity. In contaminated (class III) and infected (class IV) wounds, antibiotics serve a therapeutic, rather than a prophylactic, role and should be used routinely in these cases.
Antibiotic selection and timing
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In order to be achieve optimal prophylaxis, antibiotics ought to be in the bloodstream, and thus at the surgical site, at the time of incision. Antibiotics given at the conclusion of the procedure are not as effective in preventing infection, as they are not incorporated into the coagulum of the wound. Once the surgical wound is closed, the risk of infection decreases significantly. As the majority of dermatologic procedures are of short duration, a single preoperative dose of antibiotics 1 h before the start of the case is sufficient. In rare cases with an extended dermatologic procedure, a second dose of antibiotics can be administered 6 h postoperatively. The choice of antibiotic is based on the surgical site’s most likely causative organism (Table 37-1). Staphylococcus aureus is the most common wound infection in cutaneous surgery.
Table 37-1 Antibiotic prophylaxis for heavily colonized or high-risk patients Situation
Antibiotic
Regimen (1 h preoperative dose)
Skin
Cephalexin Dicloxacillin Clindamycin Vancomycin
1 g orally 1 g orally 300 mg orally 500 mg IV
Oral/respiratory mucosa
Cephalexin Amoxicillin Clindamycin
1 g orally 1 g orally 300 mg orally
Gastrointestinal/ genitourinary mucosa
Cephalexin Trimethoprim/ sulfamethoxazole Ciprofloxacin
1 g orally 1 double-strength tablet orally 500 mg orally
Other pathogens that need to be considered in some situations include Streptococcus viridans (oral mucosa) and Escherichia coli (perineal and genital location). First-generation cephalosporins are an ideal initial choice for the treatment of wound infection because of their coverage of staphylococcal organisms, common Gram-negative organisms such as E. coli, and certain Proteus species. They are rapidly absorbed when taken orally and have good tissue penetration. The estimated cross-reactivity in penicillin-allergic patients is 5–10%. Isoxazolyl penicillins, such as dicloxacillin and nafcillin, can also be used as they provide coverage for most strains of streptococci and β-lactamase-producing bacterial strains such as S. aureus. Aminopenicillins, such as ampicillin and amoxicillin, have better Gram-negative, enterococcal, and group A streptococcal coverage. However, they are not effective against β-lactamase-producing bacteria, and thus are more commonly used in procedures involving oral mucosa. Clindamycin, macrolides (i.e. erythromycin or azithromycin), trimethoprim-sulfamethoxazole, and ciprofloxacin can all be considered in patients with a penicillin or cephalosporin allergy, with the specific choice based on the site of surgery and thus the presumed causative organism. Vancomycin is generally limited to those cases where methicillin-resistant S. aureus (MRSA) is suspected, as it requires intravenous administration and adjustment in patients with impaired renal function.
Treatment of wound infection Postoperative surgical site infection is quite uncommon in dermatologic surgery procedures, with an incidence of 1–3%. Infections typically present 4–7 days after surgery with increased erythema, tenderness, warmth, and purulent drainage. Sutures can be removed to allow for drainage of exudate. In cases where infection leads to dehiscence, the wound can be packed or allowed to heal by second intention. Scar revision can be performed at a later date. A culture should be performed prior to initiating empiric antibiotics to determine sensitivities. S. aureus is the most common pathogen, and cephalexin or dicloxacillin is an appropriate first-line treatment. Those patients with a penicillin allergy can be treated with clindamycin. Although this antibiotic has been associated with colitis, the short courses that are typically used with surgical site infection generally do not present a problem. In those communities or institutions with a high incidence of MRSA, antibiotic choice can be modified based on community sensitivities (e.g. doxycycline or trimethoprim-sulfamethoxazole). Ciprofloxacin can be used for those infections with a higher likelihood of Gram-negative or Pseudomonas organisms (e.g.
Endocarditis prophylaxis The American Heart Association (AHA) updated its recommendations on infective endocarditis (IE) prophylaxis in 2007. The overall conclusions were that bacteremia from daily activities is much more likely to cause IE than bacteremia associated with dental procedures, and that far fewer patients are now recommended to have antibiotic prophylaxis. Antibiotic prophylaxis has been limited to patients with the conditions listed in Box 37-2. All other cardiac conditions, including mitral valve prolapse and other forms of congenital heart disease, no longer require prophylaxis for any procedure. Antibiotic prophylaxis is reasonable when procedures involve manipulation of gingival tissue, perforation of oral mucosa, or incision or biopsy of the respiratory mucosa, or are performed on infected skin, but only in patients with underlying cardiac conditions associated with the highest risk of adverse outcome, as outlined in the box below. Antibiotic prophylaxis solely to prevent infective endocarditis is not recommended for gastrointestinal or genitourinary procedures. The AHA reaffirmed its 1997 statement regarding medical procedures, including incision or biopsy of surgically scrubbed skin, that do not require antibiotic prophylaxis. Antibiotic pro-
Box 37-2 Cardiac conditions associated with the highest endocarditis risk • Prosthetic cardiac valve or prosthetic material used for cardiac valve repair • Previous infectious endocarditis • Congenital heart disease (CHD)* • Unrepaired cyanotic CHD, including palliative shunts and conduits • Completely repaired congenital heart defect with prosthetic material or device, during the first 6 months after the procedure • Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization) • Cardiac transplantation recipients who develop cardiac valvulopathy * Except for conditions listed above, antibiotic prophylaxis is not recommended for any other form of CHD. Adapted from Wilson et al. (2007)
phylactic regimens for those selected high-risk patients should be a single dose of antibiotic administered 1 h before the procedure (Table 37-3). There are no formal guidelines regarding the use of antibiotics in patients with orthopedic prosthetic devices undergoing dermatologic surgery. However, guidelines for dental procedures in patients with joint replacement can be extrapolated to certain procedures. Patients with joint replacement probably do not need prophylactic antibiotics for clean wounds. If mucosa is invaded, prophylaxis may be appropriate and reasonable in the small number of patients who might be at high risk of joint infection. Consultation with orthopedic surgery is appropriate in determining whether antibiotic prophylaxis is necessary.
Preparation for surgery
ear). Antibiotic choice should be modified based on culture results.
American Dental Association, American Academy of Orthopedic Surgeons: Antibiotic prophylaxis for dental patients with total joint replacements. J Am Dent Assoc 2003 Jul; 134(7):895–899. Amici JM, et al: A prospective study of the incidence of complications associated with dermatologic surgery. Br J Dermatol 2005; 153:967–971. Hurst EA, et al: Infectious complications and antibiotic use in dermatologic surgery. Semin Cutan Med Surg 2007; 26:47–53. Maragh SL, et al: Antibiotic prophylaxis in dermatologic surgery: updated guidelines. Dermatol Surg 2005; 31:83–91. Messingham MJ, Arpey CJ: Update on the use of antibiotics in cutaneous surgery. Dermatol Surg 2005; 31:1068–1078. Otley CC: Perioperative evaluation and management in dermatologic surgery. J Am Acad Dermatol 2006 Jan; 54(1):119–127. Review. Wilson W, et al: Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116:1736–1754. Wright TI, et al: Antibiotic prophylaxis in dermatologic surgery: advisory statement 2008. J Am Acad Dermatol. 2008 Sep; 59(3):464–473.
Preoperative antisepsis Many surgical preparations are available. Alcohol is commonly used for minor clean procedures, such as biopsies. However, since it has only weak antimicrobial activity, it is not recommended for more extensive procedures. Chlorhexidine has a broad spectrum against Gram-positive and Gram-negative organisms, a rapid onset of activity, sustained residual activity even after being wiped off, and is nonstaining. Chlorhexidine has been reported to cause both
Table 37-3 Endocarditis prophylaxis regimen (single dose 1 h prior to procedure) Situation
Agent
Adults
Children
Able to take oral medication
Amoxicillin
2 g
50 mg/kg
Unable to take oral medication
Ampicillin or Cefazolin or ceftriaxone
2 g IM/IV
50 mg/kg IM/IV
1 g IM/IV
50 mg/kg IM/IV
Allergic to penicillins or ampicillin and able to take oral medication
Cephalexin* or Clindamycin or Azithromycin or clarithromycin
2 g
50 mg/kg
600 mg
20 mg/kg
500 mg
15 mg/kg
Cefazolin or ceftriaxone* or Clindamycin
1 g IM/IV
50 mg/mg IM/IV
600 mg IM/IV
20 mg IM/IV
Allergic to penicillins or ampicillin and unable to take oral medication
* Cephalosporins should not be used in patients with a history of anaphylaxis, angioedema, or urticaria with penicillins or ampicillin. Adapted from Wilson et al. (2007)
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ototoxicity and keratitis from direct tympanic or ocular contact. However, this is mainly in patients under general anesthesia who cannot respond to immediate irritation associated with ocular contact, a problem that is avoided in most dermatologic procedures performed under local anesthesia. Betadine and all iodine-containing preparations have an excellent bactericidal activity within several minutes of application. However, they are often irritating to the skin, leave a residual color, can be absorbed in premature infants, and must dry before the procedure if they are to act as an effective antimicrobial agent. Hexachlorophene is not bactericidal against many Gramnegative organisms. It has the potential for neurotoxicity in children and teratogenicity in pregnancy. Hydrogen peroxide has no significant antiseptic properties, and thus it is not suitable for sterile skin preparation. If hair must be removed prior to surgery, this should be done in a manner that does not leave open skin (i.e. cuts or scratches), which can serve as a conduit for infection. Preoperative shaving has been associated with a higher rate of bacterial infection secondary to cutting of the skin surface. Thornton Spann C, et al: Topical antimicrobial agents in dermatology. Clin Dermatol 2003; 21:70–77.
Anesthesia Anesthetics work by blocking sodium influx into neurons and preventing depolarization and blockage of action potential. Small unmyelinated C-fibers, which carry pain and temperature sensation, are more easily blocked than larger myelinated A-fibers, which carry pressure sensation and motor function. This difference translates clinically, with patients under local anesthesia not experiencing pain from the sharp incision, but still maintaining the sensation of pressure during the procedure. All local anesthetics have a similar structure, consisting of three parts: an aromatic hydrophobic ring, an intermediate chain, and an amine end. The aromatic hydrophobic portion is lipophilic and facilitates diffusion through nerve cell membranes, correlating to the potency of the anesthesia. The hydrophilic amine end contributes to the aqueous solubility of the anesthetic and is involved in binding of the molecule to the sodium channel. The intermediate chain consists of either an amide or an ester. Amides are metabolized by hepatic microsomal enzymes, while esters are metabolized in plasma by pseudocholinesterase and excreted by the kidney. The choice of anesthetic is based on a variety of factors, including patient allergy, renal or hepatic impairment, and type of procedure being performed. The workhorse anesthetic of dermatologic surgery is lidocaine, due to its rapid onset of action and intermediate duration of action. Longer-acting anesthetics, such as bupivacaine, have a delayed onset of action, but can be used in special procedures or in combination with lidocaine to maximize duration of anesthesia. All local anesthetics, with the exception of cocaine and prilocaine, cause vasodilatation due to relaxation of smooth muscle. As a result, patients experience increased surgical bleeding and shorter duration of action as the anesthesia is cleared from the surgical site due to vasodilatation. Epinephrine, which causes vasoconstriction, is often added to local anesthetics to decrease bleeding, increase duration of anesthesia, and reduce systemic side effects due to systemic absorption. Concentrations of 1 : 100 000 to 1 : 400 000 are typically used, with lower concentrations having fewer side effects while still maintaining clinical efficacy. As the vasoconstrictive effect of epinephrine takes 15 min for onset, the surgeon must allow adequate time prior to starting the procedure. Epinephrine is a strong α- and β-adrenergic receptor agonist, and has an absolute contraindi866
cation in hyperthyroidism and pheochromocytoma. Large amounts of epinephrine must be used cautiously in patients with severe hypertension or narrow-angle glaucoma, and in pregnancy. Patients taking β-blockers, monoamine oxidase inhibitors, tricyclic antidepressants, and phenothiazines are more sensitive to epinephrine. While the subject of much controversy, epinephrine is safe to use in well-vascularized areas, such as the ear, nose, and genitals. Reports of necrosis are likely due to excessive volume being placed, which can cause a physical tamponade of vessels, rather than being a direct result of epinephrine. Sodium bicarbonate (8.4%) can be added (1:10 ratio) in order to reduce the pain and burning associated with the lower pH of lidocaine with epinephrine. However, sodium bicarbonate can reduce epinephrine activity with time, thus requiring freshly mixed preparations on a regular basis.
Side effects The most common side effect of local anesthetic is injection site pain. Buffering with sodium bicarbonate, using a small-gauge needle (i.e. 30 gauge), using ice or vibratory distraction at the injection site, injecting slowly into the subcutaneous tissue (rather than the dermis), warming the anesthesia, minimizing the number of injections, and placing subsequent injections in an already anesthetized location can minimize the pain associated with local anesthesia. Vasovagal reactions are common during anesthesia administration. Patients should lie flat during the injection to reduce this occurrence. Cold compresses and placing the patient in a Trendelenburg position can help if symptoms occur. Maximum dosage of anesthesia has traditionally been accepted as 5 mg/kg of 1% plain lidocaine and 7 mg/kg of 1% lidocaine with epinephrine. These numbers have been based on old industry-based studies, not found in the medical literature. Experience with tumescent liposuction has taught that dosages up to 55 mg/kg are well tolerated and safe in certain clinical situations. Bupivacaine has a greater risk of cardiac toxicity than lidocaine, because of its longer duration of action. Most true allergic reactions to local anesthetics have been reported with esters. The metabolite p-aminobenzoic acid (PABA) is responsible for ester allergies. There is no crossreactivity between ester and amide classes of anesthetics, so allergy to one type does not preclude the use of the other. True systemic amide allergy is extremely rare. Thorough questioning of patients who report allergy often reveals a vasovagal reaction or epinephrine sensitivity. If local anesthetic use is precluded, intradermal injection with diphenhydramine can be used. Drowsiness can be a side effect when large doses of this agent are used. Bacteriostatic saline, with the benzyl alcohol preservative acting as the anesthetic agent, is often sufficient to provide the brief anesthesia needed to perform small procedures. Topical anesthetics can be effectively used for many laser procedures, as well as decreasing pain associated with pinpricks of local anesthesia. These products require an extended time of application and/or occlusion in order to penetrate the stratum corneum and work effectively. The level of anesthesia obtained with these topical agents is often inconsistent. They are more effective on mucosa, due to the absence of the corneal barrier. There are numerous lidocaine-containing products in a variety of preparations. Eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA, AstraZeneca, Wilmington, DE) has also been used extensively. Prilocaine-induced methemoglobinemia has been reported in children due to the increased systemic absorption of prilocaine from certain topical products. Direct application of ice can reduce injection site pain. Ethyl chloride spray rapidly chills the skin and can be used for small
Amin SP, Goldberg DJ: Topical anesthetics for cosmetic and laser dermatology. J Drugs Dermatol 2005; 4:455–461. Koay J, Orengo I: Application of local anesthetics in dermatologic surgery. Dermatol Surg 2002; 28:143–148.
Anatomy A thorough understanding of anatomy is critical when performing dermatologic surgery. The vascular supply, sensory
and motor innervation, and muscles of facial expression all play a role in the successful surgical outcome (Figs 37-1 to 37-3; Box 37-4). Several key danger zones are worthy of mention. The temporal branch of the facial nerve is at greatest risk for injury when it runs superficial to the deep temporalis fascia as it crosses the zygomatic arch. Care must be taken to undermine bluntly in a plane above the SMAS (superficial muscular aponeurotic system). Injury to the temporal nerve results in brow ptosis and inability to raise the eyebrow. The danger zone for the marginal mandibular nerve lies where it crosses over the body of mandible, just anterior to the masseter muscle. Injury to the marginal mandibular nerve causes asymmetrical ipsilateral lip elevation and inability to show the lower teeth.
Superficial temporal artery • Anterior branch • Parietal branch
Preparation for surgery
curettage procedures or needle insertion. Refrigerated forced air or water-chilled sapphire crystals can help reduce pain associated with laser procedures. Ophthalmic solutions of proparacaine 0.5% or tetracaine 0.5% can provide rapid anesthesia and are useful when placing corneal shields.
Supratrochlear artery Supraorbital artery Dorsal nasal artery
Zygomatico-orbital artery
External nasal artery Infraorbital artery
Angular artery Transverse facial artery
Buccal artery
Superior labial artery Facial artery Mental artery
Inferior labial artery Submental artery
Fig. 37-1 Arterial supply of the face. Light pink designates arteries derived from the internal carotid artery; dark pink, from the external carotid artery. With permission from Bolognia JL, Jorizzo JL, Rapini RP (eds): Dermatology. 2nd edn. London: Mosby, 2008. Fig. 37-2 The facial (motor) nerve. With permission from Bolognia JL, Jorizzo JL, Rapini RP (eds): Dermatology. 2nd edn. London: Mosby, 2008.
Superficial temporal artery Facial nerve (superior division) • Temporal branch • Zygomatic branch • Temporofacial branch Stylomastoid foramen Facial nerve (inferior division) • Posterior auricular branch • Cervicofacial branch • Buccal branch • Marginal mandibular branch • Cervical branch
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Ophthalmic nerve (V1) • Supraorbital nerve (lateral branch) • Supraorbital nerve (medial branch) • Supratrochlear nerve • Infratrochlear nerve • Lacrimal nerve • External nasal branch (anterior ethmoidal nerve) Maxillary nerve (V2) • Zygomaticotemporal nerve • Zygomaticofacial nerve • Infraorbital nerve
Fig. 37-3 The trigeminal (cranial nerve V) and cervical plexus cutaneous sensory nerves. The concha and external auditory canal are variably innervated by branches of the vagus, glossopharyngeal, and facial nerves. With permission from Bolognia JL, Jorizzo JL, Rapini RP (eds): Dermatology. 2nd edn. London: Mosby, 2008.
Mandibular nerve (V3) • Auriculotemporal nerve • Buccal nerve • Mental nerve Cervical plexus • Lesser occipital nerve (C2) • Great auricular nerve (C2, C3) • Transverse cervical nerve (C2, C3)
Box 37-4 Innervation of the muscles of facial expression via cranial nerve VII (the facial nerve) Temporal branch • • • •
Frontalis muscle (m.) Corrugator supercilii m. Orbicularis oculi m. (upper portion) Auricular m. (anterior and superior; also known as the temporoparietalis m.)
Posterior auricular branch • Occipitalis m. • Auricular m. (posterior)
Zygomatic branch • • • •
Orbicularis oculi m. (lower portion) Nasalis m. (alar portion) Procerus m. Upper lip muscles • Levator anguli oris m. • Zygomaticus major m.
Buccal branch
• Nasalis m. (transverse portion) • Upper lip muscles • Zygomaticus major and minor m. • Levator labii superioris m. • Orbicularis oris m. • Levator anguli oris m. • Lower lip muscles (orbicularis oris m.)
Marginal mandibular branch • Lower lip muscles • Orbicularis oris m. • Depressor anguli oris m. • Depressor labii inferioris m. • Mentalis m. • Risorius m. • Platysma m. (upper portion)
Cervical branch • Platysma m.
• Buccinator m. (muscle of mastication) • Depressor septi nasi m. With permission from Bolognia JL, Jorizzo JL, Rapini RP (eds): Dermatology. 2nd edn. London: Mosby, 2008.
The spinal accessory nerve is at risk in a region of the neck delineated by the clavicle inferiorly, the sternocleidomastoid muscle anteriorly, and the trapezius muscle laterally and posteriorly. Damage to the nerve causes a winged scapula, inability to shrug the shoulder, difficulty abducting the shoulder, shoulder drop, and chronic shoulder pain.
Equipment The choice of instruments and suture depends on the pro cedure being performed. Most simple, in-office biopsies are performed in a “clean” rather than sterile manner, and 868
require minimal instrumentation. More complex excisional and reconstructive surgery is generally performed with sterile technique and employs a surgical tray with a wider range of instruments (Box 37-5). For procedures requiring sutures, absorbable material is used for deeper, layered closures, whereas surface sutures are generally nonabsorbable or fastabsorbing (Box 37-6). The large number of suture choices relates to both the type of procedure performed and the anatomic location treated. Choices include absorbable and nonabsorbable, synthetic and nonsynthetic, monofilament and braided. There are a variety of other characteristics one must consider when choosing which suture to use. Memory is the ability of the suture to return to its original shape after
Box 37-5 Cutaneous surgical instruments and supplies Scalpel handle (flat No. 3) Blade (No. 15) Needle holder (appropriate size) Sharp curved iris scissors, tissue-cutting scissors Blunt undermining scissors Skin hook (dull-tipped, 2–4-prong) Hemostats Forceps (1 × 2 teeth, with suture platform) Skin preparatory scrub in sterile basin Sterile towels Sterile gauze and cotton-tipped swabs Hyfrecator cover Suture Suture scissors Blade remover
Biopsies
• • • • • • • • • • • • • • •
Fig. 37-4 Shave biopsy. Lesion is pinched up with thumb and finger and biopsy performed with sweeping strokes.
Box 37-6 Examples of common skin suture material Absorbable • • • • • • •
Gut (chromic, plain) Polyglycolic acid (Dexon®) Polygalactin 910 (Vicryl®) Polydioxanone (PDS®) Polytrimethylene carbonate (Maxon®) Poliglecaprone 25 (Monocryl®) Glycomer 631 (Biosyn®)
twisted braided braided monofilament monofilament monofilament monofilament
Nonabsorbable • • • • • •
Silk Nylon (Ethilon®, Dermalon®) Nylon (Surgilon®, Nurolon® Polypropylene (Prolene®, Surgipro®) Polyester (Ethibond®, Mersilene®, Dacron®) Polybutester (Novafil®)
braided monofilament braided monofilament braided monofilament
deformation, which results in poor handling and decreased knot security. Plasticity is the ability of the suture to retain its new shape after it has been stretched. Elasticity is the ability of a suture to return to its original length and shape after stretching, an important factor to consider in relation to the resulting edema associated with surgery. The coefficient of friction is the ease with which the suture slides through tissue and is directly related to knot security. Capillarity is the ability of the suture to wick away fluid, with braided sutures having an increased tendency to trap fluid and bacteria. All have appropriate applications and a detailed discussion is beyond the scope of this chapter. In general, for procedures requiring buried suture, a synthetic braided suture is a common choice. The 50% tensile strength for this class of suture is about 3 months. Additionally, it is less palpable under the skin. For procedures on the trunk and extremities (i.e. areas under tension), a monofilament absorbable suture may be a better choice, as the tensile strength may last for a greater length of time. The thicker skin in these areas may hide the palpability of this class of suture, making it more acceptable to patients. Epidermal approximation in more delicate areas is more appropriately closed with smaller 5-0 or 6-0 sutures. Absorbable sutures (e.g. gut) may be considered in sensitive areas where suture removal may be painful or difficult (e.g. eyelids) or in children. Facial sutures are often taken out in 4–7 days to decrease the chance of forming track marks from epithelialization of the suture puncture site, whereas sutures on the scalp, neck, and body are often left in for approximately 2 weeks. Running subcuticular sutures can
be left in for 3 weeks to add tensile strength to wounds without the risk of suture marks.
Biopsies When performing a skin biopsy, the clinician should consider the lesion characteristics, reason for biopsy (i.e. diagnostic versus cosmetic), and site. Shave biopsies can range from a superficial scissor snip of an epidermal growth to deep shave excisions of papillary dermal processes. Punch biopsies are most often used for dermal lesions, sampling deeper than shave biopsies, but requiring sutures. Excisional biopsies remove an entire clinical lesion and are the biopsy of choice for pigmented lesions suspicious for melanoma. Incisional biopsies remove a portion of a clinical lesion and are often performed on larger plaques or patches when an excisional biopsy is not cosmetically acceptable or feasible. A wedge biopsy is a deep incisional biopsy that can sample pathologic tissue and adjacent normal tissue, and is especially useful for pathologic diagnosis of certain inflammatory conditions (e.g. panniculitis, fasciitis). Shave biopsies are best suited to pedunculated, papular, or otherwise exophytic lesions. Using a deep or rolled shave, samples can also be obtained of macular or indurated lesions, provided the necessary histologic changes reside in the epidermis or papillary dermis. Infiltration of local anesthesia distends and elevates the lesion, increases skin turgor, affords greater resistance to the blade, and facilitates undercutting the lesion. Using either a 15-blade scalpel or a razor blade, which can be flexed to achieve the desired depth, a horizontal incision is made and the lesion removed with sweeping strokes (Fig. 37-4). Hemostasis is attained with 35% aluminum chloride solution. Sharp scissor biopsy is best suited to pedunculated lesions. Iris or Gradle scissors are used to snip the base of the lesion. In many cases, this can be done without anesthesia. Chemical hemostasis, electrocautery, or simple pressure can be used to control bleeding. The dermatologic punch is commonly used for both excisional and incisional biopsies (Fig. 37-5). When performing a punch biopsy, the skin should be stretched perpendicular to the relaxed skin tension lines. The elliptical wound resulting from the release of the tension can be suture-closed in a linear fashion without redundancy or puckering associated with circular wounds. The punch is placed on the skin perpendicular to the surface. While the surgeon applies gentle pressure, it is 869
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A
B
C
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E
Fig. 37-5 Punch biopsy. A, Lesion to be removed. B, Skin stretched perpendicular to relaxed skin tension lines and punch inserted with twisting motion. C, Specimen is carefully grasped and removed. D, Resultant elliptical defect. E, Sutures in place.
rotated back and forth and advanced to the hub. The specimen is carefully grasped to avoid crush artifact and the base is cut. Sutures are typically placed to achieve hemostasis, but punch sites that are allowed to heal by second intention have been shown to heal with a similar cosmetic outcome. A variation of the punch biopsy can be used to remove larger subcutaneous nodules. Narrow-hole extrusion is a surgical technique that uses a punch biopsy to make a small cutaneous portal through which larger benign growths (e.g. lipoma) can be extruded (Fig. 37-6). This technique allows the evacuation of large subcutaneous growths with a relatively small surface incision.
Suture technique Proper suture placement is essential to obtain the desired final result. Sutures are used to close any dead space, reduce bleeding, provide tensile strength and minimize tension to facilitate wound healing, and achieve epidermal wound approximation to maximize cosmetic outcome. Instrument-tied knots are the most common sutures used in dermatologic surgery. Various suturing techniques can be employed, based on factors such as size, anatomic location, and thickness of the surgical wound. Buried subcutaneous sutures are used for larger or deeper wounds to reduce the chance of wound dehiscence. Proper placement is key to achieving eversion of the wound edges 870
and decreasing tension (Fig. 37-7). The stitch is in the dermis and fat, with the knot cut short and buried to reduce tissue reaction and “spitting” sutures. Simple epidermal interrupted sutures are one of the most versatile stitches used in dermatology. They are best used for closure of small punch biopsies, or for larger layered excision or flap repairs. They are especially useful in high-tension wounds, as a single suture can be removed and the surgeon can assess the wound for any dehiscence. For wound edges with a step off the opposing epidermal edges, the surgeon places the suture more superficially at the higher side and deeper on the lower side to even the edges (Fig. 37-8). The vertical mattress suture is useful for reducing tension, closing dead space, and achieving wound eversion (Fig. 37-9). It can function as both the buried and the superficial suture. As this suture has a high tendency to leave track marks and strangulate the skin, it must be used strategically and removed sooner than traditional sutures. The horizontal mattress suture reduces tension and can be used as a retention suture when attempting to close larger wounds (Fig. 37-10). It can cause strangulation and necrosis of poorly vascularized tissue and should be used with caution when closing flaps. Running sutures can be used for epidermal closure in wounds under little tension and with closely approximated wound edges. Placement is much faster than simple interrupted sutures, as knots are only used at each end of the wound. The running locked suture is a variant of the simple
Biopsies A
B
C
D
Fig. 37-6 Narrow-hole extrusion of lipoma. A, 4 mm punch in center of lipoma. B, Hemostat used to loosen lipoma. C, Extrusion of lipoma through narrow hole. D, Entire lipoma removed.
A
B
A 2
1
2
1
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Fig. 37-8 Step-off correction. A, To correct a step-off deformity, place a simple interrupted suture superficially on the higher wound edge (1) and deeply on the lower wound edge (2). Numbers indicate entry points of the needle. B, Tying this suture results in even wound edges. With permission from Robinson JK, Hanke CW, Sengelmann RD, Siegel DM (eds): Surgery of the Skin. Philadelphia: Mosby, 2005.
2
1
C 37-7 Buried dermal sutures. Numbers indicate entry points of Fig. the needle. A, Conventional buried suture placement results in mild wound eversion. B, Buried vertical mattress suture placement results in moderate to significant wound eversion. With permission from Robinson JK, Hanke CW, Sengelmann RD, Siegel DM (eds): Surgery of the Skin. Philadelphia: Mosby, 2005. 1
2
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A
B
A
4 1 1
3
3 4 2 2
C B
Fig. 37-9 Placement of the vertical mattress stitch. A, The needle is placed 5–10 mm from the wound edge, and a deeply seated simple interrupted suture is placed (1)(2). Numbers indicate entry points of the needle. B, The needle is redirected back across the wound more superficially, penetrating the skin edge 2–4 mm from the wound on both sides (3). C, Final appearance of this suture after tying. With permission from Robinson JK, Hanke CW, Sengelmann RD, Siegel DM (eds): Surgery of the Skin. Philadelphia: Mosby, 2005.
running suture and involves passing the needle through the previous loop (Fig. 37-11). This technique creates pressure along the wound edge and can be used in highly vascularized regions for additional hemostasis. Running subcuticular sutures typically use a non-absorbable suture and are used for trunk and extremity closures where sutures are left for 2–3 weeks. Since the suture is buried, it can be left in place for a longer period of time without developing cross-hatch marks (Fig. 37-12) A single loop coming out in the middle of larger wounds can help facilitate removal of the suture. Alternatively, absorbable suture can be used and eliminate the need for removal. Christenson LJ, et al: Primary closure vs second-intention treatment of skin punch biopsy sites: a randomized trial. Arch Dermatol 2005 Sep; 141(9):1093–1099. Krunic AL, et al: Running combined simple and vertical mattress suture: a rapid skin-everting stitch. Dermatol Surg 2005 Oct; 31(10): 1325–1329. Lee KK, et al: Surgical revision. Dermatol Clin 2005 Jan; 23(1):141–150, vii. Moy RL, et al: A review of sutures and suturing techniques. J Dermatol Surg Oncol 1992 Sep; 18(9):785–795.
Cryosurgery Cryosurgery is used for the treatment of numerous benign, premalignant, and malignant skin lesions. This modality is extensively employed by almost every dermatologist, owing to its ease of use, cost-effectiveness, and versatility. Postoperative wound care is relatively simple and complica872
Fig. 37-10 Horizontal mattress suture. A, To place this suture, begin with a widely spaced simple interrupted suture (1) (2). Numbers indicate entry points of the needle. Move laterally down the wound 3–5 mm, and place another interrupted suture in the opposite direction as the first (3) (4). B, The appearance of this suture when tied. With permission from Robinson JK, Hanke CW, Sengelmann RD, Siegel DM (eds): Surgery of the Skin. Philadelphia: Mosby, 2005.
tions are infrequent. Although a number of cryogens have been used (including ethyl chloride, CO2, and NO), liquid nitrogen, with a boiling point of −195.6°C, is most widely utilized. The mechanism of injury in cryosurgery is the result of multiple factors, including mechanical damage to cells resulting from intracellular and extracellular ice crystal formation, exposure to high electrolyte concentrations in surrounding non frozen or thawing fluid, recrystallization patterns during thaw, and ischemia caused by vascular stasis and damage. Rapid freezing causes intracellular ice crystals that are more destructive than the extracellular crystals formed during slow freezing. Tissue damage is maximized with a slow thaw time, which causes increased solute gradients and greater cell destruction. Multiple freeze–thaw cycles can further increase damage to the target lesion. There are several techniques for cryosurgery. The simplest is the use of a cotton-tipped applicator. Varying the amount of pressure applied and the length of contact of the applicator to the skin can control the depth of freeze. Additionally, the volume of liquid nitrogen can be increased or decreased by
1
2
3
3 2
5 4
adding or removing cotton from the applicator tip. As viruses have been shown to survive in liquid nitrogen, cotton-tipped applicators should never be reintroduced to the storage container. Rather, a small amount of liquid nitrogen should be transferred to an individual container and discarded after use. Spray application is one of the most commonly used methods of cryosurgery. This technique uses a hand-held liquid nitrogen spray unit with an adjustable nozzle to vary the size of the stream delivered. An insulating cone or a disposable otoscope speculum can be used to focus the delivery of liquid nitrogen, resulting in a deeper freeze and finer control with less damage to uninvolved skin (Fig. 37-13). Basal cell carcinomas (BCCs) can be treated effectively with cryosurgery. Freezing to reach a target temperature of approximately −50°C, as measured by a thermocouple, is appropriate for management of these tumors. This translates to a thaw time of approximately 60 sec, with a freeze margin of approximately 5 mm (Fig. 37-14). It is important to recognize that the
Cryosurgery
1
Fig. 37-11 Running block suture. A running simple suture is placed, passing the needle through the loop created by the last suture. This locking suture facilitates hemostasis. Numbers indicate entry points of the needle. With permission from Robinson JK, Hanke CW, Sengelmann RD, Siegel DM (eds): Surgery of the Skin. Philadelphia: Mosby, 2005.
Fig. 37-12 Running subcuticular suture. Multiple horizontally placed dermal sutures are placed in succession on alternating wound edges. This results in epidermal and dermal closure without visible suture marks. Numbers indicate entry points of the needle. With permission from Robinson JK, Hanke CW, Sengelmann RD, Siegel DM (eds): Surgery of the Skin. Philadelphia: Mosby, 2005.
pain associated with such treatment requires local anesthesia. In a review of published data, Kokoszka et al found a recurrence rate of less than 10% for primary small, noninfiltrating (i.e. superficial and nodular) BCC treated with cryosurgery. Some have suggested that initially treating the tumor with curettage, followed by cryosurgery, can lead to cure rates consistent with curettage and electrodesiccation. However, Kuijpers et al have suggested that standard excision provides higher cure rates than curettage and cryosurgery, and recommend that excision be used as the preferred treatment for BCC, due to the higher cure rate, better cosmetic outcome, and faster healing rates. Side effects of cryosurgery are similar to those of other ablative procedures (e.g. curettage and electrodesiccation), and include blistering, crusting, pain, a 3–4-week healing period, and scarring. As melanocytes are more susceptible to thermal damage than keratinocytes, hypopigmentation can often be seen, especially in individuals with darker skin tones. While 873
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A
B
Fig. 37-13 A, Cryoplate with multiple sized openings. B, Disposable otoscope speculum with tip cut off.
Fig. 37-14 Cryosurgery. A, Basal cell carcinoma on the posterior helix. B, Cryosurgery to neoplasm. C, 1 week later, with necrosis and sloughing of treatment area. D, Final result several months later.
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* C
D
pigment alterations are more frequently seen with longer freeze–thaw times, these changes can be observed even with very brief treatment cycles. A self-limited hyperplastic or pseudoepitheliomatous healing response may occur approximately 2–4 weeks after freezing. Nerve injury can occur during cryosurgery. Anatomic locations with superficial nerves (e.g. lateral aspects of the fingers, ulnar groove of the elbow, preand post-auricular skin) are especially susceptible to this complication. Techniques to limit this risk include tenting the skin up and away from the nerve, ballooning the skin with lidocaine, or sliding the skin back and forth over the underlying fascia during treatment to limit exposure to the underlying nerve. Alopecia can occur when treating hair-bearing areas. 874
Both atrophic and hypertrophic scars can be seen following cryosurgery. Kokoszka A, Scheinfeld N: Evidence-based review of the use of cryosurgery in treatment of basal cell carcinoma. Dermatol Surg 2003; 29:566. Kuijpers DI, et al: Surgical excision versus curettage plus cryosurgery in the treatment of basal cell carcinoma. Dermatol Surg 2007; 33:579–587. Lindemalm-Lundstam B, Dalenbäck J: Prospective follow-up after curettage-cryosurgery for scalp and face skin cancers. Br J Dermatol 2009; 161:568–576. Nordin P: Curettage-cryosurgery for non-melanoma skin cancer of the external ear: excellent 5-year results. Br J Dermatol 1999; 140:291.
The curette has long been a standard tool in the dermatologist’s surgical management of neoplasm. This round, semisharp knife is available in sizes from 0.5 to 10 mm, allowing for the removal of a variety of lesions. Since it is not as sharp as a scalpel, the curette does not easily cut through normal skin. Therefore, it is best suited for use on soft or friable lesions, such as warts, seborrheic and actinic keratoses, the papules of molluscum contagiosum, or selected basal and squamous cell carcinomas. The proper selection of lesion, location, and the size of the curette, combined with the surgeon’s technique, all play a role in both the therapeutic and cosmetic outcome. The skin should be stabilized with the nondominant hand while the curette is held like a pencil. Curettage should be performed in a centripetal manner (from the outside in) to avoid stripping sun-damaged skin and creating a larger wound. To ensure complete destruction, curettage should be performed in multiple directions to produce symmetrical wound margins. A large curette is used for initial debulking, followed by a smaller curette to remove any residual foci or extensions. Curettage is complete when the “gritty,” firm sensation of normal dermis is felt and slight punctate dermal bleeding occurs. Curettage, combined with electrodesiccation (C&E), is widely used for the treatment of BCC and squamous cell carcinomas (SCC) (Fig. 37-15). Silverman et al reviewed the cure rates of primary BCC treated with C&E over a 27-year period at New York University. The result of the study stratified low-, middle-, and high-risk anatomic locations and the risk of recurrence following C&E of primary BCC. Low-risk anatomic sites (neck, trunk, and four extremities) had a 5-year recurrence rate of 3.3%. Middle-risk sites (scalp, forehead, pre- and post-auricular, and malar areas) had an overall recurrence rate of 12.9%, but this was reduced to 5% when limited to noninfiltrative carcinomas of less than 1 cm. High-risk sites (nose, paranasal, nasolabial groove, ear, chin, mandibular, perioral, periocular areas) had an overall recurrence rate of 17.5%, but a more acceptable 5% recurrence rate was achieved when treatment was limited to lesions of less than 6 mm. In addition to size and anatomic location, the histologic subtype is an important factor in the effectiveness of C&E. Infiltrative and micronodular BCC are not appropriate for C&E, while it can be considered a therapeutic option in superficial and nodular subtypes. SCC in situ may be appropriately treated with C&E, while in most circumstances invasive SCC would not typically be amenable to this modality.
A
There is little agreement regarding the requisite number of cycles of C&E. Indeed, treating all lesions identically with a particular number of cycles may lead to overtreatment of some lesions and undertreatment of others. In general, accepted therapy employs three cycles to treat most malignant lesions. However, smaller superficial malignancies may be treated with fewer cycles; the rationale is to improve cosmetic outcome, while still achieving acceptable cure rates. None the less, the success of C&E relies on the surgeon’s ability to identify by feel and appearance the tissue to be ablated. Finally, C&E should be replaced by excision if curettage extends into subcutaneous tissue. As such, lesions that have been previously biopsied using a punch that has extended into the subcutaneous fat may be less amenable to C&E.
Electrosurgery
Curettage
Barlow JO, et al: Treatment of basal cell carcinoma with curettage alone. J Am Acad Dermatol 2006 Jun; 54(6):1039–1045. Goldman G: The current status of curettage and electrodesiccation. Dermatol Clin 2002; 20:569. Rodriguez-Vigil T, et al: Recurrence rates of primary basal cell carcinoma in facial risk areas treated with curettage and electrodesiccation. J Am Acad Dermatol 2007; 56:91–95. Sheridan AT, Dawber RP: Curettage, electrosurgery and skin cancer. Australas J Dermatol 2000; 41:19. Silverman MK, et al: Recurrence rates of treated basal cell carcinomas. Part 2: Curettage-electrodesiccation. J Dermatol Surg Oncol 1991; 17:720.
Electrosurgery Electrosurgery comprises a variety of surgical techniques, applications, and apparatus. In general, the tissue effect is created by heat delivered to or generated in the tissue as a result of an electrical current. Various forms of electrosurgery are routinely used by dermatologists for applications such as destruction, hemostasis, excisions, and cosmetic procedures. An understanding of the different modalities and their applications can improve surgical outcome (Fig. 37-16).
Electrocautery Electrocautery is most often performed today with batterypowered, hand-held, disposable units. Direct current is passed through a metal treatment tip. Resistance to the flow of current causes heat to be generated, which can be adjusted by the intensity of the current. Hemostasis is achieved by direct heating of the tissue; no electrical current passes through the patient. As such, this device may be considered in patients with implantable cardiac devices sensitive to electric current.
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Fig. 37-15 Curettage and electrodesiccation. A, Curettage of squamous cell carcinoma in situ. B, Electrodesiccation immediately following.
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Fig. 37-16 Electrosurgery waveforms. 60Hz Alternating current
Unaltered sine wave
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Electrodesiccation and electrofulguration Electrodesiccation (from the Greek desiccate, meaning “dry”) and electrofulguration (from the Greek fulgur, meaning “lightning”) represent the most commonly employed uses of electrosurgery in dermatology. In electrodesiccation, the electrode tip is in contact with the tissue; with electrofulguration, a 1–2 mm separation between the tip and the tissue produces a spark. Electrodesiccation causes a deeper wound, while electrofulguration is more superficial. A highly damped (decreasing amplitude) waveform of high voltage and low amperage is produced by a spark-gap generator. As this is a monoterminal current, a grounding electrode on the patient is not required. Electrodesiccation/fulguration produces superficial destruction, as the carbonization on the treated surface limits damage to deeper tissue. This type of electrosurgery has numerous applications in the daily practice of dermatology. Superficial, small dermal tumors, such as syringomas or seborrheic keratoses, may be treated with electrodesiccation. Insertion of the fine epilating needle into the tumor is followed by the application of low current until a surface bubbling occurs. The small amount of char is then removed with a curette, resulting in a smooth surface appearance. In addition, skin tags, warts, and fine telangiectases may all be effectively removed by this technique. Electrodesiccation or fulguration is commonly employed in treatment of many BCCs and SCCs (see above section on curettage). It is also useful in excisional surgery to obtain hemostasis. The field must be dry, since the destruction by this current is superficial and will not be transmitted through blood.
Electrocoagulation Electrocoagulation employs moderately damped current with a lower voltage and higher amperage. The patient is incorporated into a biterminal circuit. Electrocoagulation causes 876
greater tissue damage and deeper penetration than electrodessication or electrofulguration.
Electrosection Electrosection employs an undamped, low-voltage, highamperage current in a biterminal fashion. This technique has the advantage of cutting with simultaneous hemostasis. As such, it is used for bloodless excisional surgery of protuberant masses and growths, such as rhinophyma. There is vaporization of tissue with little heat spread. Care must be taken with this technique, as maintaining an appropriate depth can be difficult, given the ease with which the device can cut through skin. When the device is properly used, fine surgical excisions can be produced, with minimal trauma to surrounding tissue and excellent hemostasis. Various handpiece attachments, including scalpels, needles, wire loops, and balls, can further adapt the instrument to the specific procedure. Care must be taken when using electrosurgery in a patient with a pacemaker or implantable cardioverter-defibrillator, especially if the procedure is performed within a few centi meters of the device. Although modern devices are better shielded and less likely to respond to external electrical interference, it is always prudent to deliver current in short bursts. Additionally, consideration should be given to the use of electrocautery (heat only, no electrical transmission) or a bipolar device (current transmitted between two tips) when treating these patients. Yu et al recently reviewed the use of electrosurgery in patients with cardiac devices and offer a complete discussion of the subject. Aferzon M, Millman B: Excision of rhinophyma with high-frequency electrosurgery. Dermatol Surg 2002; 28:735. Matzke TJ, et al: Pacemakers and implantable cardiac defibrillators in dermatologic surgery. Dermatol Surg 2006; 32:1155–1162. Rex J, et al: Surgical management of rhinophyma: report of eight patients treated with electrosection. Dermatol Surg 2002; 28:347.
Excisional technique The fusiform or elliptical excision is the workhorse procedure used to treat invasive skin cancers, as well as benign skin lesions needing extirpation (Fig. 37-17). The basic principle of
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Wagner RF Jr: Medical and technical issues in office electrolysis and thermolysis. J Dermatol Surg Oncol 1993; 19:575. Yu SS, et al: Cardiac devices and electromagnetic interference revisited: new radiofrequency technologies and implications for dermatologic surgery. Dermatol Surg 2005; 31:932.
Fig. 37-17 Elliptical excision. A, Ellipse is designed along relaxed skin tension lines with a 3:1 length to width ratio. B, Incision made into subcutaneous tissue. C, Removal using tissue scissors in even plane. D, Blunt undermining of skin edges using skin hook. E, Buried interrupted tension-bearing absorbable sutures placed. F, Epidermal approximation using nonabsorbable running subcuticular sutures, with interruption in center of wound for easier removal.
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the fusiform ellipse is excision of a specimen oriented with its longest axis along skin tension lines and its width not exceeding one-third of its length. The ellipse can be curved in a crescentic or “lazy S” pattern to align the final scar better with skin tension lines. If the procedure is performed with the correct dimensions (usually a length to width ratio of 3 : 1) and a 30° angle at each pole, standing cutaneous cones at the two extremes of the excision are generally avoided. Standing cutaneous cones represent excess tissue bunching at the poles of a skin closure and should be “sewn out” or excised by triangulation or M-plasty if needed. Undermining, using sharp or blunt dissection of the skin from underlying subcutaneous tissue, reduces wound tension and helps with wound edge eversion.
healing, wounds that are adjacent to a free margin may result in a pull and distortion. This may affect surrounding anatomic structures (e.g. pull on a nasal rim or eyelid). The wounds may heal with hypertrophic or pigmentary changes. However, there are areas and situations where allowing a wound to heal by second intention is appropriate. These include superficial wounds in concave areas (e.g. medial canthus, conchal bowl, and junction between the nose and cheek), partial thickness wounds involving the mucosa of the lip, or certain clinical situations, such as elderly or frail patients with decreased cosmetic concerns (Fig. 37-18). Wound care is simple and post operative restrictions are minimal.
Flaps
Skin flaps and grafts Choosing whether to close a wound by linear closure, local skin flap, or skin graft, or allowing it to heal by second intention can be complex. Important considerations include patient concerns, local tissue movement, adjacent anatomic structural preservation and function, and cosmesis.
Second intention Second intention wound healing yields excellent results in appropriate clinical settings. As there is contraction in wound
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Local skin flaps are geometric segments of tissue contiguous with a skin defect that are advanced, rotated, or transposed to close a wound. Advantages of flaps include better approximation of skin texture and color, hiding incision lines, redirecting tension vectors, and covering exposed cartilage and bone. Flap survival is based on the preservation of the random blood supply along the pedicle. Consideration of both the primary movement of the flap (the actual movement of the flap into the defect) and secondary movement (movement of surrounding tissue in reaction to the flap movement) is critical when designing the repair (Fig. 37-19).
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Fig. 37-18 Second intention. A, Mohs defect. B, Final result 9 months later.
Fig. 37-19 Advancement flap movement. Burow's triangle
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Fig. 37-20 Single arm advancement flap. A, Advancement flap designed on nasal sidewall. B, Final wound closure.
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Fig. 37-21 Island pedicle flap. A, Mohs defect. B, Final wound closure. C, 6 weeks postoperatively.
Advancement flap An advancement flap moves almost entirely in one linear direction (Fig. 37-20). The classic advancement flap involves the creation of a rectangular pedicle, which slides into position over the primary surgical defect. The key suture advances the flap and closes the primary defect. Tissue redundancies at the base of the flap can be removed by triangulation. As survival of the distal tip of the flap depends on blood supply from the base, a maximum length : width ratio of 3:1 should be designed. If insufficient movement is obtained with a single advancement flap, a bilateral advancement (O-H) can be employed, such that each flap advances to cover half the defect. This repair can be used in eyebrow or helical rim repairs. Single arm advancement flaps (O-L) and bilateral single arm advancement flaps (O-T) are similar to classic advancement flaps, except that only a single incision is made and the standing cone is removed by triangulation. These flaps have the advantage of a larger pedicle providing blood supply and allow a linear portion of the flap to be hidden in an existing rhytid for better cosmetic outcome. Common sites for single arm advancement flaps include the nasal sidewall, helical rim, upper lip, forehead, and eyebrow. The island pedicle flap is a specific variant of an advancement flap (Fig. 37-21). This flap depends on a subcutaneous vascular pedicle for its blood supply and has all of the epidermal connections severed by incisions. Care must be taken in designing island pedicle flaps as the incision lines surrounding the flap can result in a patch-like appearance in the final
outcome. The best cosmetic results are achieved when at least one of the incision lines can be hidden in a existing rhytid or anatomic boundary.
Rotation flap The rotation flap can conceptually be considered a variation of the advancement flap, in that it slides into position in much the same way, albeit in an arcuate manner. Tension vectors from this pulling action are directed along the arc of rotation in reverse fashion (Fig. 37-22). Rotation flaps are often used to close large defects when there is insufficient tissue laxity (Fig. 37-23). The flap has the advantage of good survival secondary to the large pedicle and the ability to recruit skin from a great distance. A back cut can be used to reduce pivotal restraint and provide greater tissue movement, but may compromise the vascular pedicle. Variations include bilateral rotation flap (O-Z) (Fig. 37-24) or dorsal nasal rotation flap (Fig. 37-25).
Transposition flaps In the case of the transposition flap, the flap is elevated, transposed over intervening tissue, and sutured into the primary defect (Fig. 37-26). The tension vector is redirected across the closure of the secondary defect (i.e. the area originally occupied by the flap). This is especially helpful for defects that are adjacent to anatomic free margins. The key suture closes the secondary defect, and the flap is then lifted 879
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Fig. 37-22 Rotation flap movement. With permission from Robinson JK, Hanke CW, Sengelmann RD, Siegel DM (eds): Surgery of the Skin. Philadelphia: Mosby, 2005.
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Fig. 37-23 Rotation flap. A, Rotation flap designed with M-plasty. Redundant skin from cheek is borrowed to repair defect. B, Final closure.
Fig. 37-24 O-Z rotation flap. A, Flap designed. B, Final wound closure.
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Fig. 37-25 Dorsal nasal rotation flap. A, Mohs defect. B, Final wound closure. C, 8 weeks postoperatively.
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Choice of a particular type of flap must take multiple factors into consideration, including location of defect, availability of tissue movement, surrounding structures, effects of tissue movement, and blood supply. Full discussion of flaps is beyond the scope of this chapter and is available in multiple referenced texts. The successful design and execution of flap repairs can be complex, and requires appropriate and extensive training.
Skin grafts 2. Secondary defect
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Fig. 37-26 Transposition flap movement.
and transposed into position over the primary defect. The prototype of this flap is the rhombic flap (Fig. 37-27). Other examples include bilobed flaps (Fig. 37-28), nasolabial/ melolabial flaps, banner flap, Z-plasty, and Webster’s 30° flap (Fig. 37-29).
Skin grafts are employed when primary closure or flap closure is not an available option. By definition, a graft is completely excised from the donor site and is devitalized (i.e. no intrinsic blood supply). Success is predicated on the reattachment of vascular supply to the graft from the defect. Grafts offer the advantage of fewer incision lines, as compared to local flaps. However, the lack of color and texture match due to the remote donor location of grafts is a potential disadvantage. Grafts can be categorized as full, split, or composite. Choice of when to use each of these depends on the depth of the defect, vascular supply, and concern about skin cancer recurrence. Full-thickness skin grafts have a full dermis and are the most common grafts used in dermatologic surgery. The graft is defatted, trimmed to fit the defect, anchored in place with peripheral and basting sutures, and secured with a tie-over dressing. Common donor sites include pre-auricular cheek, post-auricular crease, conchal bowl, upper eyelid, upper inner arm, or clavicle. Full-thickness grafts can produce an excellent cosmetic result if executed properly (Fig. 37-30). However, the increased skin thickness results in an increased metabolic demand and a higher rate of necrosis and failure. Imbibition occurs during the first 24–48 h after graft placement. The graft is sustained by passive diffusion of nutrients from the wound bed during this stage. It becomes edematous, and the fibrin network attaches the graft to the bed. Inosculation is the next stage, with revascularization from linkage of dermal vessels in graft to wound bed. Neovascularization occurs from capillary ingrowth to the graft from recipient base and sidewalls. Full circulation can be restored in 7 days and depends on the graft thickness and vascularity of the wound bed. 881
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Fig. 37-28 Bilobed flap. A, Mohs defect. B, Final wound closure. C, 6-week follow- up. C
Fig. 37-27 Transposition flap. A, Mohs defect. B, Final wound closure. C, 3-month follow-up.
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Split-thickness skin grafts have only a partial dermis and are useful for covering large areas or for improved surveillance in tumors with a high risk of recurrence. Small grafts can be harvested freehand with No. 15 blade or with a hand-held Weck blade using various guards to determine graft thickness (Fig. 37-31), while larger grafts can be obtained using a power dermatome (Fig. 37-32). Grafts can be meshed in order to provide coverage for larger defects. In comparison to fullthickness skin grafts, split-thickness grafts have a higher rate of survival and shorter healing time, do not require repair of the donor site, and are a good choice for poorly vascularized areas due to lower metabolic demand. However, they have a higher degree of contraction, lack skin appendages, and provide a poorer cosmetic match. Composite grafts most commonly consist of skin and underlying structure (e.g. cartilage), and are predominately used to repair such wounds as full-thickness alar rim defects. These grafts have an increased nutrient requirement and thus are more likely to fail. Free cartilage grafts can be used for reconstruction of the ear and nasal ala or tip. Adams DC, Ramsey ML: Grafts in dermatologic surgery: review and update on full- and split-thickness skin grafts, free cartilage grafts, and composite grafts. Dermatol Surg 2005; 31:1055–1067. Goldman GD: Rotation flaps. Dermatol Surg 2005; 31:1006–1013. Krishnan R, et al: Advancement flaps: a basic theme with many variations. Dermatol Surg 2005; 31:986–994. Leonard AL, Hanke CW: Second intention healing for intermediate and large postsurgical defects of the lip. J Am Acad Dermatol 2007; 57:832–835.
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Fig. 37-30 Full-thickness skin graft. A, Mohs surgery defect. B, Final wound closure. C, 3-year follow-up.
Mott KJ, et al: Regional variation in wound contraction of Mohs surgery defects allowed to heal by second intention. Dermatol Surg 2003 Jul; 29(7):712–722. Pipitone MA, Gloster HM Jr: Repair of the alar groove with combination partial primary closure and second-intention healing. Dermatol Surg 2005 May; 31(5):608–609.
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Fig. 37-31 Harvesting of split-thickness skin graft. Mastoid process is an excellent source. Hair will regrow at donor site and hide the wound. Hairs remaining in the graft are above the level of the bulb and will not persist once the graft takes.
Rohrer TE, Bhatia A: Transposition flaps in cutaneous surgery. Dermatol Surg 2005; 31:1014–1023.
Mohs micrographic surgery Frederic Mohs initially developed this technique at the University of Wisconsin in the 1930s as a means for margin control during surgical excision of skin cancer. The original technique used zinc chloride paste to fix tissue in vivo, followed by surgical excision. Drs Theodore Tromovitch and Samuel Stegman modified this technique in the 1970s to a fresh-frozen tissue variant that continues to be used today. While the basic surgical principles in Mohs micrographic surgery are similar to those used in standard excision, there are unique challenges encountered with Mohs surgery. A complete understanding of pathology, anatomy, cutaneous oncology, advanced surgical reconstruction, and management of surgical complications is critical to a successful patient outcome. Any dermatologist performing Mohs micrographic surgery should be well trained in this technique and all the accompanying challenges of surgical and postoperative care. Mohs micrographic surgical excision is a tissue-sparing technique that employs frozen-section control of 100% of the surgical margin. This evaluation of the entire surgical margin using horizontal sections (not vertical, as used in standard sectioning), combined with precise mapping, allows for the highest cure rate of cutaneous neoplasms (Fig. 37-33). In addition, the sparing of normal adjacent tissue can improve cosmesis and decrease the risk of functional defects in a sensitive anatomic location. Any tumor that has a contiguous growth pattern would be a candidate for Mohs micrographic surgical excision. Immunohistochemical stains can be used in specific cases to help identify residual tumor. There are multiple indications for Mohs micrographic surgical excision (Box 37-7, Fig. 37-34). Mohs surgery provides cure rates of 99% for primary BCCs, and 95% for recurrent BCCs. SCCs on the skin and lip treated with Mohs surgery have a 5-year recurrence rate of 3.1% (versus 10.9% for other modalities). SCC on the ear treated with Mohs surgery has a 5-year recurrence rate of 5.3% (versus 18.7% for other modalities). Locally recurrent SCC also had a reduced recurrence rate when treated with Mohs surgery, as compared to other modalities (10% versus 23.3%). Other tumors that can be successfully 884
Fig. 37-32 Harvesting of split-thickness skin graft with powered dermatome.
Box 37-7 Indications for Mohs surgery • Recurrent or incompletely excised nonmelanoma skin cancer • Tumors with aggressive histologic subtypes (i.e. infiltrative, morpheaform, micronodular, perivascular, or perineural involvement) • Tumors with poorly defined clinical margins • High-risk location >0.4 cm (H-zone of the face, eyes, ears, nose) • Large tumors (>1.0 cm on face; >2.0 cm on trunk or extremities) • Cosmetically and functionally important areas, including genital, anal, perianal, hand, foot, and nail units • Tumors arising in immunosuppressed patients • Tumors arising in previously irradiated skin or scar • Genetic conditions with increased risk of neoplasms (i.e. basal cell nevus syndrome or xeroderma pigmentosa)
treated by Mohs surgery include dermatofibrosarcoma protuberans, atypical fibroxanthoma, and microcystic adnexal carcinoma. Mohs micrographic surgical excision of melanoma continues to be debated. Bricca et al demonstrated comparable 5-year local recurrence rates, metastasis rates, and diseasespecific survival rates in head and neck melanomas treated with Mohs micrographic surgery, as compared to standard excision. In contrast, Walling et al showed that staged excision for melanoma resulted in lower recurrence rates and similarsized defects compared to Mohs surgery. Bricca GM, et al: Cutaneous head and neck melanoma treated with Mohs micrographic surgery. J Am Acad Dermatol 2005; 52:92. Leibovitch I, et al: Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years. J Am Acad Dermatol 2005 Aug; 53(2):253–260. Leibovitch I, et al: Basal cell carcinoma treated with Mohs surgery in Australia II. Outcome at 5-year follow-up. J Am Acad Dermatol 2005 Sep; 53(3):452–457. Rowe DE, et al: Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol 1989; 15:315. Rowe DE, et al: Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol 1989; 15:424.
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Fig. 37-33 The Mohs surgery process.
Fig. 37-34 H-zone of the face.
Rowe DE, et al: Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol 1992; 26:976. Thomas CJ, et al: Mohs micrographic surgery in the treatment of rare aggressive cutaneous tumors: the Geisinger experience. Dermatol Surg 2007 Mar; 33(3):333–339. Thosani MK, et al: Current progress of immunostains in Mohs micrographic surgery: a review. Dermatol Surg 2008 Dec; 34(12):1621–1636. Walling HW, et al: Staged excision versus Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma. J Am Acad Dermatol 2007 Oct; 57(4):659–664.
Photodynamic therapy Photodynamic therapy (PDT) involves the activation of a photosensitizer by visible light in the presence of oxygen, resulting in the creation of reactive oxygen species, which selectively destroy the target tissue.
Photodynamic therapy
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The first requirement for PDT is delivery of either a systemic or a topical photosensitizing drug. Systemic photosensitizing molecules are large, lipophilic molecules that require intra venous administration to reach the target site. One of the major disadvantages of these systemic drugs is the prolonged period of phototoxicity. Examples include porfimer sodium and hematoporphyrin derivative. The benzoporphyrin derivative monoacid ring A (verteporfin) has a shorter period of photosensitivity (
