Hospital-Based Dermatopathology: An Illustrated Diagnostic Guide 3030358194, 9783030358198

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Hospital-Based Dermatopathology An Illustrated Diagnostic Guide Mai P. Hoang Maria Angelica Selim  Editors

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Hospital-Based Dermatopathology

Mai P. Hoang  •  Maria Angelica Selim Editors

Hospital-Based Dermatopathology An Illustrated Diagnostic Guide

Editors Mai P. Hoang Professor of Pathology Harvard Medical School Director of Dermatopathology Massachusetts General Hospital Boston, MA USA

Maria Angelica Selim Professor of Pathology and Dermatology Director, Dermatopathology Unit Duke University Medical Center Durham, NC USA

ISBN 978-3-030-35819-8    ISBN 978-3-030-35820-4 (eBook) https://doi.org/10.1007/978-3-030-35820-4 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To Hòa and Talya (MPH) To my family for always being there with unending support and wisdom and to my mentors and colleagues who are a source of encouragement and inspiration. I would also like to dedicate this book to you, the reader, committed to the care of patients. (MAS)

Introduction and Acknowledgments

The recent Burden of Skin Diseases Report has cited that common skin diseases represented a healthcare cost in the United States of approximately 46 billion dollars in 2013 [1], being the majority managed by non-­dermatologists. Therefore, it is not surprising that hospitalized patients with skin problems on non-dermatology inpatient services are a source of confusion for their hospitalists. Dermatologic consultations have a very large impact on the care of the hospitalized patients. In a 13-month retrospective chart review of 243 consecutive dermatology consultations by Connolly et al. [2], 77% were from the internal medicine, intensive care units, and hematology/oncology services. The common cutaneous conditions include infections (24%), drug eruption (22%), and inflammatory dermatoses (21%). These hospitalized patients often take multiple medications for comorbidities attributing to the frequent drug eruptions. Dermatology consultation resulted in altered or additional treatment in 72% of the cases [2]. When the authors analyzed the temporal relationship between the onset of the cutaneous disease and hospitalization, the skin condition was the reason for admission or coincided with admission in majority of cases [2]. Although common skin conditions account for a large majority of dermatologic consultations in a University Hospital setting, hospitalists continue to struggle with accurately recognizing and appropriately managing common skin problems. Very often, an urgent skin biopsy would be obtained by inpatient dermatology consult team, and its result will guide or change the clinical management in majority of cases. As inpatient dermatology consultation is promoted, the involvement of pathologists in turn will be increased. Awareness of these dermatologic conditions will result in accurate diagnosis, appropriate treatment, subsequently shortened hospitalization, and decreased cost. In this book, we aim to bridge this gap by providing a concise reference of the histologic and clinical findings of dermatologic conditions encountered in the inpatient setting. The text is divided into 20 chapters. Histopathologic images and corresponding clinical photographs facilitate clinical pathologic correlation of the conditions discussed in each chapter. Bulleted summary for quick easy-to-read reference and diagnostic pearls is provided for each of the discussed entities. Each chapter ends with several case studies in which clinical presentation, histologic interpretation, and work-up of these challenging scenarios are outlined. This book represents an international collaboration and a wealth of clinical expertise and years of experience of authors from Africa, Asia, Europe, vii

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Introduction and Acknowledgments

and North and South America. Many special thanks to all contributing authors for their exceptional efforts in making this book project possible. We greatly appreciate their generosity in sharing their fantastic cases and excellent pearls of wisdom. Many thanks to the Springer team, including Senior Editor Richard Hruska, this book’s Developmental Editor Kevin Wright, Production Editor Sheik Mohideen, Project Manager Inicko Bharathi and the entire production team for their patience and invaluable help. We sincerely hope that this book will serve as a useful go-to guide for the readers in rendering histologic diagnosis for hospital-based or inpatient skin biopsies. Ultimately, we hope that it will contribute to the excellent care of the patients. Boston, MA, USA Durham, NC, USA

Mai P. Hoang, MD Maria Angelica Selim, MD

References 1. Lim HW, Collins SAB, Resneck JS Jr., et al. A risk adjustment approach to estimating the burden of skin disease in the United States. J Am Acad Dermatol. 2018;78(1):129–40. 2. Connolly DM, Silverstein DI. Dermatology consultations in a tertiary care hospital: a retrospective study of 243 cases. Dermatol Online J. 2015;21(8):1.

Contents

1 The Inpatient Skin Biopsy from the Dermatologist’s Perspective������������������������������������������������������������   1 Christopher R. Shea 2 Spongiotic and Psoriasiform Dermatitis����������������������������������������   5 María Teresa Fernández-Figueras and Luis Puig 3 Lichenoid and Interface Dermatitis ����������������������������������������������  41 Maria Angelica Selim and Adela Rambi G. Cardones 4 Neutrophilic and Pustular Eruptions��������������������������������������������  93 Sigrid M. C. Möckel and Dieter Metze 5 Granulomatous Dermatitis and Others ���������������������������������������� 137 Toru Ogawa, Mirian Nacagami Sotto, and Mai P. Hoang 6 Mucinosis and Disorders of Collagen and Elastic Fibers������������ 199 Franco Rongioletti, Paolo Romanelli, and Caterina Ferreli 7 Vasculitis ������������������������������������������������������������������������������������������ 245 Mai P. Hoang and Joonsoo Park 8 Vasculopathy������������������������������������������������������������������������������������ 297 Joonsoo Park and Mai P. Hoang 9 Subcorneal and Intraepidermal Immunobullous Dermatoses���������������������������������������������������������������������������������������� 349 Monika Bowszyc-Dmochowska, Mai P. Hoang, and Marian Dmochowski 10 Subepidermal Bullous Dermatoses������������������������������������������������ 399 Mirian Nacagami Sotto and Mai P. Hoang 11 Autoimmune Connective Tissue Diseases�������������������������������������� 451 Julia S. Lehman and Alina G. Bridges 12 Panniculitis �������������������������������������������������������������������������������������� 499 Mark C. Mochel, Mariangela E. A. Marques, and Mai P. Hoang 13 Infection: Bacteria, Spirochetes, Protozoa, and Infestation�������� 555 Mai P. Hoang, Toru Ogawa, and Mariangela E. A. Marques

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14 Fungal, Viral, and Rickettsial Infections �������������������������������������� 625 Francisco G. Bravo 15 Drug Reactions �������������������������������������������������������������������������������� 695 Maxwell A. Fung, Danielle M. Tartar, and Alain Brassard 16 Adverse Cutaneous Reactions to Chemotherapeutic Agents������������������������������������������������������������������������������������������������ 757 Mai P. Hoang and Daniela Kroshinsky 17 Transplant-Related and Metastatic Malignancies������������������������ 797 Rami N. Al-Rohil and Maria Angelica Selim 18 Human Immunodeficiency Virus (HIV)-Associated Dermatoses and Malignancy���������������������������������������������������������� 823 Wayne Grayson 19 Inpatient Pediatric Dermatopathology������������������������������������������ 885 Rami N. Al-Rohil and Maria Angelica Selim 20 Alopecia�������������������������������������������������������������������������������������������� 919 Neusa Yuriko Sakai Valente and Mai P. Hoang Index���������������������������������������������������������������������������������������������������������� 957

Contents

Contributors

Rami  N.  Al-Rohil, MBBS Assistant Professor of Pathology, Duke University Medical Center, Department of Pathology and Dermatology, Durham, NC, USA Monika  Bowszyc-Dmochowska, MD, PhD Assistant Professor, Head of Cutaneous Histopathology and Immunopathology Section, Department of Dermatology, Poznan University of Medical Sciences, Poznan, Poland Alain  Brassard, MD Professor of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA Francisco G. Bravo, MD  Associate Professor of Pathology and Dermatology, Facultad de Medicina Alberto Hurtado, Universidad Peruana Cayetano Heredia, Lima, Peru Alina G. Bridges, DO  Associate Professor of Dermatology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA Adela  Rambi  G.  Cardones, MD, MHSc Associate Professor of Dermatology, Duke University Medical Center, Durham, NC, USA Marian  Dmochowski, MD, PhD Professor of Dermatology, Head of Autoimmune Blistering Dermatoses Section, Department of Dermatology, Poznan University of Medical Sciences, Poznan, Poland María  Teresa  Fernández-Figueras, MD Assistant Professor, Universitat International de Catalunua, Head of Surgical Pathology, Hospital Universitari General de Catalunya, Barcelona, Spain Caterina Ferreli, MD  Associate Professor of Dermatology, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Sardinia, Italy Maxwell A. Fung, MD  Professor of Clinical Dermatology and Pathology, Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA Wayne  Grayson, MB, ChB, PhD, FCPath (SA) Honorary Professor, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa

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Mai  P.  Hoang, MD Professor of Pathology, Harvard Medical School, Director of Dermatopathology Services, Massachusetts General Hospital, Boston, MA, USA Daniela  Kroshinsky, MD, MPH Associate Professor of Dermatology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA Julia S. Lehman, MD  Professor of Dermatology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA Mariangela E. A. Marques, MD  Professor of Pathology, Medical School of São Paulo State University, Botucatu, Brazil Dieter Metze, MD  Professor of Dermatology, University Hospital Münster, Münster, Germany Mark  C.  Mochel, MD Assistant Professor of Pathology, Director of Dermatopathology, Virginia Commonwealth University Health System, Richmond, VA, USA Sigrid  M.  C.  Möckel, MD  Director of Dermatopathology, Department of Dermatology, Technical University of Munich, School of Medicine, Munich, Germany Toru Ogawa, MD, PhD  Visiting Dermatologist, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA Joonsoo  Park, MD, PhD Associate Professor and Chair, Department of Dermatology, School of Medicine and the Catholic University of Daegu, Daegu, South Korea Paolo  Romanelli, MD  Professor of Clinical Dermatology, Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA Franco  Rongioletti, MD Professor and Chairman, Unit of Dermatology, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Sardinia, Italy Luis  Puig, MD Professor and Director, Department of Dermatology, Hospital Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain Maria  Angelica  Selim, MD Professor of Pathology and Dermatology, Director, Dermatopathology Unit, Duke University Medical Center, Durham, NC, USA Christopher R. Shea, MD  Eugene J. van Scott Professor in Dermatology, University of Chicago, Chicago, IL, USA Mirian Nacagami Sotto, MD, PhD  Professor of Dermatology, Faculty of Medicine of the University of São Paulo, São Paulo, SP, Brazil Danielle  M.  Tartar, MD, PhD Assistant Professor of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA Neusa Yuriko Sakai Valente, MD, PhD  Professor of Dermatology, Faculty of Medicine of the University of Sao Paulo, São Paulo, SP, Brazil

Contributors

1

The Inpatient Skin Biopsy from the Dermatologist’s Perspective Christopher R. Shea

The dermatopathologic care of hospitalized inpatients poses unique challenges. Obviously, hospitalized patients are on average sicker than those being managed in ambulatory settings. This fact has several implications. First, the skin conditions of inpatients often have a more serious presentation and outcome than those occurring in outpatients seen in the course of routine practice. This is especially true when the dermatologic condition is itself the reason for hospital admission. While patients nowadays are only rarely admitted to a hospital inpatient service specifically in order to manage their skin diseases, this sometimes remains the most appropriate course, in order to work up and treat cases of erythroderma, control serious cutaneous infections, and provide intensive, skilled nursing care using soaks, wraps, hydrotherapy, etc. Dermatologists caring for patients in the inpatient setting therefore often confront more extreme presentations of skin diseases, and the resulting biopsy specimens may likewise exhibit striking features, for example, with regard to the patterns of inflammatory cell infiltrates. However, while the relative acuity and morbidity of skin disease are often greater in the hospital setting, it is also paradoxically the case that dermatologists and dermatopathologists caring for C. R. Shea (*) Section of Dermatology, University of Chicago, Chicago, IL, USA e-mail: [email protected]

inpatients may be witnesses to the earliest stages of development of skin lesions. Hospitalized patients are under close and continuous observation, affording an excellent opportunity for clinicians to note and to act upon newly arising skin complaints and changes in the cutaneous examination, and specifically to obtain an early biopsy. In such circumstances, both the clinical and the microscopic findings may be relatively subtle. The inpatient setting, particularly in academic medical centers, provides an incubator and a laboratory for unique cutaneous side effects from novel therapeutics. For example, the recent dermatopathologic literature is replete with reports of new adverse reactions to chemotherapy, biologicals, checkpoint inhibitors, etc. Many of these new dermatopathologic entities were first encountered when the novel agents were employed in hospitalized patients. Dermatopathologists working at the vanguard of modern therapeutics have the opportunity to advance the field profoundly. Given the relative urgency of dermatopathologic inpatient practice, there is a corresponding increase in demand for timely diagnosis. This time pressure is largely driven by the need for actionable information for immediate management decisions (regarding benign versus malignant diagnoses, adverse reactions to medications, ascertainment of serious infections, etc.). As a secondary consideration, sometimes clinicians exert considerable pressure to discharge their patients from the hospital as soon as this can be

© Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_1

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safely and appropriately accomplished, as the inpatient (or impatient) health-care team eagerly awaits a welcome diagnostic result that will provide a “green light” for discharge. There is no single best approach for dealing with such time pressure, and the solution may depend largely on institutional culture and standards. Some institutions have established a “hot seat” method, whereby well-trained house staff members provide early, preliminary communication of crucial results, with the understanding that these results are subject to subsequent review by the attending of record before they are to be considered final. In other settings, attending pathologists themselves may issue preliminary diagnoses. Preliminary reporting has clear advantages, but there is always the risk that the final report will be further delayed as the immediate time pressure is relieved or that final results will become displaced in the minds of clinicians, as the busy hospitalized days unroll in succession. If the dermatopathologist chooses to issue a preliminary diagnosis, it is recommended that this be formalized in a written report and that all preliminary diagnoses be captured in a quality improvement database for analysis. Another consequence of the time pressure inherent to inpatient dermatopathology is the request for expedited histologic processing of certain crucial specimens. While this is sometimes appropriate, institutional resources and procedures will govern whether it can even be undertaken. In general, performing nonstandard technical maneuvers to achieve same-day permanent sections is fraught with problems and should not be done lightly. Short-cycle processing can sometimes damage specimens unless performed with great care; only certain small specimens meeting clear medical necessity criteria are suitable. Clinicians requesting such services are advised to speak personally with the dermatopathologist to discuss whether rush processing is desirable or even feasible. Frozen section preparation (outside the usual surgical operative setting) may provide a better alternative to short-cycle processing. Frozen sections for rapid diagnosis should be considered only if a 1-day delay required to prepare perma-

C. R. Shea

nent sections will make a critical difference in management and if the particular clinical problem is amenable to diagnosis on frozen tissue (e.g., frozen sectioning is generally inappropriate for diagnosing melanoma). Frozen sectioning can be employed effectively for certain nonneoplastic conditions. To distinguish toxic epidermal necrolysis from staphylococcal scalded skin syndrome, the jelly roll method can be used as follows: snip off exfoliating/eroding epidermis, roll up like a rug on the stick of a cotton swab, cut and orient across the roll, and freeze for immediate sectioning and viewing. Also, in urgent circumstances, frozen sections can be subjected to special stains for bacteria and fungi. The multidisciplinary teams providing care to hospitalized patients are generally larger and more diverse than those working in the outpatient setting. While the diversity of such teams is a positive strength, dermatopathologists need to remember that they may be communicating through their reports with clinicians who may have little understanding of specialized dermatopathologic vocabulary or even of basic dermatology. For that reason, dermatopathologists must avoid opaque jargon and should freely employ explanatory comments when reporting inpatient skin specimens, in order to provide the clear perspective that will inform crucial management decisions. Some members of the inpatient team may not always understand the limitations of dermatopathologic diagnosis. This can lead to performance of skin biopsies in cases where the dermatopathologic diagnosis is unlikely to be definitive. An example of this is the performance of biopsy  for  suspected graft-versus-host disease (GVHD); while biopsy findings of GVHD are characteristic they are not necessarily specific, and the diagnosis of GVHD relies on correlation with clinical findings including extracutaneous manifestations. The recent wide adoption of the electronic health record has greatly benefited the practice of inpatient dermatopathology. Dermatopathologists now generally have access to a complete history, including notes from clinical encounters and procedures, radiographic images, and, most cru-

1  The Inpatient Skin Biopsy from the Dermatologist’s Perspective

cially, clinical photographs. This permits to the maximal extent a thorough clinical-pathologic correlation, the foundation of accurate diagnosis. A developing trend is the rise of dermatologic hospitalists, that is, clinical dermatologists focusing on the management of skin concerns of inpatients. Some such practitioners have undergone expanded clinical training (e.g., in internal medicine or pediatrics in addition to dermatol-

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ogy) and are ideally positioned to act as a liaison providing a dermatologic perspective to the inpatient team. Even more than for the average dermatologist occupied with outpatient cases, the dermatologic hospitalist can be most successful and effective when working in close partnership with the dermatopathologist, in order to arrive at timely, accurate management decisions regarding patients hospitalized with skin complaints.

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Spongiotic and Psoriasiform Dermatitis María Teresa Fernández-Figueras and Luis Puig

Contents Introduction

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Spongiotic Dermatitis Eczematous Dermatitis Prognosis or Clinical Course Histopathology Differential Diagnosis Pityriasis Rosea Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 7  8  10  10  13  15  15  15  15  15

Psoriasiform Dermatitis Psoriasis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 16  16  16  17  17  22

M. T. Fernández-Figueras (*) Universitat International de Catalunua, Department of Surgical Pathology, Hospital Universitari General de Catalunya, Barcelona, Spain e-mail: [email protected] L. Puig Department of Dermatology, Hospital Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain e-mail: [email protected] © Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_2

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6  ityriasis Rubra Pilaris P Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Seborrhoeic Dermatitis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Pityriasis Lichenoides Chronica Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

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Case Studies Case 1 Clinical History Microscopical Description Diagnosis Discussion Case 2 Clinical History Microscopical Description Diagnosis Discussion Case 3 Clinical History Microscopical Description Diagnosis Discussion

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References

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Introduction Spongiotic and psoriasiform patterns are probably those most commonly found among all inflammatory cutaneous diseases [1]. Both can appear in a wide range of dermatologic entities, either alone or superimposed to other histopathologic findings. The diagnosis of this group of diseases is usually established on clinical grounds, and only some challenging cases require biopsy. Not rarely those are cases that fail to present all typical microscopical features. Furthermore, there is a considerable overlap in their histopathological presentation being one of the most difficult diagnoses in dermatopathol-

ogy. However, there are subtle features that can contribute to establish a specific diagnosis or, at least, rule out some possibilities. Correlation with the clinical information (size, number, location, time of evolution, and aspect of the lesions in general and also in the specific biopsy site) is crucial to achieve full benefit of the histopathological exam [1, 2]. Spongiosis is the hallmark of a group of diseases included under the term eczematous dermatitis; it is considered a minor histopathological feature in many other entities, and it can be a superimposed event in practically all dermatological pathologies [1, 2]. Psoriasiform dermatitis includes psoriasis and other diseases that cause similar epidermal

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changes, often with parakeratosis and intracorneal neutrophilic pustules [3].

Spongiotic Dermatitis The term spongiotic dermatitis encompasses numerous dermatological entities very common in the daily practice. The presence of spongiosis as a main pattern characterizes eczematous lesions like nummular dermatitis, atopic dermatitis, allergic and irritant contact dermatitis, dyshidrotic dermatitis, xerotic eczema, id reaction, photoallergic reaction, lichen simplex chronicus, and prurigo nodularis. Despite the differences in pathogenesis and clinical presentation, there is a considerable microscopical overlap in the histopathology of these diseases [1, 2]. Spongiosis is defined by the accumulation of edema between epidermal keratinocytes. Desmosomes are stretched and become noticeable as thin intercellular bridges (Fig.  2.1). An increase in the extracellular amount of plasma collapses the keratinocytes, and some desmosomes are broken creating a reticular degeneration of the epidermis. Finally, the complete rupture of the desmosomes that served as cell unions gives rise to intraepidermal vesicles filled with plasma (Fig.  2.1). There is a tendency to eliminate plasma to the epidermal surface forming small aggregates within the stratum corneum

Fig. 2.1  Acute palmar eczema showing spongiosis with vesiculation and hyperkeratosis with absent granular. There are some lymphocytes around the superficial vascular plexus and exocytosis focused in the areas of spongiosis

Fig. 2.2  Subacute eczema combining features of chronicity and activity. On one hand, there is a prominent epidermal hyperplasia and vertical bundles of collagen within the papillary dermis. On the other hand, there is vesiculation, and collections of plasma are visible within the parakeratotic stratum corneum

that is usually parakeratotic, while the granular layer is usually absent in these areas (Fig.  2.2). The inflammatory infiltrate is formed mainly by lymphocytes that typically show exocytosis to the epidermis. The intensity of the lymphocytic infiltrate can vary widely from case to case and eosinophils are also present when there is a background of hypersensitivity. The combination of spongiotic and psoriasiform patterns characterizes seborrheic dermatitis and pityriasis rosea, with the addition of lichenoid features in the latter [4–6]. Many other dermatological diseases may eventually develop spongiosis as a minor or nonconstant alteration. Drug eruptions, Gianotti-­ Crosti syndrome [7], or erythema annulare centrifugum [8] can contain noticeable spongiotic changes that might also be prominent in viral or mycotic infections as well as in arthropod bites and scabies [9]. In miliaria rubra and miliaria profunda spongiotic features are limited to the ducts and sweat glands and the portion of epidermis on their surface [10]. Meyerson nevus is defined by the presence of eczema in the epidermis overlying a melanocytic nevus and by extension the development of spongiotic changes over any tumor is known a Meyerson phenomenon [11]. Finally, some lymphoid neoplasia such as mycosis fungoides [12] or hydroa vacciniforme-­like lymphoproliferative disorders [13] can d­isplay

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prominent spongiotic changes. Epidermal spongiosis can also arise in the setting of mostly neutrophilic or eosinophilic dermatosis, but these entities will be discussed in their corresponding chapters [12, 13].

Eczematous Dermatitis The eczematous dermatitides encompass a wide variety of diseases characterized by the development of acute, subacute, and chronic lesions, which appear upon exposure to a chemical irritant (Fig. 2.3) or phototoxic agent, a contact allergen following sensitization (Fig. 2.4) or in patients with a genetic predisposition and alterations in the immune response to environmental factors (atopic dermatitis) (Fig. 2.5). The acute phase is characterized by pruritus, erythema, edema, and vesicles confined to the area of direct exposure or according a characteristic topographic pattern (Fig.  2.6). Recurrent exposure to the irritant/allergen or repeated development of lesions and rubbing or scratching will result in chronic disease, characterized by lichenified and erythematous plaques (Fig. 2.7) with variable hyperkeratosis, scaling, crusting, and fissuring. Irritant and allergic contact dermatitis are two closely related forms of reaction to the direct or indirect contact with diverse substances [14]. Photoallergic dermatitis is also a form of reaction to exogenous chemicals that become allergens

Fig. 2.4  Allergic contact dermatitis on the ankle following exposure to nickel-containing parts of a shoe

Fig. 2.5  Involvement of extensor areas and lichenification secondary to rubbing are frequent in adult patients with atopic dermatitis

Fig. 2.3  Irritant contact dermatitis on the dorsa of the hands and the forearms, characterized by erythematous plaques with desquamation and fissuring

following exposure to ultraviolet light; it may extend to nonexposed skin, and it is less common than phototoxic dermatitis, which occurs in the absence or prior sensitization. Lesions of irritant contact dermatitis and phototoxic reactions are generally well demarcated to the areas of exposure, whereas allergic contact dermatitis

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Fig. 2.6  Acute, severe photoallergic contact dermatitis following topical application of ketoprofen gel and sun exposure

Fig. 2.8  Recurrent blisters on the lateral and dorsal aspects of the fingers characterize dyshidrotic eczema

Fig. 2.7  Repeated rubbing and scratching leads to formation of lichenified plaques in lichen simplex chronicus

can extend beyond the area of contact and may become generalized. Id reactions and autosensitization dermatitis are the result of an aberrant immune response against autologous skin antigens released by a localized cutaneous inflammation [1, 15, 16]. Dyshidrotic dermatitis (Fig. 2.8), also known as pompholyx, is a form of hand and foot eczema with multifactorial etiology [17]. Atopic dermatitis follows a characteristic topographic distribution according to the age of the patient (face and extensor surfaces in infants and young children, lichenification in flexural areas in older children and adults) and the predominant (acute, subacute, or chronic) morphology of the lesions. Asteatotic eczema, also known as xerotic eczema or eczema craquelé (Fig. 2.9), is associ-

Fig. 2.9  Asteatotic eczema, or eczema craquelé, occurs on dry, itchy, and eventually cracked skin

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Fig. 2.11  Localized rubbing and scratching in susceptible patients determine the typical appearance of prurigo nodularis

to the irritant or contact allergen can be permanently avoided, even though chronic lesions can become persistent and refractory to treatment in some cases. Atopic dermatitis is very common in infants and children but eventually improves in most cases, even though it can become difficult Fig. 2.10  Nummular eczema is characterized by coin-­ to manage, even despite systemic treatment, in shaped lesions, which can be isolated or multiple and are those cases that persist or develop in later life. frequently superinfected

ated with a disruption of the epidermal barrier function and reduction in the lipid content of the corneal layer [17, 18]. Nummular eczema (Fig. 2.10) is characterized by papules and papulovesicles that coalesce to form coin-shaped plaques, 1 to 5  cm in diameter, with oozing, crusting, and scaling, generally located on the dry skin of the limbs in elderly people; it can also be a feature of atopic dermatitis in adult patients. Lichen simplex chronicus, also known as neurodermatitis, results from chronic rubbing or scratching of eczematous disorders such as atopic or contact dermatitis, though some cases are idiopathic. Lichen simplex chronicus can acquire a papulonodular appearance known as prurigo nodularis (Fig. 2.11).

Prognosis or Clinical Course In the exogenous variants of eczematous dermatitis, the prognosis is favorable if exposure

Histopathology The spongiotic pattern is the hallmark of this group of diseases also known as “dermatitides,” which are extremely difficult to differentiate without clinicopathological correlation [1, 2, 9, 19]. Their microscopical appearance depends more on the chronology than on the specific process. Traditionally the evolution of these lesions is divided into three stages: acute, subacute, and chronic [1, 20]. The predominant features of acute lesions are a conspicuous intercellular edema with ­vesiculation and an abundant lymphocytic infiltrate in the superficial dermis with exocytosis into the epidermis. Intraepidermal serum can accumulate in the corneal layer, eventually forming a crust. Epidermal hyperplasia and parakeratosis require some time for their establishment, being usually not well-developed at this stage. In subacute lesions, the epidermis has time enough to develop acanthosis with parakeratotic

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hyperkeratosis. A brisk lymphocytic infiltrate is still present, but vesiculation is less prominent. Conversely, in chronic lesions, spongiosis is scarce and often limited to a slight widening of the intercellular spaces, epidermal hyperplasia is more intense, and there is a thick layer of hyperkeratosis with scant parakeratosis [2, 19, 21] (Fig. 2.12). In addition, some subtle features may suggest a specific diagnosis among all types of eczema:

Fig. 2.12  Chronic scrotal eczema with features of prurigo nodularis exhibiting pseudoepitheliomatous hyperplasia and scant spongiosis. The corneal layer is thick with compact orthokeratosis. There are many dermal melanophages because of chronic scratching

a

Nummular dermatitis: It is the prototype of spongiotic lesions and displays all typical features according to the chronological stage [21]. Only in case of superinfection, the morphology is altered by the presence of neutrophilic infiltrate in the superficial keratinocytes and the stratum corneum (Fig. 2.13). This complication tends to be more frequent in patients with atopic dermatitis. Atopic dermatitis: Adults with atopic dermatitis tend to display significant changes secondary to scratching. These lesions present epidermal acanthosis with hyperkeratosis showing a variable amount of parakeratosis overlying a prominent granular layer that can be indistinguishable from lichen simplex chronicus originated from any other process except for the more common presence of eosinophils (Fig.  2.14). Areas of erosion are not rare in cases with intense traumatization. Conversely, in pediatric cases, biopsy specimens show more often exudative changes that can be misinterpreted as seborrheic dermatitis [22]. Dermal eosinophils tend to be more frequent in the atopic infiltrates than in other eczema variants (Fig.  2.15), and subcorneal abscesses contain CD11c-positive myeloid cells instead of S100-positive Langerhans cells [2, 23]. Several studies have suggested that the skin in patients with atopic dermatitis is colonized by Staphylococcus aureus more frequently than in

b

Fig. 2.13 (a and b). Superinfected long-standing lesion of atopic dermatitis with diffuse spongiosis and sclerosis within the papillary dermis. There is a thick granular layer

and parakeratotic hyperkeratosis containing microabscesses of neutrophils associated with numerous cocci

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Fig. 2.14  Atopic dermatitis from an adult with irregular epidermal hyperplasia and slight spongiosis. The moderate lymphocytic infiltrate present throughout the superficial dermis contains many eosinophils

Fig. 2.16  Subcorneal collections of Langerhans cells are abundant in contact dermatitis. They are typically located in a round empty space of the superficial dermis and have a narrow superficial orifice adopting sometimes a vaselike shape. The grooved nuclear silhouette and the absence of hyperchromasia contribute to the distinction from Pautrier microabscesses characteristic of mycosis fungoides

Fig. 2.15  Perivascular eosinophils are more frequent in atopic dermatitis than in other types of eczema

controls, explaining the increased risk of infection that would favor the diagnosis of atopic dermatitis and nummular eczema versus other eczema variants [24, 25]. Irritant and allergic contact dermatitis: Both can be histologically indistinguishably [26] showing non-specific eczematous features. However, it is common to find abundant Langerhans cells within the epidermis, forming often small subcorneal abscesses with a vaselike shape [26, 27] (Fig.  2.16). Langerhans cells are also noticeable throughout the dermis in the cases of irritant contact dermatitis [2]. Hyperkeratosis is variable in allergic contact dermatitis but more frequent that in irritant contact dermatitis. In the acute phase of the later,

Fig. 2.17  Superficial necrosis in a case of acute irritant contact dermatitis

necrosis of superficial keratinocytes secondary to the direct chemical damage can be present [2, 14, 26] (Fig. 2.17). Both types can contain dermal neutrophils [2, 28] that seldom lead to the formation of pustules [29]. Lymphomatoid contact dermatitis mimics clinically and histopath-

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ologically a cutaneous B- or T-cell lymphoma. These lesions contain a dense lymphocytic infiltrate with cytological pleomorphism or hyperchromasia [30–32]. Photoallergic dermatitis: The histopathologic appearance is similar to that of other eczematous dermatitides. The absence of superficial necrotic keratinocytes (“sunburn cells”) allows differentiation from phototoxic dermatitis [33, 34]. Dyshidrotic dermatitis: The acute stage is characterized by intense spongiosis with development of large intraepidermal vesicles [1]. In addition, dyskeratotic keratinocytes, papillary dermal edema, and dilated capillaries are frequent [35], and it is not rare to find bacterial superinfection that can prevent the distinction from palmoplantar pustulosis [35]. Stasis dermatitis: Epidermal spongiosis and hyperkeratosis are usually mild, often indistinguishable from contact eczema [1], furthermore because of the increased population of Langerhans cells in the epidermis [36]. However, the presence of features of chronic vascular insufficiency such as numerous thick-walled small- or medium-sized vessels contributes to the diagnosis [37]. Asteatotic eczema: It can further complicate other eczemas such as stasis dermatitis, thickening their corneal layer [17, 18]. ID reaction (autoeczematization or autosensitization dermatitis): It appears under the microscope with non-specific spongiotic features. Lichen simplex chronicus: It is characterized by epidermal hyperplasia with minimal spongiosis, a thick granular layer and hyperkeratosis with variable amounts of parakeratosis. The epithelium of hair follicles also tends to be hyperplastic. The dermis shows dense collagenization with vertical bundles of collagen in the papillary dermis and stellated or multinucleated fibroblasts are present as a result of chronic rubbing and a variable degrees of angiogenesis [38] (Fig. 2.18). Prurigo nodularis: The most important histopathological feature that differentiates prurigo nodularis from lichen simplex chronicus is the intensity of the epidermal hyperplasia, which can raise the differential diagnosis with squamous cell carcinoma [1, 2, 39, 40].

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Fig. 2.18  Fibrosis, abundant thick-walled vessels, and multinucleated fibroblasts within the dermis of a lichen simplex chronicus

Differential Diagnosis Before establishing the histopathological diagnosis, it is important to keep in mind that there are great similarities among all forms of eczema and that spongiosis can appear superimposed on almost any dermatological disease. Furthermore, in many cases clinical information plays a pivotal role in achieving the correct diagnosis. Fungal infections can closely simulate different types of eczema, and it is advisable to perform histochemical stains in order to rule out this possibility [41], especially when scattered neutrophils are present within the epidermis or the stratum corneum. Neutrophilic infiltrates can be prominent in pustular contact dermatitis [29] and in superinfected eczemas [35, 42]. Superinfected dyshidrosis, for instance, can closely simulate palmoplantar pustulosis. An irregular epidermal hyperplasia with thin rete ridges and diffuse spongiosis with vesicle formation is in favor of dyshidrosis. Conversely, the presence of a psoriasiform epidermis with confluent parakeratosis and tortuous congestive capil-

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hyperkeratosis, scaling, crusting, and fissuring.

Fig. 2.19  Mycosis fungoides with spongiotic and psoriasiform features. The epidermis has a psoriasiform silhouette, and there is diffuse spongiosis and parakeratosis containing many neutrophils. All these deceptive features can lead to a wrong diagnosis, especially in patients with long-lasting lesions that have been already labeled as psoriasis or chronic eczema

laries within the papillary dermis with erythrocyte extravasation militate in favor of psoriasis [35]. Mycosis fungoides can also show features that are difficult to differentiate from different types of eczema. However, the density of the lymphoid infiltrate is disproportionately higher than the intensity of spongiosis (Fig. 2.19), and they are not spatially associated. However, some cases of mycosis fungoides can present with intense spongiosis [12, 43] or intraepidermal mucin deposition simulating eczema [44]. A clue for the diagnosis of lymphomatoid contact dermatitis is the presence of subcorneal Langerhans cells abscesses. Patch testing provides diagnostic confirmation [30, 45]. Nonetheless, clinicopathological correlation is essential, and immunohistochemical and molecular biology techniques can contribute to confirm the diagnosis.

Histologic Features • Epidermal spongiosis with intercellular plasma deposition and vesiculation • Epidermal hyperplasia with parakeratosis that can contain plasma collections • Predominantly perivascular lymphoid infiltrate with exocytosis to the epidermis • Histological features change over the time from spongiotic to hyperplastic and hyperkeratotic Differential Diagnosis • Fungal infections should be considered, especially when neutrophils are present within the stratum corneum. Histochemical techniques should be performed in case of any doubt. • Mycosis fungoides should be considered when there is disproportionate dense lymphoid infiltrate or when other atypical features are present. • Psoriasiform dermatitis can show eczematous changes that simulate eczema superinfection.

Takeaway Essentials

Summary

Clinically Relevant Pearls • Id reaction often secondary to infection or severe localized contact dermatitis, but can occur following BCG therapy [46], cosmetic tattooing [47], or radiotherapy [48]

Clinical Presentation • Acute phase characterized by pruritus, erythema, edema, and vesicles confined to the area of direct exposure. • Repeated exposure will result in lichenified erythematous plaques with variable

Pathology Interpretation Pearls • Lymphomatoid contact dermatitis can closely simulate mycosis fungoides [30]. Intraepidermal abscesses of Langerhans cells can be misinterpreted as Pautrier microabscesses.

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• Long-standing lesions of lichen simplex chronicus can develop malignant transformation [49]. • The histopathological features of stasis dermatitis can be very subtle. Special stains may reveal interstitial iron deposition [50] or an increased amount of mucin [51]. • Some cases of stasis dermatitis are solitary and may simulate clinically a neoplastic process [52].

Pityriasis Rosea Pityriasis rosea is a common acute papulosquamous eruption normally lasting 4 to 10  weeks and probably due to reactivation of human herpes virus (HHV)-7 and sometimes HHV-6.

Clinical Presentation Most often begins as a single 2- to 4-cm-thin oval plaque with a fine collarette of scale inside the periphery of the plaque (“herald patch”). Similar-­ appearing smaller lesions appear several days to weeks later (Fig. 2.20), typically distribute along the lines of cleavage on the trunk (“Christmas tree” pattern). There are atypical (localized, unilateral, vesicular, purpuric, etc.) variants, and many drugs have been reported to cause pityriasis rosea-like eruptions.

Fig. 2.20  Large lesions in pityriasis rosea have a characteristic oval morphology with branny peripheral desquamation

Pityriasis rosea is self-limited and requires no treatment, other than to alleviate symptoms.

tered dyskeratotic cells [53]. The presence of numerous Langerhans cells, sometimes forming subcorneal microabscesses, can be a clue for the diagnosis [54]. Parakeratosis is often discontinuous in a “staccato” pattern [53, 55]. The lymphocytic infiltrate is often mild, surrounding capillaries with edematous endothelium that present erythrocyte extravasation [53] (Fig.  2.21). Exocytosis of lymphocytes and erythrocytes is common, and eosinophils are present in some lesions, especially in drugrelated pityriasis rosea-like eruptions and in old lesions [4, 5, 56, 57].

Histopathology

Differential Diagnosis

The epidermis shows slight acanthosis, sometimes with a vaguely serrated pattern. Spongiosis is often mild and associated with a slight vacuolar change in the basal keratinocytes and scat-

Syphilis is the main differential diagnosis of pityriasis rosea from both clinical and histological points of view. Typical cases of syphilis contain numerous plasma cells, some neutro-

Prognosis or Clinical Course

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Fig. 2.21  Pityriasis rosea with multifocal hyperkeratosis, spongiosis, and small corneal collections of plasma and slight vacuolization at the basal layer. There is a mild lymphocytic infiltrate within the dermis and the dermoepidermal junction and some endothelial edema

phils, and a granulomatous background; but as a great imitator, it is, in some cases of syphilis, only the immunohistochemical demonstration of Treponema pallidum that can allow diagnosis [58]. Nonetheless, some cases have been described with false-negative results [59].

Fig. 2.22  Extensive psoriasis vulgaris in a young patient

Psoriasiform Dermatitis Psoriasis Psoriasis is a common chronic inflammatory skin disease with a strong genetic basis, characterized by keratinocyte hyperproliferation and immune activation of adaptive and innate immune cell types and a cytokine imbalance with activation of the IL-23/IL-17 pathway. Psoriasis is associated with psoriatic arthritis in up to 30% of cases.

Fig. 2.23  Inverse psoriasis on the inframammary area typically has well-defined borders, but can be complicated and triggered by intertrigo; candidiasis can be suspected in exudative lesions with peripheral pustules

Clinical Presentation Psoriasis vulgaris or chronic plaque psoriasis, the commonest variant of the disease, is characterized by erythematous and desquamative papules and plaques that tend to be symmetrical (Fig.  2.22) and localized in areas subject to friction. Nail involvement is very frequent, especially in the presence of psoriatic arthritis. Flexural (inverse)

(Fig.  2.23), scalp, genital, and palmoplantar psoriasis (Fig.  2.24) are topographical variants with peculiar presentations, and involvement of the oral and genital mucosa is not uncommon. Sebopsoriasis is a common presentation of psoriasis in seborrheic areas. Morphological variants of psoriasis include guttate (eruptive) psoriasis, with generalized small papules appearing after

2  Spongiotic and Psoriasiform Dermatitis

Fig. 2.24  The differential diagnosis of palmar psoriasis is complex, but the presence of typical nail and paronychial lesions of psoriasis can be helpful

a streptococcal infection (Fig.  2.25), circinate psoriasis, follicular psoriasis, erythrodermic psoriasis, and pustular psoriasis; the latter can be localized (Fig. 2.26) or generalized and may correspond to a monogenic autoinflammatory disease.

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Fig. 2.25  Guttate psoriasis is characterized by multiple eruptive papules appearing several days after a streptococcal infection

Prognosis or Clinical Course Guttate psoriasis is usually self-limited, but patients may eventually develop chronic plaque psoriasis. Psoriasis vulgaris is usually a lifelong disease but can be characterized by an undulating course with remissions of variable duration. Erythrodermic and generalized pustular psoriasis tend to have poorer prognosis, with severe and persistent disease.

Histopathology The microscopical hallmark is the epidermal silhouette [3] with regular acanthosis and thinning of the suprapapillary space. Rete ridges

Fig. 2.26  Palmoplantar pustulosis can be associated with psoriasis elsewhere, but in the absence of hyperkeratotic lesions on the palms and/or soles is generally considered an independent entity

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Fig. 2.27  Psoriasis with the characteristic epidermal silhouette with regular acanthosis and thinning of the suprapapillary plates. The width of rete ridges tends to be narrow at the upper papillary level. There is parakeratotic hyperkeratosis with microabscesses of neutrophils

Fig. 2.28  Layers of parakeratosis containing abundant neutrophils indicate flares of the disease. The clue “birds among fish” can be applied to this image with linear nuclear remnants of parakeratosis resembling a bank of fish and neutrophils resembling flying birds

exhibit a drop-like shape, narrow at the upper papillary level and wider close to the bottom. Fusion between adjacent rete ridges frequently leaves small “islands” of papillary dermis in the midportion (Fig.  2.27). Hyperkeratosis is also present and contains layers of basket wave or compact orthokeratotic cornification alternating with others of parakeratosis and absent granular layer (Fig. 2.28), corresponding to outbreaks of inflammation. There are intracorneal and subcorneal neutrophilic pustules which size depends fundamentally on the psoriasis variant, ranging from scattered neutrophils in erythrodermic

M. T. Fernández-Figueras and L. Puig

Fig. 2.29  Large triangular-shaped collection of neutrophils in pustular palmoplantar psoriasis. At both edges it is possible to recognize the presence of spongiform pustules

Fig. 2.30  Congestive dilated capillaries with perivascular hemorrhage in the papillary dermis of psoriasis. Superficial keratinocytes exhibit a pale cytoplasmic staining

psoriasis to large abscesses in pustular forms. In the corneal layer, neutrophils are more frequent in the areas of parakeratosis, indicating activity of the disease (Fig. 2.28), whereas those located in the upper portion of the epidermis tend to be intermixed with keratinocytes forming discrete aggregates (spongiform pustules) that can coalesce occupying large areas in the pustular forms (Fig. 2.29). The papillary dermis contains numerous dilated capillaries, often congestive with occasional perivascular hemorrhage that last until complete resolution [3, 60, 61] (Fig. 2.30). In addition, there is a mild superficial perivascular lymphocytic infiltrate that can be accompa-

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Fig. 2.32  Lichenoid changes can be occasionally found in psoriasis like in this case with conspicuous vacuolization of basal keratinocytes and a band of lymphocytic infiltrate involving the dermoepidermal layer

Fig. 2.31 Psoriasis with superimposed eczematous changes with stratum corneum containing superficial plasma-filled vesicles and a lymphocytic infiltrate abnormally dense for this disease

nied by occasional neutrophils, eosinophils, mast cells, and plasma cells [61–63]. Slight spongiosis can be observed, mainly in guttate and palmoplantar psoriasis [3]; however, spongiotic vesicles are rarely formed unless there is superimposed eczema (Fig. 2.31). Scattered lymphocytes within the epidermis, particularly above papillae, correlate with the activity of the disease, corresponding to the phenomenon of “squirting papillae.” Pallor of superficial keratinocytes, in most cases barely noticeable, is another typical feature of psoriasis (Fig. 2.30). Further changes like lichenoid changes (Fig. 2.32) or eosinophilic spongiosis have occasionally been described [61]. While the abovementioned characteristics are observed in active lesions of plaque psoriasis, the histologic appearance can suffer variations depending on its chronological stage of evolution, location, and clinical form. In the earliest lesions of psoriasis, acanthosis and hyperkeratosis are not yet developed, although the presence of many mitoses throughout the lower third of

the epidermis indicates an acceleration in proliferation. The papillary dermis shows some edema and many dilated capillaries. In the upper reticular dermis, small vessels are also congested, lined by edematous endothelial cells and surrounded by some lymphocytes, neutrophils, and mast cells. Conversely, when a psoriatic lesion comes to resolution, all distinctive alterations vanish slowly. Acanthosis is reduced, the usual suprapapillary thickness is recovered, and mitoses are rare. Keratinocytic apoptosis, decreased in the active stage of psoriasis, increases in regressing lesions contributing to its resolution [60, 64]. As a consequence, dyskeratotic elements can be present at different levels of the epidermis [61]. The granular layer returns and can be thicker than usual, while cornification is orthokeratotic. The inflammatory infiltrate disappears due to the lack of activity. In the stratum corneum neutrophils can be seen along with old layers of parakeratosis in the surface, until they are finally detached. There is often dermal fibrosis with scattered melanophages. Ectatic vessels from the papillary dermis persist until total healing, being the last remain of the disease [3, 61]. The histopathological characteristics also can change largely according to the different psoriasis variants. Pustular psoriasis, including generalized pustular psoriasis, palmoplantar psoriasis, and acrodermatitis continua of Hallopeau, an acropustular variant located on the fingertips and toes, is

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defined by the presence of large abscesses of neutrophils [3]. Non-pustulosus palmoplantar psoriasis often shows spongiosis and eventually formation of vesicles of plasma; fissures and areas of erosion or ulceration are not rare, being sometimes difficult to differentiate from eczema [65]. Rupioid psoriasis, clinically characterized by cone-shaped skin lesions and frequently associated to psoriatic arthritis, shows massive hyperkeratosis with prominent neutrophilic pustules and dermal edema [66]. The horny layer is thinner in guttate psoriasis, inverse psoriasis (Fig.  2.33), and scalp psoriasis (Fig.  2.34). Pustules are not prominent in guttate psoriasis, and there is often spongiosis. Inverse psoriasis may present corneal hydration because of the maceration of intertriginous areas. Scalp psoriasis [62, 67] is often associated to some degree of alopecia without reduction of the follicular density, as a consequence of an increased rate of follicles in catagen and telogen. Under the microscope there can be a lymphocytic infiltrate with features overlapping those of alopecia areata. Hair infundibula are often dilated [6, 67] with ostial parakeratosis, sebaceous glands also suffer frequent atrophy, and in some cases, the epidermal surface is papillomatous. Necrotic keratinocytes seem to be also especially frequent in this variant, and in some cases, scarring alopecia with granulomatous reaction against hair shafts leading to scarring and permanent hair loss develops [68, 69]. The histopathological diagnosis of erythrodermic psoriasis is often challenging, but a skin biopsy can contribute to rule out other possibilities such as drug erup-

Fig. 2.34  Scalp psoriasis with characteristic epidermal features and reduction in the size of sebaceous glands and some of the hair follicles

Fig. 2.33  Inverse psoriasis with thin corneal layer compared to the epidermal thickness

tion, atopic dermatitis, or a lymphoproliferative disorder. In a small percentage of erythrodermic psoriasis, the skin biopsy specimen will show features of p­ soriasis that are usually mild (Fig. 2.35). Whereas the psoriasiform hyperplasia is preserved, the degree of acanthosis has a high variability from case to case, hyperkeratosis and parakeratosis are not as accentuated as in other variants of psoriasis, and the inflammatory infiltrate is less abundant. Dilated capillaries at the papillary dermis can be once a more helpful clue for diagnosis [70]. Oral psoriasis (Fig.  2.36) is relatively frequent, and it is often associated with geographic tongue, a process microscopically indistinguish-

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Fig. 2.35  Typical features of psoriasis are usually difficult to recognize in erythrodermic patients. This case however presents the characteristic undulating hyperplasia of the epidermis with scant parakeratosis containing some neutrophils. Only the noticeable spongiotic changes can complicate the diagnosis

Fig. 2.37  Psoriasis in the glans of the penis showing features similar any other location. The thinning of suprapapillary dermis is a clue for the differential diagnosis from mycotic infection. However, performing special staining is always advisable to rule out this possibility

Fig. 2.36  Oral psoriasis with prominent neutrophilic spongiosis that can be difficult to differentiate from geographic tongue

able from psoriasis except for the presence of more parakeratosis and necrotic cells [71]. In the genital area, the microscopical appearance is superimposable to that in other locations [72, 73] (Fig. 2.37), except for the vulvar labia majora where it shows less hyperkeratosis, the epidermal hyperplasia is often less prominent, and there can be some degree of spongiosis [72]. A major criterion for diagnosis of nail psoriasis is the presence of neutrophils in the nail bed epithelium, while hyperkeratosis with parakeratosis, serum exudates, focal hypergranulosis, and hyperplasia of the nail bed epithelium are minor

Fig. 2.38  Ungual psoriasis with parakeratosis and microabscesses of neutrophils, indistinguishable from changes secondary to onychomycosis

criteria. The diagnostic features in nail clippings include nail plate thickening with basal hyperkeratosis, layers of parakeratosis, collections of serum and neutrophils (Fig.  2.38), and foci of hemorrhage corresponding to split hemorrhages.

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The frequent presence of superimposed fungal infection can be misleading and does not rule out psoriasis [69, 74, 75].

Differential Diagnosis Pityriasis rubra pilaris, pityriasis lichenoides chronica, seborrheic dermatitis, and lichen simplex chronicus present many overlap microscopical features with psoriasis that have been already discussed in this chapter. Pityriasis rosea (Fig. 2.21) has been traditionally included in the differential diagnosis of psoriasis although the epidermis rarely shows a psoriasiform silhouette; parakeratosis is less obvious and tends to be multifocal rather than forming layers. Furthermore, neutrophils are scarce in the epidermis that can be slightly spongiotic. Lichenoid features with basal vacuolization and occasional dyskeratosis are also common. Within the dermis there is a slight perivascular lymphocytic infiltrate that often contains extravasated erythrocytes which often migrate to the epidermis. A psoriasis-like appearance can be one of the many microscopical faces of lichen striatus. Some nutritional deficiencies, like pellagra and acrodermatitis enteropathica/glucagonoma syndrome and acquired combined nutritional deficiency presenting as psoriasiform dermatitis, can also present clinicopathological similarities to psoriasis (see Chap. 5) [76]. The observation of dyskeratosis, pallor, and necrosis of the upper epidermal layers can contribute to make their distinction. Among the infectious processes, syphilis and superficial mycotic infections, including intertriginous candidiasis, can also mimic psoriasis. Performing special stains is advisable, whenever feasible. Keratoderma blenorrhagicum, resembling pustular psoriasis and eventually developing hyperkeratotic lesions [77] (Fig.  2.39), can appear in conjunction with the characteristic triad of conjunctivitis, arthritis, and urethritis [78]. Less frequently, these patients develop lesions similar to guttate psoriasis or present features of leukocytoclastic vasculitis under the psoriasiform process [78]. The association with spondyloarthropathy in Reiter syndrome suggests a close nosological relationship with psoriasis and psoriatic arthritis.

Fig. 2.39  Keratodermal blenorrhagicum of Reiter disease. The presence of massive neutrophilic spongiosis throughout the epidermis without much tendency to the formation of large abscesses is a hallmark of the disease

Non-pustulosus palmoplantar psoriasis can be difficult to distinguish from chronic hyperkeratotic eczema, and there is an histopathological overlap between them; however the alternation of layers of orthokeratosis and parakeratosis in the stratum corneum favors psoriasis [65]. Palmoplantar pustulosis seems to be different from pustular psoriasis affecting the palms and soles, especially in Asian patients [79]; it is characterized by oval pustules that tend to be localized in the acrosyringium and lack neutrophilic spongiosis at the edges, whereas pustules in palmoplantar psoriasis are said to be triangular in shape and surrounded by spongiform pustules [80]. Pompholyx, especially when superinfected, should also be included in the differential diagnosis [35]. Psoriasiform keratosis [81] may also closely resemble psoriasis, and some malignant neoplasms such as mycosis fungoides and Bowen disease should also be included in the differential diagnosis.

Summary Clinical Presentation • The differential diagnosis of lesions with mild acanthosis and hyperkeratosis includes guttate psoriasis, eruptive lichen planus, pityriasis lichenoides,

2  Spongiotic and Psoriasiform Dermatitis

pityriasis rosea, syphilis, subacute lupus, and parapsoriasis, among others. • Palmoplantar psoriasis can be clinically indistinguishable from chronic hand eczema. Histologic Features • Regular epidermal hyperplasia with drop-like rete pegs that tend to coalesce by contact to the adjacent ones • Dilated tortuous capillaries at the papillary dermis, often congestive with erythrocytes stacked like a pile of coins • Hyperkeratosis with layers of parakeratosis (corresponding to consecutive flares) • Subcorneal or intracorneal neutrophils that range from scattered elements to macropustules Differential Diagnosis • Dermatophytosis: It can be histopathologically indistinguishable from psoriasis. In cases with equivocal clinical presentation, it is mandatory to perform a histochemical staining such as PAS or Gomori to rule out the presence of fungal structures. This is especially necessary in cases of inverse psoriasis. • Pityriasis lichenoides chronica: In spite of its resemblance to guttate psoriasis, this disease tends to show a parakeratotic corneal layer thinner at the edges (mount silhouette) without layers of orthokeratosis and shows exocytosis of erythrocytes to the epidermis and in some cases dyskeratosis and lichenoid features. • Pityriasis rosea can simulate early lesions of psoriasis, but parakeratosis occurs in stacks, and erythrocytes are more commonly seen in the epidermis. • Seborrheic dermatitis: Some patients present overlap features between seborrheic dermatitis and psoriasis. In cases of severe seborrheic dermatitis spongiosis is

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more accentuated, and the pathological findings tend to be folliculocentric. • Secondary syphilis: The presence of plasma cells and many histiocytes, sometimes forming granulomas in the infiltrate as well as a lichenoid pattern, can contribute to the distinction.

Takeaway Essentials Clinically Relevant Pearls • Minimal forms of psoriasis, e.g., nail pitting, Brunsting’s sign in the intergluteal fold, scalp or inverse psoriasis in the retroauricular folds, or erythema on the knuckles and the skin overlying the dorsal interphalangeal erythema, can provide diagnostic confirmation. Pathology Interpretation Pearls • Congestive capillaries in the papillary dermis are the first microscopical sign of disease and the last finding in disappear when the lesion solves. • Neutrophils can be difficult to recognize in the areas of parakeratosis because of their collapsed contour. They look like little knots or flying birds amid the short lines of nuclear remnants that resemble a bank of fish swimming in parallel (“birds among fish” clue) (Fig. 2.28). • The cohesion of the stratum corneum is higher in the layers of parakeratosis than in those of orthokeratosis. In some sections, orthokeratosis can disaggregate and even disappear leaving (“floating layers of parakeratosis” clue) (Fig. 2.40). • Biopsies taken from areas with vascular insufficiency can show complete absence of epidermal hyperplasia or even atrophy and scant inflammatory cells. The clue for the diagnosis in those cases is looking for tiny corneal and subcorneal pustules and identifying layers of parakeratosis.

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Fig. 2.40  Floating layers of parakeratosis as a result of the disaggregation of the orthokeratotic keratin

M. T. Fernández-Figueras and L. Puig

Fig. 2.41  Pityriasis rubra pilaris of the classical adult type is characterized by follicular lesions and spared islands of skin

Pityriasis Rubra Pilaris The disease is subclassified into six types including both hereditary and acquired forms. Classical adult and juvenile (classical and circumscribed) are the most common variants. Some cases may correspond to a superantigen-mediated process. It has been associated heterozygous mutations of CARD14 gene have been associated with psoriasis and familial rubra pilaris, with a mixed phenotype in many cases [82].

Clinical Presentation The typical features of pityriasis rubra pilaris include follicular hyperkeratosis and a reddish orange, scaling dermatitis with islands of normal skin (Fig.  2.41) as well as keratoderma of the palms and soles (Fig. 2.42); it often progresses to erythroderma (Fig.  2.43). Facial involvement is frequent and associated with ectropion.

Prognosis or Clinical Course The classical adult type often remits spontaneously within an average of 3  years, but recur-

rences are frequent. The atypical variants have less favorable prognosis as regards remission. Biological treatments used for psoriasis have been reported to be effective in pityriasis rubra pilaris.

Histopathology Compared to psoriasis, the epidermal silhouette in pityriasis rubra pilaris tends to be less psoriasiform, the suprapapillary dermis is not as thinned, and the epithelium of the upper portion of hair follicles is more hyperplastic. The most distinctive features are plugging of follicular infundibula with hyperkeratosis at the edges that has been compared to “shoulders” (Fig. 2.44), hypergranulosis, and vertical alternation of parakeratosis with orthokeratosis, which in conjunction with the horizontal alternation can give raise to a chessboard appearance [83–85] (Fig.  2.45). Intracorneal pustules are usually not very large. The granular layer tends to be preserved even in close contact with areas of parakeratosis. Spongiosis and acantholysis with or without dyskeratosis [86, 87] have been also described.

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Fig. 2.42  Thick and orange-colored keratoderma of the palms and soles is a frequent finding in classical pityriasis rubra pilaris

Fig. 2.43  Erythroderma secondary to pityriasis rubra pilaris

Fig. 2.45  Pityriasis rubra pilaris with horizontal and vertical alternance of parakeratosis (chessboard pattern)

Differential Diagnosis

Fig. 2.44  Pityriasis rubra pilaris with striking hyperkeratosis at both sides of a follicular infundibulum forming the typical “shoulders”

The main differential diagnosis is psoriasis that can also show some degree of follicular hyperkeratosis. In mild cases, a single biopsy cannot allow their distinction being often necessary to take several specimens from different areas or in different periods of outbreak. Cases with extensive acantholysis can simulate pemphigus vulgaris [87]. These acantholytic changes seem to be more common when the disease is triggered by topical treatments with imiquimod [88].

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Takeaway Essentials Clinical Relevant Pearls • Juvenile pityriasis rubra pilaris has been reported following microbial infections and can be superantigen-induced. • Pityriasis rubra pilaris can be initially indistinguishable from psoriasis; biologic agents such as infliximab have been reported both to improve and to trigger the eruption. • A psoriasiform or pityriasis rubra pilaris-­ like rash has been reported in patients under treatment with imiquimod (a ligand for toll-like receptor [TLR]7 and TLR8) beyond the area of application, paralleling the murine model of imiquimodinduced psoriasiform dermatitis [88, 89]. Pathology Interpretation Pearls • All typical features of pityriasis rubra pilaris are rarely seen in the same section, and study of sections at multiple levels is often necessary. • The vertical alternation of parakeratosis coexisting with an evident granular layer is highly characteristic of the disease. • A complete chessboard pattern in the corneal layer, although highly characteristic of the disease, is rarely found.

• Scalp and facial involvement are frequent in the classical adult type, which can progress to erythroderma. • The circumscribed juvenile variant is characterized by involvement of the extensor surfaces of the knees and elbows, whereas classical juvenile pityriasis rubra pilaris has been reported as an acute postinfectious superantigen-­related rash. Histologic Features • Psoriasiform hyperplasia accentuated around follicular ostia • Vertical and horizontal alternation of parakeratosis with slight neutrophilic infiltrate and preservation of the granular layer • Occasional acantholysis, dyskeratosis, and spongiosis Differential Diagnosis • Psoriasis can be difficult to distinguish from erythrodermic pityriasis rubra pilaris. The distribution of parakeratosis in the corneal layer and relation with hair follicles are the main differential features. • Pemphigus can be included in the differential diagnosis in cases with extensive acantholysis [87]. • Grover disease can cause epidermal hyperplasia with acantholysis and dyskeratosis, and not rarely it contains neutrophils [90]. It can be especially misleading when it appears superimposed on psoriasis.

Summary Clinical Presentation • The initial lesions of pityriasis rubra pilaris are follicular papules that coalesce leaving spared islands of apparently normal skin. • The eruption often has an orange hue, especially marked in the thick palmoplantar keratoderma which is frequently associated.

Seborrhoeic Dermatitis The exact pathogenesis of seborrheic dermatitis is unknown, but disturbances in the skin microbiome, immunologic abnormalities, keratinocyte hyperproliferation, increased sebaceous activity, and patient susceptibility appear to be involved. The response to antifungal therapy supports a pathogenic role of Malassezia furfur.

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Fig. 2.46  Erythema may be the main component of seborrheic dermatitis in patients who wash the involved areas frequently

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inflammatory changes are usually centered in ostium of hair follicles (Fig.  2.47). In the acute stage, there is a predominance of spongiosis [1]. Collections of serum in the corneal layer surrounding the ostium of hair follicles can lead to the formation of parakeratotic crusts [91]. Neutrophils can be present in the corneal layer, especially in the chronic stage when the lesion acquires noticeable psoriasiform features and spongiosis is less evident (Fig. 2.48). There is a mild lymphocytic infiltrate in the dermis containing some neutrophils and slight edema in the papillary portion. Scalp lesions in involution show often follicular plugs [6].

Clinical Presentation Seborrheic dermatitis is a common, chronic papulosquamous disorder affecting infants and adults. Typical lesions consist of pink to reddish patches and plaques (Fig.  2.46) with a yellow, branny, and sometimes greasy scale, with a characteristic distribution in areas with high concentrations of sebaceous follicles including the face, scalp, ears, suprasternal and interscapular areas, and flexures. Annular or petaloid and pityriasiform variants have been described. In many patients there is clinical overlap of seborrheic dermatitis with psoriasis.

Prognosis or Clinical Course

Fig. 2.47  Seborrheic dermatitis with spongiotic and psoriasiform features centered above the ostium of hair follicles

The infantile form occurs during the first few weeks to 3  months of life, is self-limited, and corresponds to the neonatal sebum production, which then regresses until puberty. The adult form is chronic and relapsing, peaks in prevalence and severity around the age of 40, and can be especially severe in patients with neurologic diseases (e.g., Parkinson) and in patients with acquired immunodeficiency syndrome.

Histopathology Seborrheic dermatitis shows a combination of eczematous and psoriasiform features. The

Fig. 2.48  Facial lesions of seborrheic dermatitis can contain areas indistinguishable from psoriasis

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Differential Diagnosis Distinction from psoriasis can be extremely difficult, especially in the face, but the presence of spongiosis and a folliculocentric distribution favors the diagnosis of seborrheic dermatitis [6, 19, 91]. Superficial mycosis should also be included in the differential diagnosis. Histochemical stains can demonstrate the presence of fungal infection. This finding should be distinguished from incidental yeast colonizing serous crusts. Seborrheic-like dermatitis of acquired immunodeficiency syndrome shows distinctive histological features such as an infiltrate containing plasma cells and neutrophils with leukocytoclasis and epidermal apoptosis, as well as a noticeable hyperkeratosis in chronic cases [92].

Summary Clinical Presentation • Characterized by symmetrical lesions on the medial eyebrows, forehead, upper eyelids, nasolabial folds, retroauricular regions. • external auditory canal, scalp, and neck. • Petaloid or arcuate lesions on the trunk can show follicular accentuation (Malassezia folliculitis). • Intertriginous sites such as the umbilicus, axillary, and inguinal regions show less scale due to maceration and can be difficult to differentiate from (or can overlap with) inverse psoriasis and intertrigo. Histologic Features • Eczematous features in the early stage and progressive acquisition of psoriasiform appearance • Folliculocentric, especially in eczematous lesions

Differential Diagnosis • Psoriasis: The presence of folliculocentric eczematous changes favors seborrheic dermatitis. • Superficial mycosis: Histochemical stains can contribute to rule out this possibility.

Takeaway Essentials Clinically Relevant Pearls • Seborrheic dermatitis has a characteristic distribution and is characterized by fine scaling rather than infiltration. Dark reddish and well-demarcated plaques suggest a diagnosis of psoriasis. Pathology Interpretation Pearls • The presence of plasma cells, neutrophils with leukocytoclasis, and epidermal apoptosis in a lesion clinically suggestive of seborrheic dermatitis should raise the suspicion of a seborrheic-­like dermatitis of acquired immunodeficiency syndrome.

Pityriasis Lichenoides Chronica Pityriasis lichenoides is characterized by spontaneously resolving, temporally overlapping crops of papules and is considered a variably clonal cytolytic memory T-cell lymphoproliferative in response to one or more foreign antigens.

Clinical Presentation Pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica (PLC) represent two ends of a clinicopathological continuum; both entities and intermediate forms can coexist. PLEVA manifests as recurrent crops of papules that last for

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weeks and may develop crusts, vesicles, pustules, or ulcers (Fig.  2.49). PLC papules (Fig.  2.50) persist for months and develop scales. Pityriasis lichenoides lesions can be numerous or scanty and tend to concentrate on the trunk and proximal areas of the extremities, but any region of the skin and even mucous membranes can be involved.

Prognosis or Clinical Course Pityriasis lichenoides has a variable clinical course, characterized by recurrent crops of lesions that spontaneously resolve in weeks to months. The disorder may resolve spontaneously within a few months or, less commonly, persist for years. PLEVA usually has a shorter duration than PLC.

Fig. 2.50  Crops of small papules, which persist for several weeks to months and may be capped by small wafer-­ like scales, are characteristic of pityriasis lichenoides chronica

Fig. 2.51  Pityriasis lichenoides chronica with psoriasiform epidermal hyperplasia parakeratotic hyperkeratosis in monticule and perivascular lymphoid infiltrate that also forms a band at the dermoepidermal junction

Histopathology

Fig. 2.49 Acute lesions of pityriasis lichenoides are inflamed and can become necrotic

Most lesions present a combination of psoriasiform and lichenoid features epidermis (Figs. 2.51 and 2.52) with mild spongiosis in the lower half of the epidermis and hints of vascular damage. The epidermal silhouette alternates from slightly psori-

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proximal areas of the extremities and spontaneously regress over several weeks to months. • PLC and PLEVA represent two ends of a disease spectrum; both entities and intermediate forms can coexist.

Fig. 2.52  Dense lichenoid infiltrate in a lesion of pityriasis lichenoides chronica that presents also parakeratosis with small intracorneal microabscesses

asiform to serrated. Well-established lesions show vacuolar alteration with premature differentiation of the basal layer and apoptosis. The corneal layer presents parakeratosis accentuated at the center of the lesion forming a monticule and contains scattered neutrophils [55, 85, 93]. Within the dermis there is superficial perivascular lymphoid infiltrate involving sometimes deep dermis with a wedgeshaped distribution. Endothelial cells are edematous, and there is often erythrocyte extravasation with exocytosis to the epidermis.

Histologic Features • Combination of psoriasiform and lichenoid features • Slight vascular damage with extravasation of erythrocytes that often migrate into the epidermis Differential Diagnosis • Guttate psoriasis: early lesions can be almost indistinguishable. Alternant layers of parakeratosis and orthokeratosis with absence of lichenoid features and vascular damage favors psoriasis. • Early lesions of pityriasis lichenoides et varioliformis acuta (PLEVA may be indistinguishable the chronic form.

Takeaway Essentials Differential Diagnosis Recent lesions of PLC can be extremely difficult to distinguish from guttate psoriasis. PLEVA shows much more severe changes with denser lymphocytic infiltrate, more apoptosis, and occasional ulceration. Some drug reactions can reproduce the combination of patterns typical of PLC [94, 95].

Summary Clinical Presentation • PLC typically presents as recurrent crops of erythematous scaly papules that tend to concentrate on the trunk and

Clinically Relevant Pearls • Pityriasis lichenoides chronica can be clinically indistinguishable from guttate psoriasis. Pathology Interpretation Pearls • The characteristic “mound-like” shape of the stratum corneum, thicker in the center and thinner at the edges, is more visible at a low power magnification. • Premature differentiation of the basal layers of the epidermis with basal keratinocytes looking like those of the stratum spinosum is a subtle clue for the distinction from psoriasis. • If present, a deep perivascular lymphocytic infiltrate contributes to the distinction from psoriasis.

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Case Studies Case 1 Clinical History A 15-year-old girl with facial lesions that raise the differential diagnosis of contact dermatitis to cosmetics, seborrheic dermatitis, and atopy (Fig. 2.53). Microscopical Description The biopsy shows an acanthotic epidermis with an irregular undulating outline at the dermoepidermal junction and a small vesicle (Fig. 2.54). There is diffuse spongiosis with formation of a small subcorneal vesicle filled with plasma with scattered neutrophils in its surface (Fig. 2.55). Within the dermis there is some edema and a few lymphocytes and eosinophils (Fig. 2.56).

Fig. 2.53  Reddish patches on the cheeks of a young girl

(continued)

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Fig. 2.54  Epidermal hyperplasia with slightly irregular outline, spongiosis, and a small subcorneal vesicle

Fig. 2.55  Epidermal spongiosis with elongated intercellular bridges, slight parakeratosis, and a plasma-filled subcorneal vesicle containing some few neutrophils on the surface

Fig. 2.56 The increased the spaces among collagen fibers indicate the presence of dermal edema. An eosinophil with bilobated nuclei and red cytoplasmic granules can be seen in the middle

Diagnosis Atopic dermatitis. Discussion The inflammatory infiltrate is minimal in this biopsy, especially when it is compared to the diffuse spongiosis that lead to the formation of a tiny subcorneal vesicle. We would expect a more cellular response in contact dermatitis [14]. The presence of several eosinophils favors (continued)

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the diagnosis of atopy [2]. The neutrophils present on the surface of the vesicle could raise the differential diagnosis with seborrheic dermatitis [19], but in absence of other features of this disease, they can be considered a consequence of the superficial erosion. A previous history of atopy and absence of contact with cosmetics supports the diagnosis.

Case 2 Clinical History A 69-year-old woman presents with severe stasis dermatitis (Figs. 2.57, 2.58, and 2.59). Microscopical Description The biopsy shows a slightly atrophic epidermis with hyperkeratosis (Fig. 2.60). Small subcorneal (Fig. 2.61) and intracorneal pustules (Fig. 2.62) are also visible. There is diffuse dermal sclerosis. In the upper dermis it contains a moderately dense perivascular lymphocytic infiltrate and many vessels with forming discrete aggregates. The vessel walls are thick, and there are many extravasated erythrocytes.

Figs. 2.57, 2.58, and 2.59  Erythematous desquamative plaques on the lower legs and dorsa of the feet in a middle-­aged woman

(continued)

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Fig. 2.60  Slight epidermal hyperplasia with “flying parakeratotic layers” a clue for the diagnosis of psoriasis. Sclerotic dermis with aggregates of small vessels surrounded by some lymphocytes, suggestive of vascular insufficiency

Fig. 2.61  Subcorneal pustule of neutrophils. Sclerotic dermis with vascular extravasation and mild perivascular lymphocytic infiltrate

Fig. 2.62  Intracorneal pustule associated with foci of parakeratosis

(continued)

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Diagnosis Psoriasis in an area with venous insufficiency. Discussion The clinical diagnosis of psoriasis in areas with significant venous insufficiency can be difficult, and the microscopical features are often misleading due to the absence of the characteristic psoriasiform epidermis. Instead of undulating acanthosis, there is often atrophy. The diagnosis then will rely on the presence of corneal and subcorneal microabscesses or hyperkeratosis with alternance of orthokeratosis and parakeratosis. The clue to recognize that we are dealing with and area of chronic vascular disease is the presence of sclerotic dermis with aggregates of small thick-walled vessels and some hemorrhage or iron deposition [50].

Case 3 Clinical History A 66-year-old man presented with multiple actinic keratoses controlled with topical treatments. After receiving imiquimod as a treatment for actinic keratosis located in the suprasternal region, he developed a severe irritation that quickly evolves into erythroderma (Figs. 2.63 and 2.64). Microscopical Description A biopsy taken in the first week showed only slight acanthosis accentuated around the ostium of hair follicles (Figs. 2.65 and 2.66) and an area of acanthosis showing striking acantholysis and parakeratotic hyperkeratosis. At a higher magnification, it is possible to appreciate also the existence of occasional dyskeratotic cells close to the surface (Fig. 2.67). A second biopsy taken 2 weeks later showed a psoriasiform epidermis with irregularly distributed areas of parakeratosis (Fig. 2.68).

Fig. 2.63  Red patches with mild scaling and occasional islands of spared skin on the back of an elderly man

(continued)

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Fig. 2.64  Red, scaly patches on the dorsum of the right foot and the ankle of the same patient

Fig. 2.65  A striking acantholytic area is visible on the right side of the biopsy. On the left side, changes are more subtle and limited to acanthosis accentuated around a hair follicle that shows a small follicular plug

Fig. 2.66  At a higher magnification, the follicular plug visible in the Fig. 2.65 shows hints of parakeratosis

(continued)

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Fig. 2.67  At a higher magnification, the acantholytic area shows dyskeratosis with formation of “corps ronds,” similar to those present in the so-called acantholytic dyskeratotic dermatosis such as Darier disease

Fig. 2.68  The second biopsy taken from the patient shows a pronounced undulated epidermal hyperplasia without thinning of the suprapapillary. There is hyperkeratosis with extensive parakeratosis irregularly distributed

Diagnosis Pityriasis rubra pilaris triggered by a local treatment with imiquimod. Discussion The diagnostic of this patient relies in the combination of features present in both biopsies, the clinical appearance, and the correlation with the history of imiquimod as a trigger of the process. There are several reports that link the use of imiquimod with the development of pityriasis rubra pilaris [88, 89]. In the first biopsy (Fig. 2.65), the psoriasiform epidermal hyperplasia was not as well-developed as in the second (Fig. 2.67), but there was hyperkeratosis at the edges of a hair follicle (Fig. 2.65) and one area of acantholysis with dyskeratosis (Fig. 2.66), both findings typical from pityriasis rubra pilaris.

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38 Acknowledgments Clinical pictures for case study 3 were provided by Dr. Juan Antonio Moreno Romero, Department of Dermatology, Hospital Universitari General de Catalunya. Sant Cugat. Barcelona.

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2  Spongiotic and Psoriasiform Dermatitis 32. Smets K, Busschots A, Hauben E, Goossens A. B-cell lymphomatoid contact dermatitis caused by methylisothiazolinone and methylchloroisothiazoli­ none. Eur J Dermatol. 2018;28(1):91–3. 33. Lehmann P, Schwarz T. Photodermatoses: diagnosis and treatment. Dtsch Arzteblatt Int. 2011;108(9):135–41. 34. Stein KR, Scheinfeld NS.  Drug-induced photoallergic and phototoxic reactions. Expert Opin Drug Saf. 2007;6(4):431–43. 35. Yoon SY, Park HS, Lee JH, Cho S. Histological differentiation between palmoplantar pustulosis and pompholyx. J Eur Acad Dermatol Venereol. 2013;27(7):889–93. 36. Bahmer FA, Lesch H.  Density of Langerhans’ cells in ATPase stained epidermal sheet preparations from stasis dermatitis skin of the lower leg. Acta Derm Venereol. 1987;67(4):301–4. 37. Sundaresan S, Migden MR, Silapunt S. Stasis dermatitis: pathophysiology, evaluation, and management. Am J Clin Dermatol. 2017;18(3):383–90. 38. Annessi G, Petresca M, Petresca A.  Pretibial pruritic papular dermatitis: a distinctive cutaneous manifestation in response to chronic rubbing. Am J Dermatopathol. 2006;28(2):117–21. 39. Phelps RG, Miller MK, Singh F.  The varieties of “eczema”: clinicopathologic correlation. Clin Dermatol. 2003;21(2):95–100. 40. Kacerovska D, Portelli F, Michal M, Kazakov DV. Acquired elastotic hemangioma-like changes and eccrine sweat duct squamous metaplasia in lichen simplex chronicus/prurigo nodularis-like lesions of the knee and elbow. J Cutan Pathol. 2017;44(7):605–11. 41. Wick MR, Patterson JW.  Diagnostic histochemistry in non-neoplastic skin diseases. Semin Diagn Pathol. 2018;35(6):390–8. 42. Gong JQ, Lin L, Lin T, Hao F, Zeng FQ, Bi ZG, et al. Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br J Dermatol. 2006;155(4):680–7. 43. Riveiro-Falkenbach E, Ruano Y, Garrido M, Ortiz-­ Romero PL, Rodríguez-Peralto JL.  Acral mycosis fungoides with epidermal microvesiculation mucinosis. Am J Dermatopathol. 2015;37(8):632–4. 44. Hu SW, Ratech H, Naeem R, Latkowski J-A, Kamino H.  Mycosis fungoides with epidermal mucinosis: a variant of mycosis fungoides with a spongiosis-like pattern. J Cutan Pathol. 2015;42(10):730–8. 45. Orbaneja JG, Diez LI, Lozano JL, Salazar LC.  Lymphomatoid contact dermatitis: a syndrome produced by epicutaneous hypersensitivity with clinical features and a histopathologic picture s­ imilar to that of mycosis fungoides. Contact Dermatitis. 1976;2(3):139–43. 46. Lowther C, Miedler JD, Cockerell CJ.  Id-like reaction to BCG therapy for bladder cancer. Cutis. 2013;91(3):145–6, 151. 47. Tattoo reactions in an HIV patient: autoeczematization and progressive allergic reaction to red ink after antiretroviral therapy initiation [Internet]. [cited 2019 Feb 16]. Available from: https://www.ncbi.nlm.nih. gov/pmc/articles/PMC4809398/.

39 48. Bosworth A, Hull PR. Disseminated eczema following radiotherapy: a case report. J Cutan Med Surg. 2018;22(3):353–5. 49. Tiengo C, Deluca J, Belloni-Fortina A, Salmaso R, Galifi F, Alaibac M.  Occurrence of squamous cell carcinoma in an area of lichen simplex chronicus: case report and pathogenetic hypothesis. J Cutan Med Surg. 2012;16(5):350–2. 50. Northcutt AD, Tschen JA.  The routine use of iron stain for biopsies of dermatoses of the legs. J Cutan Pathol. 2015t;42(10):717–21. 51. Fernandez-Flores A.  Study on mucin in normal-­ appearing leg skin. Am J Dermatopathol. 2017;39(3): 163–70. 52. Weaver J, Billings SD.  Initial presentation of stasis dermatitis mimicking solitary lesions: a previously unrecognized clinical scenario. J Am Acad Dermatol. 2009;61(6):1028–32. 53. Chuh A, Zawar V, Karad G. A case-control study on the take-off sign in lesional skin biopsies of patients with pityriasis rosea. Iran J Pathol. 2016;11(4):416–7. 54. Neoh CY, Tan AWH, Mohamed K, Sun YJ, Tan SH. Characterization of the inflammatory cell infiltrate in herald patches and fully developed eruptions of pityriasis rosea. Clin Exp Dermatol. 2010;35(3):300–4. 55. Brade SP.  Parakeratosis. J Am Acad Dermatol. 2004;50(1):77–84. 56. Drago F, Ciccarese G, Parodi A. Pityriasis rosea and pityriasis rosea-like eruptions: how to distinguish them? JAAD Case Rep. 2018;4(8):800–1. 57. Panizzon R, Bloch PH.  Histopathology of pityriasis rosea Gibert. Qualitative and quantitative light-­ microscopic study of 62 biopsies of 40 patients. Dermatologica. 1982;165(6):551–8. 58. Flamm A, Parikh K, Xie Q, Kwon EJ, Elston DM. Histologic features of secondary syphilis: a multicenter retrospective review. J Am Acad Dermatol. 2015;73(6):1025–30. 59. Putri I, Mercer SE, Phelps RG, Levitt JO.  False-­ negative anti-treponemal immunohistochemistry in secondary syphilis. Int J Dermatol. 2013;52(2):172–6. 60. Weatherhead SC, Farr PM, Jamieson D, Hallinan JS, Lloyd JJ, Wipat A, et al. Keratinocyte apoptosis in epidermal remodeling and clearance of psoriasis induced by UV radiation. J Invest Dermatol. 2011;131(9):1916–26. 61. Chau T, Parsi KK, Ogawa T, Kiuru M, Konia T, Li C-S, et al. Psoriasis or not? Review of 51 clinically confirmed cases reveals an expanded histopathologic spectrum of psoriasis. J Cutan Pathol. 2017;44(12):1018–26. 62. Shah VV, Lee EB, Reddy SP, Wu JJ. Scalp psoriasis with increased hair density. Cutis. 2018;102(1):63–4. 63. Penn L, Brinster NK.  Eosinophils among the histological features of psoriasis. Am J Dermatopathol. 2019;41(5):347–9. 64. Laporte M, Galand P, Fokan D, de Graef C, Heenen M.  Apoptosis in established and healing psoriasis. Dermatol Basel Switz. 2000;200(4):314–6. 65. Aydin O, Engin B, Oğuz O, Ilvan S, Demirkesen C. Non-pustular palmoplantar psoriasis: is histologic differentiation from eczematous dermatitis possible? J Cutan Pathol. 2008;35(2):169–73.

40 66. Salamon M, Omulecki A, Sysa-Jedrzejowska A, McCauliffe DP, Woźniacka A.  Psoriasis rupioides: a rare variant of a common disease. Cutis. 2011;88(3):135–7. 67. Werner B, Brenner FM, Böer A.  Histopathologic study of scalp psoriasis: peculiar features including sebaceous gland atrophy. Am J Dermatopathol. 2008;30(2):93–100. 68. Runne U, Kroneisen-Wiersma P.  Psoriatic alo pecia: acute and chronic hair loss in 47 patients with scalp psoriasis. Dermatol Basel Switz. 1992;185(2):82–7. 69. Fonseca GP, Werner B, Seidel G, Staub HL.  Comparative microscopic analysis of nail clippings from patients with cutaneous psoriasis and psoriatic arthritis. An Bras Dermatol. 2017;92(1):21–5. 70. Tomasini C, Aloi F, Solaroli C, Pippione M. Psoriatic erythroderma: a histopathologic study of fortyfive patients. Dermatol Basel Switz. 1997;194(2): 102–6. 71. Picciani BLS, Domingos TA, Teixeira-Souza T, Santos V de CBD, Gonzaga HF de S, Cardoso-­ Oliveira J, et  al. Geographic tongue and psoriasis: clinical, histopathological, immunohistochemical and genetic correlation – a literature review. An Bras Dermatol. 2016;91(4):410–21. 72. Hoang MP, Selim MA, editors. Vulvar pathology. New York: Springer; 2015. 499 p. 73. Dauendorffer J-N, Renaud-Vilmer C, Cavelier-Balloy B.  Male genital psoriasis. Ann Dermatol Venereol. 2014;141(6–7):466–72; quiz 465, 473. 74. Kaul S, Singal A, Grover C, Sharma S.  Clinical and histological spectrum of nail psoriasis: a cross-­ sectional study. J Cutan Pathol. 2018;45(11):824–30. 75. Haneke E. Nail psoriasis: clinical features, pathogenesis, differential diagnoses, and management. Psoriasis Auckl NZ. 2017;7:51–63. 76. Toberer F, Hartschuh W, Wiedemeyer K.  Glucagonoma-associated Necrolytic migratory erythema: the broad spectrum of the clinical and Histopathological findings and clues to the diagnosis. Am J Dermatopathol. 2019;41(3):e29–32. 77. Chudomirova K, Abadjieva T, Yankova R.  Clinical tetrad of arthritis, urethritis, conjunctivitis, and mucocutaneous lesions (HLA-B27-associated spondyloarthropathy, Reiter syndrome): report of a case. Dermatol Online J. 2008;14(12):4. 78. Magro CM, Crowson AN, Peeling R. Vasculitis as the basis of cutaneous lesions in Reiter’s disease. Hum Pathol. 1995;26(6):633–8. 79. Yamamoto T.  Clinical characteristics of Japanese patients with palmoplantar pustulosis. Clin Drug Investig. 2019;39(3):241–52. 80. Yamamoto T.  Extra-palmoplantar lesions associated with palmoplantar pustulosis. J Eur Acad Dermatol Venereol. 2009;23(11):1227–32. 81. Fujii M, Tanaka H, Nagahata H, Honma M, Ishiko A, Ishida-Yamamoto A.  Psoriasiform keratosis

M. T. Fernández-Figueras and L. Puig shows abnormal keratinization and increased number of T-helper 17 cells in psoriasiform keratosis implying a pathogenic link to psoriasis. J Dermatol. 2019;46(4):e120–2. 82. Craiglow BG, Boyden LM, Hu R, Virtanen M, Su J, Rodriguez G, et al. CARD14-associated papulosquamous eruption: a spectrum including features of psoriasis and pityriasis rubra pilaris. J Am Acad Dermatol. 2018;79(3):487–94. 83. Soeprono FF.  Histologic criteria for the diagno sis of pityriasis rubra pilaris. Am J Dermatopathol. 1986;8(4):277–83. 84. Magro CM, Crowson AN.  The clinical and histomorphological features of pityriasis rubra pilaris. A comparative analysis with psoriasis. J Cutan Pathol. 1997;24(7):416–24. 85. Wick MR. Psoriasiform dermatitides: a brief review. Semin Diagn Pathol. 2017;34(3):220–5. 86. Cowen P, O’Keefe R.  Pityriasis rubra pilaris and focal acantholytic dyskeratosis. Australas J Dermatol. 1997;38(1):40–1. 87. Lilo MT, Yan S, Chapman MS, Linos K.  Pityriasis Rubra Pilaris with extensive follicular acantholysis resembling pemphigus vulgaris: a case report. Am J Dermatopathol. 2019;41(1):37–9. 88. Gómez-Moyano E, Crespo-Erchiga A, Vera Casaño A, Sanz Trelles A.  Pityriasis rubra pilaris with focal acantholytic dyskeratosis during treatment with imiquimod 5% cream. Actas Dermosifiliogr. 2010;101(10):898–900. 89. Atanaskova Mesinkovska N, Dawes D, Sood A, Bergfeld W. Acantholytic pityriasis rubra pilaris associated with imiquimod 3.75% application. Case Rep Dermatol Med. 2011;2011:412684. 90. Fernández-Figueras M-T, Puig L, Cannata P, Cuatrecases M, Quer A, Ferrándiz C, et  al. Grover disease: a reappraisal of histopathological diagnostic criteria in 120 cases. Am J Dermatopathol. 2010;32(6):541–9. 91. Al-Mohammedi F, Crawford RI, Martinka M. Biopsies of facial dermatoses made simple. Arch Pathol Lab Med. 2014;138(4):550–2. 92. Soeprono FF, Schinella RA, Cockerell CJ, Comite SL.  Seborrheic-like dermatitis of acquired immunodeficiency syndrome. A clinicopathologic study. J Am Acad Dermatol. 1986;14(2 Pt 1):242–8. 93. Joshi R. Stratum corneum findings as clues to histological diagnosis of pityriasis lichenoides chronica. Indian J Dermatol Venereol Leprol. 2008;74(2):156– 7; author reply 157. 94. Mutgi KAJ, Milhem M, Swick BL, Liu V. Pityriasis lichenoides chronica-like drug eruption developing during pembrolizumab treatment for metastatic melanoma. JAAD Case Rep. 2016;2(4):343–5. 95. López-Ferrer A, Puig L, Moreno G, Camps-Fresneda A, Palou J, Alomar A. Pityriasis lichenoides chronica induced by infliximab, with response to methotrexate. Eur J Dermatol. 2010;20(4):511–2.

3

Lichenoid and Interface Dermatitis Maria Angelica Selim and Adela Rambi G. Cardones

Contents Introduction

 43

Lichen Planus Etiology and/or Pathogenesis Clinical Presentation Prognosis or Course Histopathology Differential Diagnosis

 43  43  43  45  45  49

Adult Blaschkitis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Course Histopathology Differential Diagnosis

 51  51  51  51  52  52

Lichenoid and Granulomatous Dermatitis Etiology and/or Pathogenesis Clinical Presentation Histopathology Differential Diagnosis

 52  52  52  52  53

M. A. Selim (*) Department of Pathology and Dermatology, Duke University Medical Center, Durham, NC, USA e-mail: [email protected] A. R. G. Cardones Department of Dermatology, Duke University Medical Center, Durham, NC, USA e-mail: [email protected]

© Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_3

41

M. A. Selim and A. R. G. Cardones

42 Erythema Multiforme Etiology and/or Pathogenesis Clinical Presentation Prognosis or Course Histopathology Differential Diagnosis

 53  53  54  55  55  55

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Course Histopathology Differential Diagnosis

 57  57  58  59  59  59

Fixed Drug Eruption Etiology and/or Pathogenesis Clinical Presentation Prognosis or Course Histopathology Differential Diagnosis

 61  61  61  62  62  62

Erythroderma Etiology and/or Pathogenesis Clinical Presentation Prognosis or Course Histopathology Differential Diagnosis

 63  63  64  66  66  66

 rug-Induced Delayed Multi-organ Hypersensitivity/Drug Reaction D with Eosinophilia and Systemic Symptoms (DRESS) Etiology and/or Pathogenesis Clinical Presentation Prognosis or Course Histopathology Differential Diagnosis

 68  69  69  70  70  70

Graft-Versus-Host Disease Etiology and/or Pathogenesis Clinical Presentation Prognosis or Course Histopathology Differential Diagnosis

 71  72  73  74  75  78

Pityriasis Lichenoides Etiology and/or Pathogenesis Clinical Presentation Prognosis or Course Histopathology Differential Diagnosis

 80  80  80  81  81  81

Vignettes Case 1 Clinical History Microscopic Description Diagnosis Discussion Case 2 Clinical History Microscopic Description Diagnosis Discussion

 84  84  84  84  86  86  86  86  86  87  87

3  Lichenoid and Interface Dermatitis

43

Case 3 Clinical History Microscopic Description Diagnosis Discussion

 88  88  88  89  89

References

Introduction Inflammatory diseases in the skin with lichenoid and interface reaction patterns include a heterogeneous group of disorders that share the presence of damage of the epidermal basal layer. The histogenesis of these disorders is diverse including cell-mediated and humoral immune reactions, among others. Analyzing features of the inflammatory reaction like the nature and degree of basal layer damage, amount and distribution of dyskeratotic cells, as well as composition, density, and distribution of the inflammatory reaction and coexistence of another tissue reaction can lead to a precise diagnosis. This chapter reviews the classic diseases representing these inflammatory patterns with emphasis in diagnostic criteria and useful clues to discriminate among these disorders.

Lichen Planus Lichen planus (LP) is a papulosquamous eruption that can affect cutaneous and mucosal surfaces.

Etiology and/or Pathogenesis A cell-mediated immune reaction has been proposed as pathogenesis for the development of LP. The reaction is triggered by an alteration of the antigenicity of keratinocytes, conceivably originated by a viral infection, drugs, or an allogeneic cell [1]. Cytotoxic CD8+ appears to play a role in the cell-mediated immune reaction by rec-

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ognizing an antigen associated with MHC class I on keratinocytes, while CD4+ lymphocytes, in greater number, play a “helper” role by secretion of Th1 cytokines. The interaction between CD8+ cytotoxic lymphocytes and keratinocytes will lead to death by apoptosis [2]. Lymphokines produced by T lymphocytes like interferon (IFN)gamma, interleukins (IL-1, IL-4, IL-6), perforin, granzyme B, Tia-1, and tumor necrosis factor are some of the effectors producing the keratinocyte apoptosis [3]. The other pathway involves the binding of Fas ligand (FasL) to Fas, which triggers a caspase cascade [4]. It is believed that activated CD8+ cells will induce keratinocyte apoptosis through either granzyme B or Fas/FasL pathways. Gene expression profiling in LP has identified type I IFN genes actively expressed, possibly produced by plasmacytoid dendritic cells that play a major role in cytotoxic skin inflammatory reactions. In addition, matrix metalloproteinases by disrupting the basement membrane may play a role in interrupting survival signals for basal keratinocytes. Evidence of oxidative stress and imbalance in the antioxidant defense system is seen in LP; however, its role in the pathogenesis of this inflammatory process has not been elucidated. Rare cases of familial presentation associated with HLA-D7 have been reported [5].

Clinical Presentation The characteristic lesion of LP consists of violaceous, flat-topped papules, which are usually pruritic (Fig. 3.1). A network of fine white lines

44

also called Wickham striae can be seen in the surface and periphery of the lesions, especially those located in mucosal surfaces (e.g., oral and genital). LP has a predilection for the flexor surface of the wrists, trunk, thighs, and genitalia. Oral lesions are common, with isolated cases of esophageal involvement reported. LP localizes in an area of radiation is believed to represent an isomorphic response [6]. It can also develop in scars secondary to herpes zoster infection [7]. Nail and oral manifestations can be the only involved areas of the disease. LP has been reported to be associated with immunodeficiency states, internal malignancies, Still disease, primary biliary cirrhosis, ulcerative colitis, hypothyroidism, chronic hepatitis C infection, hepatitis B vaccination, influenza vaccination, pemphigus, and radiotherapy, among others. Clinical variants, occurring by themselves or coexisting with typical lesions of LP, include atrophic, annular, hypertrophic, linear, ulcerative (erosive), oral actinic, follicular, pemphigoides, and bullous types and lupus erythematosus-­lichen planus overlap syndrome. Atrophic LP  Clinically present as plaques with central atrophy and the presence of typical papular lesions of LP at the peripheral edge.

M. A. Selim and A. R. G. Cardones

Annular LP  This rare variant can be seen involving the axilla, penis, extremities, and groin. The lesions show central clearing with purple to white annular edge. Hypertrophic LP  Shins are the most characteristic location; however, more generalized presentation has been described. The patient presents with single or multiple plaques with verrucous surface that can last for several years. In long-­standing lesions, squamous cell carcinoma has been described [8]. Linear LP  This variant represents less than 1% of LP. It frequently affects the lower extremities and may follow the lines of Blaschko. Ulcerative (erosive) LP  This variant is characterized by ulcerated and bullous lesion on the feet. These patients may also show oral lesions, genital lesions, alopecia, and classic LP lesions in other locations. Involvement of the vulva, vagina, and mouth (the vulvovaginal-gingival syndrome) has been reported. Long-standing lesions can evolve to squamous cell carcinoma (SCC). Oral LP  Oral involvement has a prevalence of 0.5–2%. Patients are typically middle age to older people. Female predominance has been reported. Clinically, it presents as a white plaque surrounded by white striae. The usual course of this variant expands to many years with unusual spontaneous remission. SCC is a rare complication [9]. Desmocollin-1 and E-cadherin expression has been found to be a predictor for the development of cancer. Actinic LP  In this variant the lesions are mainly located in sun-exposed areas of the body. It most frequently affects young patients from Oriental origin. Pigmentation is associated with this variant that simulates melasma.

Fig. 3.1  Lichen planus: Violaceous flat-topped papules

Follicular LP  Also called lichen planopilaris. It is characterized by keratotic follicular-based

3  Lichenoid and Interface Dermatitis

erythematous papules; half of these patients has developed or will develop in the course of the disease classic lesions of LP in other parts of the body. The end result of this disease is a scarring alopecia. The Graham-Little-Piccardi-Lassueur syndrome is an uncommon but closely related entity that encompasses cicatricial alopecia of the scalp, variable alopecia of the axillae, and groins and follicular keratotic lesions of glabrous skin [10].

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Histopathology

Histologically, the classic changes of LP in the epidermis include hyperkeratosis without parakeratosis, acanthosis, and wedge-shaped areas of hypergranulosis, especially located in the acrosyringia and acrotrichia (openings of the sweat gland and hair follicle, respectively) (Fig.  3.2a, b). The term “sawtooth” has been applied to describe the pointy ends of the epidermal rete ridges. Basal damage in the epidermis takes the LP pemphigoides  This uncommon variant shows form of Civatte bodies or dyskeratotic cells the coexistence of the LP and a heterogeneous (Fig. 3.2c). The papillary dermis shows periodic group of subepidermal blistering disorders simi- acid-Schiff (PAS)-positive diastase-resistant collar to bullous pemphigoid. Patients show tense loid bodies. This damage of the basal layer is bullae, mainly affecting extremities arising in associated with a band-like infiltrate of lymphonormal or erythematous skin. The pathogenesis cytes admixed with histiocytes. Plasma cells can of LP pemphigoides appears to be secondary to be seen in areas such as the face, posterior neck, epitope spread. The damage of the basement intertriginous sites, and genitalia. In more membrane seems to liberate antigen, with subse- advanced lesions, melanophages, fibrosis, and quent formation of circulating antibodies ending milia are also noted. Detachment at the level of in blister formation. The target antigen is within the damaged dermoepidermal junction will crethe C-terminal NC16A domain of the 180-kDA ate clefts also known as Caspary-Joseph space. bullous pemphigoid antigen. Variation of the previously described histologic features of classic lesions of LP can be Bullous LP  The vesicles or bullae are developed seen in the different variants. The atrophic varionly in the lichenoid papules, probably as a result ant will show epidermal thinning with loss of of severe basal damage and associated edema. rete ridges in conjunction with a less dense dermal inflammatory infiltrate, especially in the Lupus erythematosus-lichen planus overlap center of the lesion. Annular LP has a distincsyndrome  These patients show clinical, histo- tive superficial lichenoid reaction with marked logic, and immunopathological features of both number of a­ poptotic keratinocytes at the tips of diseases. In most cases the manifestation of the rete ridges. In hypertrophic LP, the epiderlupus erythematosus is of chronic discoid and mis with hyperplasia displays marked hypersystemic type. and parakeratosis (Fig.  3.3a). Secondary changes of lichen simplex chronicus due to scratching are frequently noted. The basal damage and inflammation in this variant are more Prognosis or Course pronounced at the tip of the rete ridges Most of the cases of LP resolve spontaneously (Fig. 3.3b), and the inflammatory infiltrate conwithin 12  months after onset leaving post-­ tains not only lymphocytes and histiocytes but inflammatory hyperpigmentation [11]. SCC is also plasma cells and eosinophils (Fig. 3.3c). In a rare complication of oral and vulvar LP and erosive LP, the squamous epithelium shows disof the hypertrophic and ulcerative variants ruption, and the band-like infiltrate usually contains plasma cells. Oral LP mimics the changes [12, 13].

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a

b

c

Fig. 3.2  Lichen planus: The lesion shows a band-like chronic inflammatory reaction in the upper dermis (a) with epidermal acanthosis displaying V-shaped hyper-

granulosis (b). Damage of the basal layer takes the form of Civatte bodies (arrow head) and vacuolar changes. Rete ridges with sawtooth appearance can be seen (arrow) (c)

seen in the cutaneous counterpart, although this variant is more inflamed and plasma cells and neutrophils are usually present in the infiltrate. Although the histologic features of lichen planus actinicus are similar to those seen in classic LP, the increased number of melanophages and focal parakeratosis as well as a mild form of inflammation differentiates it. In lichen planopilaris the lichenoid reaction involves the basal layer of the follicular epithelium at the level of the infundibulum and isthmus (Fig. 3.4a–c). In one third of the patients, the lichenoid reaction pattern can be seen also in the interfollicular epidermis. The end stage of the inflammatory process produces destruction of the hair folli-

cles replaced by linear tracts of fibrosis. The sebaceous glands and arrector pili muscles are also destroyed. LP pemphigoides classically shows a cell-poor subepidermal bulla with mild perivascular infiltrate of lymphocytes, neutrophils, and eosinophils. The roof and periphery of the bullae have lichenoid inflammatory changes. Direct immunofluorescence (DIF) shows IgG, C3, and C9 in the basement membrane zone with the indirect split skin immunofluorescence showing the reactivity to the roof of the split. Bullous LP shows the characteristic findings of classic LP with severe inflammatory reaction and associated dermoepidermal damage leading to vesicle and/or bullae formation

3  Lichenoid and Interface Dermatitis

a

47

b

c

Fig. 3.3  Hypertrophic lichen planus: In hypertrophic LP, the epidermis shows hyperplasia with marked hyper- and parakeratosis (a). The basal damage and inflammation in this

variant are more pronounced at the tip of the rete ridges (b), and the inflammatory infiltrate contains not only lymphocytes and histiocytes but also plasma cells and eosinophils (c)

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a

b

c

Fig. 3.4  Lichen planopilaris: In lichen planopilaris the lichenoid reaction involves the basal layer of the follicular epithelium at the level of the infundibulum and isthmus

(a). Follicular plugging is noted (b). The upper portion of the follicles shows vacuolar alteration and dyskeratotic cells associated with band-like chronic inflammation (c)

3  Lichenoid and Interface Dermatitis

(Fig.  3.5). Lupus erythematosus-­lichen planus overlap syndrome may show the LP changes associated with dermal mucin and peri-eccrine chronic inflammation. DIF in classic lesions of LP shows reactivity with complement and immunoglobulins (IgM) at the level of colloid bodies in the papillary dermis. Fibrin is present at the level of the basal layer with extension to the papillary dermis. Using a range of antibodies, immunofluorescent analysis shows the damage of the basement membrane at the level of the lamina lucida region.

Fig. 3.5  Bullous lichen planus: Bullous LP shows the characteristic findings of classic LP with severe inflammatory reaction and associated dermoepidermal damage leading to vesicle and/or bullae formation

a

49

Differential Diagnosis An important distinction is differentiating between LP and LE. LE as opposed to LP will present epidermal atrophy with marked vacuolar alteration of the basal layer rather than the “sawtoothing” presentation of LP.  In addition, LE can also show thickening of the basement membrane associated with superficial and deep perivascular and periadnexal inflammation (around hair follicles and eccrine glands). Dermal mucin highlighted by colloidal iron stain can also point to LE. Lichenoid drug reaction can be difficult to separate from LP; however, the presence of numerous eosinophils as well as the presence of parakeratosis is usually associated with a drug reaction (Fig. 3.6a, b). Of paramount importance is the clinical history of drug exposure. In lichen planus-like keratosis or lichenoid keratosis, the classic clinical presentation consists of a sudden appearance of solitary or few lesions with a predilection to involve arms and presternal area. These lesions are believed to represent an attempted cell-mediated immune rejection of several different lesions like solar lentigos, seborrheic keratoses, viral warts, etc. The presence of a mixed inflammatory infiltrate in the biopsy, parakeratosis, and evidence of the precedent lesions may help in favoring lichen planus-­ like keratosis.

b

Fig. 3.6  Lichen planus-like drug reaction: This type of drug reaction can be difficult to separate from lichen planus (a); however, the presence of numerous eosinophils (arrows) favors a drug reaction (b)

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Lichenoid actinic keratosis or actinic cheilitis also displays a lichenoid inflammatory reaction. However, actinic keratosis or actinic cheilitis will display a degree of keratinocytic atypia exceeding that seen with inflammation and frequently can be viewed beyond the area of inflammation. The early stage of lichen sclerosus shares with LP the presence of a band-like lymphohistiocytic infiltrate obscuring the dermal-epidermal interface as well as vacuolar alteration of the basal layer. However, the squamatization of the basal layer (loss of basilar keratinocytes phenotype) and sawtoothing are not usually seen in early lichen sclerosus (LS). Also edema and early homogenization of papillary collagen are findings pointing toward LS. Additional findings seen in early LS are the presence of columnar parakeratosis overlyilng epidermis with presence of dyskeratotic keratinocytes arranged in groups. In EM and fixed drug eruption, the dense bandlike infiltrate that obscures the basal layer characteristic of LP is not frequently seen. Two clues favoring EM over LP are the normal thickness of the epidermis and the basket woven stratum corneum, evindece of the acute presentaiton of EM. In addition, fixed drug eruption infiltrate has other inflammatory cells like plasma cells and eosinophils. Furthermore, dyskeratotic cells in LP are usually found at the dermoepidermal junction or dermis, while in EM and fixed drug eruption they may be seen throughout the entire thickness of the epidermis with a tendency to cluster. Atrophic LP can resemble poikilodermatous lesions of LE; on the other hand, hypertrophic LP can overlap with hypertrophic LE. Late stages of lichen planopilaris with its characteristic perifollicular scarring can resemble other forms of scarring alopecia like central centrifugal scarring alopecia. The presence of well-organized inflammation around the follicles with vacuolar alteration of the outer root sheath and presence of dyskeratotic cells favor lichen planopilaris. The identification of interfollicular lichenoid inflammatory pattern in the epidermis will further support this diagnosis. Discoid lupus erythematosus is also a consideration; the presence of dermal mucin

and peri-eccrine inflammation will point toward the diagnosis of lupus erythematosus. LP pemphigoides can be separated from bullous LP by the presence of neutrophils and eosinophils as bullous LP only shows lymphohistiocytic infiltrate. The distinction between a well-differentiated SCC and hypertrophic LP can be a diagnostic challenge. The clinical history of involvement of the lower extremities with presence of classic lesions of LP elsewhere favors the interpretation of hypertrophic LP over SCC. In addition, microscopically hypertrophic LP lacks the degree of cytologic atypia seen in SCC.

Summary Clinical Presentation • Classic LP: flat-topped papules, which are usually pruritic. • Atrophic LP: plaques with central atrophy and the presence of typical papular lesions of LP at the peripheral edge. • Annular LP: central clearing with purple to white annular edge. • Hypertrophic LP: single or multiple plaques with verrucous surface that can last for several years, especially seen on shins. • Linear LP: affect the lower extremities and follow the lines of Blaschko. • Ulcerative (erosive) LP: ulcerated and bullous lesion on the feet. These patients may also show oral lesions, genital lesions, alopecia, and classic LP lesions in other locations. • Oral LP: white plaque surrounded by white striae. • Follicular LP (lichen planopilaris): erythematous and keratotic follicularbased papules leading to scarring alopecia. • LP pemphigoides: this uncommon variant shows the coexistence of the LP and a heterogeneous group of subepidermal blistering disorders.

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• Lupus erythematosus-lichen planus overlap syndrome: these patients show clinical, histologic, and immunopathological features of both diseases. Histologic Features • Classic LP: –– Hyperkeratosis without parakeratosis –– Vacuolar changes of basal layer with dyskeratotic cells –– “Sawtooth” rete ridges –– Band-like lymphocytic infiltrate with admixed histiocytes • Variant of LP: –– Hypertrophic LP: shows parakeratosis and mixed dermal infiltrate. –– LE/LP overlap syndrome: besides the classic lichenoid inflammatory features, there is presence of dermal mucin and periadnexal inflammation. Differential Diagnosis • Lichenoid drug reaction • Lichen planus-like keratosis • Lichenoid actinic keratosis • Lichen sclerosus before developing sclerosis • Fixed drug reaction • Squamous cell carcinoma

Take-Away Essentials Clinical Relevant Pearls • If the clinical presentation does not match the classic clinical description, a lichen planus-like drug reaction should be suspected. • Squamous cell carcinoma can develop in patient suffering from LP. Pathology Interpretation Pearls • Parakeratosis and eosinophils should alert about the presence of a medication

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mimicking LP, unless the lesion is an example of hypertrophic LP. Immunohistochemical/Molecular Findings • Be aware that LP can display a clonal T-cell population.

Adult Blaschkitis Adult blaschkitis is a rare inflammatory dermatosis also known as acquired relapsing self-healing Blaschko dermatitis.

Etiology and/or Pathogenesis The etiology of this disease remains elusive. Chromosome 18 abnormalities have been reported in involved skin in comparison to clinically normal-appearing skin. The latter raises the possibility of cutaneous genetic mosaicism [14]. Other postulated etiologic factors include medications and emotional distress [15].

Clinical Presentation Clinically, adult blaschkitis presents as a relapsing unilateral but most common bilateral linear eruption. It affects adult in the fourth decade, predominantly males [16–18]. Patients mainly complain of pruritus. The primary lesions are papules and vesicles affecting different body sites; however, the trunk appears to be the most frequent location. Characteristically, this eruption has a typical linear distribution and lasts days to 2 weeks.

Prognosis or Course Adult blaschkitis is a benign inflammatory condition that recurs over a period of months to years.

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Histopathology Histologically, adult blaschkitis is characterized for a spongiotic inflammatory pattern, although a rare case of interface changes has also been published [19]. No lichenoid inflammation around adnexal structures is seen in adult blaschkitis.

would favor adult blaschkitis over lichen striatus. Pathology Interpretation Pearls • The presence of inflammation around the eccrine glands is a helpful clue to diagnose lichen striatus.

Differential Diagnosis Adult blaschkitis raises the differential diagnosis of lichen striatus. It has been proposed that there is no reason to separate these two diseases [20]. However, adult blaschkitis differs clinically by affecting predominantly adults, truncal distribution, presence of vesicles, rapid resolution, and relapsing course. Pruritus is also rare in lichen striatus. Furthermore, lichen striatus is seen mainly in children, and the biopsy will show a band-like inflammatory inflammation and presence of peri-eccrine lymphocytic infiltrate with scattered plasma cells.

Summary Clinical Presentation • Relapsing bilateral linear eruption frequently affecting the trunk • Primary lesion: papules and vesicles • Adult in the fourth decade, predominantly males Histologic Features • Spongiosis and lichenoid inflammation have been described. Differential Diagnosis • Lichen striatus

Take-Away Essentials Clinical Relevant Pearls • The age group and anatomic distribution, adults with trunk involvement,

Lichenoid and Granulomatous Dermatitis In 2000, Magro and Crowson described an inflammatory dermatosis with combined features of lichenoid and granulomatous dermatitis [21].

Etiology and/or Pathogenesis The pathogenesis of this disease is unknown. Proposed etiologies encompass medications, coexisting medical illness, and infections. The most recent medication implicated in this reaction pattern is nivolumab, a human IgG4 lichenoid antiPD1 monoclonal antibody therapy [22].

Clinical Presentation This disease presents mainly in adults (5–86 years old); however, pediatric cases have been reported. Females are slightly more frequently affected than males. Clinically, the patient shows lichenoid papules, especially localized in extremities and trunk. The head and neck can also be affected.

Histopathology As the name implies, histologic features of the skin biopsy show a band-like infiltrate of lymphocytes and histiocytes. The histiocytic component of the inflammation has been described in a wide variety of patterns: loosely aggregated granulomas in the upper dermis, cohesive granulomas, diffuse interstitial granulomatous inflammation, scattered giant cells, and granulomatous vasculitis [21]. Cases

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described secondary to medications may show parakeratosis, keratinocytic necrosis, and eosinophils [21, 23]. Lymphocytic atypia may also be noted in lesions associated with medications [21].

Differential Diagnosis The presence of lymphocytic atypia, especially in those cases secondary to a medication, raises the differential diagnosis of a lymphoproliferative disorder like mycosis fungoides (MF). MF can present in addition to the atypical lymphocytes with a component of histiocytes in the form of multinucleated giant cells or granulomas. Lichenoid and granulomatous dermatitis will fail to show the lining of atypical lymphocytes along the basal layer and presence of Pautrier microabscesses.

Summary Clinical Presentation • Lichenoid papules, especially localized in extremities and trunk • Adult with slight female predominance Histologic Features • Band-like infiltrate of lymphocytes and histiocytes. • The granulomatous component of the infiltrate is organized as loosely aggregates, cohesive granulomas, and interstitial granulomatous pattern. • Lymphocytic atypia has been reported. Differential Diagnosis • Mycosis fungoides

Take-Away Essentials Clinical Relevant Pearls • Should be considered as part of cutaneous reactions seen in monoclonal

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antibody therapy)

therapy

(e.g.,

anti-PD1

Pathology Interpretation Pearls • Parakeratosis, keratinocytic necrosis, and eosinophils are seen in cases secondary to medications.

Erythema Multiforme Erythema multiforme (EM) is a hypersensitivity reaction characterized by acute onset of self-­ limiting cutaneous lesions that sometimes extend to mucosal surfaces. EM can be classified as major and minor type. EM major is characterized by severe mucosal involvement and may be associated with systemic symptoms (e.g., fever and arthralgia). On the other hand, EM minor refers to EM with minimal to no mucosal disease and no associated systemic symptoms.

Etiology and/or Pathogenesis A wide range of factors have been implicated as causative agents; the most frequent are viral and bacterial infections, medications, autoimmune diseases, and neoplastic conditions [24]. Infections account for approximately 90% of cases [25–27]. Infection with herpes simplex type 1 is a common precipitating factor for minor forms [28]; on the other hand, Mycoplasma pneumoniae infection and drugs are culprits in more severe cases [29, 30]. Other infections associated with EM include cytomegalovirus, Lyme disease, syphilis, orf, Chlamydia pneumoniae, HTLV-1, and hepatitis B, among others. Infectious etiologies may also present with certain patterns of involvement such is the case of M. pneumonia infection; it may present with mucositis as saw in Stevens-Johnson syndrome, particularly in children in the absence of skin lesions [31, 32]. Epstein-Barr virus has been associated with minor and persistent forms of EM [33, 34]. Numerous drugs have been implicated as triggers for EM; the most frequents are sulfonamides, antiepilep-

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tics, antibiotics, and nonsteroidal anti-­develop EM.  HLA-DQB1∗0301 allele has been inflammatory drugs. Certain drugs have higher detected more frequently in patients with EM incidence of producing EM in certain populations than normal controls [41]. like penicillin-related EM and the pediatric population. Additional medications incriminated as EM etiologic agents are nystatin, aminopenicil- Clinical Presentation lins, doxycycline, allopurinol, cyclophosphamide, cocaine, phenytoin, and tramadol, among others. EM most often presents with cutaneous lesions EM reactions have also been reported associated and to a lesser extent with mucosal disease. A with allergic contact dermatitis, poison ivy [35], wide range of clinical lesions including erythemtattoo, intravenous injection of vinblastine [36], atous macules, papules, urticarial plaques, vesiand site of radiation therapy in patients treated cles, and bullae characterize EM (Fig.  3.7a, b). with antiepileptic medications [37]. The term “multiforme” reflects this fact. Still EM is a cell-mediated immune reaction to one most lesions appear similar in a patient at a given of the many etiologies listed above. In the case of time with changes in the presentation during the herpes simplex, lymphocytes react with viral disease course. The most typical EM lesion is antigen-positive cells containing the herpes DNA named “target lesion” and consists of three compolymerase gene [38, 39]. Two types of lympho- ponents: a dusky central area or blister, a dark red cytes constitute the cell-mediated reaction: T inflammatory zone surrounded by a pale ring of lymphocytes carrying the V-beta2 phenotype and edema, and an erythematous halo at the periphery CD8+ lymphocytes with natural killer cell activ- of the lesion. Target lesions are usually less than ity [40]. In EM major the number of CD8 + lym- 3 cm in diameter. “Atypical target lesions” refer phocytes with cytotoxic profile is larger than to raise palpable lesions with only two zones of Foxp3 regulatory cells and CD4+ lymphocytes. color and/or poorly defined periphery [42]. When Cytokine IFN-gamma is the effector in herpes-­ bullae and epidermal detachment are present, associated EM induced by HSV-specific CD4+ they do not exceed the 10% of body surface area. Th1 cells, while in drug-induced EM, major Lesions tend to be symmetrically distributed in tumor necrosis factor (TNF-alpha), perforin, and the extensor surface of extremities, particularly granzyme B are effectors involved in the epider- the palms, subsequently spread in a centripetal mal destruction. Genetic susceptibility may be a manner. Koebner phenomenon, lesions developfactor increasing susceptibility of a person to ing in the area of trauma, has been described.

a

b

Fig. 3.7  Erythema multiforme: Erythematous macules with focal bullous formation and erosions (a). Target lesions are seen in acral location (b)

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Most of the patients are asymptomatic, though some complain of itching or burning sensation. Mucosal lesions involve the oral, ocular, and/ or genital mucosa as erythema with painful erosions and or bullae. Oral involvement (e.g., vermillion lip, buccal mucosa, labial mucosa, nonattached gingiva, and tongue) is the most frequent non-cutaneous affected area, with rare cases extending to the pharynx and upper respiratory tract [25]. M. pneumoniae has a tendency to present with a prominent mucositis, atypical target lesions, and a non-acral distribution of the cutaneous lesions. In patients with significant mucosal involvement, prodromal symptoms (e.g., fever, malaise, myalgia) are frequently seen; they are rare in mild cases of EM. Rowell syndrome refers to the occurrence of EM-like lesions in patients suffering from lupus erythematosus.

Prognosis or Course The clinical course of EM is usually self-limited, resolving in a period of weeks without significant sequelae. In herpes simplex virus (HSV)associated EM, the eruption occurs approximately 2–17 days after the episode of herpes simplex. EM can also be triggered by subclinical recurrences of HSV infection. Uncommonly, the disease may recur over the course of years. A subset of patients suffers from EM episodes over many years leading to increased morbidity, average of six episodes per year with a mean duration of disease ranging from 8 to 10 years. This presentation is called recurrent EM and has been associated with HSV infection, vulvovaginal candidiasis, menses, and hepatitis C, among others. Persistent EM is a rare variant characterized by uninterrupted occurrence of typical and atypical EM lesions. This presentation has been associated with viral infection (e.g., HSV, Epstein-Barr virus, hepatitis C), inflammatory bowel disease, and malignancy.

Histopathology EM shows an interface reaction consisting of vacuolar alteration of the basal layer associated

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with mild to moderate lymphocytic infiltrate, some of which is present in the basal layer obscuring the dermoepidermal interface (Fig.  3.8a). Apoptosis is the mechanism behind the presence of dead keratinocytes seen in the epidermis; they are located not only at the level of the basal layer but also at higher levels. The epidermis frequently shows basket-weave stratum corneum, evidence of its acute presentation (Fig.  3.8b). The interface changes can also be seen in adnexal structures (e.g., acrosyringium and hair follicles) (Fig. 3.8c). It has been postulated that the concentration of dyskeratotic cells in the acrosyringium is usually associated with a drug etiology, especially when associated with eosinophils in the infiltrate [43]. Marked involvement of the basal layer by the inflammatory reaction leads to cleft formation at the dermoepidermal junction with presence of numerous dyskeratotic keratinocytes in the roof of the blister. The dermal infiltrate in EM consists mainly of lymphocytes with a few macrophages located around superficial and mid-dermal vessels. Eosinophils can be seen, although few in number, commonly as part of EM secondary to medications. Severe cases of EM may display histologic features overlapping with toxic epidermal necrolysis with scarce inflammatory reaction and confluent necrosis and detachment of the overlying epidermis. Mucosal lesions in EM show similar histologic features to those seen in cutaneous surfaces with the addition of more prominent spongiosis leading to vesicular formation. DIF shows IgM and C3 highlighting the degenerative keratinocytes or cytoid bodies. In addition, there is frequent detection of granular staining of C3 along the dermoepidermal junction. C3 deposition in the papillary dermis can be seen in early lesions.

Differential Diagnosis The clinical and histologic features of EM are characteristic to enable a diagnosis in most of the cases. However, if an early lesion or the periphery of a targetoid lesion is sample, the changes may not be specific. Among bullous disorders, paraneoplastic

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a

c

b

Fig. 3.8  Erythema multiforme: The changes are noted mainly in the upper dermis obscuring the dermoepidermal junction (a). The epidermis shows basket-weave stratum corneum and an interface reaction consisting of vacuolar

alteration of the basal layer and dyskeratotic cells associated with lymphocytic infiltrate (b). These changes are also seen in eccrine glands (c)

pemphigus can mimic EM as it present with polymorphous skin lesions including lesion reminiscent of EM.  The presence of suprabasal acantholysis and DIF finding can separate both disorders. Fixed drug eruption (FDE) can also show changes that mimic EM. The presence of deep perivascular infiltrate and neutrophils in the infiltrate points toward FDE. FDE has few clinical lesions that present in

the same anatomic location of the first outbreak. A thorough medication history may contribute to the diagnosis. Both Stevens-Johnson syndrome (SJS) and EM may present with mucosal and atypical target lesions. Clinically the presence of macular atypical target lesions and a medication as a trigger will favor SJS. In addition, SJS show less inflammatory cells than EM. Pityriasis lichenoides acuta

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shares with EM the presence of vacuolar changes at the basal layer, dyskeratotic cells, and perivascular lymphocytic infiltrate; however pityriasis lichenoides acuta has a greater degree of parakeratosis and exocytosis of acute inflammatory cells, lymphocytic vasculitis, as well as a wedge-shaped dermal infiltrate. Histologically, graft-versus-host disease (GVHD) should be considered in the differential diagnosis. The presence of compact hyperkeratosis in association with hypergranulosis favors GVHD.  Furthermore, the history of transplantation is of paramount importance in supporting the interpretation of GVHD.

Summary Clinical Presentation • EM major: severe mucosal involvement and may be associated with systemic symptoms (e.g., fever and arthralgia). • EM minor: EM with minimal to no mucosal disease and no associated systemic symptoms. • Present with a wide range of clinical lesions including erythematous macules, papules, urticarial plaques, vesicles, and bullae. The term “multiforme” reflects this fact. • The most typical lesion: target lesion. • Oral involvement is the most frequently affected non-cutaneous area. • Usually self-limited, resolve in weeks without sequelae. Histologic Features • Epidermis with vacuolar alteration of the basal layer. • The acute nature of the disease is reflected in the frequent absence of alteration of the stratum corneum. • Dyskeratotic cells at the basal layer, they can also be seen in upper epidermis. • The lymphocytic infiltrate is seen around superficial vessels and obscuring the dermoepidermal junction. • Eosinophils can be present.

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Differential Diagnosis • SJS/TEN • Paraneoplastic pemphigus • Fixed drug eruption • GVHD

Take-Away Essentials Clinical Relevant Pearls • The term EM major should not be considered a synonym for Stevens-Johnson syndrome. • Frequently the culprit of this cytotoxic reaction is identified in the form of a viral and bacterial infection or medications. • In bullous EM, immunofluorescent test should be considered to rule out autoimmune bullous disorders. Pathology Interpretation Pearls • The presence of eosinophils in the infiltrate and concentration of dyskeratotic cells in the acrosyringium points to a drug as trigger. • Mucosal EM may have a pronounced spongiotic component.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions characterized by marked necrosis and detachment of the epidermis. Ninety percent of these patients present two or more mucosal site involvements (e.g., ocular, oral, and genital).

Etiology and/or Pathogenesis The most common trigger of SJS/TEN is medications in both adults and children. The risk for

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SJS/TEN appears to be restricted to the first 8 weeks of exposure to the drug. In a quarter of the cases, a medication cannot be clearly identified. This number of cases appears to be higher in the pediatric population. The most commonly implicated drugs include allopurinol, aromatic antiepileptic drugs, antibacterial sulfonamides, and nonsteroidal anti-inflammatory drugs. Conventional and targeted anticancer medications have also been implicated in these reactions (e.g., thalidomide, afatinib, vemurafenib, and tamoxifen). Infections are the second most common trigger of SJS/TEN, being Mycoplasma pneumoniae infection the most frequent, especially for children. In over one third of SJS/TEN cases, a cause cannot be identified. Risk factors for SJS/TEN include genetic factor (e.g., HLA-­ B∗15:02, HLA-B∗15:11, HLA-A∗31:01, and HLA-A∗24:02), HIV infection, underlying immunologic disease (e.g., systemic lupus erythematosus), malignancies especially hematologic cancers, and possibly physical factors (e.g., ultraviolet light or radiation therapy). Although the pathogenesis behind SJS/TEN is partially understood, lesions are suggested to be the result of a cell-mediated cytotoxic reaction against keratinocytes leading to apoptosis. Th2 profile mediates the response in SJS/TEN, while erythema multiforme is characterized by a dominant Th1 profile. Drugs can trigger an immunologic response by directly binding to the major histocompatibility complex class I and the T-cell receptor leading to clonal expansion of drug-­ specific cytotoxic T-cell that kills keratinocytes directly or indirectly through other cells that release death mediators like granulysin.

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fevers often exceeding 39 °C proceed by 1–3 days from the appearance of the mucocutaneous lesions. Lesions start on the face and thorax and spread to the other body areas in a symmetrically pattern. Cutaneous lesions start as ill-defined coalescing erythematous macules displaying purpuric center. These lesions will progress to vesicles and bullae formation (Fig. 3.9a), and within days the skin begins to slough resulting in large, raw painful areas of denuded skin. Many cases begin with diffuse erythema. The skin appearance in advanced stages of SJS/TEN is similar to that seen in extensive thermal injury. It is based on the percentage of body surface area involved by sloughing skin that the patient is classified as SJS, TEN, or SJS/TEN overlap: 1. Stevens-Johnson syndrome  – mucosal ero sions and epidermal detachment below 10% of total body area. 2. Stevens-Johnson syndrome/toxic epidermal necrolysis overlap (SJS/TEN)  – epidermal detachment between 10% and 30%. 3. Toxic epidermal necrolysis  – epidermal detachment more than 30%. Nails may be shed. Atypical target lesions with darker center may be seen (see erythema multiforme for description of target lesion and atypical target lesion).

Patients complain of pain frequently disproportionate to the degree of cutaneous changes observed. The mucosal lesion, preceding or following the cutaneous lesions, is seen in 90% of the patients. Oral mucosal and the vermillion border are commonly involved as painful hemorrhagic erosions (Fig.  3.9b). Clinical Presentation Stomatitis and mucositis lead to impaired oral intake. Ocular involvement is reported in The incidence of SJS and TEN ranges from two around 80% of the patients in the form of to seven cases per million per year [44]. SJS is severe conjunctivitis with purulent discharge more frequent than TEN, three cases to one. SJS/ and corneal ulceration. Patients with ocular TEN can occur at any age and is more common in involvement complain of pain and photophowomen (male to female ratio of 2:1). Influenza-­ bia. Although ocular involvement frequently like symptoms (e.g., myalgia and arthralgia) with resolves without sequelae, in half of the

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a

59

b

Fig. 3.9  Stevens-Johnson syndrome and toxic epidermal necrolysis: Coalescing erythematous macules evolving to bullae formation (a). Mucositis presents in this patient as erosive painful erythematous lesions (b)

patients it leaves dryness, scarring, and pain. Urethritis is seen in two thirds of patients with SJS/TEN leading to urinary retention. In female patients external genital involvement will produce adhesions and stenosis of the vagina. Pharyngeal mucosa is affected in nearly all patients.

rounded sometimes by lymphocytes (satellite cell necrosis). The cases that have more exuberant lymphocytic infiltrate in the dermis have a worse prognosis [45]. Sweat ducts show basal layer apoptosis that can lead to necrosis of the duct. In the healing phase, dermal melanophages and milia can be seen.

Prognosis or Course

Differential Diagnosis

The acute phase of SJS/TEN lasts 8–12  days. Reepithelialization may require 2–4  weeks. In severe cases with extensive skin detachment, acute complications include marked loss of fluids, electrolyte imbalance, hypovolemic shock with renal failure, infection, and multiple organ dysfunction syndrome. The overall mortality rate for SJS/TEN is around 12–30%, ranging from approximately 10% for patients suffering from SJS up to 50% in TEN patients.

Staphylococcal scalded skin syndrome (SSSS) is a major clinical differential diagnosis. SSSS is the result of the exfoliative exotoxin types A and B, with better prognosis than TEN. SSSS shows only superficial rather than full-thickness epidermal necrosis like TEN (Fig.  3.11). Erythema multiforme (EM) shares with SJS/TEN the presence of dyskeratotic cells and bullae formation. However, EM will present with typical target lesions, and the skin manifestations will be located mainly in extremities. Bullae and epidermal detachment are limited to less than 10% of body surface area. In contrast to EM, SJS/TEN is mainly associated with a medication. Epidermal necrosis due to ischemia also can present with full-thickness necrosis as TEN. Search of other evidence of deep ischemia such as eccrine sweat gland necrosis and evidence of inflammation and thrombi/emboli may help to support an ischemic

Histopathology Histologically, developed lesions show subepidermal bullae with overlying epidermal necrosis and sparse perivascular lymphocytic infiltrate (Fig.  3.10a–c). Early lesions show epidermis with individual apoptotic keratinocytes sur-

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a

b

c

Fig. 3.10  Stevens-Johnson syndrome and toxic epidermal necrolysis: The biopsy shows expensive areas of epidermal necrosis (a). At the edge of the bullae, vacuolar

changes of the basal layer and dyskeratotic cells are noted (b). The roof of the bullae consists of full-thickness epidermal necrosis with basket-weave stratum corneum (c)

Summary

Fig. 3.11  Stevens-Johnson syndrome and toxic epidermal necrolysis: The sloughing skin shows epidermis with basket-weave stratum corneum due to the acute presentation of the disease and full-thickness necrosis. Note marked collection of serum and fibrin underneath the necrotic epidermis

origin of the changes. Exposure with superficial toxic agents can lead to epidermal necrosis; clinical history is essential to rule out this differential diagnosis.

Clinical Presentation • Incidence: 2–7 cases per million per year. • Occur at any age, female most frequently affected. • Influenza-like symptoms precede the mucocutaneous lesion. • Severe mucocutaneous reaction characterized by necrosis and detachment of the epidermis. • Based on the percentage of body surface area involved by sloughing that the patient is classified as SJS, TEN, or SJS/ TEN overlap.

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Histologic Features • Subepidermal bullae with overlying epidermal necrosis. • Sparse perivascular lymphocytic infiltrate. • Isolated eosinophils may be seen. • At the periphery of the lesion, dyskeratotic cells can be seen. • Healing phase with dermal melanophages and milia formation. Differential Diagnosis • Staphylococcal scalded skin syndrome • EM

Take-Away Essentials Clinical Relevant Pearls • The patients share complications with patients suffering from extensive burns; a prompt diagnosis is strongly recommended. • Frozen section analysis of the sloughing skin can be considered for a short turnaround diagnosis. Pathology Interpretation Pearls • The edge of the blister should be included in the sample, not only to keep the integrity of the lesion but also to identify the interface changes for diagnosis. • Presence of dyskeratotic cells in the acrosyringium and eosinophils in the infiltrate points to drug as the culprit.

Fixed Drug Eruption Etiology and/or Pathogenesis Fixed drug eruption (FDE) is an uncommon and recurrent type IV hypersensitivity reaction trig-

61 Table 3.1 Frequent drug offenders in fixed drug eruption Ibuprofen Cyclooxygenase-2 inhibitors NSAIDs Pseudoephedrine Metronidazole Fluconazole Carbamazepine

Trimethoprim-­ sulfamethoxazole Tetracycline Metronidazole Griseofulvin Barbituric acid 3-hydroxy-3-methyl-glutaryl-­ coenzyme reductase inhibitors

gered within hours of taking the offending drugs. More than 100 drugs have been implicated as triggers of this reaction; major offenders are analgesics, antibiotics, and sedatives (Table  3.1). Factors that may complicate the identification of the culprit include patients with multiple medications, cross-reactivity between multiple drugs, and when a drug is a component of other medications (e.g., phenolphthalein in laxatives). In rare situations, more than one drug can produce FDE in one patient, and these agents are not necessarily related [46]. The term “fixed drug-like eruption” has been proposed when the offending medication cannot be identified [47].

Clinical Presentation Clinically, FDE typically presents as a round to oval erythematous lesion that can evolve to blister and erosion. The time lapse between first exposure and the clinical lesion is approximately 1–2 weeks. This period is reduced to 24 hours and even “minutes” in subsequent exposures. Ensuing lesions recur at the same site of the primary event, and with new episodes, additional lesions may appear. The lesion when subsides leave behind a hyperpigmented maucle (Fig.  3.12). However, hypopigmentation may be seen in naturally heavily pigmented skin. Frequent anatomic locations involved include the face, lips [48], buttocks, and genitals [49, 50]. It has been proposed that certain medications have a propensity to involve specific anatomic locations, such is the case of tetracyclines and cotrimoxazole that tend to involve the glans penis [51], whereas antimalarial mainly

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a

Fig. 3.12  Fixed drug reaction: Round to oval erythematous to brown macule that can evolve to blister and erosion. Marked hyperpigmentation can be seen after several flare-ups

b

involves the face and lips. Patients may complain of itching or burning sensation, but systemic manifestations like malaise or fever are uncommon. There appears to be a genetic susceptibility with an increased incidence in patients with HLA-B22 and HLA-A30 B13 Cw6 [51, 52].

Prognosis or Course Resolution of the lesion is achieved with the withdrawal of the medication. CD4 CD25+ T-cells appear to migrate into the epidermis and by releasing IL-10 play a role in the resolution of the reaction.

Histopathology Histologically, an established FDE lesion shows epidermis with vacuolar alteration of the basal layer and Civatte body formation (Fig.  3.13a). The inflammatory reaction tends to obscure the dermal epidermal junction, as saw in erythema multiforme and some cases of pityriasis lichenoides et varioliformis acuta (PLEVA). Inflammatory cells can be seen at different levels of the epidermis leading to the presence of dead keratinocytes above the basal layer. The infiltrate is composed not only by lymphocytes but also admixed neutrophils and eosinophils. Melanin incontinence and melano-

Fig. 3.13  Fixed drug reaction: Lesion shows epidermis with vacuolar alteration of the basal layer and Civatte body formation (a). Inflammatory cells can be seen at different levels of the epidermis leading to the presence of dead keratinocytes above the basal layer. The infiltrate is composed not only by lymphocytes but also admixed neutrophils and eosinophils. Melanin incontinence and melanophages are noted (b)

phages are noted (Fig.  3.13b). Bullous formation in the form of subepidermal clefting is the result of basal keratinocytic damage. Spongiotic vesiculation is present in the eczematous variant, and changes similar to urticarial reaction can also be seen in rare variants.

Differential Diagnosis Common findings seen in FDE and EM include vacuolar alteration of the basal layer, presence of apoptotic keratinocytes at different levels of the epidermis, and a perivascular dermal infiltrate. Clinically, the documentation of an isolated or few lesions recurring at the same site

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supports the diagnosis of FDE. In addition, the presence of inflammation in FDE is deeper than EM with a frequent admixed neutrophils and eosinophils. Certain presentations of PLEVA can also mimic EM and FDE.  The wedgeshaped dermal infiltrate and changes of lymphocytic vasculitis point to the diagnosis of PLEVA.

Summary Clinical Presentation • Isolated or few recurrent round to oval erythematous lesion(s) that can evolve to blister(s) and erosion(s). • Ensuing lesions recur at the same site of the primary event. • Time lapse between first exposure and the clinical lesion is approximately 1–2  weeks, 24  hours, and even “minutes” in subsequent exposures. • Patients may complain of itching or burning sensation. Histologic Features • Epidermis with vacuolar alteration of the basal layer and Civatte body formation. • Dead keratinocytes seen at basal layer and above. • Perivascular to band-like lymphocytic infiltrate with admixed neutrophils and eosinophils. • In recurrent lesions, melanophages are seen in dermis. Differential Diagnosis • Erythema multiforme • Pityriasis lichenoides et varioliformis acuta

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tion of the lesion is essential to reach a diagnosis. • The diagnosis is confirmed by eliciting the lesion with exposure and resolving it with cessation of the drug. • This hypersensitivity to a medication in this patient is lifelong; the cure is only with cessation of the medication. Pathology Interpretation Pearls • The presence of deep melanophages and mixed inflammatory infiltrate is a good clue to differentiate this disease from other cytotoxic reactions. Immunohistochemical/Molecular Findings • In recurrent lesions histologic features of acute and chronic inflammation coexist.

Erythroderma Erythroderma, also known as exfoliative dermatitis, is a severe and sometimes life-threatening condition that present with diffuse erythema and scaling involving most of the body surface (per definition ≥90% of the skin area surface). Erythroderma is a clinical presentation of a wide range of cutaneous and systemic diseases (e.g., atopic dermatitis, psoriasis, etc.), drug hypersensitivity reactions, and malignancies (e.g., Sézary syndrome). Erythroderma is an uncommon condition with an annual incidence of approximately 1 per 10,000 in the adult population [53]. It most frequently affects adults with a mean age of 42–61 years with a male predominance.

Etiology and/or Pathogenesis Take-Away Essentials Clinical Relevant Pearls • Thorough clinical history with emphasis on medication exposure and evolu-

A wide range of cutaneous and systemic disorders can evolve or present with erythroderma. The diverse causes of erythroderma can be organized in four main categories: (a) exacerbation of a preexisting dermatitis, (b) hypersensitivity drug reaction, (c) uncommon causes, and (d) idiopathic

64 Table 3.2 Erythroderma Etiologies of erythroderma Preexisting dermatosis Psoriasis, atopic dermatitis, seborrheic dermatitis, allergic contact dermatitis, photosensitivity syndromes, pityriasis rubra pilaris, stasis dermatitis, pemphigus foliaceus, bullous pemphigoid, and HIV infection Drugs Phenytoin, penicillin, isoniazid, trimethoprim, sulfonamides, antimalarials, thiazides, gold, chlorpromazine, calcium carbimide (cyanamide), nifedipine, roxatidine, imatinib, allopurinol, and NSAIDs Malignancies Cutaneous T-cell lymphoma (CTCL): mycosis fungoides type and Sézary syndrome and less frequently solid tumors Idiopathic

(Table 3.2). The most common cause of erythroderma is a preexisting inflammatory dermatosis, being the most frequent atopic dermatitis and psoriasis [54, 55]. Triggers of erythroderma in psoriatic patients include the abrupt discontinuation of systemic corticosteroids or immunosuppressant therapy, a systemic illness like HIV infection, phototherapy burns, and medications (e.g., antimalarial and lithium). Hypersensitivity drug reaction, the second most common cause, represents approximately 20% of the cases. It is caused by a wide range of medications; some of the most frequent culprits include penicillin, sulfonamides, carbamazepine, phenytoin, and allopurinol, among others [56]. A range of drug reactions like maculopapular/morbilliform eruption to drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN) may present with an episode of erythroderma. Uncommon causes include cutaneous T-cell lymphoma (e.g., Sézary syndrome and erythrodermic mycosis fungoides) and other hematologic malignancies, solid organ tumors, immunobullous diseases, connective tissue diseases, and infection. Approximately 30% of the cases of erythroderma will fall under the category of “idiopathic” or with no clear underlying cause. However, these patients need long-term follow-­up as they may reveal the etiology of the erythroderma over time. The pathophysiology of erythroderma is not completely

M. A. Selim and A. R. G. Cardones

understood. These patients suffer from an increased mitotic activity and a decreased transit time of keratinocytes through the skin layers ending in exfoliation. This phenomenon leads to significant loss of nucleic acids and proteins through the skin. It is believed that a complex collaboration of cytokines (e.g., tumor necrosis factor and interleukins 1 and 2), chemokines, and intercellular adhesion molecules is responsible for the recruitment of inflammatory cells and elevated epidermal turnover. A Th1 cytokine profile has been detected by immunohistochemical studies in erythroderma associated with inflammatory dermatosis; however, a Th2 profile is seen in patients with Sézary syndrome. Therefore, different pathophysiologic pathways may be leading to a common clinical presentation of erythroderma.

Clinical Presentation Clinically, erythroderma can develop within hours or gradually over months (Fig.  3.14). A sudden

Fig. 3.14 Erythroderma: Diffuse erythema involving trunk

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onset is frequently seen in cases of drug hypersensitivity reactions. Morbilliform or urticarial eruption may be the first stage, and then erythematous patches increase in size and coalesce into generalized bright red erythema. On the other hand, erythroderma as part of cutaneous or systemic disease usually develops gradually. The early erythematous patches may still have the characteristics of the underlying disease; however, specific findings of the original disease are frequently lost in fully developed erythroderma. By definition, over 90% of the body surface needs to be involved by erythema to diagnose erythroderma. The erythema can range from bright pink (characteristic of drug reactions) or salmon pink with spared areas (e.g., pityriasis rubra pilaris) to dusky red (chronic erythroderma like in psoriasis or Sézary syndrome). Scale usually appears after more than 1  week duration, especially abundant in the setting of underlying psoriasis. The skin is warm to the touch, and the patient usually complains of pain or itch. Patients frequently appear uncomfortable and complain of feeling cold. In chronic erythroderma, changes of lichen simplex chronicus and e­ rosions/ulcerations may be seen secondary to scratching. The skin is usually indurated and leathery on palpation. Palmoplantar keratoderma is usually associated with pityriasis rubra pilaris and Sézary syndrome (SS). Hair (e.g., telogen effluvium) and nail changes (e.g., nail dystrophy, nail pitting, paronychia, and onychomadesis) can accompany the erythema. Ocular involvement in the form of blepharitis, epiphora, and ectropion can be seen especially in chronic erythroderma as part of SS. Oral mucositis and genitourinary involvement may be seen in erythroderma associated with immunobullous disease, SJS/TEN, and GVHD. Extracutaneous findings include constitutional symptoms and signs of high-output cardiac failure. Lymphadenopathy, splenomegaly, and hepatomegaly may be also seen but in chronic cases with an underlying lymphoma. When CTCL is suspected as etiology for the erythroderma (SS and erythrodermic mycosis fungoides), the recommended peripheral blood

65 Table 3.3 Diagnostic criteria for Sézary syndrome (ISCL/WHO-EORTC) Absolute Sézary count > or = 1000/ml CD4/CD8 ratio > or = 10 (due to the clonal expansion of CD4+ cells by flow cytometry) Aberrant expression of pan-T-cell antigens by flow cytometry Demonstration of T-cell clonality by Southern blot or PCR-based methods, or cytogenetic demonstration of an abnormal clone (WHO classification requires demonstration of the clonally related T cells (Sézary cells) in the skin, peripheral blood, and lymph node) ISCL International Society of Cutaneous Lymphomas, WHO-EORTC World Health Organization (WHO) and European Organization for Research and Treatment of Cancer (EORTC) Note: 80% or more erythrodermic skin involvement by atypical T cells (WHO classification also requires generalized lymphadenopathy)

examination includes complete blood count with differential, peripheral blood flow cytometry/ fluorescent-­ activated cell sorting and/or T-cell markers (CD3, CD4, CD8, CD7, CD26) and T-cell receptor (TCR) gene rearrangement (either using BIOMED-2 primers or next-generation deep sequencing). SS is characterized by the triad of erythroderma, lymphadenopathy, and peripheral blood involvement by atypical T cells (Sézary cells). Recently, the International Society of Cutaneous Lymphomas (ISCL) and European Organisation for the Research and Treatment of Cancer (EORTC) had further defined these diagnostic criteria (Table  3.3). Erythrodermic MF would not have the degree of blood involvement as seen in SS. Although erythroderma is in general well tolerated, patients with extremes of age and serious comorbidities may experience complications. Significant disturbances in fluid and electrolyte regulation and thermoregulation are seen in these patients. Furthermore, the shunting of blood through the skin due to vasodilation may lead to high-output cardiac failure, frequently seen in older or compromised patients. The cutaneous fissuring and ulcers increase the incidence of superficial bacterial infection; sepsis with Staphylococcus aureus may also occur.

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Prognosis or Course Generalization of the cutaneous erythema may be in days or months subject to the etiology behind the erythroderma. After a period of 2–6  days, exfoliation starts, from flexural areas to the rest of the body. The duration of the erythroderma is variable from weeks in drug reactions to years in underlying cutaneous or systemic diseases. Increased morbidity and mortality are noted in these patients. Erythroderma mortality ranges from 4% to 64%. Factors associated with unfavorable clinical outcome include advanced age, comorbidities, and need for hospitalization. Erythroderma associated with inflammatory dermatosis usually improves within weeks to months after implementation of treatment, although recurrences are not uncommon. Erythroderma secondary to a drug usually resolves in 2–6 weeks after withdrawal of the medication. On the other hand, erythroderma associated with SS is usually of long term as the disease commonly is refractory to treatment with poor outcome.

Histopathology Depending on the underlying etiology, changes in erythroderma may be subtle requiring multiple biopsies to reach a diagnosis [57]. Although the histopathology may reveal the underlying etiology of the erythroderma, frequently it is not specific with epidermal acanthosis, spongiosis, and perivascular inflammation [58]. The degree of change also will depend on the stage of the disease and the severity of inflammation [59, 60]. Biopsies are most helpful in cases associated with CTCL and less frequently to psoriasis and spongiotic dermatitis [57]. For instance, SS in a third of the cases present with nondiagnostic perivascular infiltrate of larger angulated T cell [60]; however, there are biopsies displaying the classic presence of atypical lymphocytes with variable epidermotropism, lining and tagging of the basal layer, and presence of Pautrier microabscesses (Fig. 3.15a, b). In cases with concern but not definitive findings, immunohistochemistry in combination with TCR gene rearrangement stud-

M. A. Selim and A. R. G. Cardones

ies may be further contributory to delineate the nature of the infiltrate. Malignant T cells in SS are derived from mature skin-homing central memory T cells that express hallmark receptors (CD3 + CD4 + CLA + CCR4 + CCR7 + CCR10 +) and lack certain pan-T-cell markers (CD7, CD26 most typical) (Fig. 3.15c–f). The presence of clonal TCR test further supports the interpretation of SS. In some SS patient, the diagnosis is reached by obtaining a biopsy from an enlarged lymph nodes and/or examination of the peripheral blood with a demonstration of a consistent matching T-cell clone in the peripheral blood, lymph node, and skin. Features of psoriatic erythroderma resemble those observed in early lesions of psoriasis such as mild epidermal hyperplasia, areas of parakeratosis with a few neutrophils, and red cell extravasation in papillary dermis [61]. Blood vessels in the upper dermis are tortuous and dilated. As a cautionary note, mild spongiosis is common even when there is an underlying psoriasis. Drug-related cases might simulate lymphoproliferative disorders with abundant lymphocytic exocytosis and few lymphocytes with atypia in the form of angulated irregular enlarged nuclei. Eosinophils can be seen in both entities. Rare dyskeratotic cells may point toward a drug reaction over SS.  DIF tests should be entertained in the workup of a biopsy with intraepidermal or subepidermal bullae.

Differential Diagnosis As the histologic features are only helpful in establishing the diagnosis in about 40% of cases [62], the differential diagnosis is broad. Frequently the changes of a biopsy of erythroderma are those of non-specific subacute or chronic spongiotic dermatitis. Erythroderma associated with underlying psoriasis can be identified and differentiated from other etiologies as it shows enough of the characteristic of early psoriasis in the form of mild epidermal hyperplasia with mounds of parakeratosis with a few neutrophils and red cell extravasation. Cases of erythroderma as part of atopic dermatitis will have a history of chronic relapsing derma-

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a

b

c

d

e

f

Fig. 3.15  Erythroderma: The biopsy shows epidermotropic atypical lymphocytes; minimal perivascular lymphocytic infiltrate is also noted (a). The atypical lymphocytes display lining along the basal layer and formation of Pautrier microabscesses (b). CD3 decorates the majority of

the lymphocytes (c). The intraepidermal component is predominantly CD4 + (d), while CD8 antibody decorates scattered perivascular lymphocytes (e). CD7 demonstrates significant decreased expression (f). The histologic and immunoprofile support the diagnosis of Sézary syndrome

titis with predilection of face and flexural areas and personal or family history of atopy (asthma or allergic rhinitis). Areas of sparing dermis and presence of hyperkeratotic palms will favor pityriasis rubra pilaris. The presence of parakeratosis

in the ostium of the hair follicle and “checkerboard” parakeratosis would also point to this disease; however, they are sometimes difficult to find. Drug-related erythroderma can simulate SS; however, the presence of dyskeratotic cells in the

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epidermis and the absence of significant abnormalities in peripheral blood will point toward a drug reaction.

Summary Clinical Presentation • Diffuse erythema and scaling involving most of the body surface (per definition ≥90% of skin area surface). • Frequently affect adults with a mean age of 42–61  years with a male predominance. • Erythema: bright pink (characteristic of drug reactions) or salmon pink with spared areas (e.g., pityriasis rubra pilaris) or dusky red (chronic erythroderma like in psoriasis or Sézary syndrome). • Scale appears after more than 1  week duration, especially abundant in a case of underlying psoriasis. • Skin warm to touch and patient complain of feeling cold. • In chronic cases lichen simplex chronicus secondary to scratching is seen. • Signs of high-output cardiac failure. • Adenopathy, splenomegaly, and hepatomegaly, especially in chronic cases secondary to lymphoma. Histologic Features • Frequently it is not specific: epidermal acanthosis, spongiosis, and perivascular inflammation. • Classic changes seen in mycosis fungoides can be seen in a subset of patients with SS (e.g., epidermotropic atypical lymphocytes with lining and tagging of the basal layer and Pautrier microabscesses). • Psoriatic erythroderma: epidermal hyperplasia with parakeratosis and few neutrophils in the stratum corneum. • Hypersensitivity reaction to a drug: presence of dyskeratotic cells and eosinophils.

Differential Diagnosis • Atopic dermatitis • Psoriasis • Pityriasis rubra pilaris • Hypersensitivity drug reaction • Malignancies, especially syndrome

Sézary

Take-Away Essentials Clinical Relevant Pearls • Clinical follow-up is necessary in those patients with no clear etiology, as they may develop with time the etiology. • Drugs are the most frequent trigger of erythroderma with acute presentation. Pathology Interpretation Pearls • Multiple biopsies may be necessary to reach a diagnosis in patients suffering from erythroderma. • As biopsies in Sézary syndrome may not be specific, they are not part of the diagnostic criteria. Immunohistochemical/Molecular Findings • If Sézary syndrome is suspected, recommend peripheral blood studies and TCR test. • Immunofluorescent tests may help in the identification of immunobullous disorders.

 rug-Induced Delayed Multi-organ D Hypersensitivity/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) DRESS is an infrequent but potentially life-­ threatening drug-induced hypersensitivity reaction that encompasses skin eruption, hematologic abnormalities, lymphadenopathy, and internal

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organ involvement [63, 64]. Numerous terms have been utilized to describe these types of drug reactions presenting with skin eruption, systemic symptoms, and visceral involvement. Some of the terms used include drug reaction with ­eosinophilia and systemic symptoms, drug rash with eosinophilia and systemic symptoms, drug-­ induced hypersensitivity syndrome, or drug hypersensitivity syndrome [64, 65]. The variation of terminology reflects the absence of widely accepted diagnostic criteria.

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marker of stimulation of these cells and not the initial event in the pathogenesis [67].

Clinical Presentation

The incidence of DRESS is unknown, although we know frequencies of certain specific medications like anticonvulsant (e.g., carbamazepine and phenytoin), 1–5 per 10,000 patients and even higher for lamotrigine (1 per 300 adults and 1 per 100 children exposed). DRESS usually affects adults without sex predilection; however pediatric Etiology and/or Pathogenesis cases have been reported [68]. The diagnosis of DRESS is suspected if the patient presents, after Antiepileptic agents (e.g., carbamazepine, receiving a new medication 2–6  weeks before lamotrigine, phenytoin, phenobarbital) and allo- clinical onset, with the following signs and symppurinol are the most frequent medications associ- toms: skin eruption, fever (38  °C–40  °C), facial ated with DRESS [66]. Other medications also edema, and enlarged lymph nodes. The cutaneous associated with this hypersensitivity reaction are manifestations of DRESS consist of a morbillisulfonamides, dapsone, minocycline, vancomy- form eruption that evolve in 20–30% of cases to cin, and kinase inhibitors (e.g., imatinib, confluent erythema or exfoliative dermatitis sorafenib, and vemurafenib), among others. involving >90% of the total body surface with folTwo factors are implicated in the pathogenesis licular accentuation The face and upper part of the of DRESS: a drug-specific immune response and trunk and extremities are initially affected. The a virus reactivation. A drug-specific immune facial edema, seen in 50% of the patients, is symresponse is an essential factor with DRESS being metric, persistent, and associated with mucous one with the strongest activation of drug-specific membranes inflammation. T cells among all phenotypes of cutaneous The three most frequently affected organs are adverse drug reactions. Reactivation of several the liver, kidney, and lung. Hepatitis is usually virus of the herpes family (HHV-6, HHV-7, asymptomatic and only detected by abnormal Epstein-Barr virus (EBV), and cytomegalovirus) liver function test (serum level of alanine aminois a common event in patients with DRESS. Virus transferase greater than twice the normal value reactivation may contribute to some of the symp- and/or alkaline phosphatase greater than 1.5 toms or complications of this disease. Disease times the normal value on at least two different relapses were related to the detection of HHV-6 in dates). Interstitial nephritis is seen in 1–30% of peripheral blood; this may suggest that viral reac- DRESS patients with moderate increase in creatitivation may play a role in phenotype and sever- nine levels, low-grade proteinuria, and abnormal ity of DRESS. All these findings suggest that the urinary sediment. Non-specific symptoms like initial event in DRESS is a viral reactivation that cough, fever, and tachypnea/dyspnea usually leads to the expansion of T-cell population cross-­ denote pulmonary involvement. Chest radiograph reacting with the drug. It is believe that the tissue or CT scan can show evidence of interstitial damage seen in this patient is the result of acti- pneumonitis and pleural effusion. Several other vated cytotoxic CD8+ T cells directed against the organs can be involved in DRESS including the virus antigens. As latent viruses can be harbored heart (myocarditis, pericarditis), pancreas (panin cells of the immune system, the reactivation creatitis), brain (encephalitis, meningitis), and and release of viruses may also be explained as a muscle (myositis), among others.

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Clinical suspicion can be further supprted by the presence in the laboratory of eosinophilia (>700/microL) and lymphocytosis (absolute lymphocytes count > ­ 4500/microL) with or without atypical lymphocytes in peripheral blood. Testing of EBV, HHV-6, HHV-­7, and cytomegalovirus by quantitative polymerase chain reaction (PCR) is frequently performed in these patients as reactivation is suspected to be a marker of prolonged course and increased risk of complications. Reactivation of HHV-6 and other viruses can be seen in 40–60% of tested patients.

Prognosis or Course DRESS is characterized by a prolonged latency, usually 2–8 weeks between exposure and presentation of clinical manifestations, associated with a prolonged course with frequent relapses regardless of discontinuation of the trigger. During the course of the disease, reactivation of latent human herpes virus infection is commonly seen. The skin eruption and visceral involvement frequently recover in 6–9 weeks from drug withdrawal [68]. In less than a quarter of the patients, the disease may persist for months with remissions and relapses. Relapses have been associated with HHV-6 activation, while prolonged course has been reported with a more severe liver involvement.

a

Fig. 3.16  Drug reaction with eosinophilia and systemic symptoms (DRESS): The biopsy shows focal vacuolar alteration of the basal layer associated with dyskeratotic

Histopathology Cutaneous biopsy may show a range of inflammatory patterns, and more than one pattern can be seen in one biopsy. In a review of 50 DRESS biopsies, the inflammatory patterns in order of frequency seen include interface, spongiotic, erythema multiforme-like, and acute generalized exanthematous pustulosis (AGEP)-like patterns [69]. In other reports, the histology is described as non-­specific. In most of the biopsies, the epidermis exhibits acanthosis, spongiosis, vacuolar changes of the basal layer, and presence of dyskeratotic cells (Fig. 3.16a). Perivascular lymphocytic infiltrate with variable number of admixed eosinophils is also seen (Fig. 3.16b). Sometimes, the lymphocytic infiltrate may display atypia or be so exuberant raising the suspicion of a lymphoproliferative disorder. Immunohistochemical stains will show that most of the lymphocytes in the infiltrate consist of CD8+ cytotoxic T cells.

Differential Diagnosis Histologic features of DRESS raise a wide differential diagnosis that parallels to the wide range of inflammatory patterns seen in this disease, from spongiotic dermatitis to interface dermatitis or AGEP or EM/TEN. It is the exposure to a medication known to be associated with DRESS and

b

cells (a). Perivascular lymphocytic infiltrate with eosinophils is also seen (b)

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the presence of the hematologic abnormalities and systemic symptoms and organ involvement that will lead to a final diagnosis.

Pathology Interpretation Pearls • Similar to other drug reactions, DRESS combines inflammatory patterns: spongiotic and interface patterns

Summary Clinical Presentation • History to exposure to a drug (latency 2–6 weeks) • Morbilliform eruption to erythroderma, facial edema • Hematologic abnormalities (eosinophilia >700/microL and/or atypical lymphocytosis) • Systemic symptoms and organ involvement: –– Fever (38 °C–40 °C [100.4 °F–104 °F]) –– Enlarged lymph nodes –– Abnormal liver function tests –– Renal impairment –– Interstitial pneumonia and/or pleural effusion –– Myocarditis Histologic Features • Epidermal spongiosis with vacuolar alteration of basal layer • Dyskeratotic cells • Perivascular lymphocytic infiltrate • Frequent presence of eosinophils Differential Diagnosis • Eczematous dermatitis dermatitis) • Interface dermatitis • AGEP • EM/TEN

liform drug reactions are between 4 and 9 days.

(spongiotic

Take-Away Essentials Clinical Relevant Pearls • DRESS has a prolong latency (2–6 weeks), while most of the morbil-

Immunohistochemical/Molecular Findings • Reactivation of HHV-6 and other viruses in more than half of the tested patients

Graft-Versus-Host Disease Graft-versus-host disease (GVHD) is a multisystem disorder that complicates transplant patients. Commonly it targets the skin, gastrointestinal tract, lung, and liver. GVHD classically occurs in bone marrow transplant patients but also can follow solid organ transplantation, transfusion of non-irradiated blood or blood products to immunosuppressed patient, and as a complication of transplacental transfer of maternal lymphocytes to an immunodeficient fetus. Because cutaneous GVHD shares similar clinical and histologic findings in a variety of other skin diseases, thorough consideration of the differential diagnosis is essential for the management of these patients. In the past, GVHD was divided into acute (aGVHD) and chronic (cGVHD) if the manifestations occur before or after 100 days from transplantation, respectively. This concept has been challenged as signs of acute and chronic disease can occur outside these designated periods; presently the classification is based on clinical findings rather than a time period [70]. The National Institutes of Health (NIH) consensus criteria classify histopathologic manifestations as “possibly” and “likely” GVHD [71] (Table 3.4) or as common to both acute and chronic. Patients with GVHD are subclassified using the timing of presentation and features seen in these patients:

72 Table 3.4 NIH consensus criteria for diagnosis of GVHD Histologic criteria for GVHD by organ system: skin Apoptosis in epidermal basal layer or lower Malpighian layer or infundibulum/outer root sheath/ hair bulge of hair follicle or acrosyringium/sweat ducts  +/− Lichenoid inflammation  +/− Vacuolar change  +/− Lymphocytic satellitosis Recommendations for final diagnostic categories Possible GVHD Likely GVHD Evidence of GVHD but patient Clear evidence of GVHD with or has other possible without mitigating explanations: infection, factors ulceration, drug GVHD most likely but no or limited clinical history available GVHD validated by nonexistence of contending diagnosis Original table modified from Shulman et al. [71]

Classic aGVHD  Patients present within 100  days of transplant and show features of aGVHD.  Diagnostic and distinctive features of cGVHD are absent. Persistent, recurrent, late-onset aGVHD  Patients present greater than 100 days post-transplant with features of aGVHD.  Diagnostic and distinctive features of cGVHD are absent. Classic cGVHD  Patients may present at any time post-transplant. Diagnostic and distinctive features of cGVHD are present. There are no features of aGVHD. Overlap syndrome  Patients may present at any time post-transplant with features of both cGVHD and aGVHD.  On occasion, this is also named “acute on chronic” GVHD. GVHD affects patients who receive an allogeneic hematopoietic cell transplant despite intensive prophylaxis with immunosuppressive ­ therapy (rate ranges from 9% to 50% of HCT transplants from HLA identical siblings [72, 73].

M. A. Selim and A. R. G. Cardones

aGVHD is also common in matched unrelated donors. Risk factors to develop aGVHD include the degree of HLA disparity, gender disparity between donor and recipient, intensity of transplant conditioning, aGVHD prophylactic regimen, and source of graft (peripheral blood or bone marrow > than umbilical cord blood). aGVHD may resolve or in 35% of cases evolve to cGVHD [74]. The risk of cGVHD is 11 times greater if the patient experienced aGVHD.

Etiology and/or Pathogenesis GVHD occurs when immune cells transplanted from a nonidentical donor (the graft) identified the transplanted or recipient (the host) as foreign leading to an immune reaction that causes disease in the transplant recipient. The pathogenesis is complex and involved multiple steps, some of them unknown. However, GVHD needs the conversion of three factors: (1) the graft must contain immunologically competent cells; (2) the host must possess antigens that are lacking in the graft; therefore, they will appear foreign to the host; and (3) the host must be incapable to mount a reaction against the graft allowing graft cells to attack the host. GVHD is mainly a T-cell-­ mediated disease. The T cells of the graft will mainly attack the host major histocompatibility complex (MHC) molecules if the donor MHC differs. Mismatching other antigens named minor histocompatibility antigens also appears to trigger the development of GVHD.  Another factor postulated to play a role in the development of GVHD is the damage of the gastrointestinal system due to the conditioning regimen. This damage allows bacterial translocation or the enhance stimulation of toll-like receptors leading to an increased cytokine release by macrophages/monocytes and T-cell activation. Circulating transplanted T cells are also activated through the interaction with the vascular endothelium (TCR-­peptide-­MHC interaction) and antigen-­presenting cells. These circulating activated transplanted T cells begin to proliferate releasing a range of pro-­inflammatory cytokines (e.g., TNF-alpha) that are potent pro-inflamma-

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tory and immunoregulatory mediator. In addition, the circulating activated transplanted T cells can damage the host cells through perforindepending cytolysis and Fas-mediated apoptosis. Regulatory cells will play a role in controlling the ultimate response of GVHD.

Clinical Presentation Acute GVHD (aGVHD) affects the skin, gastrointestinal tract, liver, and hematopoietic system. Cutaneous lesions are frequently the earliest manifestation appearing 2–4  weeks after transplantation. Typically, they begin as erythematous blanchable macules affecting the ears, palms, or soles. Other sites of involvement are as follows: the neck, face, and upper back [75, 76]. With time, lesions become generalized taking a morbilliform appearance (Fig. 3.17). Papules with smooth surface or hyperkeratosis and post-­ inflammatory hyperpigmentation also occur. Severe presentations include erythroderma, bullae, and extensive sloughing. Patients may complain of pruritus or burning sensation; this may precede the cutaneous lesions. Grading aGVHD includes cutaneous, gastrointestinal, and liver stages. Cutaneous staging is based on the extent of body surface area (BSA) involvement: stage 1, less than 25% BSA; stage 2, between 25% and 50% BSA; and stage 3, more than 50% BSA.  Erythroderma with bullae represents stage 4 [77]. When the latter is present, it is sufficient to grade the patient as grade 4. The stages of gastrointestinal involvement are based on the severity of the diarrhea, while the stages of liver involvement are based on the total bilirubin levels.

Fig. 3.17  aGVHD: Morbilliform rash affecting lower extremity

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Erythema, erosions/ulcers, xerostomia, and lichenoid lesions characterize oral involvement. It is difficult to separate these changes from mucositis secondary to chemotherapy administered in preparation for the transplant. It is believed that lesions present for more than 3 weeks after transplant with involvement of the hard palate most likely represent aGVHD [78]. The most frequent extracutaneous manifestations of aGVHD include persistent nauseas and/ or emesis, abdominal cramps with diarrhea, and a rising serum bilirubin concentration. In the absence of extracutaneous manifestations (e.g., liver abnormalities and gastrointestinal symptoms), it is difficult to diagnose aGVHD and differentiate it from other skin eruptions that can occur in this clinical setting; rigorous clinical and pathologic correlation are essential to reach a diagnosis. Other organs less commonly involved in aGVHD include hematopoietic system (cytopenias and hypogammaglobulinemia especially IgA deficiency), eyes (photophobia, hemorrhagic conjunctivitis, and lagophthalmos), the kidney (nephritis and nephrotic syndrome), and the lung (interstitial pneumonitis). Chronic GVHD (cGVHD), a major cause of morbidity and mortality in transplanted patients, may affect a wide range of organs with skin manifestations being the most frequent site of involvement. A panel of experts in the National Institutes of Health Consensus determined that lichen planus-­like lesions, sclerotic manifestations, and poikilodermatous changes are clinical features that are diagnostic of cGVHD [79]. Lichen planus-­like cGVHD is characterized by erythematous to violaceous papules and plaques, especially located in the dorsal aspects of the hand and feet, upper extremities, and trunk (Fig. 3.18). Lesions mimic true lichen planus, and patient may complain of pruritus. Lichen planus changes can also be seen only affecting hair follicles and with a Blaschko line distribution. Sclerotic manifestations may arise in areas of previous lichen planus-like cGVHD lesions or in normal skin. Depending on the depth of the sclerosis, different clinical presentations can be seen. Lichen sclerosus-­like lesions are characterized by superficial dermal sclerosis associated with hypertrophic

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Fig. 3.18  cGVHD, lichenoid type: Erythematous to violaceous papules and plaques involving the upper extremities

or atrophic epidermis. They in are usually seen the upper back as white thin plaques. In morphealike lesions, the sclerosis involves the entire dermis. The lesions are firm with pigmentary alteration ranging from hyperpigmented to hypopigmented and even skin-colored papules and plaques with loss of adnexal structures. Involvement of skin over articulation may restrict function (Fig.  3.19). Koebner phenomenon, lesions appearing in areas of trauma, may be seen. Deep sclerosis/eosinophilic fasciitis shows sclerosis in the septae of the subcutaneous tissue and fascia. Clinically, subcutaneous involvement presents as cellulitis-like rippled appearance of skin, while fascia involvement leads to prominent linear demarcation with contractures limiting motion. Pain and edema are seen especially in eosinophilic fasciitis like changes. Poikiloderma-­ type lesions in cGVHD consist of patches with mottled pigmentation and telangiectasias. Unusual presentations of cGVHD clinically mimicking lupus erythematosus and atopic dermatitis have been published. Oral lesions can be seen in 83% of the patients with manifestations similar to those seen in oral lichen planus: white plaque with reticulated or lacy border (Wickham’s striae) affecting the buccal mucosa, tongue, lips, or palate. Erosions and ulcerations can also be seen associated with pain and may inhibit oral intake. Perioral sclerosis can happen increasing the difficulty for oral hygiene and nutrition. Sicca symptoms may be secondary to inflammation of salivary glands. Diagnostic changes sufficient to

Fig. 3.19  cGVHD, sclerotic type: Firm lesion with hypopigmented skin. Involvement of skin over articulation may restrict function

establish the diagnosis of cGVHD besides the cutaneous and oral manifestations described above include presence of lichen planus-like lesions and scarring with stenosis of genitalia, strictures, or stenosis of the upper to mid third of the esophagus, bronchiolitis obliterans diagnosis with lung biopsy. Other manifestations that can be seen in cGVHD but are not sufficient for diagnosis include scarring and nonscarring alopecia, a variety of nail disorders (nail dystrophy to total nail loss), and ocular changes (e.g., conjunctivitis, keratoconjunctivitis sicca) (Table 3.5).

Prognosis or Course The severity of aGVHD is defined by an evaluation of degree of involvement of the skin, liver, and gastrointestinal tract. The stages of each organ are compiled in an overall grade, which has prognostic significance. Grade 2 is considered mild disease, while grade 4 life-threatening.

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Table 3.5  Diagnostic and distinctive clinical manifestations of chronic graft-versus-host disease Organ or site Skin

Diagnostic (sufficient to establish the diagnosis of chronic GVHD) Poikiloderma Lichen planus-like features Sclerotic features Morphea-like features Lichen sclerosus-like features

Nails

Scalp and body hair

Mouth

Lichen-type features

Eyes

Genitalia

Distinctive (seen in chronic GVHD, but insufficient alone to establish a diagnosis of chronic GVHD) Depigmentation Papulosquamous lesions

Dystrophy Longitudinal ridging, splitting, or brittle features Onycholysis Pterygium unguis Nail loss (usually symmetric; affects most nails) New onset of scarring or nonscarring scalp alopecia (after recovery from chemoradiotherapy) Scaling, Loss of body hair Xerostomia Mucocele Mucosal atrophy Pseudomembranes Ulcers New-onset dry, gritty, or painful eyes Cicatricial conjunctivitis Keratoconjunctivitis sicca Confluent areas of punctate keratopathy Erosions (female and male genitalia) Fissures (female and male genitalia) Ulcers (female genitalia)

Lichen planus-like features Lichen sclerosus-like features Vaginal scarring or stenosis Phimosis or urethral scarring or stenosis GI tract Esophageal web Strictures or stenosis in the upper to mid third of the esophagus Lung Bronchiolitis obliterans diagnosed with lung biopsy Air trapping and bronchiectasis on chest CT Myositis or polymyositis Fasciitis Muscle, Joint stiffness or contractures secondary to fascia, and joints fasciitis or sclerosis Diagnosis of chronic GVHD requires the presence of at least one diagnostic clinical sign of chronic GVHD or the presence of at least one distinctive manifestation confirmed by relevant tests in the same or another organ. Alternative diagnoses for clinical symptoms must be excluded.

Original table modified from Filipovich et al. [70] and Jagasia et al. [79]

Estimated 5-year survival for grade 3 and grade 4 is 25% and 5%, respectively [80]. However, these survival numbers are changing due to recent preventive treatments, and also they may vary depending on the organ affected as a stage IV cutaneous GVHD has better outcome than stage IV gastrointestinal GVHD. Although attempts to define a new staging system to better reflect prognosis and permits patient comparison have been done [81], no universal acceptance has been achieved.

Histopathology Histologically, aGVHD is an interface dermatitis with the characteristic epidermal vacuolar changes of the basal layer and dyskeratotic cells as well as a perivascular lymphocytic infiltrate in the superficial dermis (Fig. 3.20a, b). These changes can also be seen in the adnexal structures (Fig. 3.20c, d). The infiltrate in GVHD developed after solid organ transplant is more exuberant than that seen following bone marrow transplantation [82].

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a

b

c

e d

Fig. 3.20  aGVHD: The epidermis shows vacuolar changes of the basal layer and dyskeratotic cells as well as a perivascular lymphocytic infiltrate in the superficial der-

mis (a, b). Satellitosis is noted (arrow) (c). These changes can also be seen extending along the acrosyringium of sweat glands (d) and hair follicles (e)

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Migration of lymphocytes to the ­ epidermis is common. Satellite necrosis (two or more lymphocytes surrounding an apoptotic keratinocytes) has been described in this disease (Fig.  3.20e). Severe presentation of aGVHD demonstrates subepidermal bullae with full-­thickness epidermal necrosis. Lerner et  al. [83] described the following system to classify histologic features of aGVHD: • Grade 0  – normal skin or changes not referable to GVHD • Grade 1 – vacuolization of the basal layer at the dermal-epidermal junction • Grade 2 – basal layer vacuolization, necrotic epidermal cells, lymphocytic infiltrate • Grade 3  – grade 2 changes plus cleft formation at the dermal-epidermal junction • Grade 4 – grade 2 changes plus separation of the epidermis from the dermis Biopsies taken early in the course of GVHD may show non-specific changes in a retrospective study of 40 slides taken between 3 and 21 days after HCT, the histologic findings were non-specific in all cases [84]. The histologic features in a skin biopsy in a skin biopsy have poor correlation with clinical severity or prediction of clinical outcome [85, 86]. Moreover, normal-appearing skin may show histologic abnormalities [87].

a

Fig. 3.21  cGVHD, lichenoid type: The changes resemble idiopathic lichen planus with the presence of hyperkeratosis, hypergranulosis, and epidermal acanthosis with saw-

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Presently, it is unknown whether the skin biopsy influences the decision to treat or affect the outcome. Some studies have found little evidence to support this procedure [85, 86]. Even though there is no strong evidence to support a biopsy to diagnose aGVHD, a biopsy may provide information that added to other clinical findings can lead to the diagnosis of aGVHD or establish an alternative explanation for the skin manifestations. cGVHD histology varies depending on the type of skin involvement. Lichen planus-like papules resemble lichen planus with the presence of hyperkeratosis, hypergranulosis, and epidermal acanthosis with sawtooth rete ridges displaying vacuolar alteration of the basal layer associated and dyskeratotic cells (Fig. 3.21a, b). Band-like lymphocytic infiltrate is noted in the upper dermis. Sclerotic lesions may present lichen planus-like changes in the epidermis. Lichen sclerosus-like lesions display epidermal atrophy and homogenization of collagen in the superficial dermis as well as dermal edema. When the sclerosis affects most of the dermis in the form of thickened collagen bundles, producing the square shape of the biopsy (Fig. 3.22a, b), with loss of periadnexal fat (Fig. 3.22c) or disappearance of the adnexal structures, a diagnosis of morpheaform cGVHD can be rendered. The changes are indistinguishable from those seen in

b

tooth rete ridges (a). Vacuolar alteration of the basal layer, associated dyskeratotic cells, and a band-like lymphocytic infiltrate is noted (b)

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a

b

c

Fig. 3.22  cGVHD, sclerotic type: The dermis displays thickened collagen bundles, producing the square shape of the biopsy (a), (b), with loss of periadnexal fat (c). These changes characterize morpheaform cGVHD

specimens from true morphea/systemic sclerosis. Sclerotic GVHD involves the subcutaneous tissue in the form of thickening of the septae.

Differential Diagnosis The differential diagnosis of patients presenting with cutaneous aGVHD includes drug eruption, viral exanthem, eruption of lymphocyte recovery, engraftment syndrome, erythema multiforme, and toxic epidermal necrolysis. Differentiation between aGVHD and a drug reaction sometimes cannot be accomplished. Morbilliform eruption usually occurs 7–10 days after the first exposure. This period of time is reduced to 1–2 days after re-exposure. Drug reactions usually start in the torso, while aGVHD affects head, neck, and acral locations. Although the presence of eosinophils raises the concern of a drug reaction, its presence does not rule out aGVHD [88]. Viral infections (e.g., HHV-6, HHV-7, and cytomegalovirus, among others) can present with a morbilliform eruption. Biopsies of the viral exanthema show

subtle changes such as vacuolar alteration of the basal layer and perivascular lymphocytic infiltrate. Disease-specific clinical presentations and laboratory test may be useful to support the viral etiology of the eruption. Eruption of lymphocyte recovery consists of the return of lymphocytes to the peripheral circulation following marrow ablative therapy like in chemotherapy. This is a self-­ limited skin eruption associated with transient fever. Contrasting with aGVHD, gastrointestinal and hepatic abnormalities do not occur. Histologically it is very difficult to separate these two entities as both show finding similar to grade 1 or grade 2 of aGVHD [89]. Engraftment syndrome presents with a cutaneous eruption similar to aGVHD, fever, and signs of capillary leak syndrome (e.g., noncardiogenic pulmonary edema, weight gain, and hypoxia). It is considered to be part of the reaction to autologous HCT [90]. Erythema multiforme shares with aGVHD the presence of necrotic keratinocytes, subepidermal clefts, and vacuolization of basal keratinocytes. The clinical identification of target and targetoid lesions and the presence of collections of dys-

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keratotic cells in the epidermis point toward erythema multiforme. Severe cases of aGVHD share histologic features with toxic epidermal ­necrolysis such as the presence of subepidermal bullae and full-thickness epidermal necrosis making differentiation extremely difficult. Several disorders can mimic cGVHD. Lichen planus-like lesions may be less angular and may have a less well-defined border than lichen planus; however only the clinical history of transplantation will be able to separate these two entities. Lichenoid drug reaction and pityriasis lichenoides chronica share with cGVHD lichenoid type the presence of erythematous papules and a histologic pattern of interface dermatitis. The sclerotic variant of cGVHD can mimic lichen sclerosus, morphea, systemic sclerosis, and eosinophilic fasciitis. The clinical history of transplantation is seminal to reach a final diagnosis. Despite the fact that some helpful clues may differentiate aGVHD from some mimickers, it is necessary to keep in mind that there is no consistent histologic feature or constellation of findings that reliably diagnosed GVHD based on pathology alone. Therefore, clinical history is paramount when GVHD is a diagnostic consideration as it turns subtle or non-specific histologic features into predictive findings.

Summary Clinical Presentation • aGVHD affects the skin, GI, liver, and hematopoietic system –– Involve the ears, palms, or soles. The neck, face, and upper back can also be affected. –– Typically present as erythematous blanchable macules. –– With time, lesions generalize taking a morbilliform appearance and later on post-inflammatory hyperpigmentation. –– Patient may complain of pruritus. –– Oral involvement can be seen: erythema, erosions, ulcers, and xerostomia.

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–– Extracutaneous manifestations: nausea, emesis, abdominal cramps, diarrhea, and rising serum bilirubin concentration, among others. • cGVHD, skin is the most frequent site of involvement –– Lichen planus-like cGVHD: violaceous papules and plaques, especially located in dorsal hand and feet, arms, and trunk. –– Sclerotic cGVHD: superficial sclerosis will mimic lichen sclerosus, while deep sclerosis will present like morphea/scleroderma. Histologic Features • aGVHD: –– Squamous epithelium with vacuolar alteration of the basal layer. –– Dyskeratotic cells, sometimes surrounded by lymphocytes also called “satellitosis.” –– Perivascular chronic inflammation. –– Isolated eosinophils can be seen. –– Adnexal structures also may display vacuolar alteration and dyskeratotic cells. • cGVHD: –– Lichen planus-like cGVHD: Epidermal acanthosis with vacuolar changes of the basal layer and dyskeratotic cells Band-like chronic inflammation –– Sclerotic cGVHD: Thickening of collagen bundles with loss of space among fibers affecting upper dermis, lichen sclerosus-like lesions Thickening of collagen bundles with loss of space among fibers affecting entire dermis, morphea-­ like lesions Differential Diagnosis • aGVHD: a drug reaction, viral exanthema, and EM • cGVHD: lichen planus, lichen sclerosus, and morphea/scleroderma

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Take-Away Essentials Clinical Relevant Pearls • Early detection of GVHD is key to avoid morbidity in these patients. • A negative biopsy does not rule out GVHD, as the histologic changes may be patchy without a perfect correlation with the clinical presentation. • Learning the date of transplantation is essential as time affects the degree of development of histologic findings. • Selection of an area with adnexal structures to biopsy may increase the chances to detect the interface changes associated with GVHD. Pathology Interpretation Pearls • Clinical history is of paramount importance when GVHD is a diagnostic consideration as it turns subtle histologic changes into predictive features.

Pityriasis Lichenoides Pityriasis lichenoides is a self-limited dermatoses with a spectrum of clinical presentations and uncertain etiopathology. The acute presentation or pityriasis lichenoids et varioliformis acuta (PLEVA) is characerized by hemorrhagic papules that resolve with varioliform scars; while the less severe presentation consists of small scaly maculopapules, pityriasis lichenoides chronica (PLC). The distinction between acute and chronic presentation is not always possible with overlapping cases, a not uncommon finding.

Etiology and/or Pathogenesis The pathogenesis of pityriasis lichenoides is uncertain. It has been postulated a cell-mediated immune mechanisms, probably secondary to a viral infection (e.g. Epstein-Barr virus, ­parvovirus

B19, adenovirus, HIV, HHV-8, and herpes zostervaricella virus) [91]. Pityriasis lichenoides has been reported in patients suffering from lymphomatoid papulosis [92]. Although it is favored to be two different diseases pathogenetically [93]; they are part of the spectrum of clonal T-cell lymphoproliferative disorders [94]. Besides the infectious and lymphoproliferative theories of pathogenesis, an immune complex-­mediated vasculitis etiology has also been proposed, although least favored. Occasionally, PLC has been described to arise following the use of systemic medication such as TNF-alpha inhibitors (e.g., adalimumab and infliximab).

Clinical Presentation Pityriasis lichenoides may develop at all ages; however, it has a predilection for males in the second and third decades of life with no gender predilection. The pediatric presentation is most frequent of the chronic type. Other characteristics most commonly seen in the pediatric rather than adult cases include unremitting course, greater lesion distribution, more depigmentation, and lower response to conventional treatment [95]. Lesions may vary in number, from a few to several hundreds, affecting commonly the anterior aspect of the trunk and the flexor surfaces of the proximal parts of the extremities. Individual lesions classically last from weeks to several months. Rarely the patient may complain about pruritus; most cases are asymptomatic. PLEVA presents as a papular eruption that may become hemorrhagic or crusted leading to superficial varioliform scar in the healing state. The rare ulceronecrotic variant, also called Mucha-­ Habermann disease, is usually accompanied by constitutional symptoms. Occasionally, this variant is fatal [96]. The chronic form is more scaly and less hemorrhagic, presenting as red-brown inflammatory papules and macules with a classic centrally adherent “mica” scale. In dark-skinned patients, marked post-inflammatory hypopigmentation is common. PLC may evolve from PLEVA or arise independently.

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Prognosis or Course The median duration of the disease is approximately 20  months (range, 3–132  months) in patients with PLC and 18  months (range, 4–108 months) for PLEVA. Three quarters fo the patients present with multiple episodes. Pediatric presentation has a more unrelenting course. A form of mycosis fungoides that mimics or arises in association with pityriasis lichenoides has been reported in the pediatric population as well as adults [97]. Magro and colleagues included pityriasis lichenoides with the T-cell dyscrasias [98]. Furthermore, additional study found that half of all cases of PLC had a monoclonal and/or oligoclonal T-cell repertoire. Interestingly, a recent study found nearly one fifth of the cases diagnosed as PLC showed a predominantly gamma-delta T-cell phenotype, even though the cases show a benign clinical course. The authors proposed that the few cases that progressed to mycosis fungoides might be the result of a control mechanism led by the CD8+ and CD4/CD25+ regulatory T cells [99].

Histopathology Histologically, PLEVA is characterized by epidermis with basal vacuolar changes, spongiosis, and numerous degenerated keratinocytes at different epidermal levels, especially in the upper layers. In severe or advanced cases, extensive epidermal necrosis is seen. Parakeratosis is common as well as the presence of neutrophils forming a keratotic crust (Fig.  3.23a, b). Superficial perivascular moderately dense inflammatory infiltrate is noted, sometimes involving the lower dermis with a wedge-shaped pattern (Fig. 3.23c). In florid cases, perivascular neutrophils with exocytosis are seen. The vessels may display endothelial swelling and extravasation of red blood cells. Rare cases of leukocytoclastic vasculitis have been reported [100]. Papillary dermis edema is variable present. The histologic findings of PLC closely resemble those seen in PLEVA; both show lymphocyte

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exocytosis, interface dermatitis, mild spongiosis, superficial lymphocytic infiltrate, and dermal hemorrhage. However, in PLC the changes are subtle and mostly superficial than in PLEVA (Fig. 3.24). There are small areas of basal vacuolar changes associated with focal lymphocytic exocytosis and rare dyskeratotic cells. Lymphocytic vasculitis is rarely detected. Late lesions display dermal fibrosis and presence of melanophages. Immunohistochemical studies have demonstrated that the majority of the inflammatory cells are CD3+ T-cell lymphocytes, mainly cytotoxic/ suppressor CD8+ type in PLEVA, while CD4 appears to dominate the infiltrate in PLC [94]. Moreover, T-cell intracellular antigen 1 (TIA-1) is most frequently detected in PLEVA infiltrate than PLC cells which show increased detection of FOXP3, a marker of T regulatory cells.

Differential Diagnosis PLEVA can occasionally mimic EM. The presence of marked inflammatory exocytosis in association with wedge-shaped perivascular dermal lymphocytes with lymphocytic vasculitis will point toward PLEVA.  Lymphomatoid papulosis (LyP) can also be considered in the differential diagnosis to the point that some authors described the latter as pityriasis lichenoides with atypia. In addition, both diseases may show CD30 expression and the presence of a clonal T-cell gene rearrangement. However, the degree of atypia seen in LyP is quite striking; on the other hand, CD30 is only focally detected in pityriasis lichenoides. Some variant of mycosis fungoides may be difficult to separate from PLC, both clinically and histologically. A recent study revealed four patients with eventual diagnoses of papular mycosis fungoides whom had small reddish brown papules believed to by PLC. Additional biopsies in these patients demonstrated ­characteristic findings of mycosis fungoides. In these cases clinicopathologic correlation is crucial.

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a

b

c

Fig. 3.23  Pityriasis lichenoides et varioliformis acuta (PLEVA): The low power shows interface changes associated with superficial and deep perivascular inflammatory infiltrate with a wedge-shaped distribution (a). The epi-

Fig. 3.24  Pityriasis lichenoides chronica (PLC): Like PLEVA, PLC shows lymphocyte exocytosis, interface dermatitis, and superficial lymphocytic infiltrate. In PLC the changes are subtle and mostly superficial

dermis displays parakeratosis with neutrophils in the stratum corneum, dyskeratotic cells at different levels of the epithelium, and vacuolar changes of the basal layer (b). Mixed perivascular inflammation is seen in these cases (c)

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Summary

Take-Away Essentials

Clinical Presentation • Self-limited dermatosis, approximately 20  months, affecting most frequently males in the second and third decade. • PLEVA: acute presentation of hemorrhagic papules that resolve with varioliform scars. • PLC: chronic presentation with small maculopapular lesions with centrally adherent “mica” scale. • Lesions from acute and chronic presentation can coexist in one patient.

Clinical Relevant Pearls • When considered as part of the differential diagnosis of a papular eruption in a child, PLC is the most frequent presentation. • Pediatric cases may be unusual as they display a more unremitting course with larger number of lesions and more pronounce pigmentary alteration.

Histologic Features • PLEVA –– Epidermal acanthosis with hyperand parakeratosis –– Dyskeratotic cells at different levels of the epidermis –– Wedge-shaped perivascular inflammatory infiltrate –– Red cell extravasation • PLC –– Epidermis with focal vacuolar alteration of the basal layer –– Few dyskeratotic cells –– Mild perivascular superficial chronic inflammation Differential Diagnosis • Lymphomatoid papulosis • Mycosis fungoides

Pathology Interpretation Pearls • The presence of CD30+ cells in pityriasis lichenoides should not be misinterpreted as evidence of a CD30+ lymphoproliferative disorder. Immunohistochemical/Molecular Findings • A positive T-cell clone can be detected; therefore, this diagnostic tool cannot be used to differentiate pityriasis lichenoides from mycosis fungoides. • When interpreting the immunoprofile of the infiltrate, keep in mind the age of the lesion.

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Vignettes Case 1 Clinical History A 34-year-old male visits the ER due to a rapid spread of a papulomacular erythematous rash affecting the arms, trunk, and palms. Focally blisters are noted (Fig. 3.25). The lesions in the hands were round with dusky center (Fig. 3.26). Recently, the patient was treated for a urinary tract infection. Microscopic Description The biopsy shows effacement of the dermoepidermal junction with superficial perivascular chronic inflammation (Fig. 3.27). The epidermis demonstrates vacuolar alteration of the basal layer and dyskeratotic cells (Fig. 3.28a). These changes are also seen affecting the sweat glands (Fig.  3.28b). Perivascular lymphocytic infiltrate of the superficial vascular plexus is noted admixed with some eosinophils. Brown-Brenn or tissue Gram stain shows bacterial forms in the stratum corneum.

Fig. 3.25  Focal blister formation in a patient with papulomacular erythematous rash

(continued)

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Fig. 3.26  Round lesions involving the palm with dusky center

Fig. 3.27  The biopsy shows effacement of the dermoepidermal junction associated with superficial perivascular inflammation

(continued)

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a

b

Fig. 3.28  Vacuolar alteration and dyskeratotic cells are seen in the epidermis (a) and eccrine glands (b)

Diagnosis Erythema multiforme (EM) Discussion This is a cytotoxic reaction most frequently secondary to infection and medications. The marked involvement of the acrosyringium of the sweat glands and eosinophils in the infiltrate favors a reaction secondary to a medication. The presence of palmar lesions with target appearance also favors the diagnosis of EM.

Case 2 Clinical History A 42-year-old female with recurrent lesion on the arm (Fig. 3.29). Microscopic Description The biopsy shows vacuolar alteration of the basal layer with numerous dyskeratotic cells at ­different levels of the epidermis. Melanophages and perivascular lymphocytic infiltrate with admixed eosinophils are noted (Fig. 3.30a, b). (continued)

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Fig. 3.29 Recurrent erythematous macule on the upper arm

a

Fig. 3.30  The biopsy shows interface changes with a band-like inflammatory reaction (a). The epidermis displays numerous dyskeratotic cells at different lev-

b

els. A mixed infiltrate of lymphocytes and eosinophils associated with melanophages can be seen (b)

Diagnosis Fixed drug eruption Discussion Interface changes can be seen in different type of drug reactions. However, fixed drug eruption usually shows presence of melanophages, neutrophils, and eosinophils in the infiltrate. In addition, the clinical history of recurrent lesions after exposure to a medication in the same anatomic location is essential for the diagnosis of this disease.

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Case 3 Clinical History A 50-year-old male presenting in the emergency room with erythroderma (Fig. 3.31). Microscopic Description There is a band-like lymphocytic infiltrate in the upper dermis with focal epidermotropism (Fig. 3.32a, b). No Pautrier microabscesses are noted or high-grade lymphocytic atypia. The immunoprofile (CD3, CD4, CD8, and CD7) fails to show significant abnormalities.

Fig. 3.31  Diffuse erythroderma affecting the trunk

a

b

Fig. 3.32  The sections show a band-like lymphocytic infiltrate in upper dermis (a) with focal epidermotropism (b). The lymphocytes show mild atypia

(continued)

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Diagnosis Sézary syndrome (SS). Discussion SS originates from skin-homing central memory T cells. It usually affects older men. Besides the 80% total body surface area showing erythema, these patients present high blood tumor burden with positive clonality by T-cell gene rearrangement in the blood (either with BIOMED-2 primers or more recently, next-generation deep sequencing); absolute Sézary cell count ≥1000/mm3, expanded CD4+ or CD3+ cells with CD4/CD8 ratio of ≥10; flow cytometry, expanded CD4+ cells with abnormal immunophenotype, including loos of CD7 (≥40%) or CD26 (≥30%). One third of the cases can present with non-­specific changes in the skin biopsy; only 38% of patients suffering from SS show classic histologic features associated with mycosis fungoides. The biopsy of this patient shows minimal abnormalities. The diagnosis of SS in this case was reached by detecting an absolute count of Sézary cells of ≥1000/mm3, positive T-cell clone, and flow cytometry demonstrating expanded CD4+ cells with abnormal immunophenotype, including loss of CD7 (≥40%).

References 1. Morhenn VB.  The etiology of lichen planus. A hypothesis. Am J Dermatopathol. 1986;8(2):154–6. 2. Sugerman PB, Satterwhite K, Bigby M. Autocytotoxic T-cell clones in lichen planus. Br J Dermatol. 2000;142(3):449–56. 3. Shiohara T.  The lichenoid tissue reaction. An immunological perspective. Am J Dermatopathol. 1988;10(3):252–6. 4. Choi HJ, Ku JK, Kim MY, Kang H, Cho SH, Kim HO, et  al. Possible role of Fas/Fas ligand-mediated apoptosis in the pathogenesis of fixed drug eruption. Br J Dermatol. 2006;154(3):419–25. 5. Mahood JM. Familial lichen planus. A report of nine cases from four families with a brief review of the literature. Arch Dermatol. 1983;119(4):292–4. 6. Kim JH, Krivda SJ.  Lichen planus confined to a radiation therapy site. J Am Acad Dermatol. 2002;46(4):604–5. 7. Shemer A, Weiss G, Trau H. Wolf’s isotopic response: a case of zosteriform lichen planus on the site of healed herpes zoster. J Eur Acad Dermatol Venereol. 2001;15(5):445–7. 8. Singh SK, Saikia UN, Ajith C, Kumar B. Squamous cell carcinoma arising from hypertrophic lichen planus. J Eur Acad Dermatol Venereol. 2006;20(6):745–6. 9. 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(2):207–14.

10. Bardazzi F, Landi C, Orlandi C, Neri I, Varotti C. Graham Little-Piccardi-Lasseur syndrome following HBV vaccination. Acta Derm Venereol. 1999;79(1):93. 11. Irvine C, Irvine F, Champion RH.  Long-term follow-up of lichen planus. Acta Derm Venereol. 1991;71(3):242–4. 12. Patel GK, Turner RJ, Marks R.  Cutaneous lichen planus and squamous cell carcinoma. J Eur Acad Dermatol Venereol. 2003;17(1):98–100. 13. Halonen P, Jakobsson M, Heikinheimo O, Riska A, Gissler M, Pukkala E. Cancer risk of Lichen planus: a cohort study of 13,100 women in Finland. Int J Cancer. 2018;142(1):18–22. 14. Lipsker D, Cribier B, Girard-Lemaire F, Flori E, Grosshans E.  Genetic mosaicism in an acquired inflammatory dermatosis following the lines of Blaschko. Arch Dermatol. 2000;136(6):805–7. 15. Keegan BR, Kamino H, Fangman W, Shin HT, Orlow SJ, Schaffer JV. “Pediatric blaschkitis”: expanding the spectrum of childhood acquired Blaschko-linear dermatoses. Pediatr Dermatol. 2007;24(6):621–7. 16. Lee HJ, Kang WH, Hann SK.  Acquired Blaschko dermatitis: acquired relapsing self-healing Blaschko dermatitis. J Dermatol. 1996;23(9):639–42. 17. Megahed M, Reinauer S, Scharffetter-Kochanek K, Milde P, Hölzle E, Goerz G, et  al. Acquired relapsing self-healing Blaschko dermatitis. J Am Acad Dermatol. 1994;31(5 Pt 2):849–52. 18. Grosshans EM. Acquired Blaschko linear dermatoses. Am J Med Genet. 1999;85(4):334–7. 19. Han S-H, Song H-J, Hong W-K, Lee H-S, Choi G-S, Shin J-H.  A case of adult blaschkitis with

90 features of interface dermatitis. Br J Dermatol. 2008;159(1):247–8. 20. Hofer T. Lichen striatus in adults or “adult blaschkitis?.” There is no need for a new naming. Dermatology. 2003;207(1):89–92. 21. Magro CM, Crowson AN.  Lichenoid and granulomatous dermatitis. Int J Dermatol. 2000;39(2): 126–33. 22. Diaz-Perez JA, Beveridge MG, Victor TA, Cibull TL.  Granulomatous and lichenoid dermatitis after IgG4 anti-PD-1 monoclonal antibody therapy for advanced cancer. J Cutan Pathol. 2018;45(6):434–8. 23. Crowson AN, Magro CM, Mihm MC. Interface dermatitis. Arch Pathol Lab Med. 2008;132(4):652–66. 24. Margolis RJ, Bhan A, Mihm MC, Bernhardt M.  Erythema multiforme in a patient with T cell chronic lymphocytic leukemia. J Am Acad Dermatol. 1986;14(4):618–27. 25. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. 1983;8(6):763–75. 26. Weston WL. Herpes-associated erythema multiforme. J Invest Dermatol. 2005;124(6):xv–xvi. 27. Weston WL, Brice SL, Jester JD, Lane AT, Stockert S, Huff JC. Herpes simplex virus in childhood erythema multiforme. Pediatrics. 1992;89(1):32–4. 28. Weston WL, Brice SL.  Atypical forms of herpes simplex-associated erythema multiforme. J Am Acad Dermatol. 1998;39(1):124–6. 29. Tay YK, Huff JC, Weston WL.  Mycoplasma pneumoniae infection is associated with Stevens-Johnson syndrome, not erythema multiforme (von Hebra). J Am Acad Dermatol. 1996;35(5 Pt 1):757–60. 30. Schalock PC, Brennick JB, Dinulos JGH. Mycoplasma pneumoniae infection associated with bullous erythema multiforme. J Am Acad Dermatol. 2005;52(4):705–6. 31. Schalock PC, Dinulos JGH.  Mycoplasma pneumoniae-­ induced Stevens-Johnson syndrome without skin lesions: fact or fiction? J Am Acad Dermatol. 2005;52(2):312–5. 32. Vanfleteren I, Van Gysel D, De Brandt C.  Stevens-­ Johnson syndrome: a diagnostic challenge in the absence of skin lesions. Pediatr Dermatol. 2003;20(1):52–6. 33. Hughes J, Burrows NP. Infectious mononucleosis presenting as erythema multiforme. Clin Exp Dermatol. 1993;18(4):373–4. 34. Carrera C, Alsina M, de Pablo IM, Iranzo P, Herrero C.  Erythema multiforme presenting as cholestatic acute hepatitis caused by Epstein-Barr virus. J Eur Acad Dermatol Venereol. 2006;20(10):1350–2. 35. Werchniak AE, Schwarzenberger K.  Poison ivy: an underreported cause of erythema multiforme. J Am Acad Dermatol. 2004;51(5 Suppl):S159–60. 36. Arias D, Requena L, Hasson A, Gutierrez M, Domine M, Martin L, et  al. Localized epidermal necrolysis (erythema multiforme-like reaction) following intravenous injection of vinblastine. J Cutan Pathol. 1991;18(5):344–6.

M. A. Selim and A. R. G. Cardones 37. Duncan KO, Tigelaar RE, Bolognia JL.  Stevens-­ Johnson syndrome limited to multiple sites of radiation therapy in a patient receiving phenobarbital. J Am Acad Dermatol. 1999;40(3):493–6. 38. Kokuba H, Imafuku S, Huang S, Aurelian L, Burnett JW. Erythema multiforme lesions are associated with expression of a herpes simplex virus (HSV) gene and qualitative alterations in the HSV-specific T-cell response. Br J Dermatol. 1998;138(6):952–64. 39. Aurelian L, Kokuba H, Burnett JW.  Understanding the pathogenesis of HSV-associated erythema multiforme. Dermatology. 1998;197(3):219–22. 40. Kokuba H, Imafuku S, Burnett JW, Aurelian L.  Longitudinal study of a patient with herpes-­ simplex-­ virus-associated erythema multiforme: viral gene expression and T cell repertoire usage. Dermatology. 1999;198(3):233–42. 41. Khalil I, Lepage V, Douay C, Morin L, al-Daccak R, Wallach D, et al. HLA DQB1∗0301 allele is involved in the susceptibility to erythema multiforme. J Invest Dermatol. 1991;97(4):697–700. 42. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129(1):92–6. 43. Zohdi-Mofid M, Horn TD. Acrosyringeal concentration of necrotic keratinocytes in erythema multiforme: a clue to drug etiology. Clinicopathologic review of 29 cases. J Cutan Pathol. 1997;24(4):235–40. 44. Rzany B, Mockenhaupt M, Baur S, Schröder W, Stocker U, Mueller J, et  al. Epidemiology of erythema exsudativum multiforme majus, StevensJohnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry. J Clin Epidemiol. 1996;49(7): 769–73. 45. Quinn AM, Brown K, Bonish BK, Curry J, Gordon KB, Sinacore J, et  al. Uncovering histologic criteria with prognostic significance in toxic epidermal necrolysis. Arch Dermatol. 2005;141(6):683–7. 46. Ozkaya-Bayazit E.  Independent lesions of fixed drug eruption caused by trimethoprim-sulfamethoxazole and tenoxicam in the same patient: a rare case of polysensitivity. J Am Acad Dermatol. 2004;51(2 Suppl):S102–4. 47. George AO, Ogunbiyi AO.  Fixed drug eruption and fixed drug-like eruption. Int J Dermatol. 2005;44(4):349–50. 48. Chan HL. Fixed drug eruptions. A study of 20 occurrences in Singapore. Int J Dermatol. 1984;23(9):607–9. 49. Kuokkanen K. Erythema fixum of the genitals and the mucous membranes. Int J Dermatol. 1974;13(1):4–8. 50. Nussinovitch M, Prais D, Ben-Amitai D, Amir J, Volovitz B. Fixed drug eruption in the genital area in 15 boys. Pediatr Dermatol. 2002;19(3):216–9. 51. Ozkaya E.  Fixed drug eruption: state of the art. J Dtsch Dermatol Ges. 2008;6(3):181–8. 52. Ozkaya-Bayazit E, Akar U.  Fixed drug eruption induced by trimethoprim-sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype. J Am Acad Dermatol. 2001;45(5):712–7.

3  Lichenoid and Interface Dermatitis 53. Sigurdsson V, Steegmans PH, van Vloten WA.  The incidence of erythroderma: a survey among all dermatologists in The Netherlands. J Am Acad Dermatol. 2001;45(5):675–8. 54. Pal S, Haroon TS.  Erythroderma: a clinico-etiologic study of 90 cases. Int J Dermatol. 1998;37(2): 104–7. 55. Sigurdsson V, Toonstra J, Hezemans-Boer M, van Vloten WA.  Erythroderma. A clinical and follow-up study of 102 patients, with special emphasis on survival. J Am Acad Dermatol. 1996;35(1):53–7. 56. Akhyani M, Ghodsi ZS, Toosi S, Dabbaghian H. Erythroderma: a clinical study of 97 cases. BMC Dermatol. 2005;5(1):5. 57. Walsh NM, Prokopetz R, Tron VA, Sawyer DM, Watters AK, Murray S, et  al. Histopathology in erythroderma: review of a series of cases by multiple observers. J Cutan Pathol. 1994;21(5):419–23. 58. Abrahams I, McCarthy JT, Sanders SL. 101 cases of exfoliative dermatitis. Arch Dermatol. 1963;87:96–101. 59. Ram-Wolff C, Martin-Garcia N, Bensussan A, Bagot M, Ortonne N. Histopathologic diagnosis of lymphomatous versus inflammatory erythroderma: a morphologic and phenotypic study on 47 skin biopsies. Am J Dermatopathol. 2010;32(8):755–63. 60. Zip C, Murray S, Walsh NM.  The specificity of histopathology in erythroderma. J Cutan Pathol. 1993;20(5):393–8. 61. Tomasini C, Aloi F, Solaroli C, Pippione M. Psoriatic erythroderma: a histopathologic study of forty-five patients. Dermatology. 1997;194(2):102–6. 62. Botella-Estrada R, Sanmartín O, Oliver V, Febrer I, Aliaga A.  Erythroderma. A clinicopathological study of 56 cases. Arch Dermatol. 1994;130(12): 1503–7. 63. Husain Z, Reddy BY, Schwartz RA.  DRESS syndrome: Part I.  Clinical perspectives. J Am Acad Dermatol. 2013;68(5):693.e1–14. 64. Bocquet H, Bagot M, Roujeau JC.  Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg. 1996;15(4):250–7. 65. Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses. Allergol Int. 2006;55(1):1–8. 66. Kardaun SH, Sekula P, Valeyrie-Allanore L, Liss Y, Chu CY, Creamer D, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169(5):1071–80. 67. Roujeau J-C, Dupin N. Virus reactivation in drug reaction with eosinophilia and systemic symptoms (Dress) results from a strong drug-specific immune response. J Allergy Clin Immunol Pract. 2017;5(3):811–2. 68. Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124(7):588–97.

91 69. Ortonne N, Valeyrie-Allanore L, Bastuji-Garin S, Wechsler J, de Feraudy S, Duong T-A, et  al. Histopathology of drug rash with eosinophilia and systemic symptoms syndrome: a morphological and phenotypical study. Br J Dermatol. 2015; 173(1):50–8. 70. Filipovich AH, Weisdorf D, Pavletic S, Socié G, Wingard JR, Lee SJ, et  al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I.  Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945–56. 71. Shulman HM, Cardona DM, Greenson JK, Hingorani S, Horn T, Huber E, et  al. NIH Consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II.  The 2014 Pathology Working Group Report. Biol Blood Marrow Transplant. 2015;21(4):589–603. 72. Jagasia M, Arora M, Flowers MED, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119(1):296–307. 73. Lee S-E, Cho B-S, Kim J-H, Yoon J-H, Shin S-H, Yahng S-A, et  al. Risk and prognostic factors for acute GVHD based on NIH consensus criteria. Bone Marrow Transplant. 2013;48(4):587–92. 74. Flowers MED, Inamoto Y, Carpenter PA, Lee SJ, Kiem H-P, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117(11):3214–9. 75. Peñas PF, Zaman S. Many faces of graft-versus-host disease. Australas J Dermatol. 2010;51(1):1–10. 76. Goddard DS, Horn BN, McCalmont TH, Cordoro KM.  Clinical update on graft-versus-­host disease in children. Semin Cutan Med Surg. 2010;29(2): 92–105. 77. Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai acute GVHD international consortium. Biol Blood Marrow Transplant. 2016;22(1):4–10. 78. Vargas-Díez E, García-Díez A, Marín A, Fernández-­ Herrera J. Life-threatening graft-vs-host disease. Clin Dermatol. 2005;23(3):285–300. 79. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21(3):389–401. 80. Cahn J-Y, Klein JP, Lee SJ, Milpied N, Blaise D, Antin JH, et  al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Société Française de Greffe de Moëlle et ThérapieCellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood. 2005;106(4):1495–500.

92 81. Leisenring WM, Martin PJ, Petersdorf EW, Regan AE, Aboulhosn N, Stern JM, et  al. An acute graft-­ versus-­ host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens. Blood. 2006;108(2):749–55. 82. Walling HW, Voigt MD, Stone MS.  Lichenoid graft vs. host disease following liver transplantation. J Cutan Pathol. 2004;31(2):179–84. 83. Lerner KG, Kao GF, Storb R, Buckner CD, Clift RA, Thomas ED.  Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors. Transplant Proc. 1974;6(4):367–71. 84. Kuykendall TD, Smoller BR. Lack of specific ity 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(6):1081–5. 85. Kohler S, Hendrickson MR, Chao NJ, Smoller BR. Value of skin biopsies in assessing prognosis and progression of acute graft-versus-host disease. Am J Surg Pathol. 1997;21(9):988–96. 86. Zhou Y, Barnett MJ, Rivers JK.  Clinical sig nificance of skin biopsies in the diagnosis and management of graft-vs-host disease in early postallogeneic bone marrow transplantation. Arch Dermatol. 2000;136(6):717–21. 87. Vassallo C, Brazzelli V, Alessandrino PE, Varettoni M, Ardigò M, Lazzarino M, et  al. Normal-looking skin in oncohaematological patients after allogenic bone marrow transplantation is not normal. Br J Dermatol. 2004;151(3):579–86. 88. Marra DE, McKee PH, Nghiem P. Tissue eosinophils and the perils of using skin biopsy specimens to distinguish between drug hypersensitivity and cutaneous graft-versus-host disease. J Am Acad Dermatol. 2004;51(4):543–6. 89. Horn TD, Redd JV, Karp JE, Beschorner WE, Burke PJ, Hood AF.  Cutaneous eruptions of lymphocyte recovery. Arch Dermatol. 1989;125(11):1512–7.

M. A. Selim and A. R. G. Cardones 90. Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27(9):893–8. 91. Almagro M, Del Pozo J, Martínez W, Silva JG, Peña C, Yebra-Pimentel MT, et al. Pityriasis lichenoides-­ like exanthem and primary infection by Epstein-Barr virus. Int J Dermatol. 2000;39(2):156–9. 92. Vonderheid EC, Kadin ME, Gocke CD.  Lymphomatoid papulosis followed by pityriasis lichenoides: a common pathogenesis? Am J Dermatopathol. 2011;33(8):835–40. 93. Willemze R, Scheffer E.  Clinical and histologic differentiation between lymphomatoid papulosis and pityriasis lichenoides. J Am Acad Dermatol. 1985;13(3):418–28. 94. Shieh S, Mikkola DL, Wood GS.  Differentiation and clonality of lesional lymphocytes in pityriasis lichenoides chronica. Arch Dermatol. 2001;137(3): 305–8. 95. Wahie S, Hiscutt E, Natarajan S, Taylor A. Pityriasis lichenoides: the differences between children and adults. Br J Dermatol. 2007;157(5):941–5. 96. Malnar T, Milavec-Puretic V, Rados J, Zarkovic K, Dobric I.  Febrile ulceronecrotic pityriasis lichenoides et varioliformis acuta with fatal outcome. J Eur Acad Dermatol Venereol. 2006;20(3):303–7. 97. Wang S-H, Hsiao C-H, Hsiao P-F, Chu CY. Adult pityriasis lichenoides-like mycosis fungoides with high density of CD8-positive T-lymphocytic infiltration. J Eur Acad Dermatol Venereol. 2007;21(3):401–2. 98. Magro C, Crowson AN, Kovatich A, Burns F.  Pityriasis lichenoides: a clonal T-cell lymphoproliferative disorder. Human Pathol. 2002;33(8): 788–95. 99. Magro CM, Crowson AN, Morrison C, Li J.  Pityriasis lichenoides chronica: stratification by molecular and phenotypic profile. Human Pathol. 2007;38(3):479–90. 100. Fink-Puches R, Soyer HP, Kerl H. Febrile ulceronecrotic pityriasis lichenoides et varioliformis acuta. J Am Acad Dermatol. 1994;30(2 Pt 1):261–3.

4

Neutrophilic and Pustular Eruptions Sigrid M. C. Möckel and Dieter Metze

Contents Introduction

 96

Subcorneal Pustular Dermatosis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 96  96  96  96  97  97

Erosive Pustular Dermatosis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 97  97  98  98  98  98

Pustular Dermatoses of Infancy Toxic Erythema of Neonate Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Eosinophilic Pustular Folliculitis of Infancy Etiology and/or Pathogenesis Clinical Presentation

 99  99  99  99  100  100  100  100  100  101

S. M. C. Möckel (*) Unit of Dermatopathology, Department of Dermatology, Technical University of Munich, School of Medicine, Munich, Germany e-mail: [email protected] D. Metze Department of Dermatology, University Hospital Münster, Münster, Germany e-mail: [email protected] © Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_4

93

S. M. C. Möckel and D. Metze

94  rognosis or Clinical Course P Histopathology Differential Diagnosis Infantile Acropustulosis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 101  101  101  102  102  102  102  102  102

Acute Generalized Exanthematous Pustulosis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 103  103  103  103  103  103

Generalized Pustular Psoriasis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 104  104  104  105  105  105

Erythema Elevatum Diutinum Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 106  106  106  106  107  107

Bowel-Associated Dermatosis-Arthritis Syndrome Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 108  108  109  109  109  109

Neutrophilic Eccrine Hidradenitis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 110  110  110  110  110  111

Sweet Syndrome Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 111  111  112  112  113  114

Neutrophilic Dermatosis of the (Dorsal) Hands Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 114  114  115  115  115  115

4  Neutrophilic and Pustular Eruptions

95

Pyoderma Gangrenosum Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 115  115  116  116  116  117

Neutrophilic Urticarial Dermatosis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 118  118  118  118  118  118

Erythema Marginatum Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 119  119  119  119  119  119

Neutrophilic Drug Eruption Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 120  120  120  121  121  121

Eosinophilic Cellulitis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 122  122  122  122  122  122

Hypereosinophilic Syndrome Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 123  123  123  123  124  124

 osinophilic Polymorphic and Pruritic Eruption Associated E with Radiotherapy Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 125  125  125  125  125  125

Case Studies Case 1 Clinical History Microscopic Description Diagnosis

 127  127  127  127  128

S. M. C. Möckel and D. Metze

96 Case 2 Clinical History Microscopic Description Diagnosis Discussion Case 3 Clinical History Microscopic Description Diagnosis Discussion Case 4 Clinical History Microscopic Description Diagnosis Discussion

 128  128  128  130  130  130  130  130  132  132  132  132  132  133  133

References

Introduction Dermatopathology has played a major role in the diagnosis of inflammatory and neoplastic dermatoses. In recent years, neutrophilic and pustular dermatoses have become a major topic, as key mutations have been found, leading to a better understanding and classification of these dermatoses and their etiopathology.

Subcorneal Pustular Dermatosis Etiology and/or Pathogenesis First described by Sneddon and Wilkinson in 1956, the exact pathomechanism of this sterile pustular eruption has not been unraveled yet. As subcorneal pustular dermatosis (SCPD) has been observed to be associated with several systemic diseases, i.e., monoclonal gammopathies and other lymphoproliferative disorders, especially multiple myeloma [1], there might be a certain predisposition for immune dysregulation [2]. Clinical reports of successful off-label use of tumor necrosis factor (TNF) blocking agents in SCPD [3] might reflect the role of TNF-alpha as one of the chemotactic factors implicated in neutrophil recruitment in the skin [4]. There is debate, whether SCPD is

 133

an independent disease entity or rather represents a subentity of other diseases [5]. The differentiation between SCPD, acute generalized exanthematous pustulosis (AGEP), and psoriasis can be difficult; an overlap with IgA pemphigus has been reported [6, 7].

Clinical Presentation SCPD typically presents in middle-aged women [8] but can affect all age groups. Cases reported in children and adolescents often showed atypical features [9]. Patients present with relapsing symmetrical pustular eruptions affecting trunk, intertriginous areas, and flexural aspects of the extremities. Pustules can involve palms and soles as well. Face and mucous membranes are rarely affected. The flaccid pustules rupture easily, leading to superficial scaling, crusting, and faint hyperpigmentation [8].

Prognosis or Clinical Course Unless there is association with an underlying malignancy, the disease shows a benign course. The pustules are initially sterile, but secondary infection may occur.

4  Neutrophilic and Pustular Eruptions

Histopathology Early lesions show superficial perivascular neutrophilic infiltrates with occasional eosinophils. There is transepidermal migration of neutrophils forming subcorneal pustules without spongiosis or frank acantholysis.

97

Differential Diagnosis • Pustular psoriasis • IgA pemphigus • Superficial candidiasis • Impetigo • Acute generalized exanthematous pustulosis

Differential Diagnosis Pustular psoriasis typically has suprabasilar mitotic figures and some spongiosis. IgA pemphigus is characterized by intraepidermal vesicles, pustules, and variable acantholysis; intercellular IgA deposits are seen in direct immunofluorescence (DIF). In superficial candidiasis there is spongiform pustulation and fungal elements that are stained in periodic acid-Schiff (PAS) stain. Impetigo can be bullous with formation of subcorneal bulla and few acantholytic cells containing Gram-positive cocci. AGEP is characterized by subcorneal or superficial intraepidermal pustules with mild spongiosis. However, spongiform pustulation is less prominent as compared to in pustular psoriasis. Often, there are apoptotic keratinocytes or eosinophils.

Takeaway Essentials Clinical Relevant Pearls • Check for underlying associated disorders (monoclonal gammopathies, lymphoproliferative disorders, pyoderma gangrenosum, and superinfection). Pathology Interpretation Pearls • A histologic diagnosis is not possible. The mentioned differential diagnoses must be ruled out clinically, by immunofluorescence and microbiologic tests.

Summary

Erosive Pustular Dermatosis

Clinical Presentation • Typically affects middle-aged women but can affect all age-groups. • Relapsing symmetrical confluent pustular eruptions affecting trunk, intertriginous areas, and flexural aspects of the extremities.

Etiology and/or Pathogenesis

Histologic Features • Subcorneal pustules “sitting on” epidermis, perivascular infiltrate with neutrophils and occasional eosinophils, no significant spongiosis, and acantholysis.

First described by Burton and Pye in 1977 and 1979, erosive pustular dermatosis (EPD) is a rare dermatosis, mostly involving sun-damaged scalp. It can also be seen on otherwise atrophic skin [10]. EPD mostly occurs in elderly women but has also been reported in infants. Predisposing factors include trauma, burns, cryotherapy, photodynamic therapy, radiotherapy, actinic damage, herpes zoster, immunosuppression, perinatal scalp injury, chronic venous insufficiency of the lower extremities, autoimmune thyroiditis, and rheumatoid arthritis [11].

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Clinical Presentation Initially, there is a painless scale crust and ­surrounding edema. Subsequently, serpiginous lesions with confluent pustules and non-healing erosions with an erythematous border develop (Fig.  4.1). Previous or concomitant adjacent squamous cell carcinoma is frequent  [12]. Erosive plaques with overlying pustules may be disseminated and involve mucosa [11].

Prognosis or Clinical Course When located on the scalp, EPD may result in superficial scarring alopecia.

Histopathology Affected skin is ulcerated with variable crusting and pseudoepitheliomatous hyperplasia, surrounded by intact atrophic epidermis, parakeratosis, and rarely subcorneal pustules. Dermal infiltrate is variably dense, consisting of lymphocytes, admixed neutrophils, and plasma cells (Fig. 4.2). Involved hair follicles gradually disappear, and scarring becomes obvious.

Fig. 4.1  Large erosive plaques with overlying, almost confluent, pustules, and hyperkeratosis surrounded by a serpiginous border of erythema on the scalp and islands of atrophic hairless skin

Fig. 4.2  Hyperplastic epidermis with a diffuse dermal infiltrate composed of neutrophils and occasional lymphocytes, macrophages, and eosinophils. Within the epidermis there is a large neutrophilic abscess

Differential Diagnosis Amicrobial pustulosis associated with autoimmune disease has a similar histology but affects young women. Pustular ulcerative dermatosis of the scalp mainly affects African young men with malnutrition. Folliculitis decalvans has a mixed inflammatory infiltrate containing variable plasma cells; neutrophils and macrophages may extend into the deep dermis and subcutis. There is destruction of hair follicles with shafts lying free in the dermis. Eosinophilic pustulosis Ofuji is characterized by an eosinophilic infiltrate. Pustular psoriasis typically has subcorneal pustules, suprabasilar mitotic figures, and some spongiosis. Pemphigus vulgaris has intraepidermal vesicles and variable acantholysis; intercellular deposits in DIF.  In localized cicatricial pemphigoid, a subepidermal bulla and a mixed inflammatory infiltrate containing eosinophils and neutrophils may be seen; there are deposits along the basement membrane in DIF. Pyoderma gangrenosum, early stage, has subepidermal edema and a dermal neutrophilic infiltrate that may involve hair follicles. The overlying epidermis becomes necrotic. Infectious skin diseases such as bacterial fol-

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liculitis and inflammatory tinea capitis should be considered as differential diagnoses; microbiological diagnostics may help to distinguish these. Temporal arteritis is characterized by a granulomatous arteritis involving the inner media with prominent giant cells, surrounded by an inflammatory infiltrate with variable lymphocytes, macrophages, and eosinophils.

Summary Clinical Presentation • Typically affects older women • Often preceded by trauma, compression, and diverse treatments of actinic keratosis • Possible association of autoimmune disorders (Hashimoto thyroiditis, rheumatoid arthritis) • Serpiginous lesions with confluent pustules and erosions Histologic Features • Ulceration with variable crusting, surrounded by intact atrophic epidermis, parakeratosis, and rarely subcorneal pustules • Variably dense dermal infiltrate with neutrophils and plasma cells • Hair follicles gradually disappear, and scarring becomes obvious Differential Diagnosis • Amicrobial pustulosis associated with autoimmune disease • Pustular ulcerative dermatosis of the scalp • Folliculitis decalvans • Eosinophilic pustulosis Ofuji • Pustular psoriasis • Autoimmune bullous dermatoses (pemphigus vulgaris, localized cicatricial pemphigoid) • Pyoderma gangrenosum, early stage • Infectious skin diseases • Temporal arteritis

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Takeaway Essentials Clinical Relevant Pearls • Rapid onset of bizarre pustular plaques with negative microbiology • Check for preceding trauma, procedures, underlying associated disorders Pathology Interpretation Pearls • Dense and diffuse neutrophilic inflammation with destruction of hair follicles • Ulceration, loss of hairs, and scarring in the late stage

Pustular Dermatoses of Infancy In infancy, noninfectious, self-limiting vesicular and pustular dermatoses can occur. This group is comprised of toxic erythema of neonate [erythema toxicum (neonatorum)], eosinophilic pustular folliculitis of infancy, and infantile acropustulosis with toxic erythema of neonate being the most frequent disease within this group. They share clinical and histological features.

Toxic Erythema of Neonate  tiology and/or Pathogenesis E Toxic erythema of neonate [erythema toxicum (neonatorum)] is quite common, affecting up to 50% of neonates within the first days of life. The etiology is unclear, but some have discussed an immune response to initial cutaneous microbial colonization [13, 14]. In another study, immune system maturity influenced by health of the neonate at birth, gestational age, and birthweight was considered an etiological factor [15]. Clinical Presentation More than 30% of the neonates develop disseminated erythematous macules with papules and pinpoint pustules within 12 to 48 hours after birth mostly on the trunk. Palms and soles are typically spared [16].

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 rognosis or Clinical Course P The transient eruption resolves within a few days without any sequelae. Often, there is associated blood eosinophilia. Histopathology In early stages, there is a perivascular and perifollicular mixed inflammatory infiltrate with ­predominance of eosinophils and some exocytosis. Subcorneal or intraepidermal vesicles and follicular pustules are filled with eosinophils. Established lesions contain more eosinophils than neutrophils [17]. Differential Diagnosis Eosinophilic pustular folliculitis of infancy is a condition that persists a few months up to 5 years. Infantile acropustulosis frequently affects palms and soles; subcorneal pustules usually contain predominantly neutrophils and only occasional eosinophils. In transient neonatal pustular melanosis, the inflammatory infiltrate is predominantly neutrophilic. Vesiculopustules resolve leaving pigmented macules that show increased melanin in basal and suprabasal keratinocytes. Incontinentia pigmenti, vesicular stage almost only affects girls. It is characterized by eosinophilic spongiosis. In miliaria rubra, vesicles are related to acrosyringia rather than hair follicles and typically contain mononuclear cells rather than eosinophils. Infectious skin diseases (bacterial, herpes, candidiasis) need to be excluded; microbiological diagnostics may help. In Langerhans cell histiocytosis, the dermal infiltrate can show epidermotropism and usually contains typical Langerhans cells with a variable amount of eosinophils.

Summary Clinical Presentation • Disseminated erythematous macules, papulovesicles, and pustules sparing palms and soles • Transient eruption in first days of life lasting only a few days • Full resolution without sequelae

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Histologic Features • Follicle centered mixed infiltrate with predominance of eosinophils • Follicular pustules are rich in eosinophils Differential Diagnosis • Eosinophilic pustular folliculitis of infancy • Infantile acropustulosis • Transient neonatal pustular melanosis • Incontinentia pigmenti, vesicular stage • Miliaria rubra • Infectious skin diseases

Takeaway Essentials Clinical Relevant Pearls • Most frequent, asymptomatic, and self-­ limiting pustular eruption of infancy Pathology Interpretation Pearls • Intrafollicular, sometimes subcorneal and intraepidermal pustules rich in eosinophils

 osinophilic Pustular Folliculitis E of Infancy  tiology and/or Pathogenesis E In eosinophilic pustular folliculitis of infancy (pediatric (childhood) eosinophilic pustular folliculitis, eosinophilic pustulosis of the scalp) first described by Lucky in 1984, the etiology is unknown [18]. However, in a small number of cases, it might be associated with atopy. In contrary to the adult type, human immunodeficiency virus (HIV) infection is very rarely present [19]. There is a male predilection [20]. The existence of eosinophilic pustular folliculitis of infancy as a distinct inflammatory disease has been questioned by Ziemer and Böer. They critically stated

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that most of the previously reported cases did not show “eosinophilic folliculitis” histologically and that, clinically, these cases represented a group of miscellaneous eosinophil-rich dermatoses including scabies, insect bites, and linear IgA-dermatosis [21].

Clinical Presentation Recurrent itchy follicular papules and pustules mainly develop on the scalp although face, extremities, and trunk may also show grouped aggregates of follicular pustules. Blood eosinophilia is elevated in the majority of cases. Lesions usually present within the first year of life but may present as early as the first day of life [20].  rognosis or Clinical Course P During the disease course, patients are usually in good general condition. Recurrent eruptions may require topical or even systemic treatment and persist from 3 months to 5 years [20]. Histopathology Histologic features are not very distinctive and specific compared to classic, adult-type eosinophilic pustular folliculitis [22]. There is an eosinophil-­rich spongiotic pustule involving the infundibular part of the hair follicle. The dermal, perifollicular-centered infiltrate is composed of lymphocytes, eosinophils, mast cells, and macrophages. It may at times be so heavy that there is disruption and destruction of the wall of the hair follicle [23]. A PAS stain should always be performed to rule out dermatophyte infection. Differential Diagnosis In toxic erythema of neonate, eosinophilic pustules are related to the hair follicle and epidermis. However, the condition is non-pruritic and persists only a few days. Infantile acropustulosis frequently affects palms and soles; subcorneal pustules usually contain predominantly neutrophils and only occasional eosinophils. In transient neonatal pustular melanosis, the inflammatory infiltrate is predominantly neutrophilic; vesiculopustules resolve leaving pigmented macules that show increased melanin in basal and suprabasal keratinocytes. In superficial IgA pemphigus, DIF

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and indirect immunofluorescence (IIF) studies are positive. Pustular lesions in pyoderma gangrenosum are characterized by a dense neutrophilic infiltrate in the dermis. Infectious skin diseases (dermatophyte and bacterial infection, scabies infestation) should be excluded.

Summary Clinical Presentation • Recurrent itchy follicular papules and pustules mainly on the scalp, also face, extremities, and trunk • Lesions usually present within the first year of life and persist from 3 months to 5 years • Not HIV-related Histologic Features • Eosinophil-rich spongiotic pustule involving the infundibular part of the hair follicle • Follicle centered mixed infiltrate with predominance of eosinophils • Exclude dermatophyte infection by PAS stain Differential Diagnosis • Toxic erythema of neonate • Infantile acropustulosis • Transient neonatal pustular melanosis • Superficial IgA pemphigus • Pustular lesions in pyoderma gangrenosum • Infectious skin diseases

Takeaway Essentials Clinical Relevant Pearls • Disseminated itchy papules and pustules Pathology Interpretation Pearls • Eosinophilic spongiosis and pustulosis related to the openings of the hair follicle

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• Eosinophilic dermal inflammation and eosinophil-rich spongiotic pustules involving the infundibular part of the hair follicle

Infantile Acropustulosis  tiology and/or Pathogenesis E This uncommon pustular dermatosis usually presents in the first year of life, but onset can be at birth. There is a marked predilection for black male infants. The etiology is unknown; however, an association to atopy and hypereosinophilia has been reported, and a history of scabies infection may be related [24, 25]. Clinical Presentation Recurrent crops of severely pruritic vesiculopustules and papules are located on the distal parts of the extremities, particularly on the palms and soles.  rognosis or Clinical Course P Lesions often persist for 1–2 weeks and may recur every 2–4  weeks. The disease resolves spontaneously at the age of 2 or 3 years. Histopathology Early lesions show intraepidermal pustules with neutrophils and varying numbers of eosinophils evolving into subcorneal pustules [26]. There is a sparse superficial perivascular mixed infiltrate. DIF and IIF studies are negative. Differential Diagnosis Toxic erythema of neonate is characterized by eosinophilic pustules related to the epidermis and hair follicle. However, the condition is non-­pruritic and persists only a few days. In transient neonatal pustular melanosis, the inflammatory infiltrate is predominantly neutrophilic. Vesiculopustules resolve leaving pigmented macules that show increased melanin in basal and suprabasal keratinocytes. In

superficial IgA p­ emphigus, DIF and IIF studies are positive. Infectious skin diseases (scabies infestation, candida, dermatophyte, and herpes simplex virus infection) should be excluded. Dyshidrotic eczema rather is a disease of late childhood.

Summary Clinical Presentation • Vesiculopustules and papules are located on the distal parts of the extremities, particularly on the palms and soles Histologic Features • Intraepidermal pustules with neutrophils and varying numbers of eosinophils evolving into subcorneal pustules • Rule out dermatophyte infection by PAS stain Differential Diagnosis • Toxic erythema of neonate • Transient neonatal pustular melanosis • Superficial IgA pemphigus • Pustular lesions in pyoderma gangrenosum • Infectious skin diseases • Dyshidrotic eczema

Takeaway Essentials Clinical Relevant Pearls • Recurrent itchy vesiculopustules and papules with a predilection for palms and soles Pathology Interpretation Pearls • Epidermal pustules on acral site • Infection by dermatophytes and infestation by scabies must be ruled out by deeper sections and PAS

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 cute Generalized Exanthematous A Pustulosis Etiology and/or Pathogenesis Acute generalized exanthematous pustulosis (toxic pustuloderma, AGEP) is characterized by rapidly evolving sterile pustular eruption on an erythrodermic background. Frequent triggers are various antibiotics, terbinafine, chloroquine, and diltiazem. Rarely, AGEP may follow viral infection, i.e., enteroviruses [27].

Clinical Presentation

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Histopathology There are multiple subcorneal and intraepidermal pustules with mild spongiosis and a variable superficial dermal inflammatory infiltrate with neutrophils and variable amounts of eosinophils (Figs. 4.4 and 4.5). Apoptotic keratinocytes may be seen. The papillary dermis is edematous, and blood vessels may be stuffed by neutrophils and show vasculitic changes with fibrinoid degeneration of the vessel walls.

Differential Diagnosis Due to overlapping clinical and histological features, the differentiation of AGEP from pustular

The rapidly progressive pustular eruption consists of sterile, pinpoint, sometimes confluent non-follicular pustules on a background of pruritic or burning erythroderma (Fig.  4.3). The eruption is accompanied by fever and leukocytosis. Rarely, lesions may be vesicular, bullous, targetoid, or hemorrhagic, and rarely erosive mucositis is seen.

Prognosis or Clinical Course Usually, pustules resolve within a few days after cessation of the offending drug, leaving a characteristic collarette-like desquamation.

Fig. 4.3  Multiple pinpoint, non-follicular pustules on erythrodermic skin with desquamation

Fig. 4.4 Epidermis with mild spongiosis and large intraepidermal und subcorneal pustules

Fig. 4.5  The superficial perivascular infiltrate contains neutrophils and some eosinophils. Within the intraepidermal pustule, there are some acantholytic keratinocytes

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psoriasis may be very difficult or even imposTakeaway Essentials sible. However, the presence of eosinophils in the inflammatory infiltrate and apoptotic keraClinical Relevant Pearls tinocytes in the epidermis favors the diagnosis • Rapid progressive pustular eruption of AGEP.  DIF helps to distinguish the subcordeveloping within a few hours after neal pustular variant of IgA pemphigus from administration of the offending drug AGEP and pustular psoriasis. Halogenoderma is due to long-term intake of iodine and bromide-­ Pathology Interpretation Pearls containing agents (e.g., antiepileptics and seda• Pustular and psoriasiform dermatitis tives). These can cause ulcerative, pustular with apoptotic keratinocytes and/or plaques. Histologically, there are pseudocarcinoeosinophils matous hyperplasia, intrafollicular neutrophilic abscesses, and dense dermal neutrophilic infiltrates. Fungal infection as candidiasis and dermatophytoses can present with pustular eruptions. Therefore, PAS stain is obligatory in all pustular Generalized Pustular Psoriasis eruptions.

Etiology and/or Pathogenesis

Summary Clinical Presentation • Rapidly progressive pustular eruption on a background of pruritic or burning erythroderma accompanied by fever and leukocytosis Histologic Features • Subcorneal and intraepidermal pustules with mild spongiosis and a variable superficial dermal inflammatory infiltrate with neutrophils and variable amounts of eosinophils • Variable leukocytoclastic vasculitis Differential Diagnosis • Pustular psoriasis • IgA pemphigus • Halogenoderma • Fungal infection: PAS stain obligatory!

General pustular psoriasis (GPP von Zumbusch) is an acute and rare manifestation of psoriasis [28]. Predisposing factors are pregnancy, withdrawal of systemic glucocorticoid treatment, hypocalcemia, infection, and locally irritating agents as well as UV exposure. A minority of pustular psoriasis cases are caused by rare and damaging mutations in genes like IL-36RN, CARD14, or AP1S3 [29]. IL-36 is close to IL-1 that has been implicated in the early pathogenetic mechanism in the model of bimodal immune activation in psoriasis, acting as an autoinflammatory factor [30].

Clinical Presentation Patients present with rapid progressive pustular erythroderma, fever, arthralgia, and malaise (Figs. 4.6 and 4.7). Uncommon variants include: • Annular type: a less severe variant with central clearing leading to an annular morphology.

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Histopathology

Fig. 4.6  Pustules, partly confluent, on an erythematous background and beginning desquamation

There is accumulation of neutrophils in the epidermis due to transepidermal migration of neutrophils. Most often, there is an intraepidermal spongiform macropustule (Kogoj), and by time few neutrophils migrate upward to form subcorneal and intracorneal pustules (Munro’s microabscesses) (Fig. 4.8). Other epidermal findings of psoriasis are variably present and seen especially in older and persisting lesions. Often, dilated tortuous capillaries in the papillary dermis and superficial perivascular infiltrates with neutrophils are evident.

Differential Diagnosis IgA pemphigus is characterized by acantholysis on histology, and IgA depositions on DIF help to distinguish the subcorneal pustular variant of IgA pemphigus from pustular psoriasis and AGEP. Pustular drug reactions have a lichenoid inflammatory infiltrate with apoptotic keratinocytes and admixed eosinophils are characteristic. Fungal infection by candida and dermatophytes can Fig. 4.7  Pustular psoriasis involving the acral site with almost complete destruction and loss of the nail plate

• Exanthematous type: de novo manifestation, may be triggered by infection or may represent a pustular drug reaction. • Juvenile and infantile type.

Prognosis or Clinical Course Usually, there are recurrent episodes of fever followed by pustular eruptions, accompanied by leukocytosis and general malaise. The pustular flare resolves with drying pustules and a characteristic lamellar desquamation.

Fig. 4.8 Psoriasiform epidermis with intraepidermal, subcorneal, and intracorneal pustules. There is a superficial perivascular infiltrate containing neutrophils and dilated capillaries in the papillary dermis

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p­ resent with pustular eruptions. Therefore, PAS stain is obligatory in all pustular eruptions. Impetigo can be bullous with formation of subcorneal bullae and few acantholytic cells containing Gram-positive cocci.

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• Deficiency of IL-36 receptor antagonist (DITRA) • CARD14-mediated pustular psoriasis (CAMPS)

Summary

Erythema Elevatum Diutinum

Clinical Presentation • Rapidly progressive pustular erythroderma, fever, arthralgia, and malaise

Etiology and/or Pathogenesis

Histologic Features • Intraepidermal spongiform pustule (Kogoj) and subcorneal and intracorneal pustules (Munro’s microabscesses) • Tortuous capillaries in the papillary dermis and superficial perivascular infiltrate with admixed neutrophils Differential Diagnosis • IgA pemphigus • Pustular drug reactions • Impetigo • Fungal infection: PAS stain obligatory!

Erythema elevatum diutinum (EED) is a rare inflammatory dermatosis of unknown etiology. Together with granuloma faciale, it is a distinct variant of localized leukocytoclastic vasculitis. Although the pathogenesis is unknown, an immune-complexmediated disease can be assumed as associated streptococcal infections, and rheumatological diseases have been reported. EED has also been found in patients with malignancies (e.g., myelodysplastic syndrome, multiple myeloma, lymphoma, paraproteinemia), autoimmune disorders (e.g., chronic inflammatory bowel diseases, celiac disease, rheumatoid arthritis, lupus erythematosus), and other infections (e.g., viral hepatitis, syphilis, HIV) [31].

Clinical Presentation Takeaway Essentials Clinical Relevant Pearls • Pustular erythroderma with pain and malaise Pathology Interpretation Pearls • Intraepidermal spongiform macropustule (Kogoj) and subcorneal and intracorneal pustules (Munro’s microabscesses) devoid of eosinophils and apoptotic keratinocytes Molecular Findings (In Monogenic Forms Only) • Deficiency of IL-1 receptor antagonist (DIRA)

EED presents with persistent, symmetrical, firm, and red to brown papules and nodules that may coalesce to form indurated plaques of several centimeters with round to polycyclic shape. Although asymptomatic in most cases, onset might be accompanied by pruritus, burning or stinging sensations. Lesions are preferentially located on the extensor sides of the extremities in the proximity or over the joints; however buttocks, trunk, and rarely palms and soles have been involved in a few rare cases. Typically, patients are in their third to fifth decade, and both sexes are equally affected [32].

Prognosis or Clinical Course Established lesions may be tender to palpation and be accompanied by arthralgia. The lesions

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usually persist for years regressing slowly and might resemble keloids or tumors clinically and also histologically [33]. They might become yellowish resembling a xanthomatous process. Cases associated with HIV more often show atypical locations and have an onset at an earlier age [34]. Systemic involvement has been reported exceptionally [35].

Histopathology Early lesions show typical features of leukocytoclastic vasculitis with fibrinoid necrosis and infiltration of the vessel walls by neutrophils. The infiltrate consists of neutrophils with leukocytoclasia interstitially in the upper part of the dermis accompanied by few perivascular lymphocytes and eosinophils (Figs. 4.9 and 4.10). When fully developed, the infiltrate becomes nodular and sometimes diffuse with neutrophils, leukocytoclasia, eosinophils, lymphocytes, plasma cells, and histiocytes throughout the dermis and variably upper subcutis. Vasculitis varies with minimal inflammation up to vascular occlusion followed by fibrosis in late lesions. At sites of nodular infiltrates concentric, onion shell-like fibrosis and collagen bundles with storiform pattern accompanied with numerous fibrocytes form (Fig. 4.11). The infiltrate consists of macrophages and neutrophils in variable amounts and may become granulomatous [36].

Fig. 4.10  At higher magnification leukocytoclastic vasculitis with fibrinoid necrosis and neutrophils in vessel walls becomes more obvious

Fig. 4.11  Fully developed lesion with concentric fibrosis around blood vessels and prominent collagen bundles arranged in a storiform pattern

Differential Diagnosis

Fig. 4.9  Biopsy of an early lesion showing a dense dermal neutrophilic infiltrate with leukocytoclasia

Rheumatoid neutrophilic dermatitis has a dense, diffuse neutrophilic infiltrate without relevant leukocytoclastic vasculitis. In

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Sweet syndrome there is a papillary edema and a dense neutrophilic infiltrate with leukocytoclasia but no leukocytoclastic vasculitis. Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) is characterized by a proliferation of epithelioid endothelial cells within a dense nodular eosinophilic infiltrate. Dermatofibroma and fibroblastic tumors as well as nodular late stages of EED with prominent fibrosis can be difficult to distinguish. In granuloma faciale there are more eosinophils than neutrophils in early stages, whereas granulomatous nodules in later stages are only seen in EED [37].

Summary Clinical Presentation • Persistent, symmetrical, firm, red to brown papules and nodules that may coalesce • Located preferentially on the extensor sides of the extremities and over the joints • Patients in the third to fifth decade with equal distribution in men and women Histologic Features • Early stage: leukocytoclastic vasculitis • Fully developed lesions: neutrophilic infiltrate becomes nodular and sometimes diffuse with variable degree of vasculitis, vascular occlusion, and fibrosis • Late stage: concentric fibrosis and prominent collagen bundles with numerous fibrocytes, macrophages, and neutrophils in variable amounts; sometimes granulomatous Differential Diagnosis • Rheumatoid neutrophilic dermatitis

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• Sweet syndrome • Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) • Dermatofibroma, fibroblastic tumors • Granuloma faciale

Takeaway Essentials Clinical Relevant Pearls • Persistent red to brown papules, nodules, and plaques on extensor sides of extremities and over joints Pathology Interpretation Pearls • Late lesions: concentric fibrosis intermingled with neutrophils

Bowel-Associated Dermatosis-Arthritis Syndrome Etiology and/or Pathogenesis Bowel-associated dermatosis-arthritis syndrome (BADAS) includes the previously called “bowel bypass syndrome,” described in patients with complications after intestinal bypass surgery for the cure of morbid obesity, as well as symptoms consistent with bowel bypass syndrome in patients with inflammatory bowel and liver disease [38, 39]. BADAS might be the best term to describe the spectrum of neutrophilic dermatoses in patients with gastrointestinal disease [40]. The lesions share many histological features with pyoderma gangrenosum; however they lack the rapidly progressive ulceration. Evidence suggests that gut microbiota, i.e., small intestine bacterial overgrowth, could play an important role in the pathogenesis [41–43]. Proinflammatory cytokines and effector molecules might eventually cause neutrophil-mediated inflammation.

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Clinical Presentation BADAS is characterized by flu-like symptoms and fever, arthritis, and inflammatory skin lesions consisting of papules and plaques as seen in Sweet syndrome, pustules, and ulcers reminding of pyoderma gangrenosum or nodules, abscesses, or fistulae as in hidradenitis suppurativa (Fig. 4.12) [39]. Also, acne and neutrophilic panniculitis can be associated [44].

Prognosis or Clinical Course Restoring bowel flow usually resolves BADAS. However, systemic immunosuppression and/or antibiotics might be necessary to control symp-

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toms. Patients with Crohn disease might suffer from complicating disseminated abscesses [45]. Skin symptoms may even precede the gastrointestinal disease and recur with exacerbation of the associated gastrointestinal disease.

Histopathology Histological findings are non-specific. Lesions show variable dermal edema and necrosis with perivascular and interstitial neutrophil-rich infiltrate that mostly involves the dermis but can expand into the subcutis, resulting in erythema nodosum-like panniculitis (Figs. 4.13 and 4.14). Leukocytoclasia and vascular damage with endothelial swelling and at times fibrin deposition are variably present. Sometimes, eccrine hidradenitis or folliculitis is seen.

Differential Diagnosis

Fig. 4.12  Polycyclic ulcer with slightly raised erythematous border and erythematous papules and plaques in the surrounding on the right lower leg of a patient with Crohn disease Figs. 4.13 and 4.14 Dermal neutrophilic infiltrate with neutrophilic exocytosis in the epithelia (4.13) and neutrophilic panniculitis (4.14)

To rule out infection, special stains including PAS and Grocott should be performed; clinical history is essential. Sweet syndrome typically has a subepidermal edema with a dermal neutrophilic infiltrate devoid of necrosis. Neutrophilic dermatosis of the hands usually affects acral sites. Leukocytoclastic vasculitis may be indistinguishable histologically. However, in BADAS vascular damage is usually milder and limited to some endothelial swelling.

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Clinical correlation may prove helpful. Erythema nodosum may be indistinguishable in erythema nodosum-like lesions of BADAS [46]. Also here, clinical history may be helpful. Rheumatoid neutrophilic dermatitis may be indistinguishable histologically. Clinical history may prove to be helpful. The histology of pyoderma gangrenosum may be similar, but clinically PG is marked by rapid and expansile cutaneous ulcers.

Summary Clinical Presentation • Gastrointestinal disease preceded or complicated by fever, flu-like symptoms, arthritis, and inflammatory skin involvement Histologic Features • Neutrophilic infiltrate in the dermis with variable expansion into the subcutis • Variable leukocytoclasia, dermal edema, and necrosis Differential Diagnosis • Infection • Sweet syndrome • Neutrophilic dermatosis of the hands • Leukocytoclastic vasculitis • Rheumatoid neutrophilic dermatitis • Pyoderma gangrenosum

Neutrophilic Eccrine Hidradenitis Etiology and/or Pathogenesis First reported in patients receiving cytarabine for acute myelogenous leukemia, neutrophilic eccrine hidradenitis (NEH) is a rare neutrophilic dermatosis occurring mostly in patients treated with chemotherapy (cytarabine and anthracyclines) for a hematologic malignancy [47]. Subsequently, similar eruptions were reported in patients with other malignancies and under other chemotherapeutics and targeted therapies such as cetuximab and imatinib [48–50]. Recently, NEH has been described in melanoma patients treated with BRAF inhibitors [51]. NEH has also been observed in patients with HIV infection and Behçet disease [52, 53]. The pathogenesis is unclear; however it is thought that the drug accumulates in the sweat glands leading to a direct toxic effect and apoptosis [47, 54]. Others hypothesize that NEH may be part of the spectrum of neutrophilic dermatoses as Sweet syndrome and pyoderma gangrenosum [55].

Clinical Presentation Patients are febrile and develop a polymorphous eruption with variably asymptomatic or painful erythematous to violaceous macules, papules, plaques, nodules, and pustules most often on the trunk and upper extremities. Lesions usually present within 1 or 2 weeks after starting chemotherapy.

Prognosis or Clinical Course Takeaway Essentials Clinical Relevant Pearls • Neutrophilic dermatosis in the context of gastrointestinal disorders • To establish the diagnosis, clinicopathological correlation is necessary Pathology Interpretation Pearls • Dense neutrophilic infiltrate with variable signs of necrosis

Lesions regress spontaneously within 1 to 3 weeks. However, they might recur with reintroduction of the culprit drug.

Histopathology There is a deep dermal and variable subcutaneous infiltrate of neutrophils around and within the eccrine secretory coils with vacuolar degeneration and variable necrosis of secretory epithelium. Squamous metaplasia may be seen.

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Summary Clinical Presentation • Febrile patients with polymorphous eruption • Asymptomatic to painful erythematous to violaceous macules, papules, plaques, nodules, and pustules on the trunk and upper extremities • Usually related to antineoplastic agents

Fig. 4.15 Neutrophils surrounding eccrine secretory coils, sparing the ductal segments

Histologic Features • Deep dermal and variable subcutaneous infiltrate of neutrophils around eccrine secretory coils with vacuolar degeneration and variable necrosis of secretory epithelia • Variable squamous metaplasia Differential Diagnosis • Idiopathic plantar hidradenitis in children

Takeaway Essentials

Fig. 4.16  There is necrosis of the secretory epithelium

Involvement of apocrine glands is possible (Figs. 4.15 and 4.16) [54].

Differential Diagnosis Idiopathic plantar hidradenitis (idiopathic recurrent palmoplantar hidradenitis in children, neutrophilic eccrine hidradenitis in children) is characterized by painful erythematous papules, plaques, and nodules as well as pustules that develop on the soles and may involve the palms, also. Neutrophils are centered on the ductal part of the eccrine gland and usually do not involve the secretory part with variable abscess formation [56]. There is no squamous syringometaplasia.

Clinical Relevant Pearls • Rare neutrophilic dermatosis occurring mostly in patients treated with chemotherapy (cytarabine and anthracyclines) or other oncological therapies Pathology Interpretation Pearls • Perieccrine neutrophilic infiltrate associated with necrosis of the secretory epithelium sparing the myoepithelial layer

Sweet Syndrome Etiology and/or Pathogenesis Sweet syndrome (SS) (acute febrile neutrophilic dermatosis), first described in 1964 by Robert Douglas Sweet [57], is the prototypic member of neutrophilic dermatoses. While up to 50% of

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cases are idiopathic, about one-third is associated with internal malignancies [58]. Based on etiology Sweet syndrome is categorized into classic, malignancy-associated, and drug-induced subtypes. The classic subtype usually occurs in women of middle-age and often is associated with infections of the upper respiratory tract, vaccination, inflammatory disorders, or pregnancy [59]. Inflammatory bowel disease (IBD) is a frequently reported associated inflammatory disorder [60]. The paraneoplastic subtype is associated with hematological malignancies and myeloproliferative or myelodysplastic disorders, especially AML and myelodysplastic syndrome (MDS), whereas solid malignancies are seen less frequent [61, 62]. Granulocyte-colony stimulating factor (G-CSF) is the most commonly reported medication in drug-induced Sweet syndrome [63]. The exact pathogenesis of Sweet syndrome has not been elucidated. However, the cytokine G-CSF seems to be an important cytokine triggering SS and attracting neutrophils [63]. Also, elevated levels of Th1-cytokines such as interferon-­gamma and IL-2 are reported [64]. An elevated expression of IL-1beta in skin of SS patients supports the classification of SS into the group of autoinflammatory diseases [65]. Finally, there is rising evidence to suggest a role for genetics in the pathogenesis of SS and neutrophilic dermatoses in general [66, 67].

Clinical Presentation A prior upper respiratory infect may precede the sudden onset of bilateral, edematous, tender plaques or nodules that may become vesiculobullous in the setting of fever, leukocytosis, and malaise (Fig. 4.17). Lesions favor the head and neck area and upper and lower extremities. Less frequent and atypical presentations include targetoid lesions. Lesions can affect internal organs and the mucosae as well, presenting with burning eyes and oral ulcerations [68]. Su and Liu defined diagnostic criteria requiring major and minor criteria for the diagnosis of SS [69] that were further elaborated by Marzano et al. [37] (Table 4.1).

Fig. 4.17  Edematous, tender erythematous papules, and plaques on the back of a febrile patient Table 4.1  Major and minor criteria for the diagnosis of Sweet syndrome

Major criteria

Minor criteria

Rapid onset of skin lesions (tender erythematous plaques and nodules, bullae, targetoid lesions) Clinical Histological Dense neutrophil infiltration without leukocytoclastic vasculitis Clinical Fever >38C History of upper respiratory tract or gastrointestinal infection Presence of hematologic or solid neoplasia or inflammatory bowel diseases or pregnancy Good response to corticosteroids Laboratory Erythrocyte sedimentation rate > 20 mm/h White blood cells >8 × 10E9/L Neutrophils >70% High C-reactive protein

Based on Marzano et al. (2013)

Prognosis or Clinical Course Patients with vesiculobullous lesions that may progress to pyoderma gangrenosum-like ulcers, extensive, asymmetrical distribution, and histiocytoid clinicopathological variant seem to have a higher propensity for an underlying malignancy [37, 70]. In classical SS skin lesions can persist for weeks to months if untreated and typically respond promptly to

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systemic corticosteroids. More recently, successful management of SS with TNF antagonists has been reported [71, 72]. In malignancy-associated SS, the course of the cutaneous manifestation can parallel the response to oncological treatment.

Histopathology There is a diffuse-interstitial infiltrate predominantly of mature neutrophils in the upper half of the dermis without evidence of vasculitis. Frequently, an edema of the papillary dermis is present which may result in subepidermal vesiculation (Figs. 4.18 and 4.19). The dermal infiltrate may contain cells with predominantly monocytic-histiocytic appearance (Fig.  4.20). Attention needs to be paid to immunohistochemistry in these cases, as the infiltrate is positive for CD68 (KP1), a marker for neutrophils and macrophages. Staining of the histiocytoid cells for myeloperoxidase serves as a proof that in fact these cells are immature neutrophils [73]. It is important to differentiate this variant of SS from leukemia cutis or inflammatory dermatoses with monocytic infiltrates. In lesions of longer duration, leukocytoclasia with nuclear dust is possible. If present, leukocy-

Fig. 4.19 An interstitial neutrophilic infiltrate and leukocytoclasia

Fig. 4.20  Dermal infiltrate with predominantly histiocytic appearance

Fig. 4.18  There is a dense dermal neutrophilic infiltrate and prominent edema of the papillary dermis

toclastic vasculitis appears to be secondary instead of primary and does not exclude the diagnosis of SS.  Rarely, the epidermis can become pustular. In later lesions, macrophages become more apparent, and there may be macrophages containing phagocytosed neutrophils. Lymphocytes are sparse and only perivascular. The neutrophilic infiltrate may extend into the subcutis and present as septal, lobular, or mixed septal and lobular panniculitis. Subcutaneous extension of the neutrophilic infiltrate is more frequently reported in SS with underlying malignancy.

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Differential Diagnosis Erythema elevatum et diutinum is characterized by leukocytoclastic vasculitis with concentric fibrosis; it is usually located over extensor surfaces of joints. Granuloma faciale also has leukocytoclastic vasculitis, however, with extensive perivascular fibrin deposits and eosinophils. Lobular neutrophilic panniculitides are also seen in infectious panniculitis (microbiology, polymerase chain reaction (PCR) assay), alpha-1 antitrypsin deficiency, and artefactual panniculitis (foreign body material). In neutrophilic eccrine hidradenitis, neutrophils are mainly perieccrine, and there is necrosis of eccrine coils (drug-­induced, cold-induced). Pyoderma gangrenosum has necrosis and large ulceration with an undermined edge; clinically, there is a painful ulcer. Rheumatoid neutrophilic dermatitis has a dense neutrophilic infiltrate with variable leukocytoclasia, without vasculitis, and, rarely, there is formation of bullae. In bowel bypass syndrome/bowel-associated dermatosis-arthritis syndrome (BADAS), there is subepidermal edema with variable pustules and dense neutrophilic infiltrate.

Summary Clinical Presentation • Bilateral, edematous, tender plaques, or nodules in the setting of fever, leukocytosis, and malaise • Vesiculobullous lesions, pyoderma gangrenosum-­ like ulcers, extensive, asymmetrical distribution, and/or a histiocytoid clinicopathological variant seem to have a higher propensity for an underlying malignancy Histologic Features • Diffuse-interstitial infiltrate predominantly of mature neutrophils and papillary edema

• Histiocytoid variant: immunohistochemistry is positive for CD68 as well as myeloperoxidase – a proof that in fact these cells are immature neutrophils Differential Diagnosis • Erythema elevatum et diutinum • Pyoderma gangrenosum

Takeaway Essentials Clinical Relevant Pearls • Rapid onset of bilateral tender erythematous plaques and nodules or formation of bullae and targetoid lesions with fever, malaise, and leukocytosis • History of upper respiratory tract infection may precede • Rule out hematologic or solid neoplasia, inflammatory bowel diseases, or pregnancy • Good response to glucocorticoids Pathology Interpretation Pearls • Diffuse and dense neutrophilic dermal infiltrate in association with a prominent subepidermal edema

Neutrophilic Dermatosis of the (Dorsal) Hands Etiology and/or Pathogenesis First described in 1995 by Strutton et al. [74] as “pustular vasculitis of the hands,” neutrophilic dermatosis of the dorsal hands (NDDH) is a recently described disease, often reported with underlying hematological disorders, inflammatory bowel diseases, sarcoidosis, and less frequently with infections, trauma, and solid tumors [75–77]. In the original report by Strutton et al., leukocytoclastic vasculitis is mentioned. However, the

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biopsy referred to was only taken 1 week after disease manifestation [78]. NDDH is discussed to be a local variant of Sweet syndrome and clinically indistinguishable from atypical pyoderma gangrenosum when present on the dorsal hands [79].

Histologic Features • Diffuse-interstitial infiltrate predominantly of neutrophils and papillary edema

Clinical Presentation

Differential Diagnosis • Erythema elevatum et diutinum • Pyoderma gangrenosum • Atypical mycobacteriosis (clinically)

NDDH presents with violaceous plaques and variable edema. Lesions are usually located at the dorsal hands but can involve the lateral or palmar aspect of the hands as well. Pain, systemic symptoms such as fever, malaise and joint pain, or lymphadenopathy are variably present [80]. Laboratory studies may show leukocytosis and elevated C-reactive protein.

Prognosis or Clinical Course Lesions may develop pustulation with subsequent erosions and ulceration and develop secondary leukocytoclastic vasculitis. NDDH usually responds to treatment with topical and/or systemic glucocorticoids, dapsone, or a combination of both [81].

Histopathology There is a dense neutrophilic infiltrate in the upper dermis with papillary edema. Leukocytoclasia and perivascular fibrin deposition may be present, but endothelial cells are usually intact [75].

Differential Diagnosis Same as in Sweet syndrome

Summary Clinical Presentation • Violaceous tender plaques or nodules on the hands with variable fever, leukocytosis, and malaise

Takeaway Essentials Clinical Relevant Pearls • Considered to be a localized variant of Sweet syndrome, clinically indistinguishable from atypical pyoderma gangrenosum when present on the dorsal hands • Rule out hematologic or solid neoplasia • Good response to glucocorticoids Pathology Interpretation Pearls • Dense dermal neutrophilic infiltrate in a biopsy of the dorsal hand

Pyoderma Gangrenosum Etiology and/or Pathogenesis Pyoderma gangrenosum (PG) is a rare, chronic recurring, painful, and destructive inflammatory process of the skin with sterile dermal neutrophilic infiltrates. It may be triggered by trauma, surgical procedure (pathergy phenomenon), insect bite, folliculitis, or drug therapies, including those for treatment of concomitant disease (e.g., antagonists of tumor necrosis factor) [82]. It may be idiopathic or associated with different conditions like inflammatory bowel diseases (IBD), myeloproliferative disorders, paraproteinemia, and rheumatological disorders. PG may precede, coexist, or follow the associated systemic diseases. It may occur in the context of

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syndromes like PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne), SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis), and PASH (pyoderma gangrenosum, acne, and suppurative hidradenitis). PG has recently been included in the spectrum of autoinflammatory diseases showing abnormal activation of innate immunity with upregulation of cytokines such as IL-1beta and IL-17 [83, 84].

Clinical Presentation In 85% of cases, PG manifests as rapidly progressive painful ulcers with violaceous, raised, undermined borders, with variable malaise and fever (Fig.  4.21). In addition to the classic and most frequent ulcerative form, a number of atypical and less frequent clinical forms have been described: bullous, pustular, and superficial ­granulomatous (or vegetative) [85]. They may coexist with classic PG or occur with overlapping features of other neutrophilic diseases [84]. Pyostomatitis vegetans, also frequently associated with inflammatory bowel diseases, might be a “forme fruste” of PG.

all body sites but mostly manifests on the extensor surface of the legs. The speed of the ulcer extension can be up to 1 cm per day or more.

Histopathology Depending on the age of the lesion and the site of biopsy, PG has a variable histological picture. Vasculitis, if present, is a secondary phenomenon (Figs. 4.22 and 4.23). Ulcerating PG starts with a follicular or perifollicular suppurative inflammation. There is an extensive superficial and deep perivascular and interstitial neutrophilic infiltrate with formation of a dermal abscess. The dermis becomes necrotic. The infiltrate can reach into the subcu-

Prognosis or Clinical Course PG may show phases of relapse and remission over months to years when untreated and heal with an atrophic, cribriform scar. It may occur at

Fig. 4.21  Polycyclic large ulcer with violaceous, elevated, undermined borders, and surrounding erythema on the left lower leg

Fig. 4.22  Partially necrotic epidermis and a dense dermal neutrophilic infiltrate

Fig. 4.23 Within the neutrophilic infiltrate, there is accompanying or secondary leukocytoclastic vasculitis

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tis, with necrosis of the epidermis. At the edge of the ulcer, there is a dense lymphoplasmacellular infiltrate with erythrocytes, swollen endothelia, and fibrin deposits. Lymphocytic vasculitis can be accompanied by leukocytoclastic vasculitis, which is most likely secondary. Pustular PG has subcorneal pustules with subepidermal edema and a dense neutrophilic infiltrate. In bullous PG, there are subepidermal bullae with accumulation of neutrophils in the dermis. In superficial granulomatous PG neutrophils are admixed with a granulomatous infiltrate. The epidermis is pseudoepitheliomatous hyperplastic.

Differential Diagnosis By histology, the differential diagnosis of neutrophilic dermatoses may be impossible; clinicopathological correlation remains essential. Sweet syndrome is a neutrophilic dermatitis usually without folliculitis and ulceration. In rheumatoid neutrophilic dermatitis, there is a dermal dense neutrophilic infiltrate with variable leukocytoclasia and spongiotic vesicles, no vasculitis. In leukocytoclastic vasculitis, the neutrophilic infiltrate can be extensive in pustular/necrotic variants. However, the infiltrate is organized more perivascularly with fibrinoid necrosis of vessel walls. In Behçet syndrome there is a neutrophilic infiltrate with variable leukocytoclasia and signs of leukocytoclastic vasculitis. Amicrobial intertriginous pustulosis is characterized by a neutrophilic infiltrate, with perivascular and perifollicular accentuation; there is variable spongiosis with neutrophils and formation of subcorneal pustules. In abscess-forming neutrophilic dermatosis, a dense dermal neutrophilic infiltrate is located beneath a subepidermal edema with variable leukocytoclasia. Atypical mycobacteriosis has a variably dense suppurative-­ granulomatous infiltrate with pseudoepitheliomatous hyperplasia.

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Summary Clinical Presentation • Neutrophilic dermatosis presenting with painful ulcers, violaceous, raised, and undermined borders • Second most common cutaneous manifestation of IBD • Can be syndromic or idiopathic Histologic Features • Dense neutrophilic infiltrate, hemorrhage, necrosis of epidermis, and abscess formation • Infiltrate can be mixed neutrophilic and granulomatous with variable epidermal hyperplasia Differential Diagnosis • Sweet syndrome • Behçet syndrome • Rheumatoid neutrophilic dermatitis • Infections

Takeaway Essentials Clinical Relevant Pearls • Chronic recurring, painful and destructive inflammatory process. • Frequent association with IBD • May be triggered by trauma and surgical procedure (pathergy phenomenon) Pathology Interpretation Pearls • Diffuse and very dense dermal neutrophilic infiltrate and necrosis throughout the cutis

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Neutrophilic Urticarial Dermatosis Etiology and/or Pathogenesis Neutrophilic urticarial dermatosis (NUD) comprises a particular autoinflammatory condition within the spectrum of aseptic neutrophilic dermatoses consisting of urticarial eruptions clinically and neutrophilic dermatosis histopathologically [86]. This entity has been observed in patients with Schnitzler syndrome, Still disease, systemic lupus erythematosus, Sjögren syndrome, cryopyrin-associated periodic syndrome (CAPS), primary biliary cirrhosis, and inflammatory bowel disease [87]. Innate immune-­related events seem to play a critical role in the etiology with pathological upregulation of IL-1 [88].

Fig. 4.24 Neutrophils junction

lining

the

dermoepidermal

Clinical Presentation Patients present with recurrent urticarial rash in the context of an associated immunological disease (i.e., systemic autoimmune or autoinflammatory disease). The urticarial eruption consists of pale red, flat, or only slightly raised pruritic or non-pruritic macules, papules, or plaques. The individual lesion can last up to 48 hours [86]. The urticarial rash is accompanied by burning sensation rather than pruritus and usually does no respond to antihistamines.

Prognosis or Clinical Course The urticarial rash can be a manifestation of an inflammatory disorder (i.e., lupus erythematosus) or can be part of an autoinflammatory syndrome (e.g., CAPS). Concomitantly, there may be fever, polyarthritis, and leukocytosis.

Histopathology The epidermis is normal; there is variable neutrophilic infiltrate, predominantly interstitial, leukocytoclasia, and diapedesis of neutrophils without signs of vasculitis. Characteristically, there is neutrophilic epitheliotropism with neutrophils

Fig. 4.25  Neutrophils are seen within the ductal part of an eccrine sweat gland, so called neutrophilic epitheliotropism

between the epithelia of eccrine ducts and within the epidermis (Figs.  4.24 and 4.25) [87]. Depending on the underlying disorder, there is variable interstitial mucin.

Differential Diagnosis Sweet syndrome is a neutrophilic dermatitis with papillary edema. In leukocytoclastic vasculitis the neutrophilic infiltrate is organized more perivascularly with fibrinoid necrosis of vessel walls. In urticaria there is a perivascular and interstitial eosinophilic infiltrate with variable neutrophils and no neutrophilic epitheliotropism. Rheumatoid neutrophilic dermatitis can be indistinguishable from NUD. In neutrophilic eccrine hidradenitis,

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neutrophils are seen around and within eccrine secretory coils with additional vacuolar degeneration, variable necrosis of secretory epithelium, and squamous eccrine metaplasia.

Summary Clinical Presentation • Recurrent urticarial rash in the context of an associated immunological disease (i.e., systemic autoimmune or autoinflammatory disease) • Urticarial rash is resistant to antihistamines • Accompanied by systemic symptoms (fever, polyarthritis) and leukocytosis Histologic Features • Dermal neutrophilic infiltrate, predominantly interstitial, leukocytoclasia, and diapedesis of neutrophils without signs of vasculitis • Neutrophilic epitheliotropism serves as histological clue Differential Diagnosis • Sweet syndrome • Leukocytoclastic vasculitis • Urticaria • Rheumatoid neutrophilic dermatitis • Neutrophilic eccrine hidradenitis

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Erythema Marginatum Etiology and/or Pathogenesis Erythema marginatum is a cutaneous manifestation of rheumatic fever seen in less than 10% of cases [89]. Rheumatic fever is thought to result from a hypersensitivity reaction triggered by streptococcal infection. Erythema marginatum is also associated with hereditary angioedema [90]. It might be worth to further analyze, whether erythema marginatum should be merged into the group of neutrophilic urticarial dermatosis, a reaction pattern seen in patients with systemic inflammatory diseases, presenting with an urticarial eruption clinically and a neutrophilic dermatosis histopathologically [86, 87].

Clinical Presentation Patients present with a transient and migratory non-itchy erythematous annular eruption with pale centers. The eruption may precede an acute episode of hereditary angioneurotic edema [91].

Prognosis or Clinical Course The transient lesions spread over hours and often recur. It is defined as a cutaneous manifestation in rheumatic fever but is only seen in 1–18% of patients [92].

Takeaway Essentials

Histopathology

Clinical Relevant Pearls • Non-itching, sometimes persistent urticarial rash with systemic symptoms • Unresponsive to antihistamines

There is a perivascular infiltrate in the upper dermis with variable numbers of neutrophils and additional lymphocytes and eosinophils. Mild leukocytoclasis is possible without evidence of vasculitis.

Pathology Interpretation Pearls • Dermal neutrophilic infiltrate intermingled with eosinophils of variable density associated with neutrophilic epitheliotropism

Differential Diagnosis In Still disease and acute lupus erythematosus, neutrophilic epitheliotropism can be seen in both

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diseases that can manifest with neutrophilic urticarial dermatosis. In contrast to leukocytoclastic vasculitis, vasculitis is not evident in erythema marginatum. Urticaria can be impossible to distinguish histologically. Clinical correlation might serve to be useful.

Summary

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Neutrophilic Drug Eruption Considering the predominant histological patterns, these four drug-induced entities belong to the neutrophilic drug eruptions: Sweet syndrome, neutrophilic eccrine hidradenitis, halogenoderma, and erythema nodosum-like reaction. Halogenoderma including iododerma, bromoderma, and fluoroderma will be discussed here.

Clinical Presentation • Transient and migratory non-itchy erythematous annular eruption with pale centers • Clinical context needs to be taken into account for diagnosing underlying systemic inflammatory disorder • Often misinterpreted as urticaria

Etiology and/or Pathogenesis

Histologic Features • Superficial perivascular infiltrate with  variable numbers of neutrophils and additional lymphocytes and eosinophils • No evidence of vasculitis

Both iododerma and bromoderma usually present with acneiform papules and pustules in the face, neck, and on the back (Fig. 4.26) [93]. In more

Halogenoderma results from ingestion of either iodides, bromides, or fluorides. The pathomechanism is unclear.

Clinical Presentation

Differential Diagnosis • Urticaria • Still disease • Acute lupus erythematosus • Leukocytoclastic vasculitis

Takeaway Essentials Clinical Relevant Pearls • Non-itchy urticarial rash • Underlying systemic inflammatory disorder Pathology Interpretation Pearls • Superficial perivascular infiltrate composed of neutrophils, lymphocytes, and eosinophils, histologically otherwise not specified

Fig. 4.26  Ulcerated vegetative plaque with adjacent scar on the right lower extremity

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extreme forms, there are vesicles, bullae, nodular, and ulcerated vegetative plaques.

Prognosis or Clinical Course In general, lesions regress upon cessation of the halogenide and may result in scarring. Iodides may aggravate dermatitis herpetiformis, pyoderma gangrenosum, pustular psoriasis, and erythema nodosum [94].

Histopathology Histology varies depending on the time of biopsy and the clinical picture. In acute lesions of iododerma, there is a dense dermal neutrophilic infiltrate (Figs.  4.27 and 4.28). In longer persisting lesions, pseudoepitheliomatous hyperplasia with variable neutrophilic microabscesses, ulceration, and focal leukocytoclastic vasculitis may be seen.

Differential Diagnosis By histology, it may be impossible to distinguish halogenoderma from the entities in the differential diagnosis; clinicopathological correlation remains essential. In leukocytoclastic vasculitis, the neutrophilic infiltrate can be extensive in

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pustular/necrotic variants but is organized more perivascularly with fibrinoid necrosis of vessel walls. Abscess-forming neutrophilic dermatosis is characterized by a dense dermal neutrophilic infiltrate beneath a subepidermal edema with variable leukocytoclasia. A variably dense suppurative-­granulomatous infiltrate with pseudoepitheliomatous hyperplasia would be seen in infections.

Summary Clinical Presentation • Acneiform papules, granulomatous, or vegetative lesions Histologic Features • Acute lesions: dense dermal neutrophilic infiltrate • Longer persisting lesions: pseudoepitheliomatous hyperplasia with variable neutrophilic microabscesses, ulceration, and focal leukocytoclastic vasculitis Differential Diagnosis • Abscess-forming neutrophilic dermatosis • Leukocytoclastic vasculitis • Infections

Figs. 4.27 and 4.28  Pseudoepitheliomatous hyperplasia with neutrophilic microabscesses and dermal neutrophilic infiltrate

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Takeaway Essentials Clinical Relevant Pearls • Associated with ingestion of iodides, bromides, and fluorides, respectively • Clearing with cessation of offending agent Pathology Interpretation Pearls • Pseudoepitheliomatous hyperplasia of dilated hair follicles replete with neutrophils

Eosinophilic Cellulitis Etiology and/or Pathogenesis In 1971, Wells first described this entity as an inflammatory dermatosis. In 1979, however, Wells and Smith realized that the histopathological changes seen in eosinophilic cellulitis can be observed in many inflammatory dermatoses, e.g., insect bites [95]. In 1979 Spigel and Winkelmann first described the eponym Wells syndrome, which is different from what Wells and Smith originally described as eosinophilic cellulitis. In the literature there is more and more evidence that eosinophilic cellulitis is not a distinct entity but rather an eosinophil-rich reaction to a variety of insults [96, 97]. It can be seen in arthropod reactions, infections, parasitic infestations, urticaria, drug reactions, or hypereosinophilic syndrome [98, 99].

Prognosis or Clinical Course Lesions can progress to slate-gray morphea-like indurations and usually resolve without scarring over a few weeks. There may be recurrent episodes for months to years. Many cases resolve spontaneously, but often systemic glucocorticoids are used.

Histopathology There is a dense dermal eosinophilic infiltrate that can reach into the subcutis (eosinophilic panniculitis). Focally, there are red aggregates of degranulated eosinophils that deposit on collagen bundles forming the so-called flame figures (Fig.  4.29). Older lesions may become more granulomatous with macrophages and variably admixed multinucleated giant cells surrounding degranulated eosinophils [100].

Differential Diagnosis Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) has signs of vasculitis. Also, there are eosinophilic granulomas. In arthropod bite reaction, there is a verti-

Clinical Presentation Lesions are itchy or painful and usually affect trunk and extremities. They consist of edematous, erythematous infiltrated plaques resembling cellulitis. Variations include nodular, papulovesicular eruptions, and itchy excoriated papules.

Fig. 4.29  Red aggregates of degranulated eosinophils surrounding collagen bundles leading to basophilic degeneration and forming so called flame figures

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cally orientated dermal infiltrate and epidermal spongiosis. Vaccination granuloma has deep dermal infiltrates with characteristic blue-gray macrophages.

Summary Clinical Presentation • Infiltrated erythematous plaques resembling cellulitis, variably forming blisters • Variations include itchy vesiculopapular lesions • Recurrent episodes over months to years Histologic Features • Dense dermal eosinophilic infiltrate that can reach into the subcutis • Typical flame figures Differential Diagnosis • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) • Arthropod bite reaction • Vaccination granuloma

Takeaway Essentials Clinical Relevant Pearls • Cellulitis-like erythematous plaques with a wide variety of clinical appearances • Eosinophil-rich inflammatory reaction pattern due to various insults Pathology Interpretation Pearls • Interstitial dense eosinophilic infiltrate in the dermis and subcutis with flame figures

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Hypereosinophilic Syndrome Etiology and/or Pathogenesis Hypereosinophilic syndrome (HES) comprises rare, heterogeneous syndromes characterized by persistent hypereosinophilia (>1.5 x 10 9 /L) on at least two separate occasions associated with end-­organ damage regardless of the etiology. Almost all primary forms of HES are due to neoplastic disorders causing eosinophil lineage expansion (clonal myeloid or eosinophil disorders). In secondary (reactive) HES, the eosinophilia is driven by cytokines (IL-5) due to adverse drug reactions, parasitic infections, connective tissue diseases, lymphomas, and others. Rarely, eosinophilia is present from birth, due to an autosomal dominant mutation causing IL-5 dysregulation [101]. Idiopathic HES are the remaining group of HES with no identifiable cause in thorough workup. More recently, several studies have shown that a significant number of these “idiopathic” cases in fact have mutations in genes involved with cell function and signaling as well as abnormal findings in the bone marrow [102].

Clinical Presentation HES commonly affects the heart, lungs, central and peripheral nervous system, liver, and skin. Cutaneous lesions are seen in about 50% of cases and usually consist of pruritic erythematous papules and nodules or urticaria. Erythroderma, annular erythema, or mucosal ulcerations may be the first symptom of HES, whereas cutaneous infarction and aquagenic pruritus are other rare cutaneous presentations.

Prognosis or Clinical Course HES may be fatal due to eosinophil-mediated organ damage or due to associated malignancies underlining the need to treat with systemic glucocorticoids, targeted therapies against IL-5 or antiproliferative agents [103].

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Histopathology Depending on the type of lesion, there is variable superficial and deep mostly perivascular eosinophilic infiltrate with scattered lymphocytes, macrophages, and plasma cells. Flame figures may be seen. Rarely, there is thrombosis of small vessels [104].

Differential Diagnosis By histology, the differential diagnosis of HES may be impossible; clinicopathological correlation and careful workup remain essential. In urticaria there is a variable superficial and deep perivascular infiltrate of lymphocytes with eosinophils and also neutrophils without vasculitis or thrombosis. Dermal hypersensitivity reaction may have variable lymphocytic vasculitis, which is not a feature of HES. In urticarial stage of autoimmune bullous disorders, variable vacuolar change at the dermoepidermal junction might be an early sign of bullous disease. Immunofluorescence is often positive in autoimmune bullous disorders. Allergic contact dermatitis and atopic dermatitis are characterized by variable spongiosis or thickening of the epidermis with parakeratosis and a superficial perivascular infiltrate with variably admixed eosinophils. PUPPP (pruritic urticarial papules and plaques of pregnancy); polymorphous eruption in pregnancy has a mixed interstitial dermal infiltrate with eosinophils and lymphocytes in the upper dermis over a broad front with variably epidermal spongiosis and parakeratosis. Arthropod bite typically has a wedge-shaped infiltrate-­containing variable eosinophils. In lymphomatoid papulosis the infiltrate might be epidermotropic and contain atypical blasts. Immunohistology shows clusters of CD30-positive lymphocytes. Clinically, there is typical waxing and waning of the lesions. In mycosis fungoides (cutaneous T-cell lymphoma), the lymphocytic infiltrate may contain variable eosinophils. The papillary dermis is marked by wiry collagen bundles with interspersed atypical lymphocytes that form Darier’s nests in the epidermis (epidermotropism); there is variable

syringotropism. In DRESS (drug reaction with eosinophilia and systemic symptoms), apoptotic keratinocytes in the epidermis might be a clue for drug reaction. Incontinentia pigmenti, inflammatory stage, manifests in the first 2 weeks of life and is characterized clinically with Blaschkolinear distribution. There is an eosinophilic infiltrate with eosinophilic spongiosis and dyskeratosis. HES typically affects adults. In eosinophilic granulomatosis with polyangiitis (allergic granulomatosis, Churg-Strauss), the infiltrate contains eosinophils but is more granulomatous. Rarely, there is eosinophilic vasculitis. P-ANCA might be detectable in the serum, and in 40% of cases, indirect immunofluorescence may show por c-ANCA.

Summary Clinical Presentation • Persistent hypereosinophilia with secondary organ-damage • Variably concomitant or preceding skin lesions: itchy erythematous papules and nodules or urticarial, erythroderma, annular erythema, or mucosal ulcerations • Thorough workup to detect underlying cause, such as hematological malignancy Histologic Features • Variable perivascular and interstitial eosinophilic infiltrate with scattered lymphocytes, histiocytes, and plasma cells • Microthrombi might be present Differential Diagnosis • Urticaria • Dermal hypersensitivity reaction • Urticarial stage of autoimmune bullous disorders • Allergic contact dermatitis, atopic dermatitis • Pruritic eruption in pregnancy

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• • • •

Hyper-IgE syndrome Arthropod bite Lymphomatoid papulosis Mycosis fungoides (cutaneous T-cell lymphoma) • DRESS • Incontinentia pigmenti, inflammatory stage • Eosinophilic granulomatosis with polyangiitis (allergic granulomatosis, Churg-Strauss)

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Clinical Presentation The skin eruption is polymorphic and typically occurs during or shortly after radiation therapy; however, delays of up to 7  months have been reported [107]. It consists of erythematous papules, pustules, excoriations, and occasionally wheals, vesicles, and bullae. The eruption is accompanied by localized or generalized pruritus and generally is not confined to the irradiated areas.

Prognosis or Clinical Course Takeaway Essentials Clinical Relevant Pearls • Tissue hypereosinophilia can be a presenting sign or concomitant feature of HES marked by persisting serum hypereosinophilia and secondary organ damage requiring thorough workup and adequate treatment Pathology Interpretation Pearls • Variable dense dermal eosinophilic infiltrate histologically otherwise not specified

Eosinophilic Polymorphic and Pruritic Eruption Associated with Radiotherapy Etiology and/or Pathogenesis Eosinophilic polymorphic and pruritic eruption associated with radiotherapy (EPPER) is a complication of radiotherapy. The majority of cases reported were female patients with cervical cancer and breast cancer [105, 106]. The pathogenic mechanism is unknown. However, two mechanisms, either involving type 1 hypersensitivity or type 4 hypersensitivity reactions, are thought to play a role [105].

Most cases of EPPER resolve within a few weeks of onset. It responds well to topical glucocorticoids, antihistamines, and ultraviolet B treatment.

Histopathology Histologic features are variable. The epidermis usually is spongiotic with variable spongiotic vesiculation. Acanthosis and hyperkeratosis due to scratching are possible (Fig.  4.30). There is a superficial and deep perivascular lymphohistiocytic infiltrate with eosinophils. The infiltrate can also be interstitial and periadnexal in pustular lesions and may extend into the subcutis. In bullous lesions, the bullae resemble bullous pemphigoid.

Differential Diagnosis The histology of bullous pemphigoid may be indistinguishable; however, DIF is negative in EPPER. Also, in Wells syndrome or eosinophilic panniculitis, histology may be indistinguishable. However, clinically, EPPER has more polymorphic lesions and is associated with radiation therapy. The histology of eosinophilic pustular folliculitis (induced by chemotherapy) may be indistinguishable; however, EPPER most commonly affects the extremities and not the scalp.

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• Itchy erythematous papules, pustules, excoriations, and occasionally wheals, vesicles, and bullae Histologic Features • Variable spongiosis, superficial, and deep perivascular infiltrate with eosinophils, variable periadnexal, and interstitial infiltrates • Variable subepidermal bullae, pustules with eosinophils Differential Diagnosis • Bullous pemphigoid • Wells syndrome or eosinophilic panniculitis • Eosinophilic pustular folliculitis

Fig. 4.30  The epidermis exhibits some spongiosis, acanthosis, hypergranulosis, and parakeratosis. The superficial dermal infiltrate contains eosinophils

Takeaway Essentials

Summary

Clinical Relevant Pearls • Lesions are not confined to irradiated areas

Clinical Presentation • Polymorphic skin eruption occurring during or shortly after radiation therapy

Pathology Interpretation Pearls • Arthropod-like changes over a broad front instead of wedge-shaped distribution of the dermal mixed infiltrate

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Case Studies Case 1 Clinical History A young febrile patient presenting with painful, red nodules in both axillae during 3rd day of chemotherapy (cytarabine, daunorubicin, thioguanine) for acute myelogenous leukemia (Fig. 4.31). These lesions spontaneously regressed; however, they reappeared with readministration of chemotherapy. Microscopic Description Histologic sections show necrosis of eccrine and apocrine glands, inflammatory infiltrate of neutrophils, macrophages, and lymphocytes infiltrating glandular coils (Fig. 4.32).

Fig. 4.31  Regressing red nodules in both axillae with beginning postinflammatory hyperpigmentation

(continued)

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128

Fig. 4.32  Necrosis of eccrine and apocrine glands surrounded by an inflammatory infiltrate of neutrophils, macrophages, and lymphocytes infiltrating glandular coils

Diagnosis Neutrophilic eccrine hidradenitis Discussion It is a self-limiting inflammatory dermatosis primarily induced by chemotherapeutic agents. It should not be confused with idiopathic plantar hidradenitis where neutrophils are centered on the ductal part and do not involve the secretory part of the glandular coils.

Case 2 Clinical History A 70-year-old man presenting with painful red blotches, partly bullous, and erosive on both hands 8 days after last cycle of chemotherapy (cyclophosphamide, vincristine, adriamycin) for stage IV small cell lung cancer. Physical examination revealed violaceous and painful blotches on both hands with edematous swelling, beginning pustulation, and erosions (Fig. 4.33). Microscopic Description Histology shows normal epidermis, papillary dermal edema (Fig.  4.34), and a dense dermal neutrophilic infiltrate with leukocytoclasia and erythrocyte extravasation (Fig. 4.35). (continued)

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Fig. 4.33  Violaceous and painful blotches on back of right hand with edematous swelling and beginning postulation

Fig. 4.34  Normal epidermis, massive papillary dermal edema, and a dense dermal neutrophilic infiltrate

(continued)

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130

Fig. 4.35  A dense dermal neutrophilic infiltrate with leukocytoclasia and erythrocyte extravasation

Diagnosis Neutrophilic dermatosis of the (dorsal) hands. Discussion It is a self-limiting neutrophilic dermatosis primarily in association with hematological malignancies, inflammatory bowel disease, and sarcoidosis and less frequent associations with infection and solid neoplasms. It should be distinguished from Sweet syndrome and pyoderma gangrenosum.

Case 3 Clinical History A 17-year-old female patient with almost daily episodes of urticarial rash for 3 years, joint pain, and occasional dyspnea presenting with an urticarial rash and burning sensation, irresponsive to systemic antihistamines. Laboratory tests revealed elevated inflammatory parameters (CRP), positive ANA and dsDNA, as well as consumption of complement. Urticarial macules and plaques with slightly raised borders, surrounded by an ischemic halo (Figs. 4.36 and 4.37), were seen on the patient’s trunk and lower extremities. Microscopic Description There is a variable dense dermal neutrophilic infiltrate with neutrophilic epitheliotropism, no vasculitis (Fig. 4.38). (continued)

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Fig. 4.36  Urticarial macules and plaques with slightly raised borders, surrounded by an ischemic halo

Fig. 4.37  Disseminated urticarial macules, some of them surrounded by an ischemic halo on lower extremities

Fig. 4.38  Diffuse dermal neutrophilic infiltrate with neutrophilic epitheliotropism but no vasculitis

(continued)

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Diagnosis Neutrophilic urticarial dermatosis in a patient with systemic lupus erythematosus. Discussion Patients present with unusual urticarial rash, irresponsive to antihistamines, often accompanied by systemic symptoms due to underlying autoimmune or autoinflammatory disorder. Serological tests and histology with neutrophilic epitheliotropism are useful diagnostic tests.

Case 4 Clinical History A 53-year-old male patient presenting with painless papules and nodules on the extensor sides of elbows and ulnar site for more than 1 year (Fig. 4.39). The patient is suffering from Crohn disease. Laboratory tests showed no elevated inflammatory parameters such as C-reactive proteins. Microscopic Description There is a dense dermal neutrophilic infiltrate with leukocytoclasia and signs of leukocytoclastic vasculitis with fibrinoid necrosis and neutrophils in vessel walls (Fig. 4.40).

Fig. 4.39  Painless papules and nodules on the extensor sides of the left elbow and ulnar site

Fig. 4.40  Dense dermal neutrophilic infiltrate with leukocytoclasia and signs of leukocytoclastic vasculitis with fibrinoid necrosis and neutrophils in vessel walls in the upper dermis

(continued)

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Diagnosis Erythema elevatum et diutinum (EED). Discussion EED usually presents at extensor sides of extremities, i.e., dorsal feet, knees, and back of hands. Associations with infections, chronic inflammatory disorders, and malignancies are possible. Lesions may persist for years and regress spontaneously. Laboratory tests may show elevated ANCA.

References 1. Kasha EE Jr, Epinette WW.  Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) in association with a monoclonal IgA gammopathy: a report and review of the literature. J Am Acad Dermatol. 1988;19(5 Pt 1):854–8. 2. Kretschmer L, Maul J-T, Hofer T, Navarini AA. Interruption of Sneddon-Wilkinson subcorneal pustulation with infliximab. Case Rep Dermatol. 2017;9(1):140–4. 3. Patel R, Cafardi JM, Patel N, et al. Tumor necrosis factor biologics beyond psoriasis in dermatology. Expert Opin Biol Ther. 2011;11(10):1341–59. 4. Grob JJ, Mege JL, Capo C, et  al. Role of tumor necrosis factor-alpha in Sneddon-Wilkinson subcorneal pustular dermatosis. A model of neutrophil priming in vivo. J Am Acad Dermatol. 1991;25(5 Pt 2):944–7. 5. Pinkus H.  Is subcorneal pustular dermatosis of Sneddon and Wilkinson and entity sui generis? Am J Dermatopathol. 1981;3(4):379–80. 6. Letter LBL. Subcorneal pustular dermatosis vs pustular psoriasis. Arch Dermatol. 1974;110(1):131. 7. Navarini AA, Satoh TK, French LE.  Neutrophilic dermatoses and autoinflammatory diseases with skin involvement-innate immune disorders. Semin Immunopathol. 2016;38(1):45–56. 8. Sneddon IB, Wilkinson DS.  Subcorneal pustular dermatosis. Br J Dermatol. 1956;68(12):385–94. 9. Reed J, Wilkinson J.  Subcorneal pustular dermatosis. Clin Dermatol. 2000;18(3):301–13. 10. Patton D, Lynch PJ, Fung MA, Fazel N.  Chronic atrophic erosive dermatosis of the scalp and extremities: a recharacterization of erosive pustular dermatosis. J Am Acad Dermatol. 2007;57(3):421–7. 11. Feramisco JD, Goerge T, Schulz SE, et  al. Disseminated erosive pustular dermatosis also involving the mucosa: successful treatment with oral dapsone. Acta Derm Venereol. 2012;92(1):91–2. 12. Wilk M, Zelger BG, Hauser U, et al. Erosive pustular dermatosis of the scalp: reappraisal of an underrecognized entity. J Dtsch Dermatol Ges. 2018;16(1):15–9. 13. Marchini G, Ståbi B, Kankes K, et  al. AQP1 and AQP3, psoriasin, and nitric oxide synthases 1–3 are

inflammatory mediators in erythema toxicum neonatorum. Pediatr Dermatol. 2003;20(5):377–84. 14. Marchini G, Ulfgren A-K, Loré K, et al. Erythema toxicum neonatorum: an immunohistochemical analysis. Pediatr Dermatol. 2001;18(3):177–87. 15. Reginatto FP, Muller FM, Peruzzo J, Cestari TF. Epidemiology and predisposing factors for erythema toxicum neonatorum and transient neonatal pustular: a multicenter study. Pediatr Dermatol. 2017;34(4):422–6. 16. Van Praag MCG, Van Rooij RWG, Folkers E, et al. Diagnosis and treatment of pustular disorders in the neonate. Pediatr Dermatol. 1997;14(2):131–45. 17. Freeman RG, Spiller R, Knox JM.  Histopathology of erythema toxicum neonatorum. Arch Dermatol. 1960;82:586–9. 18. Lucky AW, Esterly NB, Heskel N, et al. Eosinophilic pustular folliculitis in infancy. Pediatr Dermatol. 1984;1(3):202–6. 19. Boone M, Dangoisse C, Andre J, et al. Eosinophilic pustular folliculitis in three atopic children with hypersensitivity to Dermatophagoides pteronyssinus. Dermatology. 1995;190(2):164–8. 20. Hernández-Martín Á, Nuño-González A, Colmenero I, Torrelo A.  Eosinophilic pustular folliculitis of infancy: a series of 15 cases and review of the literature. J Am Acad Dermatol. 2013;68(1):150–5. 21. Ziemer M, Böer A.  Eosinophilic pustular folliculitis in infancy: not a distinctive inflammatory disease of the skin. Am J Dermatopathol. 2005;27(5):443–55. 22. Nervi SJ, Schwartz RA, Dmochowski M. Eosinophilic pustular folliculitis: a 40 year retrospect. J Am Acad Dermatol. 2006;55(2):285–9. 23. Ishiguro N, Shishido E, Okamoto R, et  al. Ofuji’s disease: a report on 20 patients with clinical and histopathologic analysis. J Am Acad Dermatol. 2002;46(6):827–33. 24. Falanga V.  Infantile acropustulosis with eosinophilia. J Am Acad Dermatol. 1985;13(5 Pt 1):826–8. 25. Mancini AJ, Frieden IJ, Paller AS.  Infantile acropustulosis revisited: history of scabies and response to topical corticosteroids. Pediatr Dermatol. 1998;15(5):337–41. 26. Bundino S, Zina AM, Ubertalli S. Infantile acropustulosis. Dermatologica. 1982;165(6):615–9.

134 27. Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol. 1991;127(9):1333–8. 28. Zelickson BD, Muller SA.  Generalized pustular psoriasis: a review of 63 cases. Arch Dermatol. 1991;127(9):1339–45. 29. Navarini AA, Burden AD, Capon F, et al., ERASPEN Network. European consensus statement on phenotypes of pustular psoriasis. J Eur Acad Dermatol Venereol. 2017;31(11):1792–9. 30. Christophers E, Metzler G, Röcken M.  Bimodal immune activation in psoriasis. Br J Dermatol. 2014;170(1):59–65. 31. Gibson LE, el-Azhari RA. Erythema elevatum diutinum. Clin Dermatol. 2000;18(3):295–9. 32. Wahl CE, Bouldin MB, Gibson LE. Erythema elevatum diutinum: clinical, histopathologic, and immunohistochemical characteristics of six patients. Am J Dermatopathol. 2005;27(5):397–400. 33. Llamas-Velasco M, Stengel B, Pérez-González YC, Mentzel T. Late-stage erythema elevatum diutinum mimicking a fibroblastic tumor: a potential pitfall. Am J Dermatopathol. 2018;40(6):442–4. 34. Cardis MA, Sowash MG, Mosojane KI, et al. HIV-­ associated erythema elevatum diutinum: a case report and review of a clinically distinct variant. Dermatol Online J. 2018;24(5):15. 35. Creus L, Salleras M, Sola MA, et  al. Erythema elevatum diutinum associated with pulmonary infiltrates. Br J Dermatol. 1997;137(4):652–3. 36. Ackerman AB, Chongchitnant N, Sanchez J, Guo J. Histologic diagnosis of inflammatory skin diseases: an algorithmic method based on pattern analysis. 2nd ed. Williams and Wilkins; Philadelphia. 1997. p. 488. 37. Ziemer M, Koehler MJ, Weyers W. Erythema elevatum diutinum – a chronic leukocytoclastic vasculitis microscopically indistinguishable from granuloma faciale? J Cutan Pathol. 2011;38(11):876–83. 38. Dicken C, Seehafer J. Bowel bypass syndrome. Arch Dermatol. 1979;115(7):837–9. 39. Kemp DR, Gin D.  Bowel-associated dermatosis-­ arthritis syndrome. Med J Aust. 1990;152:43–5. 40. Ashchyan HJ, Nelson CA, Stephen S, et  al. Neutrophilic dermatoses. Part II.  Pyoderma gangrenosum and other bowel- and arthritis-associated neutrophilic dermatoses. J Am Acad Dermatol. 2018;79(6):1009–22. 41. Marzano AV, Ishak RS, Saibeni S, et  al. Autoinflammatory skin disorders in inflammatory bowel diseases, pyoderma gangrenosum and Sweet’s syndrome: a com- prehensive review and disease classification criteria. Clin Rev Allergy Immunol. 2013;45(2):202–10. 42. Ely PH.  The bowel bypass syndrome: a response to bacterial peptidoglycans. J Am Acad Dermatol. 1980;2(6):473–87. 43. Delaney TA, Clay CD, Randell PL.  The bowel-­ associated dermatosis—arthritis syndrome. Australas J Dermatol. 1989;30(1):23–7.

S. M. C. Möckel and D. Metze 44. Cugno M, Gualtierotti R, Meroni PL, Marzano AV.  Inflammatory joint disorders and neutrophilic dermatoses: a comprehensive review. Clin Rev Allerg Immunol. 2018;54(2):269–81. 45. Andre M, Aumaitre O, Papo T, et al. Disseminated aseptic abscesses associated with Crohn’s disease: a new entity. Dig Dis Sci. 1998;43(2):420–8. 46. Kennedy C. The spectrum of inflammatory skin disease following jejuno-ileal bypass for morbid obesity. Br J Dermatol. 1981;105(4):425–35. 47. Harrist TJ, Fine JD, Berman RS, et al. Neutrophilic eccrine hidradenitis. A distinctive type of neutrophilic dermatosis associated with myelogenous leukemia and chemotherapy. Arch Dermatol. 1982;118(4):263–6. 48. Marini M, Wright D, Ropolo M. Neutrophilic eccrine hidradenitis secondary to topotecan. J Dermatolog Treat. 2002;13(1):35–7. 49. Turan H, Kaya E, Gurlevik Z, et  al. Neutrophilic eccrine hidradenitis induced by cetuximab. Cutan Ocul Toxicol. 2012;31(2):148–50. 50. Dib EG, Ifthikharuddin JJ, Scott GA, et  al. Neutrophilic eccrine hidradenitis induced by imatinib mesylate (Gleevec) therapy. Leuk Res. 2005;29(2):233–4. 51. Herms F, Franck N, Kramkimel N, et al. Neutrophilic eccrine hidradenitis in two patients treated with BRAF inhibitors: a new cutaneous adverse event. Br J Dermatol. 2017;176(6):1645–8. 52. Bachmeyer C, Reygagne P, Aractingi S.  Recurrent neutrophilic eccrine hidradenitis in an HIV-1-­ infected patient. Dermatology. 2000;200(4): 328–30. 53. Nijsten TE, Meuleman L, Lambert J.  Chronic pruritic neutrophilic eccrine hidradenitis in a patient with Behçet’s disease. Br J Dermatol. 2002;147(4):797–800. 54. Brehler R, Reimann S, Bonsmann G, Metze D.  Neutrophilic hidradenitis induced by chemotherapy involves eccrine and apocrine glands. Am J Dermatopathol. 1997;19(1):73–8. 55. Bailey DL, Barron D, Lucky AW.  Neutrophilic eccrine hidradenitis: a case report and review of the literature. Pediatr Dermatol. 1989;6(1):33–8. 56. Stahr BJ, Cooper PH, Caputo RV.  Idiopathic plantar hidradenitis: a neutrophilic eccrine hidradenitis occurring primarily in children. J Cutan Pathol. 1994;21(4):289–96. 57. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol. 1964;76:349–56. 58. Rochet NM, Chavan RN, Cappel MA, et al. Sweet syndrome: clinical presentation, associations, and response to treatment in 77 patients. J Am Acad Dermatol. 2013;69(4):557–64. 59. Satra K, Zalka A, Cohen PR, Grossman ME. Sweet’s syndrome and pregnancy. J Am Acad Dermatol. 1994;30(2 Pt 2):297–300. 60. Amouri M, Masmoudi A, Ammar M, et  al. Sweet’s syndrome: a retrospective study of 90

4  Neutrophilic and Pustular Eruptions cases from a tertiary care center. Int J Dermatol. 2016;55(9):1033–9. 61. Cohen PR, Kurzrock R. Sweet’s syndrome: a review of current treatment options. Am J Clin Dermatol. 2002;3(2):117–31. 62. Marcoval J, Martín-Callizo C, Valentí-Medina F, et al. Sweet syndrome: long-term follow-up of 138 patients. Clin Exp Dermatol. 2016;41(7):741–6. 63. Bidyasar S, Montoya M, Suleman K, Markowitz AB.  Sweet syndrome associated with granulocyte colony-stimulating factor. J Clin Oncol. 2008;26(26):4355–6. 64. Giasuddin AS, El-Orfi AH, Ziu MM, El-Barnawi NY.  Sweet’s syndrome: is the pathogenesis mediated by helper T cell type 1 cytokines? J Am Acad Dermatol. 1998;39(6):940–3. 65. Imhof L, Meier B, Frei P, et al. Severe Sweet’s syndrome with elevated cutaneous interleukin-1β after azathioprine exposure: case report and review of the literature. Dermatology. 2015;230(4):293–8. 66. Miyoshi T, Yamashita K, Ohno T, et  al. Familial Mediterranean fever gene as a possible modifier of Sweet syndrome with chronic myelogenous leukemia. Acta Haematol. 2008;120(1):57–62. 67. Torrelo A, Patel S, Colmenero I, et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol. 2010;62(3):489–95. 68. Baartman B, Kosari P, Warren CC, et  al. Sight-­ threatening ocular manifestations of acute febrile neutrophilic dermatosis (Sweet’s syndrome). Dermatology. 2014;228(3):193–7. 69. Su WP, Liu HN. Diagnostic criteria for Sweet’s syndrome. Cutis. 1986;37(3):167–74. 70. Magro CM, Momtahen S, Nguyen GH, Wang X. Histiocytoid Sweet’s syndrome: a localized cutaneous proliferation of macrophages frequently associated with chronic myeloproliferative disease. Eur J Dermatol. 2015;25(4):335–41. 71. Rahier JF, Lion L, Dewit O, Lambert M. Regression of Sweet's syndrome associated with Crohn’s disease after anti-tumor necrosis factor therapy. Acta Gastroenterol Belg. 2005;68(3):376–9. 72. Cohen PR.  Neutrophilic dermatoses: a review of current treatment options. Am J Clin Dermatol. 2009;10(5):301–12. 73. Requena L, Kutzner H, Palmedo G, et al. Histiocytoid Sweet syndrome. A dermal infiltration of immature neutrophilic granulocytes. Arch Dermatol. 2005;141(7):834–42. 74. Strutton G, Weedon D, Robertson I.  Pustular vasculitis of the hands. J Am Acad Dermatol. 1995;32(2Pt1):192–8. 75. Galaria NA, Junkins-Hopkins JM, Kligman D, James WD.  Neutrophilic dermatosis of the dorsal hands: pustular vasculitis revisited. J Am Acad Dermatol. 2000;43(5Pt1):870–4. 76. Weenig RH, Bruce AJ, McEvoy MT, et  al. Neutrophilic dermatosis of the hands: for new

135 cases and review of the literature. Int J Dermatol. 2004;43(2):95–102. 77. Stransky L, Broshtilova V.  Neutrophilic dermatosis of the dorsal hands elicited by thermal injury. Contact Dermatitis. 2003;49(1):42. 78. Duquia RP, Almeida HL Jr, Vettorato G, et  al. Neutrophilic dermatosis of the dorsal hands: acral Sweet syndrome? Int J Dermatol. 2006;45(1): 51–2. 79. Walling HW, Snipes CJ, Gerami P, Piette WW. The relationship between neutrophilic dermatosis of the dorsal hands and Sweet syndrome: report of 9 cases and comparison to atypical pyoderma gangrenosum. Arch Dermatol. 2006;142(1):57–63. 80. Cravo M, Cardoso JC, Tellechea O, et  al. Neutrophilic dermatosis of the dorsal hands associated with hypopharyngeal carcinoma. Dermatol Online J. 2008;14(7):5. 81. Cohen PR.  Skin lesions of Sweet syndrome and its dorsal hand variant contain vasculitis: an oxymoron or an epiphenomenon? Arch Dermatol. 2002;138(3):400–3. 82. Jaimes-Lopez N, Molina V, Arroyave JE, et  al. Development of pyoderma gangrenosum during therapy with infliximab. J Dermatol Case Rep. 2009;3(2):20–3. 83. Marzano AV, Cugno M, Trevisan V, et  al. Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases. Clin Exp Immunol. 2010;162(1):100–7. 84. Marzano AV, Borghi A, Meroni PL, Cugno M.  Pyoderma gangrenosum and its syndromic forms: evidence for a link with autoinflammation. Br J Dermatol. 2016;175(5):882–91. 85. Powell FC, Su WPD, Perry HO.  Pyoderma gangrenosum: classification and management. J Am Acad Dermatol. 1996;34(3):395–409. 86. Kieffer C, Cribier B, Lipsker D.  Neutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature. Medicine. 2009;88(1):23–31. 87. Broekaert SM, Böer-Auer A, Kerl K, et  al. Neutrophilic epitheliotropism is a histopathological clue to neutrophilic urticarial dermatosis. Am J Dermatopathol. 2016;38(1):39–49. 88. McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med. 2006;3(8):e297. 89. Willis WF.  The gyrate erythemas. Int J Dermatol. 1978;17(9):698–702. 90. Rasmussen ER, de Freitas PV, Bygum A. Urticaria and prodromal symptoms including erythema marginatum in danish patients with hereditary angioedema. Acta Derm Venereol. 2016;96(3):373–6. 91. Farkas H, Harmat G, Fáy A, et  al. Erythema marginatum preceding an acute oedematous attack of hereditary angioneurotic oedema. Acta Derm Venereol. 2001;81(5):376–7.

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S. M. C. Möckel and D. Metze 101. Prakash Babu S, Chen YK, Bonne-Annee S, et  al. Dysregulation of interleukin 5 expression in familial eosinophilia. Allergy. 2017;72(9):1338–45. 102. Dispenza MC, Bochner BS.  Diagnosis and novel approaches to the treatment of hypereosinophilic syndromes. Curr Hematol Malig Rep. 2018;13(3):191–201. 103. Gotlib J. World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management. Am J Hematol. 2017;92(11):1243–59. 104. Fitzpatrick JE, Johnson C, Simon P, et al. Cutaneous microthrombi: a histologic clue to the diagnosis of hypereosinophilic syndrome. Am J Dermatopathol. 1987;9(5):419–22. 105. Rueda RA, Valencia IC, Covelli C, et al. Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy. Arch Dermatol. 1999;135(7): 804–10. 106. van Kester MS, Quint KD.  Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy on the skin of the right breast. JAMA Oncol. 2016;2(5):677–8. 107. Gallego H, Crutchfield CE 3rd, Wilke MS, Lewis EJ.  Delayed EPPER syndrome. Arch Dermatol. 2001;137(6):821–2.

5

Granulomatous Dermatitis and Others Toru Ogawa, Mirian Nacagami Sotto, and Mai P. Hoang

Contents Introduction

 140

Sarcoidosis Clinical Presentation Maculopapular Lesions Lupus Pernio Hypopigmented Sarcoidosis Atrophic and Ulcerative Sarcoidosis Ichthyosiform Sarcoidosis Scar Sarcoidosis Subcutaneous Sarcoidosis Sarcoidosis Alopecia Nail Sarcoidosis Prognosis or Clinical Course Histopathology Differential Diagnosis

 140  140  140  141  141  141  141  141  141  141  141  142  142  143

Blau Syndrome Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 144  144  144  144  144

Granuloma Annulare Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 145  145  146  146  147

T. Ogawa Department of Pathology, Massachusetts General Hospital, Boston, MA, USA M. N. Sotto Department of Dermatology, Faculty of Medicine of the University of São Paulo, São Paulo, SP, Brazil e-mail: [email protected]

M. P. Hoang (*) Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA e-mail: [email protected]

© Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_5

137

T. Ogawa et al.

138 Necrobiosis Lipoidica Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 147  148  148  148  149

Rheumatoid Nodule Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 150  150  150  151  151

Necrobiotic Xanthogranuloma Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 152  152  152  152  153

Crohn Disease Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 154  154  155  155  155

Palisaded Neutrophilic and Granulomatous Dermatitis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 156  156  157  157  157

Idiopathic Orofacial Granulomatosis/Melkersson-­Rosenthal Syndrome Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 158  159  159  159  159

Granulomatous Rosacea Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 161  161  161  161  162

Chronic Granulomatous Disease Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 163  163  164  164  164

Foreign Body Granulomas Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 164  165  165  165  166

Endocrine Abnormalities Scleromyxedema Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Pretibial Myxedema Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Bullous Diabeticorum

 166  166  166  167  167  167  168  169  169  169  170  170

5  Granulomatous Dermatitis and Others

139

Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 170  170  170  171

Hematologic Malignancies Systemic Amyloidosis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 171  171  172  174  174  174

Nutritional Deficiencies Pellagra Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Acrodermatitis Enteropathica Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Necrolytic Migratory Erythema Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Vitamin A Deficiency Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Vitamin C Deficiency Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 175  175  176  176  176  176  177  177  177  177  178  178  178  179  179  179  180  180  181  181  181  182  182  182  182  182

Case Vignettes Case 1 Clinical History Microscopic Description Diagnosis Discussion Case 2 Clinical History Microscopic Description Diagnosis Discussion Case 3 Clinical History Microscopic Description Diagnosis Discussion Case 4 Clinical History Microscopic Description Diagnosis Discussion

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(T-helper cell type 1) immune response. The pathogenesis of sarcoidosis involves the accumulation of macrophages and T cells resulting in granulomas. Tumor necrosis factor (TNF)-α plays an important part of the formation of granulomas, and interferon (IFN)-γ produced from CD4-positive T cells contributes to the activation of macrophages.

Cutaneous granulomatous reaction is an immune response in which epithelioid histiocytes and other inflammatory cells are seen. The etiology can be infectious (see Chapters 13 and 14) and noninfectious. Noninfectious g­ ranulomatous diseases of the skin encompass a broad group. Those of systemic diseases including sarcoidosis, Blau syndrome, Crohn disease, and chronic granulo- Clinical Presentation matous disease would have different prognosis. Localized processes include Melkersson-­Approximately one third of the patients with Rosenthal syndrome and granulomatous rosacea. systemic sarcoidosis have cutaneous lesions A number of reactive conditions yet have impli- which are classified broadly into either specific cation for systemic diseases are granuloma annu- (noncaseating epithelioid granulomas) or nonlare, rheumatoid nodule, necrobiosis lipoidica, specific. The specific cutaneous lesions of sarnecrobiotic xanthogranuloma, and palisaded neu- coidosis include many lesion types and typically trophilic and granulomatous dermatitis. present as red-brown papules or plaques (Table 5.1). The lesions are seen on the face, lips, neck, upper trunk, and extremities; and they are Sarcoidosis usually symmetrical. Erythroderma is rare. One can see the apple-jelly coloration characteristic Sarcoidosis is a chronic systemic disease of of granulomatous skin lesions on diascopy [2]. unknown etiology that frequently presents with pulmonary infiltrates, bilateral hilar lymphadenopathy, Maculopapular Lesions and ocular and cutaneous lesions. The disease most This is the most common type. Although the face commonly affects the lungs, lymph nodes, liver, is the favorite site, the eruption can be seen on the spleen, eyes, and skin. However, this disease also involves the central nervous system, oral mucosa, parotid gland, heart muscle, kidney, joints, and Table 5.1  Cutaneous lesions of sarcoidosis Nonspecific bone. Sarcoidosis affects patients of all races with Specific lesions lesions the highest annual incidence seen in Scandinavia. Very Maculopapular Erythema This disease is rare in Asians. African Americans common nodosum are affected more frequently than Caucasians in the Common Nodular United States (2.4% versus 0.84% annual inciScar sarcoidosis Lupus pernio dence) [1]. Sarcoidosis is seen mainly in adults with Subcutaneous age ranges from 25 to 45 years. Women are affected sarcoidosis more than men. Childhood sarcoidosis is rare. In the Uncommon Annular winter and spring, the greater number of the new Psoriasiform sarcoidosis patients can be seen. Hypopigmented Atrophic The development of sarcoidosis is likely multiUlcerative factorials including extrinsic antigens, genetic facOral tors, and immune responses. A variety of infectious Rare Verrucous agents including mycobacteria, fungi, mycoLichenoid Ichthyosiform plasma, and viruses have been implicated [1]. Erythrodermic Sarcoidosis can develop as a reaction to medication Morpheaform or as a paraneoplastic dermatosis. These antigens Photodistributed are a trigger for sarcoidosis; however, the host’s Sarcoidal alopecia Genital sarcoidosis immune system causes the development of sarNail sarcoidosis coidosis. Sarcoidosis results from Th1-type

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Fig. 5.3  Violaceous papules on tip of nose characteristic of lupus pernio

This type is characterized by prominent telangiectasia resulting in pink to orange-brown color. Fig. 5.1  Papules seen on the face

Hypopigmented Sarcoidosis Patches, papules, or plaques with decreased pigmentation are typically seen in dark-skinned patients.  trophic and Ulcerative Sarcoidosis A Morpheaform hypopigmented patches or atrophic plaques are present in this rare type. There is a tendency for papulonodules and other non-­ atrophic sarcoidosis lesions to ulcerate. Ichthyosiform Sarcoidosis This rare type is similar to ichthyosis acquisita or acquired ichthyosis. Favorite sites are the lower extremities.

Fig. 5.2  Multiple papules on the trunk

nape of the neck, back, buttocks, and extremities (Figs. 5.1 and 5.2). The papules may coalesce to become plaques in papular sarcoidosis. Plaque sarcoidosis has single or multiple plaques on the face, back, buttocks, and extremities.

Lupus Pernio This is known as the most characteristic type. Bluish-red nodules and plaques on the face are typically seen in African Americans (Fig.  5.3). This type is important, because it is frequently associated with chronic sarcoidosis of the lungs and the upper respiratory tract. It is known that angiolupoid sarcoidosis is a type of lupus pernio.

Scar Sarcoidosis Granulomatous infiltration is seen at sites of trauma, scar by infection such as herpes zoster, and tattoos. Subcutaneous Sarcoidosis Subcutaneous sarcoidosis (Darier-Roussy disease) involves the adipose tissue. Single or multiple plaques or nodules are seen on the extremities. Sarcoidosis Alopecia Usually sarcoidosis alopecia is patchy or diffuse. Histopathological finding is invariably a scarring alopecia. Nail Sarcoidosis Sometimes nail changes can be seen; and the signs are subungual hyperkeratosis, pitting, and clubbing [3].

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Erythema nodosum is the most common nonspecific skin manifestation of sarcoidosis, seen in approximately 10% of sarcoidosis cases. This type is usually associated with subacute or transient sarcoidosis. The lesion predominantly appears on the lower extremities. Clinically, painful and reddish lumps are present. Histopathologically, a septal panniculitis is prominent; however, granulomas are not present. Usually, the patients with erythema nodosum have systemic symptoms, fever, polyarthritis, and adenopathy. Other nonspecific cutaneous lesions include Sweet syndrome, erythema multiforme, pyoderma gangrenosum, prurigo, calcinosis cutis, vasculitis, and digital clubbing [1]. Approximately 60% of patients with cutaneous lesions exhibit systemic involvement. A third of these patients have vague constitutional symptoms such as fatigue, fever, night sweats, and weight loss. The most common clinical and pathological presentation is pulmonary sarcoidosis. Half of these patients present with hilar adenopathy that is bilateral in most cases. Pulmonary hypertension is a serious complication. About one third of patients with systemic symptoms has ocular sarcoidosis manifesting as anterior uveitis most commonly or posterior uveitis resulting in glaucoma and vision loss. In 5% of the patients, granulomatous infiltration of the heart results in cardiac sarcoidosis more commonly seen in Asian patients than Caucasians [1]. In 5–13% of patients, central nervous system involvement results in facial nerve palsy, neuroendocrine dysfunction, mass lesions, encephalopathy, seizures, peripheral neuropathy, and cognitive dysfunction. Optic neuritis can result in permanent blindness.

complications resulting in death in a quarter of the patients [4]. It is reported that patients with a moderate or severe granulomatous infiltrate in their biopsies had a more severe clinical presentation, with a more generalized skin involvement as well as a more chronic course of the disease [5].

Histopathology In a diagnostic biopsy, multiple noncaseating and epithelioid granulomas surrounded by a rim of lymphocytes and fibrosis are seen in the dermis. However, the histologic changes can be diverse including interstitial granulomas, elastophagocytosis, linear perineural granulomas, dermal mucin deposition, and lichenoid dermatitis containing plasma cells [6]. The classic sarcoidal granuloma is a circumscribed collection of epithelioid histiocytes in the superficial and deep dermis (Fig.  5.4). Noncaseating epithelioid granulomas are seen. Necrosis is not typically present in these granulomas, but it can be seen in rare cases [7]. In addition, multinucleated giant cells can be seen. Sometimes asteroid bodies and Schaumann bodies may be identified in multinucleated giant cells, but they are not specific for sarcoidosis since they can be observed in other granulomatous processes such as tuberculosis and foreign body reaction. Asteroid bodies are eosinophilic

Prognosis or Clinical Course Sarcoidosis is a chronic disease; however, it is often self-resolving in 60% of cases. Progression to pulmonary fibrosis and death can be observed in some patients. There is an increased risk for malignancy. The number of skin lesions does not appear to correlate with the severity of systemic disease. The prognosis is especially serious in African American women in whom sarcoidosis-­ related

Fig. 5.4  Aggregates of epithelioid histiocytes are seen forming noncaseating granulomas in the dermis (×100)

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Summary

Fig. 5.5  Schaumann body. Rounded laminated basophilic inclusions are seen within the cytoplasm of multinucleated giant cells (×400)

starburst inclusions, and Schaumann bodies have shell-like calcification (Fig.  5.5). CD4-positive lymphocytes typically infiltrate the center, whereas CD8-positive lymphocytes infiltrate the periphery of the granulomas.

Differential Diagnosis Diagnosis by exclusion is important for sarcoidosis. The histologic differential is broad, so clinical pathologic correlation is important to render a diagnosis. First, special stains are needed to exclude an infectious etiology including mycobacteria, leprosy, fungal, leishmaniasis, and syphilis. Tuberculoid leprosy has the smaller areas of central necrosis, compared with sarcoidosis. The granulomas in tuberculoid leprosy follow nerves, so elongated granulomas are characteristics [8]. Cutaneous tuberculosis skin lesion or lupus vulgaris shows prominent inflammatory cells especially between the granulomas. The infiltration is also seen close to the epidermis. Foreign body such as beryllium, zirconium, and tattoo can cause granulomatous inflammation; and polarized light microscopy would be helpful. Doubly refractile material, such as silica, can be seen. Metastatic Crohn disease would typically exhibit ulceration, numerous eosinophils, vasculitis, and dermal edema [5].

Clinical Presentation • Sarcoidosis is a systemic granulomatous disorder of unknown origin. • The disease most commonly affects the lungs, lymph nodes, liver, spleen, eyes, and skin. • Specific skin lesions such as lupus pernio are chronic, while nonspecific skin lesions such as erythema nodosum are acute. • Red, purple, or brown papules or plaques in cutaneous sarcoidosis while painful reddish lumps in erythema nodosum. Histologic Features • Multiple noncaseating and epithelioid granulomas surrounded by a rim of lymphocytes and fibrosis are seen in the dermis. Differential Diagnosis • Mycobacterial and fungal infections • Foreign body reaction • Metastatic Crohn disease

Takeaway Essentials Clinical Relevant Pearls • Cutaneous sarcoidosis has a variety of clinical appearance. • Severity and site of involvement differ among ethnicities and races. • Sarcoidosis can present before, concurrently, or after the development of malignancy. Pathology Interpretation Pearls • Diagnosis requires correlating clinical findings, histologic features of noncase-

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ating granulomas, demonstration of organ involvement, and exclusion of other diseases. • Asteroid bodies and Schumann bodies are not specific features of sarcoidosis.

Blau Syndrome Blau syndrome is an autosomal dominant inherited syndrome (MIM# 186580). Its clinical triad is comprised of granulomatous dermatitis, symmetric arthritis, and recurrent uveitis. CARD15/ NOD2, caspase recruitment domain gene, has been implicated to be the underlying cause [9]. Mutations of this same gene have also been found in children with early-onset sarcoidosis (MIM# 609464). Therefore, it has been proposed that Blau syndrome and early-onset sarcoidosis represent the familial and sporadic forms of the same disease in the pediatric population, respectively [10].

Clinical Presentation The age of onset is before 3–4 years of age for the majority of the patients, first with articular and cutaneous manifestations and then ocular ones [9]. Symmetric polyarthritis would involve the wrists; metacarpophalangeal, first metatarsophalangeal, and proximal interphalangeal joints of hands and feet; ankles; and rarely elbows. Joint swelling and tenderness are accompanied by synovial thickening and effusion. Skin involvement would typically be either a papulonodular eruption or multiple firm subcutaneous plaques. Clusters of yellow to brown, small papules are seen on the trunk or extremities. The eruption is often symmetric, on the trunk and/or extremities, and intermittent. Eye involvement typically presents as recurrent anterior uveitis or panuveitis manifested as eye

pain, photophobia, and blurred vision. Granulomatous uveitis is typically bilateral, chronic, and recurrent.

Prognosis or Clinical Course Joint involvement can be complicated by deformities. Eye involvement is the most relevant morbidity requiring close attention.

Histopathology Non-necrotizing granulomas with multinucleated giant cells would be seen on skin biopsy. Ultrastructural study showed the “comma-­ shaped” bodies in epithelioid cells in one case of Blau syndrome [11].

Differential Diagnosis Blau syndrome can be mistaken for juvenile rheumatoid arthritis when the initial presentation is arthritis without accompanied ocular or cutaneous findings.

Summary Clinical Presentation • An autosomal dominant inherited syndrome. • The clinical triad is comprised of granulomatous dermatitis, symmetric arthritis, and recurrent uveitis. Histologic Features • Non-necrotizing granulomas with multinucleated giant cells Differential Diagnosis • Juvenile rheumatoid arthritis • Early-onset sarcoidosis

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Takeaway Essentials Clinical Relevant Pearls • Both Blau syndrome and early-onset sarcoidosis are caused by mutations in the CARD15/NOD2 gene, and they represent the familial and sporadic forms of the same disease, respectively. • Eye involvement in Blau syndrome is the most relevant morbidity. Fig. 5.6  Red-brown annular plaque

Granuloma Annulare While the precise etiology remains unknown, diabetes mellitus, dyslipidemia, malignancy, thyroid disease, lipid abnormalities, infection, and a variety of drugs have all been described as potentially associated with granuloma annulare (GA) [12]. Delayed-type hypersensitivity reaction is thought to be the underlying mechanism.

Clinical Presentation GA can present as localized, generalized, subcutaneous (deep), or rare atypical variants (perforating). The most favorite site is the extremities, typically the lesion is present on hands or arms. Women are affected more frequently than men (ratio of 2:1), and the patients are typically under the age of 30. The commonest type is localized GA.  Flesh-colored, asymptomatic, non-scaly papules and plaques arranged in an annular configuration with central clearing are seen on the dorsal hands or feet (Figs. 5.6 and 5.7) [13]. Generalized subtype of GA has a later age of onset, middle-aged to elderly adults frequently, a more chronic or relapsing course, and a poorer response to therapy. Ten or more annular plaques affecting at least the trunk and either upper or lower, or both, extremities are seen in generalized annular GA.  Most lesions are papules, asymptomatic, or pruritic and can occur anywhere and widespread symmetrically [13].

Fig. 5.7  Flesh-colored and non-scaly nodules of deep granuloma annulare are seen on the dorsal hand

Firm, asymptomatic, and painless subcutaneous nodules are seen on the buttocks, head, and extremities of children and young adults in subcutaneous GA [14]. The lesions are similar to rheumatoid nodules, leading to the term of pseudorheumatoid nodules. Also, it is said that some cases of this variant have the relationship with trauma. Atypical forms of GA include perforating GA, palmoplantar, Blaschko linear, pustular, visceral, photosensitive GA, palmar GA, and oral GA [12]. A central umbilication with a keratotic core is seen in perforating GA. Perforating GA can be either localized to the extremities or generalized

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to the trunk and extremities in both children and adults [15].

Prognosis or Clinical Course The lesions of the localized variant are frequently self-limited and resolved within 2 years [12]. Diabetic patients with GA tends to have a prolonged and relapsing clinical course than their nondiabetic counterpart [13]. A statistically significant association between localized GA and thyroid disease has been reported; therefore, screening for thyroid disease in female patients with localized GA should be considered [16]. On the other hand, generalized GA may become chronic with infrequent spontaneous resolution. It is reported that spontaneous regression of the lesion may be seen including after biopsy, but approximately 40% of cases recur [17]. There is the possibility this disease may be associated with diabetes mellitus, hyperlipidemia, and thyroid disease. Especially generalized variant has the relationship with both Hodgkin’s and non-Hodgkin’s lymphoma [13]. Hematologic neoplasms are the most frequently associated malignancy. Others include solid tumors of the lung, breast, cervix, colon, prostate, testes, and thyroid [13]. Screening for malignancy should be considered in older patients and those with atypical variants.

Histopathology Four histopathologic patterns can be seen: interstitial (58%) (Fig.  5.8), palisaded granulomas (26%) (Fig.  5.9), sarcoidal granulomas (5%), and mixed (11%) [18]. Collagen and elastic fibers damage are seen in most of the cases [18]. Eosinophils can be prominent, especially in the subcutaneous variant [12, 19]. The interstitial infiltration of histiocytes and increased mucin are characteristic for the interstitial GA. The collagen fibers are separated by mucin. Necrobiosis is absent or scant. In palisading GA, histiocytes, lymphocytes, and fibroblasts

Fig. 5.8 A dermal interstitial infiltrate of histiocytes associated with mucin deposition (×100)

Fig. 5.9  Palisade of histiocytes is seen around a central zone of necrobiosis (×100)

surround central altered collagen and increased mucin deposition. Mucin can be seen as feathery blue-gray material on histologic sections, and both Alcian blue and Colloidal iron stains can help in highlighting the mucin deposition. Lymphocytes and eosinophils are seen; however, plasma cells are rare. In the perforating GA, transepidermal elimination of degenerated collagen is characteristic, and overlying epidermal hyperplasia is prominent. Necrobiotic debris is seen close to the epidermis. Subcutaneous GA is usually the palisading variant extending to the subcutis. The lesions of subcutaneous GA are often larger than other variants. In most cases, epidermal changes are not prominent. Necrobiosis and mucin are typically prominent. A dermal component is noted in a quarter of subcutaneous GA cases [13].

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Differential Diagnosis The clinical differential diagnosis of macular GA includes morphea, parapsoriasis, and cutaneous T-cell lymphoma. The histologic differential diagnosis of subcutaneous GA includes rheumatoid nodule, necrobiosis lipoidica, and epithelioid sarcoma. Plasmacytoid dendritic cells might play role in the pathogenesis since greater number CD123-positive cells are seen in GA than rheumatoid nodule or necrobiosis lipoidica (NL) [20]. The presence of mucin deposition helps to distinguish subcutaneous GA from rheumatoid nodule and GA from NL. The distribution pattern of GA is focal, whereas NL is diffuse. Adipophilin might highlights the lipid seen in NL and distinguish it from GA and sarcoidosis [21]. Necrosis can be seen in both GA and epithelioid sarcoma, but cytologic atypia is characteristic for epithelioid sarcoma. Ulceration is also a clue for epithelioid sarcoma. By immunohistochemistry, atypical cells are positive for keratins, epithelial membrane antigen, and vimentin and negative for INI1. Primary perforating disorders including perforating folliculitis and Kyrle’s disease are in the differential diagnosis of perforating GA.

Summary Clinical Presentation • The four main clinical variants of granuloma annulare are localized, generalized, subcutaneous, and atypical. • Localized variant: firm red-violaceous or skin-colored asymptomatic papules, often forming an annular configuration. • Generalized variant: asymptomatic or pruritic papules occurring in the middle-­ aged to elderly adults. • Subcutaneous (deep) variant: subcutaneous nodules on the head, buttocks, hands, and lower legs. • Perforating (atypical) variant: papules with central umbilication with scale crust or ulceration.

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Histologic Features • Palisading variant: histiocytes, lymphocytes, and fibroblasts surrounding central altered collagen and increased mucin deposition • Interstitial variant: interstitial infiltration of histiocytes and increased mucin deposition • Subcutaneous (deep) variant: features of the palisading variant extending to the subcutis • Perforating (atypical) variant: transepidermal elimination of degenerated collagen and overlying epidermal hyperplasia Differential Diagnosis • Rheumatoid nodule • Necrobiosis lipoidica • Primary perforating disorders • Epithelioid sarcoma

Takeaway Essentials Clinical Relevant Pearls • The lesions of the localized variant are frequently self-resolved within 2 years. • Diabetic patients with granuloma annulare tend to have a prolonged and relapsing clinical course. • Screening for thyroid disease in female patients with localized granuloma annulare should be considered. Pathology Interpretation Pearls • Presence of dermal mucin deposition helps to distinguish granuloma annulare from necrobiosis lipoidica and deep granuloma annulare from rheumatoid nodule.

Necrobiosis Lipoidica Necrobiosis lipoidica (NL) is a rare chronic ­granulomatous disease that is associated with diabetes mellitus. The incidence of NL in indi-

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viduals with diabetes is 0.3–1.2% [22]. Thyroid disorders, Crohn disease, ulcerative colitis, rheumatoid arthritis, granuloma annulare, and sarcoidosis are also commonly associated conditions [22]. Due to its increased prevalence in patients with diabetes mellitus, it has been widely accepted that microangiopathy plays a significant role in NL’s pathogenesis; however, the association between NL and diabetes mellitus remains controversial since NL can occur in patients without diabetes mellitus [23]. Immunoglobulin deposition, trauma, neutrophil defects, metabolic changes, and abnormal collagen production have also been implicated as potential causes [23].

Clinical Presentation In the study of 100 patients with NL, patients’ ages ranged from 15 to 95 years (median age 52 years, mean age 50 years) [24]. The average age of onset is 30  years in patients with type 1 diabetes and 40 years in patients with type 2 diabetes and nondiabetes [22]. There is a female predominance with female to male ratio of 3:1. Thyroid disorders were found in 15% of all cases [24]. Necrobiosis lipoidica typically presents as erythematous papules coalescing to atrophic, yellow-brown, and telangiectatic plaques in bilateral anterior lower extremities (Fig.  5.10). The scalp, face, trunk, upper extremities, and genital areas are the atypically involved sites. The most common site is the legs, especially shins. The initial asymptomatic red-brown papules and nodules erode to well-demarcated yellow-brown plaques with violaceous borders and central atrophy and telangiectasia [22]. They are usually asymptomatic, but sometimes exhibit pruritus and pain. Ulceration develops in a third of the cases, especially in male patients and in patients with concomitant diabetes mellitus. Perforation can rarely be seen. NL can exhibit Koebner phenomenon.

Fig. 5.10 Atrophic, yellow-brown, and telangiectatic plaques seen on bilateral anterior lower extremities

Prognosis or Clinical Course The clinical course of NL can be unpredictable and varied among patients. The course is typically chronic, but spontaneous remission can occur. The disease course is worse in men with greater frequency of ulceration [22]. There appears to be no correlation between the severity of NL and the severity of diabetes. Squamous cell carcinoma can rarely arise from long-standing NL [25].

Histopathology Alternating layers of necrobiosis and granulomatous changes are seen involving the entire dermis and often the subcutaneous tissue (Figs.  5.11 and 5.12). There is superficial and deep perivascular lymphocytic infiltration. Giant cells are usually Langerhans type or foreign body type. Touton giant cells may be seen occasionally. Thickened blood vessel walls can be seen. The epidermis is normal, atrophic, hypertrophic, or acanthotic. Sometimes the lesion is ulcerated. Lipid and rarely cholesterol clefts can be identified within the necrobiotic areas. Dermal mucin is typically absent. Plasma cells can be seen at the dermis and subcutaneous tissue interface.

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Summary Clinical Presentation • Well-demarcated yellow-brown atrophic plaques with violaceous borders with central telangiectasia on the legs, especially shins. • Mainly asymptomatic but sometimes pruritic or painful. • Diabetes mellitus, thyroid disorders, Crohn disease, ulcerative colitis, rheumatoid arthritis, and sarcoidosis are commonly associated conditions. Histologic Features • Alternating layers of necrobiosis and mixed inflammatory infiltrate are seen involving the entire dermis and often the subcutaneous tissue. • Dermal mucin is typically absent. Differential Diagnosis • Granuloma annulare • Necrobiotic xanthogranuloma • Sarcoidosis Figs. 5.11 and 5.12  Alternating layers of necrobiosis and granulomatous changes are seen involving the entire dermis (×40, ×100)

Differential Diagnosis GA and necrobiotic xanthogranuloma (NXG) are the main differential diagnoses. Early lesion of NL can look similar to interstitial GA. In the case of NL, granulomatous changes can be identified in the dermis widely in comparison to GA.  Also, the presence of plasma cells is characteristic for NL. The presence of lipids and lack of dermal mucin deposition on histologic sections are distinguishing features of NL [21]. Prominent necrosis and cholesterol clefts are features characteristic for NXG.

Takeaway Essentials Clinical Relevant Pearls • Necrobiosis lipoidica diabeticorum is typically found in the adult diabetic patients. Pathology Interpretation Pearls • The presence of lipids and lack of dermal mucin deposition on histologic sections are distinguishing features from granuloma annulare. • The presence of plasma cells is most characteristic. • Early lesion can resemble interstitial granuloma annulare.

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Rheumatoid Nodule Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects 1.5 to two million adults in the United States and Europe [26]. Rheumatoid arthritis can be diagnosed using the combined American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria which include joint swelling, elevated rheumatoid factors (RF), anti-cyclic citrullinated peptide (CCP) antibodies, inflammatory markers, and others [27]. Smoking, elevated serum level of rheumatoid factor, anti-CCP antibodies, and HLADRB1 have been reported as risk factors [28].

Clinical Presentation Rheumatoid nodules are the most common cutaneous manifestations of RA [26]. Firm, 2–5 cm, nontender, and mobile subcutaneous nodules are seen on the extensor or pressure joint surfaces and sites prone to repetitive trauma (Figs. 5.13 and 5.14). The lesion is single or multiple, and the size of each lesion varies from millimeters to centimeters. The number of the lesion may be over one hundred. There is no difference between men and women. It is thought that the one clear modifiable risk factor is smoking [26]. Most patients with rheumatoid nodules have positive RF, and moderate to high titers of RF is associated with this disease [26]. Other cutaneous lesions associated with RA include ulceration secondary to medium-vessel vasculitis, purpura from small-vessel vasculitis, pyoderma gangrenosum, granulomatous dermatitis, and nail fold infarcts. This disease can be seen in the patient with systemic lupus erythematosus (SLE) as well. Extra-articular manifestation of RA can involve the eyes (keratoconjunctivitis sicca, episcleritis, scleritis, peripheral ulcerative keratitis), lungs (interstitial lung disease, pulmonary nodules, pulmonary effusion), heart (pericarditis, myocarditis, cardiovascular disease), kidneys (glomerulonephritis), nervous system (peripheral neuropathy, mononeuritis multiplex, central nervous system vasculitis), and hematologic system (Felty syndrome, characterized by neutropenia and splenomegaly, pancytopenia).

Figs. 5.13 and 5.14  Non-tender and mobile subcutaneous nodules are seen on the extensor or pressure joint surfaces

Prognosis or Clinical Course The development of extra-articular manifestations of RA correlates with joint disease severity and functional impairment. Although methotrexate is the first-line therapy for moderate to severe rheumatoid arthritis, rapid development or worsening of rheumatoid nodules, accelerated nodulosis, can develop in association with it. Three quarter of patients have finger involvement, and these nodules are indistinguishable from routine rheumatoid nodules [29]. Rheumatoid nodulosis is the development of rheumatoid nodules and recurrent joint symptoms without chronic synovitis or radiographic findings [30].

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Histopathology Rheumatoid arthritis is characterized by a palisade of epithelioid histiocytes and lymphocytes surrounding a central area of necrosis in the deep dermis and subcutaneous tissue (Fig.  5.15). In one third of rheumatoid nodules, focal vasculitis can be seen. Lymphocytes, plasma cells, and eosinophils are frequently present in the surrounding stroma. Foreign body giant cells can be seen in 50% of cases [31]. In the setting of a superficial nodule, the lesion may perforate the epidermis. Pseudorheumatoid nodule refers to a subcutaneous nodule that mimics rheumatoid nodule histopathologically.

Differential Diagnosis Rheumatoid nodule tends to have more fibrin and less mucin than subcutaneous (deep) granuloma annulare. Nodules at extensor surface of the knees and elbows, similar to those of RA, can be seen in rheumatic fever. Concomitant carditis and resolution within weeks are helpful features in distinguishing rheumatic fever nodule from rheumatoid nodules [32]. Epithelioid sarcoma mimics rheumatoid nodule at low magnification histologically; however, they can be differentiated by the presence of cytologic atypia and the utilization of immunohistochemical stains.

Fig. 5.15  Palisade of histiocytes seen surrounding a central zone of fibrinoid necrosis (×100)

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Summary Clinical Presentation • Rheumatoid nodules are common cutaneous manifestation of rheumatoid arthritis seen in approximately 30% of the patients. • Present as asymptomatic and mobile subcutaneous nodules. • Positive rheumatoid factor in most cases. Histologic Features • Palisading histiocytes surround a central area of fibrin in the deep dermis and subcutaneous tissue. • Absent or minimal mucin deposition. Differential Diagnosis • Subcutaneous (deep) granuloma annulare • Nodules in rheumatic fever • Epithelioid sarcoma

Takeaway Essentials Clinical Relevant Pearls • Systemic rheumatoid arthritis medications have not shown to be effective for rheumatoid nodules. • Rapid development or worsening of rheumatoid nodules, accelerated nodulosis, can develop in association with methotrexate. • Rheumatoid nodulosis is the development of rheumatoid nodules and recurrent joint symptoms without chronic synovitis or radiographic findings. Pathology Interpretation Pearls • Focal vasculitis can be seen in a third of cases.

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Necrobiotic Xanthogranuloma Necrobiotic xanthogranuloma (NXG) is a rare chronic, progressive, multi-organ disease of unknown etiology. It is a non-Langerhans cell histiocytosis and “C group” in the revised classification of histiocytes and neoplasms of the macrophage-­ dendritic cell lineages [33]. An association with hematologic malignancies including Hodgkin lymphoma, chronic lymphocytic leukemia, smoldering myeloma, and multiple myeloma is seen in a quarter of the patients [34, 35]. Depending on the degree of systemic involvement, class II non-Langerhans histiocytic proliferations are divided into adult-onset xanthogranuloma, necrobiotic xanthogranuloma (NXG), Erdheim-Chester disease (ECD), and adult-onset asthma and periocular xanthogranuloma (AAPOX) [36]. These histiocytes are derived from bone marrow stem cells. The mononuclear-­ phagocytic pathway produces phagocytic monocytes and tissue macrophages, whereas the dendritic cell pathway produces the follicular cells of the lymph nodes and cutaneous Langerhans cells. Virus-induced process and chromosomal instability have been proposed as possible etiologies [37]. The etiology and pathogenesis of this disease are not known. Several hypotheses have been postulated regarding the pathophysiology of NXG. Some have proposed that the serum monoclonal proteins bind to lipoprotein receptors on monocytes resulting in xanthoma. Another suggests that cutaneous deposition of paraproteins and immunoglobulins elicit a foreign body giant cell reaction. Ischemia is the third proposed mechanism [35].

Clinical Presentation NXG can affect adults at any age, especially the elderly, with no gender predilection. An indurated violaceous, yellow, or red-orange papule, nodule, or plaque is the typical clinical presentation. Most cutaneous lesions (70–94%) first

appear on the trunk or extremities and then on the periorbital area [34, 37]. The periorbital region is invariably involved which can be single, multiple, unilateral, or bilateral. Blepharoptosis, restricted ocular motility, and proptosis are other ocular complications. The lesion often has telangiectasia. Ulceration, ­central atrophy, and mucosal erosions may be identified. Some patients have pain. It is associated with a paraproteinemia, typically IgG monoclonal gammopathy in 80% of the cases. Progressive multisystem disease can be seen. Extracutaneous sites are most commonly the liver (32%) and the sinuses (21%) [34, 35]. Involvement of the myocardium, lung, parotid gland, and skeletal muscle has been reported [34]. Hepatomegaly and splenomegaly can occasionally be seen.

Prognosis or Clinical Course NXG can follow either an indolent or aggressive clinical course. In the setting of indolent lesions, cutaneous lesions can rapidly recur with increasing size. The patient may develop plasma cell dyscrasias and lymphoproliferative disorders in progressive systemic histiocytic disease. It is thought that prognosis is dependent on extracutaneous involvement.

Histopathology Alternating layers of granulomatous inflammation containing histiocytes, foam cells, multinucleated giant cells, and plasma cell aggregates involve the entire dermis and extend to the subcutaneous tissue (Fig.  5.16). X-shaped necrosis within granulomas is characteristic. Atypical giant cells with many nuclei are seen adjacent to broad zones of hyaline necrobiosis containing cholesterol clefts (Fig.  5.17). Touton giant cells and asteroid bodies can be seen in some cases. Interstitial mucin can be present as well. Lymphocytes and plasma cells can be seen; however, eosinophils are rare. The foamy histiocytes

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Fig. 5.16  Alternating layers of granulomatous inflammation (×40)

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immunostain would be helpful in ruling in Erdheim-­ Chester disease. Although extensive zones of hyaline necrobiosis, lymphoid nodules, and plasma cell infiltrate can be seen in both NXG and NLD, the presence of cholesterol clefts and an association with paraproteinemia are features characteristic for NXG.  In addition, NXG exhibits a predilection for the face, while NL occurs most commonly on the lower extremities. Clinical differential diagnoses also include xanthelasma, GA, and sarcoidosis. The favorite site of xanthelasma is periorbital, but it has less infiltrating plaques. While mucin is commonly identified in GA, it is minimal in NXG. While foamy cells and cholesterol cleft are seen in NXG, both are absent in GA. Clinically, sarcoidosis is not typically yellowish. In addition, infectious diseases should be ruled out using special stains.

Summary

Fig. 5.17  Broad zones of hyaline necrobiosis containing cholesterol clefts and giant cells (×100)

and Touton giant cells are positive for CD68, CD163, and factor 13a and are negative for CD21, CD35, S100, and CD1a.

Differential Diagnosis Xanthomatous cutaneous lesions are common in Erdheim-Chester disease; therefore, clinical pathologic correlation is needed to distinguish NXG from Erdheim-Chester disease. Since 80% of Erdheim-Chester disease harbor activating kinase mutations involving MAPK pathway, immunoreactivity for BRAF V600E

Clinical Presentation • Necrobiotic xanthogranuloma is a chronic, progressive, and multi-organ disease of unknown etiology. • Multiple firm yellow-brown nodules and plaques are seen on the face, neck, and trunk. Histologic Features • Alternating layers of granulomatous inflammation affect both the dermis and subcutaneous tissue. • Broad zones of hyaline necrobiosis or X-shaped necrosis containing cholesterol clefts and Touton giant cells. Differential Diagnosis • Erdheim-Chester disease • Necrobiotic lipoidica • Xanthelasma • Xanthogranuloma

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Table 5.2  Clinical manifestations of Crohn disease

Takeaway Essentials Clinical Relevant Pearls • Most frequently involved site is the periorbital area. • The liver is the most common extracutaneous sites. • In progressive multisystem disease, involvement of the myocardium, liver, lung, parotid gland, and skeletal muscle can be seen. Pathology Interpretation Pearls • Immunoreactivity for BRAF V600E immunostain would be helpful in ruling in Erdheim-Chester disease.

Crohn Disease Crohn disease, an inflammatory condition with unpredictable periods of relapses and remissions, can affect any part of the gastrointestinal tract. In addition, a variety of other organs including the skin, eyes, liver, and joints can also be affected by Crohn disease. The etiology of Crohn disease remains unknown; however, the disease is likely multifactorial including genetic, microbial, environmental (smoking), immunologic, vascular, and psychosocial factors [38]. Genetic factors play an important role in Crohn disease with associations with NOD2 and genes that regulate autophagy such as ATG16L1 (Autophagy 16-like 1) [39]. Dysregulated immune system is dependent on the Th-1 and Th-17 pathways [38].

Clinical Presentation Crohn disease affects patients of all ages, most commonly in early adulthood years. Abdominal pain, diarrhea, rectal bleeding, weight loss, fatigue, fevers, and malnutrition are the common clinical manifestations [40]. The terminal ileum (30%), the colon (20%), and small bowel and colon (45%) are the most commonly affected

Disease-specific lesions

Reactive lesions

Disease-associated lesions

Perianal fissures or fistulae Acrochordae Metastatic Crohn Vulvoperineal Crohn disease Genital lymphedema and lymphangioma Erythema nodosum Pyoderma gangrenosum Pyostomatitis vegetans Sweet syndrome Oral aphthous ulcers Cutaneous polyarteritis nodosa Granulomatous vasculitis Leukocytoclastic vasculitis Psoriasis Vitiligo Epidermolysis bullosa acquisita Eczema Alopecia areata Acquired zinc deficiency

sites [41]. The extraintestinal sites including the skin, eyes, liver, and joints can be involved. Up to 50% can have arthritis and arthralgias. Granulomatous hepatitis, amyloidosis, fatty liver, pericholangitis, and primary sclerosing cholangitis are common hepatobiliary symptoms [42]. The cutaneous manifestations can be (1) disease-­specific lesions which have the same histopathologic findings as the underlying gastrointestinal disease, (2) reactive inflammatory lesions, and (3) associated conditions due to human leukocyte antigen (HLA) linkage phenomenon (Table 5.2) [43]. Disease-specific lesions include perianal fissures and fistulae, cutaneous abscess, acrochordae, and metastatic (cutaneous) Crohn disease. Metastatic Crohn disease is a rare granulomatous process involving a skin site away from the gastrointestinal tract. The etiology is not well-­ defined; however, prevailing theories agree that the underlying mechanism is an immunologic response to gut antigens [38]. Metastatic Crohn disease presents equally in both sexes and across all age groups [44]. Children are more likely to present with metastatic Crohn disease in the absence of gastrointestinal symptoms [44]. The presentation of metastatic Crohn disease includes multiple erythematous and violaceous plaques, nodules, and ulcerations on the extremities or

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Fig. 5.18  Erythematous and violaceous plaques

intertriginous skin and rarely the face and genital skin (Fig.  5.18) [41]. Vulvoperineal Crohn disease can present months to years prior to the gastrointestinal Crohn disease [45]. Genital lymphedema due to impaired lymphatic drainage is a rare complication of metastatic Crohn disease [46]. Orofacial granulomatosis is characterized by chronic swelling of oral and facial due to granulomatous inflammation. Reactive skin lesions include pyostomatitis vegetans, oral aphthous ulcers, pyoderma gangrenosum, Sweet syndrome, polyarteritis nodosa, granulomatous vasculitis, and leukocytoclastic vasculitis. The reactive skin lesions do not have the typical granulomatous histologic features. Disease-associated conditions include erythema nodosum, psoriasis, vitiligo, epidermolysis bullosa acquisita, eczema, and alopecia areata [41]. These lesions are likely related to human leukocyte antigen linkage and a chronic inflammatory state.

Prognosis or Clinical Course The course of cutaneous Crohn disease does not always mirror the activity of the gastrointestinal disease. Metastatic Crohn disease can present before or after the diagnosis of gastrointestinal Crohn disease. Approximately 20% of patients are diagnosed with cutaneous lesions without a preceding diagnosis of gastrointestinal Crohn disease.

Figs. 5.19 and 5.20  An example of metastatic Crohn disease showing ulceration with underlying suppurative and granulomatous inflammation (×100, ×200)

Histopathology The biopsy of metastatic Crohn disease often shows ulceration with underlying suppurative and granulomatous inflammation (Figs. 5.19 and 5.20). In a minority of cases, nodular and noncaseating epithelioid granulomas are seen in the superficial and deep dermis. Extension to the subcutaneous tissue can sometimes occur. Of note, granulomatous inflammation is often not present; therefore, clinical pathologic correlation is essential [5].

Differential Diagnosis This histologic differential diagnoses include sarcoidosis and foreign body giant cell reaction. The granulomas of sarcoidosis would be more compact, while eosinophils would be more ­

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prominent in cutaneous Crohn disease. Special stains and microbiology cultures are needed to exclude the possibility of mycobacterial and deep fungal infections. The histologic features of granulomatous cheilitis can be similar. In addition, patients with granulomatous cheilitis can have increased risk of developing Crohn disease [47]. Pyoderma gangrenosum would be in the differential diagnosis of ulcerated cutaneous Crohn disease. In the setting of cutaneous Crohn disease with genital swelling, the differential diagnosis would include granuloma inguinale, schistosomiasis, hidradenitis suppurativa, and chronic lymphedema.

Summary Clinical Presentation • The cutaneous manifestation can be seen in a third of Crohn disease and include disease-specific, reactive lesions, and associated lesions. • Disease-specific lesions include perianal fissures and fistulae, cutaneous abscess, acrochordons, and metastatic (cutaneous) Crohn disease. • Cutaneous Crohn disease: solitary or multiple nodules, plaques, ulcers, lichenoid lesions, or violaceous perifollicular papules seen on the legs, intertriginous skin, trunk, and abdomen. Histologic Features • Ulceration with underlying suppurative and granulomatous inflammation Differential Diagnosis • Cutaneous sarcoidosis • Foreign body reaction • Mycobacterial and fungal infections • Pyoderma gangrenosum for ulcerated lesion • Granuloma inguinale, schistosomiasis, hidradenitis suppurativa, and chronic lymphedema in the setting of genital swelling

Takeaway Essentials Clinical Relevant Pearls • Cutaneous Crohn can be the first manifestation of underlying gastrointestinal disease. • The course of cutaneous disease does not always correlate to that of gastrointestinal disease. Pathology Interpretation Pearls • Granulomatous inflammation does not always present.

Palisaded Neutrophilic and Granulomatous Dermatitis Also known in the past as rheumatoid papules, Churg-Strauss granuloma, and cutaneous extravascular necrotizing granuloma, the disease was termed as palisaded neutrophilic and granulomatous dermatitis (PNGD) in 1994 by Chu et  al. [48] PNGD and interstitial granulomatous dermatitis are reactive granulomatous processes caused by systemic triggers such as connective tissue diseases (lupus erythematosus), vasculitis (eosinophilic granulomatosis with polyangiitis/ Churg-Strauss syndrome), arthritides (rheumatoid arthritis), malignancy (hematologic, solid organ), and medications. It can also be associated with thyroid disease, infection, inflammatory bowel disease, and diabetes mellitus [48]. Although the etiology is unknown, abnormal neutrophil activation, circulating immune complex deposition, a delayed-type hypersensitivity reaction, or small-vessel vasculitis have been proposed as underlying mechanisms [49].

Clinical Presentation The disease affects mainly adults and rarely children. There is a predilection for women with the female to male ratio being 3:1 due to the associated systemic diseases. Symmetric flesh-colored to erythematous papules on the extensor surfaces,

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Figs. 5.21 and 5.22 Linear subcutaneous cords or bands are seen on the upper extremities

especially the elbows and fingers, or linear subcutaneous cords or bands on the proximal trunk are seen (Figs.  5.21 and 5.22) [50]. Ulceration and central umbilication with crusts or ­perforation may be present. Other presentations such as urticarial plaques, papulonodules, violaceous patches, annular papules and plaques, and annular gyrate plaques have been reported [49].

Prognosis or Clinical Course One fifth of the cases would resolve, some within 1 week. The lesions would improve if the underlying disease is under control.

Histopathology The histopathologic findings vary depending on the underlying disease or the age of the lesion. An interstitial dermatitis with small foci of degenerated collagen and occasional neutrophils and/or eosinophils would be seen in all cases (Figs. 5.23 and 5.24). A palisaded pattern is seen in approximately 60% of cases. Dense neutrophilic infiltrate and karyorrhectic debris involving the entire dermis can be seen in early lesions [51]. Occasionally the early lesions may exhibit focal leukocytoclastic vasculitis. Collagen degeneration or necrobiosis and leukocytoclasia are seen in 70% and 80% of established cases (classic lesions), respectively. Fibrosis, perivascular infiltrate of lymphocytes, and occasional eosinophils would be seen in the late stage. Dermal mucin deposition is rare or absent. Direct immunofluorescence can show fibrin and IgM deposition in the vessels [48].

Figs. 5.23 and 5.24  An interstitial dermatitis with small foci of degenerated collagen and occasional neutrophils and/or eosinophils (×100, ×200)

Differential Diagnosis When considering the differential diagnosis, it is important to be aware of the stage of the disease, namely, early, classic, and late stage. The differential diagnoses of early-stage PNGD

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include interstitial GA, neutrophilic dermatoses, and small-vessel vasculitis. Patchy neutrophilic infiltration in the upper dermis and dermal mucin deposition would be noted in GA. PNGD has an infiltrate predominantly of neutrophils and leukocytoclasis within the areas of collagen degeneration. Leukocytoclastic vasculitis would be seen in PNGD while absent in IGD. Histiocytoid Sweet disease would exhibit prominent papillary dermal edema. It is known that calcium channel blockers, HMG-CoA and TNF-α inhibitors, and reductase inhibitors can result in a granulomatous drug eruption which can mimic PGND both clinically and histopathologically. NLD is in the differential diagnosis for late-stage PGND; however, plasma cells are characteristic for NLD. The relationship among palisaded neutrophilic, granulomatous dermatitis and interstitial granulomatous dermatitis (IGD) is still controversial. Clinically, IGD preferentially affects the trunk, axillae, and medial thighs. Histopathologically, the changes of interstitial GA are focal and “top heavy” and not diffuse as seen in IGD.  Leukocytoclastic vasculitis is not typically seen in interstitial granulomatous dermatitis. Currently, it is thought that these two diseases overlap clinically and histopathologically; therefore, the term “reactive granulomatous dermatitis” has been proposed to encompass both PNGD and IGD.

Summary Clinical Presentation • Symmetric flesh-colored to erythematous papules on the extremities or linear subcutaneous cords or bands on the proximal trunk Histologic Features • Early stage: a dense infiltrate of neutrophils is seen in the entire dermis. • Classic stage: degenerated collagen surrounded by histiocytes, neutrophils, and leukocytoclasis

• Late stage: fibrosis, perivascular lymphocytic, and eosinophilic infiltrate may be seen. Differential Diagnosis • Early stage: leukocytoclastic vasculitis • Classic stage: interstitial granuloma annulare, granulomatous drug eruption, and histiocytoid Sweet syndrome • Late stage: necrobiosis lipoidica diabeticorum

Takeaway Essentials Clinical Relevant Pearls • Ulceration and central umbilication with crusts or perforation may be present. • The disease mainly affects adults and is often associated with connective tissue disorders, especially rheumatoid arthritis and systemic lupus erythematosus.

Idiopathic Orofacial Granulomatosis/Melkersson-­ Rosenthal Syndrome Orofacial granulomatosis is a term that encompasses a spectrum of disease from localized swelling in granulomatous cheilitis or ­ Miescher cheilitis to more extensive inflammation in Melkersson-Rosenthal syndrome [52]. Melkersson-Rosenthal syndrome is characterized by a triad of orofacial edema, recurrent facial paralysis, and fissured tongue (lingua plicata). However, monosymptomatic and oligosymptomatic forms are more common than the complete triad. It is a rare disease more commonly seen in Europe than America. It appears to be more common in young male adults [52, 53]. Even though hereditary and genetic predisposition, immunologic and allergic (food or dental

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materials) mechanisms, and infectious agents have been implicated as potential etiology, the pathogenesis of orofacial granulomatosis remains unknown. An association with specific human leukocyte antigen (HLA) genotypes and haplotypes has been suggested [54].

Prognosis or Clinical Course

Clinical Presentation

Histopathology

In a series of 42 cases and literature review of 220 patients, common orofacial symptoms included labial swelling, facial swelling and palsy, tongue fissure, buccal mucosa swelling, and gingival swelling [47]. Angioedema typically lasts hours to days and can be associated with urticaria, laboratory abnormalities, and family history. Orofacial swelling may be mild and recurrent, persistent, or progressive [53]. The lips are the most commonly affected site presenting with asymmetric, painless, and nonpruritic swelling (75.5%) (Fig. 5.25) [52]. Oral ulceration, gingivitis, gingival overgrowth, fissuring of the lips, and cobblestone buccal mucosa are other common clinical features [52, 53]. Lingua plicata, facial nerve palsy, and additional neurologic symptoms (tinnitus, migraine-like headaches) are seen in the setting of Melkersson-Rosenthal syndrome.

Small and loose clusters of epithelioid histiocytes surrounded by lymphocytes are seen in a background of dilated lymphatics and perivascular lymphocytic infiltrate (Figs. 5.26, 5.27 and 5.28). Multinucleated giant cells can be seen. Although it is a typical feature, granulomatous dermatitis is not required to render the diagnosis of Melkersson-Rosenthal syndrome. In the appropriate clinical setting and mimicking disorders which have been excluded, the diagnosis of orofacial granulomatosis can still be made in the absence of granulomas.

Fig. 5.25  Numerous, discrete, and coalescing papules in the perioral area

Treatment with corticosteroids and/or immunosuppressants resulted in complete or partial resolution of tissue swelling and oral ulceration in majority of the patients [52].

Differential Diagnosis The clinical differential diagnoses of recurrent orofacial swelling seen in idiopathic orofacial granulomatosis include solid facial edema (Morbihan disease) in the setting of rosacea and acne vulgaris, Crohn disease, contact dermatitis, sarcoidosis, and lymphedema [53]. Since granulomatous inflammation can also be seen ­histopathologically, solid facial edema should be considered if recurrent orofacial swelling occurs in the setting of rosacea or acne vulgaris. Elevated levels of inflammatory markers and genetic abnormality involving NOD2 (nucleotide oligomerization domain 2) gene are more likely seen in Crohn disease. A granulomatous dermatitis would be seen on biopsy of patients with sarcoidosis; therefore, clinical pathologic correlation is essential. Imaging studies and microbiology cultures would be helpful in ruling out lymphedema and infection, ­ respectively.

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Figs. 5.26, 5.27 and 5.28  Epithelioid granulomas are seen around dilated lymphatics highlighted by D2–40 immunostain (×100, ×200, ×200)

Summary Clinical Presentation • A spectrum of disease from localized swelling in granulomatous cheilitis or Miescher cheilitis to more extensive inflammation in Melkersson-Rosenthal syndrome. • Melkersson-Rosenthal syndrome is characterized by a triad of orofacial edema, recurrent facial paralysis, and fissured tongue. Histologic Features • Noncaseating granulomas in a background of dilated lymphatics and perivascular lymphocytic infiltrate

Differential Diagnosis • Morbihan disease or solid facial edema • Crohn disease • Contact dermatitis • Sarcoidosis • Lymphedema • Infection

Takeaway Essentials Clinical Relevant Pearls • Full triad of symptoms can be seen in only a minority of cases.

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Pathology Interpretation Pearls • In the appropriate clinical setting and mimicking disorders which have been excluded, the diagnosis of orofacial granulomatosis can still be made in the absence of granulomas.

Granulomatous Rosacea The diagnosis of rosacea requires at least one diagnostic cutaneous sign (fixed centrofacial erythema in a characteristic pattern that may periodically intensify, phymatous changes) or two major phenotypes (papules and pustules, flushing, telangiectasia, ocular manifestations) [55]. The National Rosacea Society Expert Committee classified rosacea into four subtypes: erythematotelangiectatic, inflammatory papulopustular, phymatous, and ocular rosacea [56]. The etiology of rosacea is not known and is thought to be multifactorial. Dysregulation of the innate immune system and microorganisms such as Demodex folliculorum and Staphylococcus epidermidis may play a role in the pathogenesis of rosacea as well as granulomatous rosacea [56, 57]. Recently, there is a case report of granulomatous rosacea arising at the site of a recurrent herpes simplex eruption, consistent with Wolf’s isotopic response [58]. In addition, granulomatous rosacea has been reported in association with HIV infection [59].

Clinical Presentation Rosacea is seen after the age of 30  years. Flushing episodes and persistent central facial erythema are noted in erythematotelangiectatic rosacea or subtype I. Transient papules or pustules would be seen in addition to the above in papulopustular rosacea or subtype II. Thickened and nodular skin, especially the nose, are seen in phymatous rosacea or subtype III. Symptoms are noted involving mainly the

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eyes in ocular rosacea or subtype IV. Morbihan syndrome is characterized clinically by erythema and solid edema of the upper face, especially the periorbital region, forehead, glabella, nose, and cheeks [60]. It occurs most commonly in women in the third or fourth decades of life. Granulomatous rosacea is considered a subtype of rosacea and is characterized by discrete, firm, brown to red papules, and yellowish nodules on the cheeks and around the mouth. While uncommon in rosacea, extra-facial lesions (axilla, groin, and thigh) can be seen in 15% of granulomatous rosacea cases [61]. On the other hand, lesions on the cheeks, chin, nose, and central part of the forehead are seen in the usual form of rosacea. Granulomatous rosacea can be seen in adults as well as children.

Prognosis or Clinical Course Rosacea is basically a chronic and progressive disease. However spontaneous regression may be seen a few years after the lesions appear. Granulomatous rosacea tends to follow a chronic course. Lesions of Morbihan syndrome persist permanently and can lead to visual impairment without treatment.

Histopathology Granulomatous infiltrates have been reported in the 10% of rosacea cases [61]. Perivascular and perifollicular lymphohistiocytic infiltrate and telangiectasia are seen in conventional rosacea. In a retrospective review of 53 granulomatous rosacea cases by Helm et al. [61], a mixed lymphohistiocytic infiltrate, predominantly histiocytic with some giant cells and epithelioid granulomas, can be seen in 40%, 34%, and 11% of cases, respectively. Granulomas, either caseating or noncaseating, should be identified within interfollicular regions (Fig.  5.29). A foreign body reaction is seen. Necrosis can be present in approximately 10% [61]. Therefore, clinical pathologic correlation is important.

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Fig. 5.29  Granulomatous rosacea. A perivascular and perifollicular infiltrate of histiocytes and lymphocytes with associated dermal telangiectasia (×40)

The biopsy of Morbihan syndrome would show vascular telangiectasia, edema, and perivascular and perifollicular chronic and granulomatous inflammation. An increased number of mast cells would be seen within the dermal infiltrate [60].

Differential Diagnosis Lupus miliaris disseminatus faciei (LMDF) presents with bilateral and symmetrical papular eruption on the central face. In the past LMDF has been thought to be a severe form of granulomatous rosacea [62]. However, recently Chougule and colleagues [63] have shown that there are differences between granulomatous rosacea and LMDF. Clinically, papular lesion on an erythematous base on face would be seen in granulomatous rosacea cases, whereas papulonodular or nodulocystic lesions on the face and neck are seen in LMDF cases. Histologically, granulomatous rosacea cases showed non-necrotizing small granulomas in a background of variable lymphoid infiltrate and telangiectasia, whereas LMDF showed large epithelioid granulomas with caseating necrosis (Figs. 5.30 and 5.31) [63]. The differential diagnoses of Morbihan syndrome include orofacial granulomatosis, sar-

Figs. 5.30 and 5.31  Epithelioid granulomas with caseating necrosis are seen in lupus miliaris disseminatus faciei (×40, ×100)

coidosis, leprosy, infection, lupus erythematosus, and foreign body reaction. Telangiectasias and dermal edema are more suggestive of rosacea rather than perioral dermatitis or orofacial granulomatosis. Tissue culture is important to rule out mycobacterial infections. Follicular plugging and dermal mucin deposition are characteristic histologic features of lupus erythematosus, whereas Demodex infestation and sebaceous hyperplasia are those of rosacea. Although only see in a subset of cases, lupus cases would more likely to contain CD123-positive plasmacytoid dendritic cells [64]. Acneiform eruption and  rosacea can be seen in vitamin B12 deficiency [65].

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Summary Clinical Presentation • Skin-colored to red-brown dome-shaped papules on the face in granulomatous rosacea • The face, especially the cheeks, chin, nose, and forehead Histologic Features • Vascular telangiectasia, edema, and perivascular and perifollicular chronic and granulomatous inflammation are seen in granulomatous rosacea. Differential Diagnosis • Perioral dermatitis or granulomatosis • Leprosy • Sarcoidosis • Lupus erythematosus • Foreign body granuloma • Vitamin B12 deficiency

orofacial

Takeaway Essentials Clinical Relevant Pearls • Granulomatous rosacea can be seen in both adults and children. • Morbihan syndrome is characterized clinically by erythema and solid edema of the upper face. • Papular lesion on an erythematous base on face would be seen in granulomatous rosacea cases, whereas papulonodular or nodulocystic lesions on the face and neck are seen in lupus miliaris disseminatus faciei cases.

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Pathology Interpretation Pearls • Granulomatous rosacea cases showed non-necrotizing small granulomas in a background of variable lymphoid infiltrate and telangiectasia, whereas lupus miliaris disseminatus faciei showed large epithelioid granulomas with caseating necrosis.

Chronic Granulomatous Disease Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by recurrent bacterial and fungal infections and defective clearing of excessive inflammation. Genetic defects impair one of the five subunits of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Phox) enzyme complex which generates reactive oxygen species (ROS) vital for microbial killing by phagocytic cells [66]. Most males (65%) have the X-linked recessive form (gp91phox or CYBB gene), with associated absence of cytochrome b559, followed by the autosomal recessive (30%) form (p47phox or NCF1 gene) in females. Only 5% are due to mutations in CYBA, NCF-2, and NCF-4 genes [66]. Female carriers of X-linked CGD may have discoid lupus erythematosus due to recurrent antigenic stimulation leading to antibody formation.

Clinical Presentation Recurrent and life-threatening bacterial and fungal infections usually begin in the first years of life. The median age of disease onset was 3.5  months (range: 1 to 6  months). The disease usually involves the skin, lymph nodes, liver, lungs, bones, and gastrointestinal tract. Sepsis and brain infection are rare. In North America,

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infections are most commonly due to Staphylococcus aureus, Aspergillus spp., Nocardia spp., Serratia marcescens, and Burkholderia cepacia complex. Other clinical symptoms include eczematous dermatitis, cutaneous granulomas, persistent rhinitis, ulcerative stomatitis, blepharitis, keratoconjunctivitis, diarrhea, and abscesses of the liver, spleen, lungs, bones, and perianal area [66, 67].

Prognosis or Clinical Course The overall survival is currently approximately 90% [67]. In endemic area, children with CGD are at great risk of tuberculosis. Aspergillus lung infections are associated with a high mortality rate. Dysregulated inflammation in CGD predisposes these patients to autoimmune diseases.

Histologic Features • An exuberant inflammatory response to infection Differential Diagnosis • Infections

Takeaway Essentials Clinical Relevant Pearls • Patients with very low NADPH superoxide production have worse overall outcome. • Chronic granulomatous disease can be cured with hematopoietic transplantation.

Histopathology

Foreign Body Granulomas

Both viable and nonviable fungal elements would elicit an exuberant inflammatory response. Granulomatous inflammation in the gastrointestinal tract mimicking Crohn disease has been reported [68].

Most foreign body granuloma is induced by external foreign material, for example, silicone (liquid or gel), paraffin, beryllium, zirconium, talc, sea urchin spine, tattoo inks, suture material, and others. However, foreign body granuloma is also caused by endogenous agents such as keratin, hair, urate crystals, calcium deposits, and others. The clinical presentation of foreign body granuloma is variable; therefore, clinical history is vital especially for the cases induced by exogenous materials. Granulomas responding to foreign materials can be separated into two groups: foreign body granulomas and epithelioid or hypersensitivity granulomas [69]. In the foreign body reaction pattern, there are histiocytes and multinucleated giant cells surrounding the foreign materials. The giant cells are usually foreign body type; however, Langerhans type can also be seen. In addition, lymphocytes, plasma cells, and neutrophils are present. On the other hand, the epithelioid or hypersensitivity granuloma reaction pattern, a

Differential Diagnosis A variety of infections would be in the differential diagnoses.

Summary Clinical Presentation • Recurrent and life-threatening bacterial and fungal infections begin usually in the first years of life.

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delayed hypersensitivity reaction, is characterized by lymphohistiocytic response with sarcoidal or tuberculoid granulomas.

Clinical Presentation Red papules, nodules, and plaques are typically seen. Sometimes ulceration can be present. In the setting of tattoo, erythematous nodules and plaques are seen. In the case of silica granulomas, papules and nodules can be seen. A persistent eruption composed of red-brown papules is seen in zirconium granuloma. There are two patterns of berylliosis: systemic berylliosis and localized beryllium granulomas. The skin lesion of berylliosis eventually becomes ulcerated [70]. Regarding aluminum, single or multiple nodules may be seen after the injection of vaccines or allergen desensitization extracts containing absorbed aluminum [71]. This is a rare form of hypersensitivity reaction. Bovine collagen implants commonly induce induration and erythema at the site; however, localized t­issue necrosis can be seen as well. The site of suture granuloma appears erythematous clinically.

Prognosis or Clinical Course Surgical removal of the foreign body granuloma should be considered. Patient of systemic berylliosis with pulmonary involvement will likely result in death [72].

Histopathology The most classic pattern is “Swiss cheese” appearance by paraffin or silicone. Numerous round or ovoid cavities represent spaces representing what remains after the silicone removed by tissue processing [73]. Residual silicone would be birefringent on polarized light microscopy. Aluminum can be identified by macrophages containing granular purplish-gray deposits and especially by lymphocytic nodules with ­lymphoid follicles at the injection sites. Titanium can be detected as brown-black particles within macrophages. As to zinc-induced granuloma, they can see rhomboidal crystals of zinc insulin. In the

Fig. 5.32  Sarcoidal tattoo. Pigment is noted within the cytoplasm of dermal histiocytes (×400)

skin lesion of systemic berylliosis, focal or no caseation can be present [72]. On the other hand, there is central necrosis in the setting of local beryllium granulomas [74]. Beryllium cannot be detected histopathologically. The histopathologic reactions to tattoos are diverse ranging from spongiotic, lichenoid, granulomatous, to pseudolymphomatous reactions [75]. The pseudolymphomatous reaction is characterized by a dense lymphohistiocytic infiltrate with occasional eosinophils and histiocytes with intracytoplasmic dark, granular, non-refractile foreign material [76]. The color of tattoo is variable, for example, red (cinnabar), blue (cobalt), green (chromium), and purple (manganese). Fraga and Prossick [77] have reported a series of cases with overlying epidermal hyperplasia resembling squamous cell carcinoma in some tattoo cases. Granulomatous tattoo reactions have been reported as cutaneous manifestation of systemic sarcoidosis (Fig. 5.32) [78]. In the case of silica, non-color crystals may be identified within the cytoplasm of the giant cells. Silica crystals are doubly refractile and birefringent rhomboid crystals under polarized light microscopy. The blue-green or yellow-brown talc crystals can be seen within the granulomas. Talc can be detected as white birefringent particles with polarized light [79]. The implanted bovine collagen looks paler than normal collagen with associated inflammatory reaction. In the case of suture granuloma, histological granulomatous pattern with suture material is variable (Fig.  5.33). Granular material surrounded by granulomas can be seen in the dermis, similar to intralesional corticosteroids.

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Takeaway Essentials Clinical Relevant Pearls • The initial presentation of sarcoidosis can be at the site of tattoo. Pathology Interpretation Pearls • The histopathologic reactions to tattoos are diverse ranging from spongiotic, lichenoid, granulomatous, to pseudolymphomatous reactions. Fig. 5.33  Suture granuloma. A palisade of histiocytes is seen surrounding suture materials (×100)

Differential Diagnosis Sarcoidosis is the main differential diagnosis for some foreign body granulomas including tattoo, zirconium, beryllium, and silica. Polarized microscopy should be performed when granulomas are present. The clinical appearance of pencil granuloma can closely resemble malignant melanoma. Noncaseating granulomas present as a delayed foreign body reaction to retained pencil-­core fragments [80].

Summary Clinical Presentation • The clinical presentation of foreign body granuloma is variable; however, typically red papules, nodules, and plaques are seen. Histologic Features • Foreign body response with histiocytes and giant cells surrounding foreign material • Sarcoidal or tuberculoid granulomas Differential Diagnosis • Sarcoidosis (tattoo, zirconium, beryllium, and silica)

Endocrine Abnormalities Cutaneous eruptions associated with underlying endocrine abnormalities including scleromyxedema associated with paraproteinemia, pretibial myxedema or thyroid dermopathy, and bullous diabeticorum of long-standing diabetes mellitus.

Scleromyxedema Scleromyxedema or generalized lichen myxedematosus is rare. This disease is mostly seen in the middle-aged adults or older and in the patients of both sexes. It is a fibromucinous disorder of unknown etiology. In most of the cases, paraproteinemia, typically IgG with lambda light chain, is associated with this disease. However, the relationship between scleromyxedema and IgG is not clear. Sometimes other classes of immunoglobulins can be identified. Some have suggested that the paraproteins act as autoantibodies that incite fibroblasts to proliferate and to produce mucin. Others have speculated that circulating interleukin 1, tumor necrosis factor, and transforming growth factor beta could be the contributing factors [81].

Clinical Presentation Four diagnostic criteria are needed: (1) a generalized papular eruption, (2) associated monoclonal gammopathy, (3) lack of concomitant thyroid disease, and (4) histologic features of dermal mucin

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deposition and fibroblastic proliferation [81]. Numerous symmetric, firm, 2–3 mm papules on a background of diffuse sclerosis can be seen on the head, face, neck, hands, forearms, upper trunk, buttocks, and extremities (Fig. 5.34). The lesions are often pruritic. The papules may arrange in a linear pattern. In the advanced stage, erythematous plaques may be seen. The disease is often associated with lambda gammopathy. Neurologic, cardiac, gastrointestinal, respiratory, and articular manifestations can be seen in addition to the cutaneous symptoms. Localized lichen myxedematosus or papular mucinosis is comprised of five subtypes: a discrete form, acral persistent papular mucinosis, self-healing papular mucinosis, papular mucinosis of infancy, and a pure nodular form.

 rognosis or Clinical Course P The course of scleromyxedema is essentially progressive. This disease may cause sclerodactyly and decreased joint mobility. One case with spontaneous remission has been reported [82]. The level of the paraprotein does not appear to correlate with the disease progression.

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pattern. Elastic fibers can be fragmented and decreased in number [83]. The overlying epidermis is either unremarkable or atrophic. Superficial perivascular lymphocytic infiltration is usually identified. Prominent perivascular infiltration of eosinophils, mast cells [83], and plasma cells [84] and granulomatous variant of scleromyxedema with Touton giant cells have been reported [85]. A superficial perivascular infiltrate of T lymphocytes was found in all specimens, whereas an interstitial infiltrate of CD68-positive epithelioid histiocytes was identified in the biopsies with an interstitial granuloma annulare-like pattern [81].

Differential Diagnosis Clinically, scleromyxedema resembles scleroderma, and the findings of papules, especially linear pattern, and the presence of IgG monoclonal gammopathy are good clues. to consider scleromyxedema. Although dermal mucin deposition is seen, scleredema would exhibit a markedly thicken dermis and lack the fibroblastic proliferation typical of scleromyxedema. Nephrogenic systemic fibrosis may not be easy to

Histopathology Rongioletti et al. [80] have reported two different histopathologic patterns: (1) a classic microscopic triad (dermal mucin deposition, fibroblast proliferation, and fibrosis) and (2) an interstitial granuloma annulare-like pattern. Marked fibroblastic proliferation and increased collagen are seen in the superficial and mid-dermis, in addition to interstitial mucin (Figs. 5.35 and 5.36). The mucin is positive at pH 2.5. The dermal collagen shows a whorled

Fig. 5.34  Scleromyxedema. Symmetric induration of the shoulder

Fig. 5.35  Dermal mucin deposition, fibroblast proliferation, and fibrosis are seen (×100)

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Histologic Features • Marked proliferation of fibroblasts, increased collagen, and interstitial mucin deposition Differential Diagnosis • Scleroderma • Scleredema • Nephrogenic systemic fibrosis

Takeaway Essentials Clinical Relevant Pearls • Association with paraproteinemia. • The papules may be arranged in a linear pattern. Fig. 5.36  Alcian blue stain highlights the dermal mucin deposition (×100)

distinguish from scleromyxedema, so clinical pathological correlation is very important. Clinically, the patients of nephrogenic systemic fibrosis do not have paraproteinemia and facial involvement. Also, the deeper involvement to the subcutis is a good clue to consider nephrogenic systemic fibrosis, histopathologically.

Summary Clinical Presentation • Scleromyxedema is a generalized form of lichen myxedematosus. • It is characterized by dermal mucin deposition, fibrosis, fibroblastic proliferation, and monoclonal gammopathy in the absence of thyroid disease. • Numerous symmetric, firm, 2–3  mm papules within a background of diffuse sclerosis can be seen in the face, neck, head, hands, forearms, upper trunk, buttocks, and extremities.

Pathology Interpretation Pearls • There are two histopathologic patterns: the classic triad and interstitial granuloma annulare-like pattern.

Pretibial Myxedema Pretibial myxedema, localized myxedema or thyroid dermopathy, is a rare form of cutaneous mucinosis that is invariably associated with autoimmune thyroid diseases. The association of pretibial myxedema with Grave’s disease and sometimes Hashimoto thyroiditis is well-known [86]. Approximately 4% of patients with Graves’ disease and 13% of patients with severe Graves’ ophthalmopathy have pretibial myxedema [87]. Cases of pretibial myxedema related to trauma has been reported. In a recent large series of 216 cases by Lan et al. [88], pretibial myxedema was classified into six variants  – nodule variant, plaque variant, diffuse swelling variant, tumor variant, mixture variant, and elephantiasis variant. The pathogenesis of pretibial myxedema remains unknown. It seems that long disease duration and severe autoimmune process are con-

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tributing factors for extrathyroidal manifestations of Graves’ disease. All patients have elevated serum levels of thyroid-stimulating hormone receptor antibodies. It has been postulated that this disease results from the stimulation of fibroblasts by long-acting thyroid stimulator or insulin-­like growth factor 1 in the serum.

Clinical Presentation Pretibial myxedema is most commonly seen on the anterior aspects of the legs of women in the fifth to sixth decades of life (Fig.  5.37). The lesions may extend to the dorsa of the feet and toes. Sometimes the lesions can be identified in the face, neck, hands, arms, shoulders, and abdomen. Typically, they consist of non-pitting

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yellow waxy plaques (Fig.  5.38). The prominent follicular openings of these lesions may impart a peau d’orange appearance. Scale and shiny white lines on pink to brownish color background are seen on dermoscopy [89]. If the lesion is small, the patient experiences mild pruritus or is asymptomatic. However, the lesion often becomes painful as it gets larger. Clubbing of fingernails and toenails or thyroid acropachy can be seen in a quarter of the patients [90].

 rognosis or Clinical Course P Most cases are asymptomatic and tend to resolve spontaneously. Complete remission can be seen in up to 26% of cases [86, 90]. While the clinical course of the nodule variant was self-limited, the remaining five variants of pretibial myxedema were chronic [88]. When occurs in association with pretibial myxedema, Grave ophthalmopathy is usually severe [86]. Tobacco has been reported to be a risk factor for extrathyroidal manifestations of Graves’ disease.

Fig. 5.37  Indurated lesions on the anterior aspect of bilateral lower extremities

Histopathology The epidermis is either unremarkable or may show hyperkeratosis with follicular plugging. Dermal collagen fibers are displaced by prominent deposition of hyaluronic acid and glycosaminoglycans in the mid and deep dermis with associated stellate fibroblasts (Fig.  5.39). This results in a thickened dermis. A superficial perivascular inflammatory infiltrate containing mast cells is often seen.

Fig. 5.38  Non-pitting yellow waxy plaques

Fig. 5.39  Prominent mucin deposition is noted between dermal collagen bundles (×200)

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Differential Diagnosis Pretibial mucinosis associated with venous stasis is in the differential diagnosis. In the setting of pretibial mucinosis, mucin is noted mainly in the papillary dermis [91]. On the other hand, the papillary dermis is typically uninvolved in pretibial myxedema. Lobular vascular proliferation of dermal thick-walled vessels and hemosiderin deposition are clues for stasis dermatitis. The attenuation of collagen fibers seen in scleredema is not present in pretibial myxedema.

Summary Clinical Presentation • Non-pitting yellow waxy plaques with prominent follicular openings • Typically associated with Grave’s disease Histologic Features • Prominent mucin deposition throughout the entire dermis • Associated stellate fibroblasts and mast cells Differential Diagnosis • Pretibial mucinosis associated with stasis dermatitis • Scleredema

Takeaway Essentials Clinical Relevant Pearls • While the most common site is the anterior aspects of the legs, lesions can be seen on any skin sites. • When occurs in association with pretibial myxedema, Graves’ ophthalmopathy is usually severe.

Bullous Diabeticorum Bullous diabeticorum is a rare disease usually associated with long-standing diabetes mellitus. It has been reported that the frequency of bullous diabeticorum is about 0.16% of diabetics, and this disease is seen more frequently in men than women [92]. While the etiopathogenesis remains unclear, roles of trauma, neuropathy, and microangiopathy have been postulated for bullous diabeticorum.

Clinical Presentation A sudden appearance of vesicles and bullae is characteristic at the beginning of this disease. Typically, they are multiple, tense, and painless. The size of the lesions ranges from a few millimeters to several centimeters. The favorite sites are the extremities including the lower legs, feet, forearm, and hands. Rarely, the lesions can be seen on the trunk. They contain a clear fluid; however, culture of the fluid is negative. In addition to infection, ulceration may be present as a secondary change [92].  rognosis or Clinical Course P In a series of 12 cases by Lipsky et al. [93], all had peripheral neuropathy, and two had secondary staphylococcal infection of their bullae. The lesions heal spontaneously without scarring within 2–5  weeks. Recurrent episodes are not uncommon, and bullous lesions on the feet can develop into chronic ulcer [92]. Histopathology Histopathological findings are variable. Typically, intraepidermal and/or subepidermal blisters are seen (Fig.  5.40). They contain fibrin and a few inflammatory cells. Spongiotic change is sometimes present. Lymphohistiocytic perivascular infiltration is present sparsely. Thickening of capillary vessels’ wall may be identified. Direct immunofluorescence (DIF) analysis is usually negative; however, there are reported cases with positive DIF studies – one showing IgM and C3 around the superficial vasculature in uninvolved

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• Tense, multiple vesicles, and bullae with a clear fluid are seen on the extremities, mainly. Histologic Features • Intraepidermal and/or subepidermal blisters with fibrin and a few inflammatory cells. • Direct immunofluorescence examination is basically negative. Differential Diagnosis • Porphyria cutanea tarda, pseudoporphyria • Bullous pemphigoid • Epidermolysis bullosa acquisita • Bullous drug eruption

Fig. 5.40  Bullous diabeticorum. A subepidermal blister containing fibrin and some inflammatory cells (×100)

skin [94] and another with vascular IgG deposition within the thickened wall of the capillaries of the superficial vascular plexus [95].

Differential Diagnosis Porphyria cutanea tarda and pseudoporphyria resemble bullous diabeticorum, clinically. Their favorite site is the hands more than feet. Bullous pemphigoid and epidermolysis bullosa acquisita must be ruled out by DIF examination. If the lesions are warm and painful, bullous cellulitis is also in the differential. The possibility of bullous drug eruptions should always be excluded.

Summary Clinical Presentation • Bullous diabeticorum is typically found in the patients of long-standing diabetes mellitus.

Takeaway Essentials Clinical Relevant Pearls • The lesions heal spontaneously without scarring within 2–5 weeks.

Hematologic Malignancies Systemic Amyloidosis Amyloidosis denotes the extracellular deposition of proteins in a beta-pleated sheet configuration that gives rise to the characteristic green birefringent on Congo red stain. The origin of amyloid is diverse with 16 different proteins which have been reported [96]. Amyloidosis can be localized or systemic in which the amyloid deposits are distributed in many organs of the body (Table 5.3). Systemic amyloidosis can be primary which can be caused by extracellular deposition of immunoglobulin light chain produced by clonal proliferation of plasma cells in setting of multiple myeloma [97]. Systemic amyloidosis can be secondary to chronic infection, rheumatoid arthritis,

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Localized

Clinical type Myeloma-associated Hemodialysis-associated Familial Mediterranean fever Muckle-Wells syndrome Familial amyloid polyneuropathy Primary localized nodular cutaneous Macular amyloid and lichen amyloidosis Pancreatic endocrine tumor Thyroid endocrine tumor Senile cerebral/Alzheimer’s associated Hereditary cerebral

Subunit of amyloid Immunoglobulin light chain Beta-2 microglobulin Serum amyloid A Serum amyloid A Prealbumin Immunoglobulin light chain Keratin fragments Proinsulin Precalcitonin Amyloid plaque core protein (APCP) Cystatin C

inflammatory bowel disease, Hodgkin’s lymphoma, and some solid tumors.

Clinical Presentation Systemic Amyloidosis Primary systemic amyloidosis is rare. The lesions are caused by amyloid L protein (AL). The type of this disease is plasma cell dyscrasias or multiple myeloma-associated, and the more common type is plasma cell dyscrasias. This disease is detected in 5% to 15% of multiple myeloma patients. Patients with systemic amyloidosis often present with carpal tunnel syndrome, macroglossia, mucocutaneous lesions, hepatomegaly, and edema. Cutaneous lesions occur in 20 to 40% of the cases and can be the first and only manifestation of the disease. Purpuric lesions and waxy, smooth, shiny, nontender, non-pruritic papules, nodules, or plaques, on flexural areas, eyelids, mouth, scalp, neck, and anogenital region, can be detected (Fig. 5.41) [98]. The typical clinical presentation is purpura or hemorrhage, but also papules, nodules, ulceration, pigmentation, blisters, alopecia, and nail dystrophy. In secondary systemic amyloidosis, amyloid A protein, derived from serum amyloidosis A (SAA), is accumulated in various organs, such as the liver, spleen, and kidneys. This disease is associated with infectious disease, such as tuberculosis and leprosy, or malignant neoplasm or severe chronic inflammatory disease such as rheumatoid arthritis. Recently, Karim et al. [99] reported a case of AA amyloidosis developed in a patient with IgG4-related disease. Skin involvement is rare. Most patients are reported to have

Fig. 5.41  Nodular amyloidosis. A nodule seen on the lower extremity

renal insufficiency or the nephrotic syndrome at the time of diagnosis [100]. Familial amyloidosis is exceedingly rare. This disease is caused by an autosomal dominant inheritance. The main clinical presentation is polyneuropathy. Patients with familial Mediterranean fever may present with erysipelas-­like lesions on the legs, urticaria, Henoch-­Schonlein purpura, and vasculitic nodules [97]. Those with Muckle-Wells syndrome present with periodic episodes of urti-

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caria, fever, limb pain, deafness, and renal amyloidosis [97]. Keratotic papules, hyperpigmentation, and hypopigmentation may be present on the extremities and trunk. Nonhealing ulcer, scar, and anhidrosis may also be seen. Localized Amyloidosis Primary localized (cutaneous) amyloidosis is mostly seen in adults, and the macular variant is often present in young adult. Lichenoid (lichen, papular) amyloidosis is the most common variant in the cases of primary localized amyloidosis. Lichen amyloidosis presents as a pruritic eruption of multiple hyperkeratotic papules and plaques on the anterior shins which can spread to the calves, ankles, and thighs [Fig. 5.42]. Rippled pattern is the common feature. There are the combined cases of both lichenoid variant and macular variant, so-called biphasic amyloidosis. It is thought that lichenoid amyloidosis may occur from macular amyloidosis, because of scratching [101]. Lichenoid amyloidosis has been reported in association with chronic Epstein-­Barr virus infection, Kimura’s disease, and angiolymphoid hyperplasia with eosinophilia [102–104]. Hyperpigmented and pruritic macules and patches are present in macular amyloidosis. Macular amyloidosis is characterized by a symmetric, pruritic eruption of small brown to gray macules on the upper back, extremities, chest, and buttocks [Fig. 5.43] [97]. The lesions often

Fig. 5.42  Lichen amyloidosis. Multiple hyperkeratotic papules seen on the shin

Fig. 5.43  Lichen amyloidosis. Brown to gray macules seen on the upper back

become confluent. Occasionally, characteristic rippled pattern or reticulated pattern can be seen. Amyloid keratin protein (AK) is found in both lichenoid amyloidosis and macular amyloidosis. Nodular cutaneous amyloidosis is rare. Immunoglobulin light chains are found in this variant. Pink-yellow, wavy nodules are identified mainly in women. In the center of the lesion, atrophic appearance with a white to yellow color may be seen. The lesion can be single or multiple. The favorite site is the legs or face. Additionally, the lesion may be seen on the neck and genital areas. Nodular amyloidosis associated with Sjogren’s disease and CREST syndrome has been reported [105, 106]. Anosacral cutaneous amyloidosis is rare. This disease is seen in the elder patients. Typically, symmetrical chloasma or brown lichenified plaque can be seen around the anus. The origin of anosacral cutaneous amyloidosis is amyloid keratin protein (AK). Sometimes the lesion is pruritic. On the other hand, primary cutaneous amyloidosis of the external ear is not pruritic [107]. Secondary localized (cutaneous) amyloidosis is found in the stroma of various skin tumors, for example, basal cell carcinoma. Secondary localized amyloidosis is also accompanied by actinic keratosis, Bowen’s disease, squamous cell carcinoma, mycosis fungoides, syringocystadenoma papilliferum, cylindroma, seborrheic keratosis, dermatofibroma, trichoepithelioma, trichoblastoma, porokeratosis, psoriasis, verruca vulgaris, intradermal nevus, nevus sebaceus, and others.

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Also, it is reported that PUVA (psoralen and ultraviolet A) therapy can induce secondary localized amyloidosis [108].

 rognosis or Clinical Course P While the biologic course of localized amyloidosis is benign, systemic amyloidosis may be lethal with the main cause of death being heart and renal failure. Histopathology In the setting of systemic amyloidosis, the amyloid deposit appears as an amorphous and fissured eosinophilic material that often exhibits green birefringence on Congo red staining under polarized light microscopy (Figs. 5.44, 5.45, and 5.46). This deposit often infiltrates the walls of blood vessels, pilosebaceous units, arrector pili muscle, the lamina propria of sweat glands and ducts, and around the adipocytes in the subcuta-

Figs. 5.44 and 5.45 Nodular deposit of amorphous eosinophilic material seen in the dermis (×100, ×200)

Fig. 5.46  Green birefringence on Congo red staining under polarized light microscopy (×100)

neous tissue. In the subcutis, amyloid materials surround adipocytes resulting in a phenomenon called “amyloid rings.” Lee et  al. [109] have reported that amyloid deposits can be seen in 97% of cases of systemic amyloidosis. The amyloid material can be identified on histologic sections in normal skin in up to 50% of patients [110]. Therefore, a biopsy of either affected or unaffected skin may provide the diagnosis. In the setting of localized amyloidosis, pink globular materials admixed with pigment laden macrophages are present in the papillary dermis in lichen and macular amyloidosis. The overlying epidermis can be hyperkeratotic and acanthotic. In nodular primary localized cutaneous amyloidosis, fissured eosinophilic materials are seen surrounding blood vessels and adnexal structures in the dermis and subcutaneous tissue. Plasma cells would be prominent. The overlying epidermis is atrophic.

Differential Diagnosis The clinical appearance of primary systemic amyloidosis may resemble blistering disorders such as bullous pemphigoid or condyloma acuminata. Clinical pathologic correlation is essential since it is impossible to differentiate localized nodular amyloidosis from nodular amyloid deposition of systemic amyloidosis on histologic grounds. Colloid or lipoid proteinosis are histologic differential diagnoses for systemic amyloidosis. However, these deposits are negative on Congo red stain. The amyloid deposits in local-

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ized or cutaneous amyloidosis are often negative with Congo red stain. Other stains such as crystal violet and thioflavin T might be of help.

Summary Clinical Presentation • Systemic amyloidosis • Primary: purpura, hemorrhage, papules, nodules, ulceration, pigmentation, blisters, and alopecia on the face, typically around the eyes • Secondary: rare skin involvement, deposits in various organs • Familial: polyneuropathy, keratotic papules, hyperpigmentation, and hypopigmentation on the extremities and trunk • Primary localized amyloidosis Lichenoid variant: pruritic papules and plaques on the lower extremities Macular variant: hyperpigmented pruritic macules and patches on the upper back, rippled pattern, or reticulated pattern Nodular variant: pink-yellow, waxy nodules on the legs or face Histologic Features • Systemic amyloidosis: amorphous and eosinophilic amyloid deposits involving blood vessels and surrounding adipocytes • Primary localized amyloidosis, nodular variant: amyloid deposits seen around blood vessels and adnexal structures in the dermis, prominent plasma cells • The amyloid deposits associated with melanophages and confined to the papillary dermis in lichen and macular amyloidosis Differential Diagnosis • Systemic amyloidosis: colloid milium, lipoid proteinosis, and nodular amyloidosis • Localized amyloidosis: lichen simplex chronicus, hypertrophic lichen planus

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Takeaway Essentials Clinical Relevant Pearls • Amyloidosis denotes the extracellular deposition of proteins in a beta-pleated sheet configuration that gives rise to the characteristic green birefringent on Congo red staining. Pathology Interpretation Pearls • The amyloid deposits in  localized or cutaneous amyloidosis are often negative with Congo red stain. • Clinical pathologic correlation is essential since it is impossible to differentiate localized nodular amyloidosis from nodular amyloid deposition of systemic amyloidosis on histologic grounds.

Nutritional Deficiencies Although uncommon in the United States and developed countries, nutritional deficiencies can still be seen in specific populations such as alcoholics, psychiatric patients, infants, and patients with malabsorption and gastrointestinal surgery. The skin is often the initial and most common presentation of the underlying vitamin and mineral deficiencies including pellagra in niacin or vitamin B3 deficiency, acrodermatitis enteropathica and necrolytic migratory erythema in zinc deficiency, phrynoderma in vitamins A, and scurvy in vitamin C deficiency. Not uncommonly, the patients would present with more than one deficiency.

Pellagra Pellagra, a photosensitive disorder, is due to deficiency of niacin or nicotinic acid or vitamin B3 or its precursor tryptophan or both. This water-­soluble vitamin is vital since greater than 100 enzymes need nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinu-

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cleotide phosphate (NADP) for various biochemical reactions. Hartnup disease, an autosomal recessive disorder, is a congenital form of niacin deficiency caused by impaired transport of amino acids across intestinal and renal epithelium [111]. It presents with pellagra-like rash on exposed skin, cerebellar ataxia, and psychosis. Pellagra is rarely seen in developed countries due to niacin fortified food. In some parts of the world where corn is the main diet, pellagra can be endemic. Pellagra occurs in association with malnutrition secondary to poverty, chronic alcoholism, malabsorption, carcinoid syndrome, drugs such as isoniazid, and human immunodeficiency virus infection [112]. There have been four theories regarding the underlying mechanism of photosensitivity in pellagra: (1) cutaneous deficiency of urocanic acid, (2) buildup of kynurenic acid, (3) deficiency of NAD/NADP, and (4) altered porphyrin metabolism [112].

Clinical Presentation Females are more commonly affected than males. Pellagra is characterized by symmetric and photosensitive skin eruption, gastrointestinal symptoms, and neurologic signs. The main mucocutaneous presentations of pellagra include photosensitivity dermatitis; perineal, genital, and mucosal skin lesions; skin thickening and pigmentation over the bony ­prominences; and sebaceous gland alterations [113]. The photodermatitis is typically bilateral and symmetrical on sun-exposed skin such as dorsum of the hands, neck, face, forearms, legs, and feet [113]. The eruption on the front of the neck is known as Casal’s necklace. The lesions are initially erythematous and pruritic and then become thickened, scaly, and hyperpigmented. Painful fissures may be seen in the palms and soles and can affect the oral and genital mucosa.  rognosis or Clinical Course P If pellagra is untreated, it can result in death in 5 years; however, the disease responds dramatically to oral nicotinamide.

Histopathology Vacuolar alteration involving the upper half of the epidermis is seen in the early stages of pellagra, similar to those of acrodermatitis enteropathica and necrolytic migratory erythema [113]. Hyperkeratosis, epidermal hyperplasia, and increased epidermal pigmentation would follow. Atrophy of the epidermis and sebaceous glands would be seen in the chronic stage. Differential Diagnosis The differential diagnoses include other nutritional deficiencies such as acrodermatitis enteropathica and necrolytic migratory erythema.

Summary Clinical Presentation • Photosensitive and symmetric skin eruption, gastrointestinal manifestations, and neurologic symptoms. • Cutaneous presentations include photosensitive dermatitis on exposed sites; perineal, genital, and mucosal skin lesions; and skin thickening and pigmentation over bony prominences. Histologic Features • Early features include vacuolar alteration involving the upper half of the epidermis. • Hyperkeratosis, epidermal hyperplasia, and increased epidermal pigmentation would follow. Differential Diagnosis • Acrodermatitis enteropathica • Necrolytic migratory erythema

Takeaway Essentials Clinical Relevant Pearls • Four “Ds” of pellagra include dermatitis, diarrhea, dementia, and death.

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Pathology Interpretation Pearls • Epidermal changes can be similar to those of acrodermatitis enteropathica and necrolytic migratory erythema.

Acrodermatitis Enteropathica Acrodermatitis enteropathica can be caused by either an inherited or acquired zinc deficiency. The inherited form of zinc deficiency is an autosomal recessive disorder due to SLC39A4 mutation on chromosome 8q24.3 [114]. This gene encodes a transporter protein Zip4 which is involved in the absorption of zinc by enterocytes. On the other hand, acquired causes of zinc deficiency include malabsorption states, central intravenous hyperalimentation with low zinc content, breast milk low in zinc, inflammatory bowel disease, chronic diarrhea, malignancy, infection, burns, pregnancy, chronic alcoholism with liver cirrhosis, alcoholic pancreatitis, anorexia nervosa, biotin deficiency, Hartnup ­disease, acquired immunodeficiency syndrome, cystic fibrosis, and renal disease.

Clinical Presentation A triad of dermatitis, alopecia, and diarrhea can be observed in one fifth of the cases. The patients typically present symptoms at 4–10 weeks of age after weaning off breast milk. Typically, a scaly, crusted, eczematous, psoriasiform, or vesiculobullous dermatitis can be seen on perioral, acral, and perianal skin (Fig. 5.47). Erosion can be seen. While nail changes can be paronychia, onycholysis, and onychodystrophy, mucosal changes include stomatitis and angular cheilitis [115]. Alopecia can be present in severe cases. Usually, the alopecia starts from the side or back of head, and then it spreads to involve the entire head. The patients may have symptoms of diarrhea and/or vomiting [116].  rognosis or Clinical Course P In the case of acquired zinc deficiency, the clinical course is prolonged and characterized by exacerbations and remissions. In severe condi-

Fig. 5.47  Serpiginous and scaly psoriasiform dermatitis of zinc deficiency

Fig. 5.48 Confluent parakeratosis and psoriasiform hyperplasia of the epidermis are seen (×100)

tion, mental disabilities and/or delayed physical growth may be seen. There is the possibility that ulcerated cases may lead to death, because of malnutrition and infection.

Histopathology Focal parakeratosis and loss of the granular layer are features of the early lesion [117]. As the lesion progresses, confluent parakeratosis and psoriasiform hyperplasia of the epidermis are seen (Fig. 5.48). The edematous and pallor degeneration is present in the superficial third of the epidermis. Bullous lesion of this disease has also been reported [115]. Necrotic keratinocytes and necrosis may be seen. On the other hand, no significant epidermal pallor but only psoriasiform hyperplasia is seen in the late stage.

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Differential Diagnosis The clinical presentation of acrodermatitis enteropathica can resemble psoriasis, seborrheic dermatitis, impetigo, and eczema. Both biotin deficiency and selenium deficiency are also in the clinical differential diagnosis [118, 119]. Recently, cow’s milk protein allergy has been reported to mimic acrodermatitis enteropathica [120]. Histologically, psoriasiform hyperplasia and pallor degeneration within the superficial third of the epidermis are seen in the patients of necrolytic migratory erythema and pellagra. Acquired bullous acrodermatitis enteropathica has been reported as a histologic mimic of pemphigus foliaceus [121].

Summary Clinical Presentation • A triad of dermatitis, alopecia, and diarrhea can be seen in a fifth of the cases. • A scaly, crusted, eczematous, psoriasiform, or vesiculobullous dermatitis can be seen on perioral, acral, and perianal skin. • Alopecia can be present in severe cases. Histologic Features • Psoriasiform hyperplasia and pallor degeneration within the superficial third of the epidermis • Early  – focal parakeratosis and hypogranulosis • Late  – necrosis and cytoplasmic vacuolation Differential Diagnosis • Clinically: psoriasis, seborrheic dermatitis, impetigo, eczema, biotin deficiency, selenium deficiency, and cow’s milk protein allergy • Histologically: necrolytic migratory erythema, pellagra

Takeaway Essentials Clinical Relevant Pearls • Dermatitis with preference for the opening sites such as periorbital, perioral, and perianal skin. • Serum levels of alkaline phosphatase can be used as a serologic marker for zinc levels since zinc is required for the activity of alkaline phosphatase. Pathology Interpretation Pearls • Epidermal changes can be similar to those of pellagra and necrolytic migratory erythema.

Necrolytic Migratory Erythema Glucagonoma, a glucagon-secreting islet cell neoplasm of the pancreas, is rare with an incidence of 1 per 20 million per year and often with metastatic disease at presentation. Necrolytic migratory erythema is often the primary symptom in approximately 70% of the patients with glucagonoma [122]. It can also be seen in patient with a malnutritional state and not only in the patient with glucagonoma syndrome, since deficiency of zinc, protein, amino acids, and essential fatty acids can cause a similar dermatitis. Prolonged and marked decrease in plasma amino acids due to hypergluconemia, liver dysfunction, and malnutrition have been thought to be the causes of necrolytic migratory erythema. Hypergluconemia may also increase epidermal arachidonic acid which in turn activate inflammatory mediators causing necrolytic migratory erythema [123].

Clinical Presentation The cutaneous eruption can occur months to years prior to the systemic symptoms; however, most patients present concurrently with weight loss, anemia, mental status changes, diabetes mellitus, stomatitis, and diarrhea [124]. Pruritic and painful cutaneous lesions are seen evolving

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Fig. 5.49  Erythematous, well-demarcated, plaques on the shoulder

Fig. 5.50  Pallor of keratinocytes within the upper aspect of the epidermis (×100)

in a recurrent, annular, and migratory pattern [124]. Initial erythematous vesicles and bullae develop into well-demarcated, confluent, circinate patches and plaques on the perorbital region, lower abdomen, perineum, buttocks, and distal extremities (Fig.  5.49). Peripheral collarette of scale and post-inflammatory hyperpigmentation are seen in resolving lesions. The lesions preferentially form at sites of trauma, i.e., koebnerization. Hair thinning, onychoschizia (nail splitting), and onycholysis can be seen. Necrolytic acral erythema, a localized variant of necrolytic migratory erythema, can be seen in association with hepatitis C [123].

cular infiltrate, and papillary dermal edema can be seen. Diffuse parakeratosis is a frequent feature [124]. Kheir et  al. [126] has emphasized four histologic patterns: (1) necrotic and vacuolated upper epidermis, (2) subcorneal pustules, (3) dermal telangiectasia of the papillary dermis, and (4) psoriasiform epidermal hyperplasia with overlying confluent parakeratosis. Dyskeratosis can be a clue for an early lesion [125]. While the early changes have been reported to be within the adnexal structures [127], parakeratosis, acanthosis, and dermal angiogenesis are seen in the older cases [126, 127]. Direct immunofluorescence studies are typically negative [124].

 rognosis or Clinical Course P The clinical course is characterized by spontaneous remissions and exacerbations. Surgical cure of the tumor and complete eradication of necrolytic migratory erythema can be achieved if the glucagonoma has not metastasized at time of diagnosis. However, tumor debulking can serve as a palliative treatment. Histopathology In early lesion, necrolysis starts at the upper stratum malphigii imparting an abrupt pattern of necrosis within the upper epidermis (Fig. 5.50) [125]. Epidermal cleft can result in vesiculation. Epidermal acanthosis with spongiosis, perivas-

Differential Diagnosis A variety of conditions termed pseudoglucogonoma syndrome is characterized by necrolytic migratory erythema in the setting of normal glucagon level. They include malabsorption, pancreatitis, pulmonary and renal glucagonoma, celiac sprue, inflammatory bowel disease, liver diseases, and infection [128]. Other disorders such as acrodermatitis enteropathica (an inherited form of zinc deficiency), acquired zinc deficiency, niacin deficiency (pellagra), and essential fatty acid deficiency can have similar histologic findings. These disorders share similar clinical presentation and histologic features

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to necrolytic migratory erythema; therefore, laboratory studies are essential to delineate the etiology. Clinically, necrolytic migratory erythema can resemble toxic epidermal necrolysis and annular erythema. Necrolytic acral erythema can mimic psoriasis and erythrokeratoderma [123].

Summary Clinical Presentation • Periorificial or acral erythematous and vesiculopustular lesions • Hair loss and nail changes Histologic Features • Pallor of keratinocytes within the upper epidermis with vacuolation and vesiculation is seen. • Diffuse parakeratosis is a common feature. Differential Diagnosis • Acrodermatitis enteropathica • Acquired zinc deficiency • Pellagra

Takeaway Essentials Clinical Relevant Pearls • Prompt recognition of necrolytic migratory erythema is important since the cutaneous eruption can be the first and only manifestation of glucagonoma syndrome. • Biopsy at the edge of an early lesion would be best for diagnosis. • Often multiple biopsies of the active borders are done prior to reaching the diagnosis.

Pathology Interpretation Pearls • The histologic features are often nonspecific. • Dyskeratosis can be a helpful clue for an early lesion. • Parakeratosis, acanthosis, and dermal angiogenesis are seen in the older cases.

Vitamin A Deficiency Vitamin deficiency is caused by dietary deficiency and/or metabolic disorder. In general, the deficiency of fat-soluble vitamin, including vitamin A, needs long periods of time. On the other hand, the deficiency of water-soluble vitamin, including vitamin C (ascorbic acid), occurs rapidly. Both vitamins A and C are essential nutrient since they cannot be produced by our body and must be obtained from diet. Vitamin A encompasses retinol, retinal, and retinoic acid. Vitamin A is required for vision, maintenance of epithelial surfaces, immune response, reproduction, embryonic growth, and development. Vitamin A is naturally found in a variety of foods including green leafy vegetables, sweet potatoes, carrots, egg yolks, and liver. The patients with vitamin A deficiency are predominantly seen in Asia and Africa [129]. The deficiency is rarely seen in the United States due to psychiatric disorder or a selective diet. A rare inherited form of vitamin A deficiency has been reported in which retinol-binding protein 4 (RBP4), a protein necessary for mobilizing stored vitamin A, is affected [130].

Clinical Presentation Vitamin A is required for night vision. Initially the patients reported nyctalopia or night blindness which is due to rod photoreceptor dysfunction. Keratinization of ocular epithelium, Bitot’s spots, wrinkling of the conjunctiva, and loss of goblet cells would subsequently develop. Other clinical features include xerophthalmia (abnor-

5  Granulomatous Dermatitis and Others

mal dryness of conjunctiva and cornea), punctate keratitis, keratomalacia (corneal melting), corneal neovascularization, and xerostomia (dry mouth). Since vitamin A is vital for the immune system, its deficiency results in an increased risk of infections, loss of mucosal integrity, and increased mortality. Phrynoderma, meaning “toad skin,” is a distinctive form of follicular hyperkeratosis. It is mainly seen in the patients with vitamin A deficiency; however, this is also seen in other nutritional deficiencies including malnutrition. In a recent clinical study of 125 cases of phrynoderma in India [131], the disease was reported to occur mainly in 5–15-year-old children with no gender predilection. Brown to skin-colored follicular keratotic plugs are identified on the extremities, especially the upper forearms and thighs, and sometimes shoulder and buttocks. The lesions are asymptomatic in approximately 90% and bilateral and symmetrical in approximately 70% of the cases [131].

 rognosis or Clinical Course P The keratotic plaques typically leave pits. Phrynoderma is often associated with nyctalopia (night blindness), xerophthalmia, and xerostomia. Histopathology In the largest series by Ragunatha et al. [131], follicular hyperkeratosis, follicular plugging, epidermal hyperkeratosis, and perivascular lymphocytic infiltration were reported as characteristic histopathologic features (Fig. 5.51) [131]. In the severe condition, eccrine glands and sebaceous glands may show squamous metaplasia [132]. Differential Diagnosis The differential diagnosis includes other nutritional deficiencies, keratosis pilaris, pityriasis rubra pilaris, lichen spinulosus, follicular lichen planus, and follicular ichthyosis. The confirmation of reduced vitamin A serum levels (T mutation. Clin Exp Dermatol. 2019;44(1): 82–4.

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Contents Introduction

 452

Lupus Erythematosus Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 453  453  453  459  459  465

Dermatomyositis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 467  467  468  471  471  473

Morphea, Systemic Sclerosis, and Limited Scleroderma Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 474  474  474  476  477  477

Sjogren Syndrome Etiology and/or Pathogenesis Clinical Features Histopathologic Features Differential Diagnosis

 478  478  479  479  480

J. S. Lehman (*) · A. G. Bridges Departments of Dermatology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_11

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452 Rheumatoid Arthritis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 480  480  481  481  481  482

Mixed Connective Tissue Disease Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 485  485  485  485  485  486

Relapsing Polychondritis Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 486  486  486  486  487  487

Autoinflammatory Conditions Etiology and/or Pathogenesis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 488  488  488  489  489  489

Case Studies Case 1 Clinical History Microscopic description Diagnosis Discussion Case 2 Clinical History Microscopic description Diagnosis: Adult-Onset Still’s Disease Case 3 Clinical History Microscopic description Diagnosis: Hypocomplementemic Urticarial Vasculitis

 491  491  491  491  491  491  492  492  492  493  493  493  493  494

References

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Introduction Autoimmune connective tissue diseases (CTD) encompass a heterogeneous collection of chronic immune-mediated conditions that may affect one or multiple organ systems. Like many autoimmune processes, CTD tend to occur in young to middle-aged women but may affect children and men. These disorders may have varied presentations, though certain clinical features, including many affecting the skin, may be characteristic for CTD.  In addition, non-

specific mucocutaneous changes may occur. For example, in the appropriate clinical setting, new photosensitivity or the development of oral ulcerations should prompt an evaluation for CTD. CTD may also present with dermatologic features such as urticaria, erythema nodosum, or leukocytoclastic vasculitis. Patients with such reactive inflammatory conditions require a careful history and physical examination for other clues of systemic disease, and it is during this evaluation that an underlying CTD are occasionally detected.

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For this category of diseases, accurate diagnosis depends on careful correlation among clinical features, laboratory studies, histopathologic findings, and clinical course, with no single feature generally being pathognomonic. Patients are usually best served by having a multidisciplinary care team, with representatives from rheumatology, dermatology, and other medical subspecialists, as directed by each patient’s pattern of disease. Generally, these patients require ongoing follow-up for monitoring of disease activity and treatment response, as well as surveillance for evolution of their disease. This chapter will provide a general overview of key systemic features of each major CTD with particular emphasis to the dermatologic and dermatopathologic manifestations.

Lupus Erythematosus Etiology and/or Pathogenesis Lupus erythematosus (LE) is a heterogeneous disease that is generally thought to be triggered by type I autoimmunity and is mediated by cytokines such as TNF-alpha and type I interferons [1]. Increasing evidence also implicates neutrophil extracellular traps (NETs) via a phenomenon termed, “NETosis” in its pathogenesis [2]. There is some evidence that a unique form of interferon released by keratinocytes, interferonkappa, plays a role in the pathogenesis of cutaneous LE [3]. Ultraviolet (UV) light, cigarette smoking, and infection can provoke lupus flares [4]. Bullous LE is a rare form of acute LE that is associated with the development of collagen VII autoantibodies [5].

Clinical Presentation The clinical presentation of LE may vary widely, ranging from limited areas of skin involvement to full-blown systemic disease involving mul-

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tiple organ systems [6]. Systemic manifestations may include nephritis, cerebritis, pleuritis, arthritis, and arthralgias. In 2012, the Systemic Lupus International Collaborating Clinics released clinical criteria for lupus that improved upon those initially proposed by the American College of Rheumatology [7]. Refined criteria from the European League Against Rheumatism and American College of Rheumatology are forthcoming [8]. Though helpful to guide diagnosis, published sets of criteria for SLE generally were developed for patient stratification for clinical research studies. These criteria are not intended to replace diagnosis by experienced clinicians. Cutaneous manifestations of lupus erythematosus can be classified by subtype [9] (Table  11.1). When it affects the skin, acute LE characteristically presents with symmetric malar erythema, the so-called butterfly rash (Fig.  11.1), though violaceous erythema may develop in other sun-­exposed areas (Fig. 11.2). Dermatologic clues to the presence of systemic lupus erythematosus (SLE) include prominent acral and mucosal involvement, as well as the development of bullous lesions (Fig.  11.3). In particular, patients with bullous LE experience tense, subepidermal blisters in sun-exposed areas (Fig.  11.4). Generally, patients with bullous LE have systemic LE with serious manifestations in other organs, such as lupus nephritis. While acute cutaneous LE tends to be seen in the setting of SLE, the other variants can be seen in SLE or as an isolated cutaneous phenomenon. A rare form of cutaneous LE, Rowell syndrome, shows features that overlap clinically with erythema multiforme major/StevensJohnson syndrome. Whether this phenomenon should be classified as a distinct entity is controversial [10]. Along with scarring, leukoderma may result in patients with darker skin types (Fig. 11.5). Subacute cutaneous LE (SCLE) typically presents with discrete or coalescing annular erythematous patches and plaques in sun-exposed areas (Fig.  11.6). In addition to annular lesions,

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454 Table 11.1  Clinical subtypes of cutaneous lupus erythematosus

Subtypes of cutaneous lupus erythematosus

Acute cutaneous lupus erythematosus

Bullous lupus erythematosus Acral lesions Malar eruption

Subacute cutaneous lupus erythematosus

Annular lesions Psoriasiform lesions Pityriasis rosea-like lesions

Fig. 11.1  Malar erythema sparing the nasolabial folds in a patient with systemic lupus erythematosus (SLE)

patients with SCLE can have psoriasiform and pityriasis rosea-like variants. Approximately 40–50% of patients with SCLE develop SLE [9]. Chronic cutaneous LE (CCLE) is the most common form of cutaneous LE. The most frequently observed subtype of CCLE is discoid LE (DLE), which may be associated with atrophic to scarred scaly erythematous patches and plaques, occasionally with ice pick depressions from follicular plugging (Fig. 11.7). This form has a predilection for the conchal bowls, face, and scalp (Fig. 11.8). Up to 40% of patients with DLE may have asso-

Chronic cutaneous lupus erythematosus

Palmar-plantar lupus erythematosus Chilblain lupus erythematosus Hypertrophic/verrucous lupus erythematosus Discoid lupus erythematosus Lupus profundus

ciated systemic disease [9]. Variants of CCLE include hypertrophic or verrucous LE (Fig. 11.9), LE panniculitis, and ulcerative lesions. In some cases, CCLE may be clinically mistaken for squamous cell carcinoma or infection; moreover in some cases, CCLE may also be associated with an increased risk of malignant transformation to squamous cell carcinoma. Lupus panniculitis presents with painful, firm, erythematous, indurated plaques or nodules on the face, buttocks, and proximal extremities (Fig.  11.10) [11]. DLE with LE panniculitis is referred to as lupus profundus. Ulceration with lipoatrophy and calcification may occur in these lesions. Tumid LE is associated with erythematous, edematous papules and plaques on the trunk that may be provoked by photo exposure and is seen in association with SLE in about 5% of patients [9]. Acral erythematous to violaceous macules and papules that may ulcerate can occur in the setting of Raynaud’s phenomenon, chilblains lupus (lupus-associated) perniosis (Fig.  11.11) [12], or occlusive vasculopathy from antiphospholipid antibody syndrome. When it affects the

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Fig. 11.2  Photodistributed erythema with erosions in a patient with SLE

Fig. 11.3  Mucosal ulcerations (upper) and pernio-like lesions (chilblains lupus erythematosus; lower) in a patient with SLE

Fig. 11.4  Tense, pauci-inflammatory subepidermal blisters in a patient with bullous LE

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Fig. 11.5 Leukoderma from lupus erythematosus

skin, neonatal lupus may present with periorbital erythema and SCLE lesions, and its early ­recognition is crucial so as to screen for potentially life-threatening complications, such as total atrioventricular heart block (Fig. 11.12) [13]. Lupus may be associated with lupus-specific (e.g., chronic cutaneous LE), lupus non-specific (e.g., lupus hair), and non-lupus forms of alopecia (e.g., telogen effluvium) (see Chap. 20) [14]. Other cutaneous manifestations of LE may include erythema nodosum, neutrophilic urti-

caria, neutrophilic urticarial dermatosis, neutrophilic dermatosis of LE [15] (Fig.  11.13), amicrobial pustulosis of the folds [16], and urticarial vasculitis (hypocomplementemic form; Fig.  11.14) and have been associated with LE [17]. Extranodal Kikuchi-like changes (histiocytic karyorrhexis) represent a rare manifestation of LE [18]. Medications may induce every form of LE [19]. For classic, anti-histone, drug-induced, SLE, frequently implicated medications include

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Fig. 11.8  Smooth, atrophic scarred regions of alopecia in a patient with chronic cutaneous (discoid) lupus erythematosus

Fig. 11.6  Subacute cutaneous lupus erythematosus in a patient with drug-induced SCLE. Clinical clues to drug-­ induced SCLE include involvement in older patients, temporal relationship between onset of rash and initiation of medication, and presence of skin lesions in sunprotected areas

Fig. 11.9  Hyperkeratotic indurated plaques in a sun-­ exposed distribution in a patient with hypertrophic/verrucous LE

Fig. 11.7  Scaring scaly erythema in the ear compatible with discoid lupus erythematosus in this patient with SLE. A malar rash is also noted

hydralazine and procainamide. There is increasing recognition of TNF-alpha inhibitors as a cause of a drug-induced syndrome mimicking SLE, a phenomenon known in the literature as TNF-alpha inhibitor-induced lupus-like syn-

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Fig. 11.10 Indurated violaceous nodules of lupus panniculitis

Fig. 11.11  Acral dusky purpuric papules in a patient with SLE

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Fig. 11.12  Neonatal lupus erythematosus often presents with periorbital or other facial erythema

Fig. 11.13  Neutrophilic dermatosis involving the dorsal fingers in a patient with SLE

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SCLE [20]. Clinical features that might suggest a drug-induced form of SCLE include older age of onset, male sex, or skin involvement in photoprotected areas. Patients frequently have circulating antinuclear antibodies, particularly in systemic LE. The presence of anti-Ro (SSA) or anti-La (SSB) antibodies may be seen in LE, with the former being of high prevalence in subacute cutaneous form. Anti-double-stranded DNA and anti-Smith antibodies increase specificity for the diagnosis Fig. 11.14 Urticarial vasculitis, showing areas with of SLE. Anti-histone antibodies may be present peripheral blanching and others with fixed erythema. in the setting of classic, drug-induced SLE [19]. Unlike urticaria, lesions are typically painful rather than Neonatal lupus most often occurs in the setting pruritic, last longer than 24 hours, and resolve with post-­ of maternal transmission of anti-Ro antibodies. inflammatory hyperpigmentation or purpura. Hypocomplementemic vasculitis has a strong correlation Mothers with affected children most often have with lupus erythematosus Sjogren syndrome [13].

 rognosis or Clinical Course P LE is a heterogeneous disease, so prognostication can be challenging. In general, LE tends to be a chronic condition with fluctuating disease activity. Patients who present initially with LE limited to the skin may develop SLE in approximately 20% of cases, though these patients tend to have mild manifestations [21]. Topical or systemic medications may be required to achieve disease control. Diligent sun protection and smoking cessation may be required to prevent disease flares.

Fig. 11.15 TNF-alpha inhibitor associated lupus-like syndrome in a patient taking TNF-alpha inhibitors for rheumatoid arthritis

drome (TAILS) (Fig. 11.15). A systematic literature review found that antifungal medications, antihypertensive medications, proton-pump inhibitors, and checkpoint inhibitors can trigger

Histopathology Acute, subacute, or chronic cutaneous LE, as well as the corresponding drug-induced forms, may all be associated with variable degrees of interface inflammation. These interface changes may be pauci-inflammatory (vacuolar interface inflammation) or associated with a brisk lymphohistiocytic lichenoid infiltrate (lichenoid interface inflammation) (Figs.  11.16, 11.17, and 11.18). Superficial and deep perivascular and periadnexal lymphohistiocytic inflammation is frequently noted, particularly in CCLE. Follicular interface inflammation, follicular hyperkeratosis, and increased dermal mucin can also be observed with CCLE. Occasionally, an associated vasculitis (Fig.  11.19) or severe keratinocyte necrosis, which may occur in

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Fig. 11.18 Histopathology of drug-induced SCLE, showing lichenoid interface dermatitis. Eosinophils were not prominent (×200) Fig. 11.16  Chronic cutaneous LE, discoid subtype demonstrates a dense superficial and deep perivascular and periadnexal lymphocytic infiltrate on low power (×40)

Fig. 11.17  On higher power in this case of chronic LE, follicular plugging, hyperkeratosis, and increased dermal mucin deposition are noted (×200)

Rowell syndrome (Fig.  11.20), may be seen. When associated with LE, urticarial vasculitis is often of the hypocomplementemic form (Fig.  11.21) [22]. This form tends to be associated with a mixed perivascular infiltrate with intravascular neutrophils, dermal edema, and mild fibrinoid necrosis of vessel walls. Eosinophils are less frequently observed in hypocomplementemic than normocomplementemic urticarial vasculitis. Erythrocyte extravasation is usually subtle, and occasionally, multiple tissue levels must be examined to identify vascular damage. Unlike atrophy typically observed in LE, epidermal hyperplasia, hyperkeratosis, and hypergranulosis can be seen, in conjunction with vacuolar interface inflammation, in verrucous or hypertrophic LE.  Tumid lupus and annular erythema of SCLE show brisk perivascular lymphohistiocytic inflammation, focal interface dermatitis, and variable degrees of mucin deposition. Lupus panniculitis shows lymphoplasmacytic aggregates in the lobules of the panniculus that may be accompanied by hyaline fat necrosis (Fig.  11.22) [11]. LE panniculitis can be identical to the panniculitis seen

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Fig. 11.19  Vacuolar interface dermatitis and leukocytoclastic vasculitis involving small- to medium-sized vessels in a patient with SLE (×200, ×400)

Fig. 11.20  Histopathologic features of a patient with Rowell syndrome, a form of lupus that clinically and microscopically can mimic erythema multiforme major/ Stevens-Johnson syndrome. Extensive vacuolar interface changes led to the development of subepidermal separation and associated epidermal necrosis (×100)

Fig. 11.21  Histopathology of urticarial vasculitis similar to leukocytoclastic vasculitis, but the infiltrate is usually less dense around blood vessels, and the degree of vessel wall necrosis is milder. Generally, normocomplementemic urticarial vasculitis has prominent eosinophils, whereas normocomplementemic urticarial vasculitis has prominent neutrophils (×100)

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Fig. 11.22  Lobular lymphoplasmacytic panniculitis with hyalinization of septae in lupus panniculitis (×40, left, upper right; ×100, lower right)

in dermatomyositis (DM), and so the authors prefer the term, “connective tissue panniculitis.” Seventy percent of patients with LE panniculitis also have DLE, and the presence of DLE with LE panniculitis is known as LE profundus. LE panniculitis occurs in 2% of patients with SLE. In antiphospholipid antibody syndrome, pauciinflammatory thrombotic vasculopathy or intravascular occlusion by fibrin thrombi can be observed in the superficial to mid-dermal vessels (Fig. 11.23). Chilblains lupus shows superficial and deep dermal perivascular and periadnexal lymphohistiocytic inflammation with dermal edema and vacuolar interface dermatitis. In this setting, the presence of interface dermatitis and increased dermal mucin and dermal interstitial fibrin exudate are clues that changes may be associated with lupus as opposed to being idiopathic [23]. Endothelial swelling may also be prominent. Bullous LE is associated with a neutrophil-rich subepidermal blister (Fig.  11.24) and requires direct immunofluorescence (DIF) testing for

Fig. 11.23  Histopathology of antiphospholipid antibody syndrome in SLE patient demonstrating occlusive vasculopathy (×100)

diagnostic confirmation as these histologic findings could also be seen in epidermolysis bullosa acquisita, bullous pemphigoid, dermatitis herpetiformis, or linear IgA bullous dermatosis, for example (see below) [24].

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Fig. 11.24  Histopathologic features of bullous SLE may include a neutrophil-rich subepidermal bulla and neutrophilic papillitis. The microscopic differential diagnosis also includes dermatitis herpetiformis, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, and bullous pemphigoid (×100)

463

trophilic infiltrate with subepidermal edema and bystander vascular damage) (Fig. 11.26). In addition, amicrobial pustulosis of the folds may show neutrophilic pustules overlying the follicular or acrosyringeal ostia in association with dermal edema. In scarring alopecia associated with LE, peri-­ infundibular lichenoid lymphocytic inflammation accompanies superficial and deep dermal perivascular inflammation and dermal mucin deposition. The changes of vacuolar interface inflammation are typically present at the interfollicular epithelium as well. Non-scarring lupus alopecia may show peribulbar lymphoplasmacytic inflammation. Increased mucin deposition may be an additional clue to the diagnosis, if present. Some dermatopathologists find an Alcian blue-periodic acid-Schiff (PAS) stain to be useful, since the Alcian blue component can highlight superficial dermal mucin, and the PAS may show a thickened or disrupted basement membrane zone. Prominent basement membrane thickening is noted in CCLE, particularly hypertrophic or verrucous LE. A heavy band of CD123 cells may be seen at the dermal-epidermal junction in hypertrophic LE, a feature that may help to distinguish this entity from hypertrophic actinic keratosis or SCC.

Fig. 11.25  Histopathology of neutrophilic urticarial dermatosis shows perivascular and interstitial neutrophils, karyorrhectic dust, dermal edema, and neutrophilic epitheliotropism (×100)

A spectrum of neutrophilic processes may be observed, ranging from neutrophilic urticaria (showing mixed perivascular dermal inflammation with neutrophils, intravascular neutrophils, and dermal edema) to neutrophilic urticarial dermatosis (showing perivascular and interstitial dermal neutrophils, karyorrhexis, dermal edema, and neutrophilic epitheliotropism) (Fig.  11.25) and neutrophilic dermatosis (dense dermal neu-

Fig. 11.26  Fibrinoid necrosis of vessel walls is observed on occasion in neutrophilic dermatosis (inset), but this phenomenon is thought to be secondary to bystander damage rather than as a primary event (×100; inset, ×200)

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Fig. 11.27  Direct immunofluorescence findings from a patient with SLE. On IgG, there was evidence of an antinuclear antibody and an extractable nuclear antibody. In addition, strong granular deposition along the basement

membrane zone was seen with IgG, IgM, and C3. The strong shaggy deposition along the BMZ was seen with fibrinogen (×200)

[25]. Moreover, CD123 may help to differentiate CCLE from mycosis fungoides and lupus panniculitis from subcutaneous panniculitis-like T-cell lymphoma, particularly when it marks at least 20% of the infiltrate or demonstrates clusters of immunoreactive cells [26]. While the ­presence of more than rare eosinophils is unusual in LE, their presence does not entirely exclude this diagnosis and does not necessarily indicate drug-­induced forms of LE [27]. Direct immunofluorescence (DIF) studies can be performed as an ancillary test. Perilesional skin should be selected for biopsy in bullous SLE or if performing a lupus band test for renal involve-

ment with SLE. A lupus band demonstrates granular deposition with multiple conjugates  – IgG, IgM, IgA, and C3 along the basement membrane zone (Fig.  11.27) [24]. A DIF should be performed from chronic, sun-exposed lesional skin to support a diagnosis of cutaneous LE and in this case would demonstrate granular deposition of multiple conjugates (most often, IgM and C3 but also IgG, IgA, and fibrinogen in some cases) along the basement membrane zone [28]. In urticarial vasculitis, a lupus band may be accompanied by perivascular deposition of IgM and/ or C3 (granular) and fibrinogen (homogeneous) (Fig.  11.28). An ANA or ENA (granular intra-

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Fig. 11.29  Direct immunofluorescence changes in bullous LE include linear deposition of IgG and/or C3 along the basement membrane zone (×200)

cytoplasmic deposition in the lower epidermal keratinocytes) pattern may be observed within keratinocytes with the IgG conjugate in a DIF taken from lesional skin in LE, as well as dermatomyositis, mixed connective tissue disease, and Sjogren syndrome. In bullous LE, a perilesional DIF demonstrates strong continuous linear deposition along the basement membrane zone which is observed with IgG > C3 and sometimes with IgM and IgA (Fig. 11.29). An indirect immunofluorescence (IIF) performed using human saltsplit skin will demonstrate a dermal pattern, and the IIF on monkey esophagus will be negative, corresponding to deposition of collagen VII autoantibodies (Fig.  11.30). In 40% of bullous SLE cases, there may also be a granular pattern along the basement membrane zone with multiple conjugates indistinguishable from non-­bullous LE.

Differential Diagnosis

Fig. 11.28  Direct immunofluorescence findings in urticarial vasculitis. A biopsy taken from an early lesion for DIF can be identical to leukocytoclastic vasculitis with granular deposition in the walls of the superficial dermal blood vessels with multiple conjugates. However, in urticarial vasculitis associated with lupus, there may also be granular deposition of Ig and C3 along the BMZ (lupus band) (×200)

When patients present with a malar eruption on the face, care should be given to differentiate it from erythematotelangiectatic rosacea. The former generally spares the nasolabial folds, while the latter characteristically involves the central face and may have associated papulopustular lesions or ocular involvement. Microscopic features of rosacea include dermal perifollicular

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ter edges. Thickening of vessel walls can also be observed in PCT. Other entities can be characterized by cell-poor subepidermal blisters and can be indistinguishable from PCT and pseudo-PCT epidermolysis bullosa, cell-poor bullous pemphigoid, epidermolysis bullosa acquisita, and bullous diabeticorum. The presence of epidermal necrosis (or dyskeratosis) in association with a subepidermal blister can be a clue to underlying vasculitis, other vascular occlusive diseases, toxic epidermal necrolysis, graft-versus-host disease, pressure or sweat gland necrosis, physical factors (sunburn, heat, thermal, chemical burn), or a phototoxic Fig. 11.30  Indirect immunofluorescence on human salt-­ drug reaction. split skin with IgG shows antibody deposition on the derWhen patients present with annular scaly mal side of the split (Indirect immunofluorescence, plaques, other papulosquamous conditions and original magnification ×20) superficial dermatophytosis must be excluded. Other mimicking clinical entities could include lymphohistiocytic inflammation, occasionally other papulosquamous disorders, such as dermatiwith a granulomatous component, sebaceous tis, psoriasis, pityriasis rosea, syphilis, and mycohyperplasia, telangiectasias, and intrafollicular sis fungoides. Generally, the anatomic pattern of Demodex mites. While it may be present focally, distribution of the skin eruption, associated clinivacuolar interface changes should not be promi- cal features, and histopathologic findings should nent in rosacea. Malar erythema may also be seen help to distinguish these entities from LE.  The in chronic actinic damage. scarring alopecia of LE may resemble that of When patients present with photosensitiv- lichen planopilaris (LPP), and a biopsy may be ity, it is critical for the medication list to be required for differentiation. The latter generally reviewed to search for possible photosensitiz- lacks prominent vacuolar interface changes of ing drugs. Consideration could also be given to the interfollicular epithelium and the superficial polymorphous light eruption, but these patients and deep dermal perivascular lymphohistiocytic display the phenomenon of “hardening” with inflammation that is seen in lupus [14]. Patterns repeated solar exposure and tend not to have of fibrosis and elastic tissue fragmentation appear facial involvement. Histopathologic findings to differ between LE and other forms of alopecia, demonstrate marked dermal edema with dense with LE having diffuse (perifollicular and interdermal perivascular lymphohistiocytic inflam- follicular) loss of elastic tissue [29]. mation. Interface dermatitis and dermal mucin The non-scarring alopecia of LE must be deposition are typically not observed. In Jessner differentiated from syphilitic alopecia, which benign lymphocytic infiltrate, patients do not may have overlying elongated rete ridges and/ have serologic or immunofluorescence evidence or lichenoid inflammation or psoriatic alopecia, for lupus, and biopsies do not show interface der- which may have overlying psoriasiform epidermatitis. Instead, dense dermal perivascular and mal hyperplasia and attenuation of sebaceous periadnexal predominantly lymphocytic inflam- glands [30]. mation is the most prominent feature. Porphyria Differentiation of lupus panniculitis from cutanea tarda (PCT) and pseudo-PCT typically subcutaneous panniculitis-like T-cell lymphoma show a pauci-inflammatory subepidermal blister can be challenging. However, the latter genwith homogeneous eosinophilic material (base- erally shows a population of CD8+ cytotoxic ment membrane zone material) adherent to blis- T-lymphocytes that have elevated Ki67 staining

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rimming adipocytes [31]. Molecular testing for T-cell clones may be useful.

Summary Clinical Presentation • Symmetrical erythema on the malar cheeks or other photo-exposed areas • Annular to round scaly erythematous patches and plaques • Atrophic, indurated scaly patches and plaques Histologic Features • Vacuolar or lichenoid interface inflammation at the dermal-epidermal junction, often extending down hair follicles, with superficial dermal mucin deposition and perivascular and periadnexal lymphohistiocytic inflammation (typical skin lesions of acute LE, SCLE, and CCLE) • Follicular hyperkeratosis (particularly in CCLE) Differential Diagnosis • Polymorphous light eruption is characterized by marked dermal edema and dermal perivascular and periadnexal lymphohistiocytic inflammation. However, PMLE is more likely to have 6dermal edema and should not have interface dermatitis or prominent dermal mucin. • Jessner benign lymphocytic infiltrate can show dense dermal perivascular and periadnexal lymphohistiocytic inflammation like LE (particularly the tumid form). Vacuolar interface changes are not prominent. Connective tissue serologic and/or immunofluorescence findings are also negative. • Dermatomyositis and other connective tissue diseases may be histopathologically indistinguishable from LE.  Eosinophils may be present in the dermal infiltrate in dermatomyositis or other connective tissue diseases.

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Takeaway Essentials Clinical Relevant Pearls • Skin eruptions worsened by sun exposure or accompanied with constitutional symptoms may represent LE. • Consider the contribution of medications to the development of LE, particularly in patients on certain associated drugs or with generalized skin involvement. Pathology Interpretation Pearls • The presence of vacuolar interface inflammation with perivascular lymphohistiocytic inflammation raises the possibility of various forms of cutaneous LE; however, these changes may also be seen in other connective tissue disorders and therefore are not entirely specific for LE. • Consider LE in patients with cutaneous neutrophilic disorders, such as neutrophilic urticarial dermatosis, urticarial vasculitis, or neutrophilic dermatosis.

Dermatomyositis Etiology and/or Pathogenesis Dermatomyositis (DM) is an autoimmune connective tissue disease belonging to the group of idiopathic inflammatory myopathies that typically affects the skin and/or muscles, although it may affect the skin exclusively (i.e., amyopathic dermatomyositis) or muscle exclusively (polymyositis (PM)). DM may be paraneoplastic, and risk factors include male sex and older age (>45  years) [31]. DM/PM can occur at any age; however, disease incidence peaks are seen in childhood and in the fifth and sixth decades of life. Family occurrences are seen only rarely. DM/PM occurs twice as often in women as in men. Rarely, dermatomyositis may be drug-­ induced [32]. Drugs such as hydroxyurea (51%

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of cases in a review of the literature) [33], penicillamine, nonsteroidal anti-inflammatory drugs (NSAIDS), beta-blockers, statins, tryptophan, and checkpoint inhibitors have been reported to induce DM-like skin lesions. A set of diagnostic criteria for DM has been proposed [34]. Definitive diagnosis depends on the presence of typical skin lesions as well as three of the other criteria  – symmetrical proximal muscle weakness with or without dysphagia or respiratory muscle involvement; abnormal muscle biopsy; elevated skeletal muscle-derived enzymes; and/or abnormal EMG results. A diagnosis of probable DM is made if there are typical skin lesions as well as two of the other criteria. DM is possible if the patient has typical skin lesions and one of the other criteria. Amyopathic DM is characterized by biopsy-confirmed classical cutaneous findings of DM without clinical or laboratory evidence of muscle disease for at least 2  years after the onset of skin disease. Amyopathic DM occurs in 10–20% of all DM patients and can affect adults and children [35, 36]. This form of DM has an even stronger female predilection than classical DM and also carries a relatively high risk of being paraneoplastic and having associated interstitial lung disease.

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Fig. 11.31  Violaceous hyperkeratotic papules (Gottron’s papules) overlying the hand joints in a patient with dermatomyositis

Clinical Presentation DM may have myriad cutaneous manifestations [37]. Gottron’s papules are violaceous, scaly, telangiectatic, flat-topped papules over the MCP, PIP, and DIP joints (Fig.  11.31). Violaceous, variably edematous macules and patches over the MCP, PIP, and DIP joints, elbows, knees, and ankles are known as Gottron’s sign. Gottron’s papules and sign are the most characteristic dermatologic features of DM. Other lesions of DM include pruritic, photo-exacerbated, symmetric, violaceous, variably edematous macules and patches and fine scaly plaques on the scalp and face (sparing the nasolabial folds); on the dorsum of the hands and fingers in a pattern of linear streaking or tracking of the extensor tendons; on the anterior neck and chest known as “V” sign; on the posterior neck, shoulder, and upper back

Fig. 11.32 Violaceous, poikilodermatous, atrophic, scaly patches on the extensor arms and Gottron sign on the elbows in a patient with dermatomyositis

known as “shawl” sign; on the lower back and flanks known as “holster” sign; and on the extensor aspects of arms and forearms and anterolateral thighs (Figs. 11.32 and 11.33). As the inflammatory process progresses, the macules, patches, and plaques on the trunk and extremities become poikilodermatous or hypopigmented, hyperpigmented, atrophic, and telangiectatic. The heliotrope refers to the violaceous variably edematous patches and plaques of the eyelids and periorbital areas (Fig. 11.34). The heliotrope and periungual

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Fig. 11.33 Shawl sign in a patient with ulcerative dermatomyositis

Fig. 11.35  Periungual erythema and telangiectasias with ragged, hypertrophic cuticles, as well as Gottron’s papules over the distal and proximal interphalangeal joints in dermatomyositis Fig. 11.34  Periorbital violaceous erythema (heliotrope rash) is characteristic in dermatomyositis

erythema and telangiectasias with or without ragged, dystrophic cuticles are highly characteristic but not pathognomonic of DM (Fig. 11.35). The heliotrope rash is not specific for DM and can also be seen in SLE, allergic contact dermatitis, sarcoidosis, trichinosis, and toxoplasmosis. Photosensitivity to UVA and UVB can be seen in up to 50% of DM patients. Calcinosis cutis can also be seen in DM (Fig. 11.36), particularly childhood DM.  Oral and conjunctival mucous membrane involvement is rare in DM.  More interesting and unusual cutaneous lesions are the mechanic’s hand sign and follicular hyperkeratosis. Mechanic’s hands sign is an underappreciated sign of DM, characterized by bilateral, symmetric, erythematous, skin-­ colored, scaly

hyperkeratotic, fissured papules and plaques on the ulnar thumb, radial index, middle fingers, and tips of the fingers with occasional extension to the palms. Patients can also have follicular hyperkeratotic papules that resemble pityriasis rubra pilaris on the arms and forearms known as the Wong’s subtype (Fig. 11.37). A diffuse, non-scarring alopecia of the scalp can also be seen in DM. In addition, subepidermal vesicles and bullae can develop as a result of increased dermal edema. Erosions and ulcers can also develop from rupture of the vesicles and bullae, epidermal atrophy, leukocytoclastic vasculitis, or calcification. Patients can present with an exfoliative erythroderma. Patients can also have a flagellate erythematous eruption on the trunk, which is characterized by linear erythematous, edematous macules and patches on the trunk and

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Fig. 11.36  Calcinosis cutis, characterized by the presence of firm, white-to-yellow subcutaneous papules that are demonstrable on radiography in a patient with dermatomyositis Table 11.2  Clinical features associated with myositis-­ specific serum autoantibodies, which may be present in dermatomyositis

Fig. 11.37  Follicular prominence and orange-brown erythema in a patient with Wong-type (pityriasis rubra pilaris-­type) dermatomyositis

proximal extremities. Rare cutaneous lesions in DM are tender, subcutaneous nodules due to panniculitis on the buttocks, trunk, and extremities as well as skin-colored, indurated papules and nodules on the trunk and extremities due to dermal mucin deposition [30, 31, 38]. Patients with myositis may complain of weakness of the proximal extremity muscle groups by endorsing difficulty with raising their arms or attempting to stand from a seated position. However, myositis may also be subclinical or absent. Dyspnea or new or worsening exercise intolerance may herald the presence of underlying interstitial pulmonary fibrosis.

Mi-2  Facial dermatosis, shawl sign, flagellate erythema; typical DM with favorable prognosis; no increased malignancy risk NXP-2 – Nuclear matrix protein-2  Associated with juvenile DM; in adults, severe DM associated with malignancy MDA5 – Melanoma differentiation-associated gene-5  Ulcerative vasculopathy with painful acral papules and ulcers, alopecia, and oral ulcers; associated with mild or high risk ILD; low malignancy risk; good prognosis in terms of myositis Jo-1 – tRNA synthetase  Mechanic’s hands, Raynaud’s phenomenon, increased risk of interstitial lung disease, low incidence of malignancy TIF-γ – Transcription intermediary factor 1-gamma  Facial dermatosis; shawl sign; malignancy associated DM and severe DM Adapted from Daly et al. (2017)

Myositis-specific antibodies (MSA) are found in 50–70% of patients with DM, and myomarker panel commercial testing for these antibodies is available (Table 11.2; Fig. 11.38). Identification of these autoantibodies allows for understanding underlying pathogenesis, diagnosis, prognosis, and potentially treatment of the associated com-

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Fig. 11.38 Painful erythematous palmar papules, Gottron sign, and Holster sign in a patient with MDA5 dermatomyositis

plications, and these autoantibodies may correlate with dermatologic phenotype and disease activity [39].

Prognosis or Clinical Course When paraneoplastic, DM is most commonly associated with ovarian or breast cancer in women or lung cancer in men [40]. Patients with paraneoplastic DM tend to have a more r­ efractory course than idiopathic DM, and their lesions are more likely to ulcerate. It is essential that patients with DM be screened and routinely evaluated for interstitial lung disease, since this can be a serious complication. There is an increased risk for interstitial lung disease associated with the mechanic’s hands presentation of DM, as well as with circulating anti-melanoma differentiation-­ associated gene 5 (MDA5) autoantibodies [41].

Histopathology DM generally shows a vacuolar interface dermatitis with epidermal atrophy, mild dermal perivascular lymphocytic inflammation with melanophages, and variable degrees of mucin

Fig. 11.39 Subtle vacuolar interface changes are observed on acral skin with the Gottron papules of dermatomyositis (×200)

deposition in the papillary dermis (Fig.  11.39). Telangiectasias may be prominent, particularly when biopsies are derived from skin lesions showing poikiloderma. Biopsies of Gottron papules show more hyperkeratosis and epidermal acanthosis rather than atrophy. In ulcerative DM, as well as MDA-5-positive dermatomyositis, a vasculopathy may be observed (Fig. 11.40). DM is sometimes misdiagnosed as LE, as the findings are similar. Occasionally, the histopathologic changes are overlooked, because they are subtle

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Fig. 11.40  Histopathology of ulcerative dermatomyositis with thrombosis of the superficial dermal vessels and vacuolar interface dermatitis (×200)

Fig. 11.41  In dermatomyositis, direct immunofluorescence demonstrates particulate intracytoplasmic staining in the basal layer keratinocytes with IgG corresponding to a positive extractable nuclear antibody (+SSA, SSB, RNP, Jo-1, and/or Smith antibodies) pattern which can be seen in DM, SCLE, Sjogren syndrome, or a mixed

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and focal. DIF studies are usually unremarkable but may show cytoid bodies with IgG, IgM, IgA, C3, and/or fibrinogen, as well as shaggy deposition of fibrinogen along the basement membrane zone. Epidermal particulate intracytoplasmic staining with IgG in the basal layer keratinocytes can be seen in DM as well as SCLE, MCTD, and Sjogren syndrome (Fig. 11.41). This finding corresponds to the presence of extractable nuclear antigens such as anti-Ro and -La antibodies. The deposition of C5-9 along the basement membrane zone is a sensitive but non-specific finding [42]. A vasculopathy with mononuclear infiltration of medium-sized vessels with fibrin deposition may be seen, particularly in patients with the

connective tissue disease. Cytoid bodies along the dermal-epidermal junction can be seen with conjugates such as IgM, IgA, and/or C3 along with shaggy fibrinogen along the dermal-­epidermal junction, corresponding to a lichenoid tissue reaction (×200, left, lower right; ×100, upper right)

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epidermal hyperplasia with attenuated granular layer, thinned suprapapillary plates, and intracorneal neutrophilic collections.

Summary Clinical Presentation • Violaceous erythema over the hand joints, elbows, knees, shoulders, or hips or around the eyes • Poikiloderma, ragged cuticles, and dilated capillaries at the proximal nail folds • Calcinosis cutis, digital ulcerations, and hand keratoderma (mechanic’s hands) in DM variants Fig. 11.42  Histopathology of calcinosis cutis shows a dermal aggregate of calcium, with variable degrees of host inflammatory response (×40)

anti-MDA5 phenotype [41]. The combination of calcinosis cutis (Fig. 11.42) and overlying vacuolar interface dermatitis should raise suspicion for dermatomyositis, particularly when seen in children.

Differential Diagnosis Other photosensitizing conditions, such as LE, medication-induced photosensitivity, may mimic DM.  For example, PMLE may resemble DM clinically, with erythema in a photodistribution; however microscopically PMLE lacks interface dermatitis and increased dermal mucin. Rarely, erythema ab igne or actinic poikiloderma may resemble the skin changes of DM clinically and microscopically, since these entities can be associated with mild vacuolar hydropic degeneration of the basement membrane zone and telangiectasias. The mechanic’s hands of DM may be confused clinically for atopic dermatitis, allergic contact dermatitis, tinea manuum (though this usually affects a single palm), hyperkeratotic hand dermatitis, or psoriasis. However, spongiosis without interface dermatitis would favor dermatitis. Biopsies of psoriasis should show regular

Histologic Features • Vacuolar interface inflammation, with mucin deposition in the superficial dermis • Calcinosis cutis or ulceration in DM variants Differential Diagnosis • Lupus erythematosus or other connective tissue diseases such as mixed connective tissue disease and Sjogren syndrome can also show vacuolar interface changes with dermal mucin. The lack of prominent perivascular or perifollicular inflammation may support DM over CCLE.  Moreover, DM can occasionally be associated with a lichenoid interface dermatitis. Therefore, clinical pathologic correlation and correlation with immunofluorescence testing, connective tissue serologies, and myomarker panel are required to establish the diagnosis of a specific connective tissue disease. • DM-like drug eruption can be indistinguishable from idiopathic DM. • Erythema ab igne may show subtle hydropic degeneration at the basal layer, as well as telangiectasias.

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Takeaway Essentials Clinical Relevant Pearls • Risk for underlying malignancy should be assessed in patients with DM. • Myositis-specific antibody profiles may have prognostic value by subclassifying various subtypes of DM. Pathology Interpretation Pearls • The histopathology of DM can be focal, subtle, and identical to LE and other autoimmune connective tissue diseases, so clinicopathologic correlation is required for a final diagnosis. If eosinophils are present in the dermal infiltrate in association with interface dermatitis, then a connective tissue disease other than LE, such as DM, MCTD, or Sjogren syndrome, should be considered.

 orphea, Systemic Sclerosis, M and Limited Scleroderma Etiology and/or Pathogenesis Morphea (localized scleroderma), progressive systemic sclerosis (SSc, scleroderma), and limited systemic sclerosis (CREST syndrome) represent three entities within the broader category of sclerosing disorders [43]. The etiology of these diseases is unknown [44]. Circulating antinuclear antibodies may be present in both morphea and SSc, while anti-centromere antibodies are characteristic in CREST syndrome or limited SSc.

Clinical Presentation Morphea, or localized scleroderma, is characterized by sclerosis of the dermis. Subcutaneous involvement can occur in generalized or linear morphea and systemic scleroderma. Despite being classified as localized scleroderma (as it is localized to the skin and subcutaneous tis-

Fig. 11.43 Peripherally erythematous to hyperpigmented centrally whitish indurated plaques in a patient with morphea

sues), morphea may develop in a limited, linear, or generalized anatomic distribution (Fig. 11.43). Patients notice the development of tightening of affected areas, characterized by hypopigmented or whitish plaques which may have preceding violaceous erythema or the so-called lilac ring and later accompanying hyperpigmentation. Postradiation morphea is a phenomenon that can occur following iatrogenic radiation [45]. In some cases, morphea can be seen with overlapping lichen sclerosus. When this happens, sclerosis is accompanied by cutaneous atrophy with cigarette paper-like wrinkling and hypopigmentation and telangiectasias of the skin. Blisters may also develop [46]. Parry-Romberg syndrome is a rare cause of hemifacial atrophy that may not only affect the skin and soft tissues but also the underlying musculoskeletal structures. Parry-­Romberg syndrome can overlap with linear morphea, also known as “en coup de sabre” (Fig.  11.44). The coexistence of chronic cutaneous lupus erythe-

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Fig. 11.44  Linear induration and dyspigmentation in a pediatric patient with linear (en coup de sabre) morphea

matosus and localized scleroderma in the same lesion with a linear distribution is rare but has been reported to occur [47]. Atrophoderma (of Pasini and Pierini) is regarded by some to be superficial morphea. Clinically, lesions are characterized by discrete to confluent round, depressed, and pigmented patches without atrophy or induration on the torso. Preliminary American College of Rheuma­ tology diagnostic criteria for SSc include [1] sclerodactyly, or tightening of the skin of the fingers, [2] pitting of pulp of the distal fingertips, and [3] basilar pulmonary fibrosis, which offer high diagnostic accuracy [48]. Patients notice the progressive tightening of the skin and joint contractures. American College of Rheumatology diagnostic criteria for CREST syndrome include three of the following: calcinosis cutis, Raynaud’s phenomenon, symptoms of esophageal dysmotility, sclerodactyly, and perioral telangiectasias and tightening (Figs. 11.45 and 11.46) [48]. Skin telangiectasias have been said

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Fig. 11.45  Patient with CREST syndrome, who has characteristic perioral tightening and facial telangiectasias

Fig. 11.46 Sclerodactyly in a patient with systemic sclerosis

to correlate directly with risk for pulmonary arterial hypertension [49]. Acral sclerosis, with ulceration, may result (Fig. 11.47). Depigmentation with follicular sparing may be seen in patients with darker skin types (Fig.  11.48). Manifestations of a very rare form of progressive SSc, Reynolds syndrome, may also include features of primary biliary cirrhosis and Sjogren syndrome.

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Fig. 11.47  Acral sclerosis in a patient with systemic sclerosis

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Fig. 11.49  Calcinosis cutis and sclerodactyly in a patient with systemic sclerosis

Table 11.3  Clinical features associated with systemic sclerosis serum autoantibodies Anti-centromere antibodies  CREST syndrome (digital ulceration, calcinosis) Anti-Scl-70 (anti-topoisomerase I) antibodies  Systemic sclerosis, increased risk for lung disease, renal disease Anti-fibrillarin (anti-U1-RNP) autoantibodies  Overlap with mixed connective tissue disease, including esophageal involvement Anti-Th/To  Severe interstitial lung disease and pulmonary arterial hypertension Anti-PM-Scl  Overlap with polymyositis Anti-RNA-polymerase III  Higher risk of renal disease; pulmonary disease is rare Anti-U3-RNP  Higher risk of interstitial lung disease with pulmonary arterial hypertension Reference: Pearson et al. (2018) Fig. 11.48  Depigmentation with follicular sparing, as well as skin tightening, in a patient with systemic sclerosis

Calcinosis cutis may occur in the setting of various connective tissue diseases including limited or systemic scleroderma, dermatomyositis (classic and juvenile forms; rarely amyopathic), SLE, lupus panniculitis, mixed/undifferentiated or overlap CTD, and RA (Fig. 11.49). Scleroderma autoantibodies can be used to distinguish variants for scleroderma (Table 11.3).

Prognosis or Clinical Course Without treatment, sclerosis tends to be progressive and can lead to loss of range of motion and/or restrictive lung disease due to tightening of the chest wall skin. Calcinosis cutis can lead to painful ulcerations. When the lungs become involved, pulmonary arterial hypertension may develop. Patients with morphea are at higher risk to develop other autoimmune diseases [50].

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a

Fig. 11.50  In the histopathology of morphea, sclerosis of dermal collagen extending to the septae is seen. Eccrine glands are located within the dermis rather than at dermal-­ subcutaneous junction, because the subcutaneous fat has

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b

been replaced by collagen. In addition, the adipose usually surrounding eccrine glands is attenuated or absent (“fat trapping”) (a: ×40, left; b: ×20, right)

Histopathology Morphea, systemic sclerosis, and limited scleroderma show pan-dermal sclerosis that may also affect the pannicular septae (Fig. 11.50). Clusters of lymphocytes and plasma cells may be present in perivascular, periadnexal, and septal pannicular regions and can help to determine disease activity (Fig.  11.51). Perieccrine fibrosis can lead to the appearance of “perieccrine trapping,” in which adipose is absent from the perieccrine region. The histopathology of morphea has been the best studied. The “line sign,” or the presence of a horizontal, sharp cutoff between dermis and subcutaneous tissue, has been shown to be a reasonably sensitive sign of morphea [51]. In some cases of morphea, histiocytes can be seen to be surrounding collagen fibers, the so-called floating sign [52]. For atrophoderma (of Pasini and Pierini), histopathologic changes include mild dermal atrophy, which may not be obvious unless normal adjacent skin is available for comparison. Collagen bundles in the mid and deep dermis are slightly thickened, edematous, and homogenized. Elastic fibers and adnexal structures are normal. There is typically basal layer hyperpigmentation with dermal melanophages. A perivascular infiltrate is composed of lymphocytes and histiocytes, and plasma cells are unusual.

Fig. 11.51  Perivascular, periadnexal, and septal lymphoplasmacytic inflammation are seen and can help determine the activity of disease in morphea. Inflammation is most likely to be observed if the biopsy is derived from the inflammatory “lilac” rim (×40, left; ×200, right)

Differential Diagnosis Precise clinical classification of sclerosing disorders typically requires clinicopathologic correlation. Morphea and scleroderma have identical histologic findings, and the clinical presentation is needed to determine the final diagnosis. The dermal sclerosis results in the appearance on low power of a square/rectangular biopsy which can also been seen in scleredema and necrobiosis lipoidica. However, scleredema has prominent

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interstitial mucin deposition throughout the dermis. In addition, biopsies of scleredema are almost always derived from the upper back or shoulders. Necrobiosis lipoidica is characterized by horizontally oriented palisaded granulomatous inflammation with deep dermal lymphoplasmacytic aggregates, and affected areas are typically found on the shins. Pannicular and fascial involvement occurs in morphea profunda, pansclerotic morphea, or eosinophilic fasciitis (EF). When present, deep dermal or fascial eosinophils may imply the presence of EF, though these are not required for diagnosis [53]. EF also may be associated with perifascial edema. Therefore, morphea profunda, pansclerotic morphea, and EF have identical histologic findings, and the clinical presentation is required to establish the final diagnosis. Postradiation morphea should be differentiated from radiation dermatitis, which may also show stellate fibroblasts and telangiectasias but typically would not show periadnexal lymphoplasmacytic inflammation or as much dermal sclerosis.

Summary Clinical Presentation • Sclerodactyly, facial skin tightening, diffuse body skin tightening • Changes of the capillaries at the proximal nail fold Histologic Features • Sclerosis of the dermis, with loss of perieccrine fat • Periadnexal lymphoplasmacytic infiltrate Differential Diagnosis • Radiation-related dermatitis may resemble postradiation morphea. While the former may show fibrosis and stellate fibroblasts, it tends not to show the dense collagen sclerosis and adnexal trapping seen in morphea. • Sclerodermoid graft-versus-host disease may resemble morphea and other sclerosing conditions microscopically; how-

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ever with sclerodermoid graft-versus-host disease, vacuolar interface dermatitis is typically present. Clinical correlation is required. • Sclerodermoid reaction to medications may be indistinguishable from autoimmune sclerosing conditions microscopically and requires a high clinical index of suspicion for diagnostic confirmation.

Takeaway Essentials Clinical Relevant Pearls • Early clinical changes in patients with sclerosing disorders may include peripheral violaceous erythema surrounding a whitish, hypopigmented plaque. Later changes include hyperpigmentation, skin thickening, and tightening. Pathology Interpretation Pearls • The histopathologic findings in morphea and scleroderma can overlap and require clinical correlation to distinguish between the different variants. The histopathologic findings in morphea profunda, pansclerotic morphea, and EF can overlap and require clinical correlation to distinguish between the different variants. • Scleroderma autoantibodies can also be used to distinguish variants for scleroderma (Table 11.3).

Sjogren Syndrome Etiology and/or Pathogenesis Sjogren syndrome (SS) is a systemic autoimmune disease of unknown cause, but genetic and environmental factors play a role. In SS, immune-­mediated inflammation causes secretory gland dysfunction, leading to sicca symptoms and systemic organ involvement ( [54]).

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Clinical Features Patients with SS generally experience xerostomatitis and xerophthalmia, but it is not uncommon for dryness to also affect the trachea and vagina. By definition, primary SS is not found in association with other autoimmune diseases, such as LE, systemic sclerosis, or RA.  Sicca symptoms need not be the presenting feature. Cutaneous lesions are seen in 50% patients with primary as SS. However, diagnosis remains challenging for clinicians and pathologists. The diagnosis may be delayed by up to 10 years, especially in patients with an occult non-sicca presentation. All patients have anti-SSA and/or anti-SSB antibodies. There is an overwhelming female predominance, and the typical age of onset is the fourth to sixth decade. In our institution’s experience, the most characteristic dermatologic manifestation of SS is annular erythema involving the upper extremity, trunk, legs, and face similar to SCLE (Fig.  11.52). Approximately 30% of patients from our institution with SS presented with either leukocytoclastic vasculitis or urticarial vasculitis. Almost 10% of patients presented with xerosis or subacute dermatitis. Patients with SS could Fig. 11.52 Annular erythema, characterized by annular, arcuate, and/ or polycyclic erythematous patches and/or plaques without much appreciable scale, is most frequently observed with Sjogren syndrome but can also be observed in SCLE. It is frequently associated with circulating anti-Ro antibodies

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also present with neutrophilic dermatoses such as Sweet syndrome or neutrophilic urticaria/urticarial dermatitis, an urticarial tissue reaction with dermal edema and a mild superficial dermal perivascular lymphocytic infiltrate with eosinophils. Pyoderma gangrenosum has also been reported to occur in association with SS ( [55]). In addition, patients may develop reactive granulomatous dermatitis in either an IGD or PNGD pattern, scarring or non-scarring alopecia, morphea-like sclerosis, septal and lobular panniculitis, necrobiotic xanthogranuloma, reactive lymphoid hyperplasia, or nodular cutaneous amyloidosis. Livedo reticularis has also been observed ( [54]).

Histopathologic Features The annular erythema seen in SS is associated with vacuolar and lichenoid interface dermatitis associated with a dermal perivascular and periadnexal lymphocytic infiltrate (Fig. 11.53). DIF can show granular intracytoplasmic IgG deposition in the basal keratinocytes corresponding to anti-­SSA or SSB antibodies and a lichenoid tissue reaction in about 30% of cases.

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Fig. 11.53  Lichenoid interface dermatitis with perivascular lymphocytic inflammation in primary Sjogren syndrome (×100)

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Differential Diagnosis • Lupus erythematosus, particularly the subacute cutaneous form, can resemble the a­nnular erythema of SS clinically and microscopically. • Gyrate erythemas may also show superficial and deep dermal perivascular and periadnexal lymphocytic inflammation but lack interface dermatitis. • Perniosis may show superficial and deep dermal perivascular and periadnexal lymphocytic inflammation, but dermal edema and endothelial cell swelling tend to be more prominent in perniosis than annular erythema, and interface dermatitis is lacking in perniosis.

Differential Diagnosis The most characteristic cutaneous manifestation of SS, annular erythema, overlaps considerably with histologic findings seen in other connective tissue diseases including cutaneous LE.  A vacuolar or lichenoid interface dermatitis can be seen in SS, which is why clinical correlation and correlation with connective tissue serologies are required, particularly as patients with both SS and SCLE can present with annular plaques and be found to have circulating serum SSA or SSB autoantibodies.

Summary Clinical Presentation • Xerostomia and xerophthalmia • Annular erythema or other dermatologic manifestations of CTD Histologic Features • Features of annular erythema include dermal perivascular and periadnexal lymphocytic inflammation with vacuolar and lichenoid interface dermatitis indistinguishable from LE or other connective tissue diseases, such as DM or MCTD.

Takeaway Essentials Clinical Relevant Pearls • Sjogren syndrome may not always present with prominent sicca syndrome and may require clinicopathologic correlation for diagnosis Pathology Interpretation Pearls • Consider Sjogren syndrome in a patient with constitutional symptoms, an annular eruption, and superficial and deep dermal perivascular and periadnexal lymphocytic inflammation with interface dermatitis on skin biopsy.

Rheumatoid Arthritis Etiology and/or Pathogenesis Rheumatoid arthritis (RA) is an immune-­mediated arthropathy mediated by CD4+ T-helper cells and Th1 immunity ( [56]). Though the primary organ affected by RA is the joints, the skin may show extra-articular manifestations of RA (57).

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Clinical Presentation RA is an erosive arthropathy that tends to affect young to middle-aged patients, with women being affected preferentially. RA presents with symmetric arthralgias, often involving the metacarpophalangeal and proximal interphalangeal joints, and it may affect other joints. Ulnar deviation of the hands can be seen in advanced disease. The shoulders, elbows, wrists, knees, and feet may also be affected. In some patients, RA can lead to instability of the cervical spine. One of the dermatologic manifestations includes rheumatoid nodule and rheumatoid papules ( [57, 58]). The sudden development of numerous rheumatoid papules can be observed in rheumatoid papulosis, often occurring after initiation of methotrexate or TNF-alpha inhibitor therapy. Infrequent cutaneous manifestations of RA include intralymphatic histiocytosis (Fig.  11.54) ( [59]), which may appear as violaceous reticulated patches in proximity to affected joints. Reactive granulomatous dermatitis is an

Fig. 11.55  Reactive granulomatous dermatitis may present with smooth oval or annular reddish-brown patches or plaques

umbrella term that has been proposed to describe a series of heterogeneous entities, all of which have been associated with RA and other connective tissue diseases. These entities are also known as ­interstitial granulomatous dermatitis (IGD), IGD with arthritis, cutaneous extravascular necrotizing granuloma (formerly Churg-Strauss granuloma), and palisaded neutrophilic and granulomatous dermatitis (PNGD). Clinically, patients can develop asymptomatic, symmetric, linear, skin-­colored or erythematous, variably umbilicated, perforated, or crusted papules, plaques, nodules, or cords (“rope sign”) on the extremities and trunk (Fig. 11.55). Rheumatoid vasculitis is a complication of RA. It is a small to large vessel vasculitis, and a similar vasculitis can occur in other connective tissue diseases including LE. Patients can present with purpura and digital infarcts and ulcers. The differential diagnosis includes ANCA-associated vasculitis, vasculitis associated with other connective tissue diseases, and infection.

Prognosis or Clinical Course RA is a chronic condition that results in permanent erosive changes of affected joints if incompletely treated. Rheumatoid papules and nodules tend to persist without therapy.

Histopathology Fig. 11.54  Reddish-brown indurated plaques in a patient with intralymphatic histiocytosis

Rheumatoid nodules appear as deep dermal to subcutaneous palisaded granulomas with prom-

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Fig. 11.56  Histopathology of intralymphatic histiocytosis shows histiocytes within lymphatic channels (×200, left; CD68 immunostain, ×200, right)

plete) granuloma annulare (Fig. 11.57). On the other end of the spectrum, a perivascular and interstitial dermal infiltrate with neutrophils and leukocytoclasis, resembling a neutrophilic dermatosis or LCV (palisaded and neutrophilic granulomatous dermatosis) may be observed. However, a true vasculitis is not present. Variable degrees of basophilic collagen degeneration and palisaded granulomatous inflammation are observed (Fig. 11.58). Fig. 11.57  Interstitial granulomatous inflammation in the interstitial granulomatous dermatitis form of reactive granulomatous dermatosis (100×)

inent fibrinoid collagen degeneration ([60]). With intralymphatic histiocytosis, aggregates of histiocytes are observed within dilated lymphatic channels (Fig. 11.56). Reactive granulomatous dermatitis is a histopathologic spectrum that can be characterized by a perivascular and interstitial dermal infiltrate of lymphocytes and histiocytes with interstitial mucin deposition resembling interstitial (or so-called incom-

Differential Diagnosis Multicentric reticulohistiocytosis may present with rheumatologic features mimicking RA, particularly before skin manifestations become prominent (Fig.  11.59) ( [61]). However, multicentric reticulohistiocytosis shows characteristic, enlarged multinucleated histiocytes with amphophilic cytoplasm, which resemble osteoclasts (Fig.  11.60). These cells should not be present in granulomatous manifestations of RA.  Fibroblastic rheumatism is a rare dermato-

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Fig. 11.58  Interstitial and palisaded granulomatous and neutrophilic inflammation with basophilic collagen degeneration seen in the palisaded neutrophilic and granulomatous dermatosis form of reactive granulomatous dermatosis (×200)

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arthropathy that presents with symmetric hand arthralgias and skin-colored firm papules overlying the hands (Fig. 11.61) ( [62]). Biopsy of these papules shows the presence of fibrosis with variable levels of fibroblastic inflammation but does not show the palisaded granulomatous inflammation seen in RA (Fig. 11.62). Histopathologically, rheumatoid nodules may resemble deep granuloma annulare. However, rheumatoid nodules have prominent fibrinoid deposition, imparting a pink-red hue to the palisaded granulomas, while granuloma annulare tends to have associated mucin, imparting a bluish hue. Epithelioid sarcoma, a process that can present with a subcutaneous nodule of the extremities, can show palisaded

Fig. 11.59 Reddish-brown indurated papules on the extensor hands, in association with a rapidly progressive, severe inflammatory arthritis, observed in multicentric reticulohistiocytosis

Fig. 11.60  Histopathology of multicentric reticulohistiocytosis shows interstitial histiocytes with osteoclast-like cytomorphology (×200)

Fig. 11.61  Fibroblastic rheumatism, characterized by skin-colored, firm, dome-shaped papules over the dorsal hands, associated with an erosive arthropathy

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Fig. 11.62  Histopathology of fibroblastic rheumatism shows dermal fibrosis with variable degrees of cellularity. Increased interstitial fibroblasts shown in inset (×40; inset, ×100)

epithelioid cells with central necrosis, thereby microscopically resembling rheumatoid nodules and other palisaded granulomatous processes. At times, additional stains, such as a keratin stain (positive in the epithelioid cells of epithelioid sarcoma) or an INI-1 stain (negative in the epithelioid cells of epithelioid sarcoma), are required to exclude epithelioid sarcoma. Infection may mimic rheumatoid nodules. Special stains for microorganisms and/or tissue cultures for fungus and ­mycobacteria are recommended when neutrophils are present or if the patient is immunocompromised.

Summary Clinical Presentation • Symmetric arthralgias of the hands, wrists, feet, and ankles in young to middle-aged individuals, with women affected more frequently than men • Subcutaneous papules and nodules overlying elbows and hand joints

Histologic Features • Rheumatoid nodules show deep dermal to pannicular palisaded granulomatous inflammation with central fibrinoid deposition • Rheumatoid papules show reactive granulomatous dermatitis (IGD or PNGD) characterized by variable degrees of interstitial dermal histiocytic inflammation with or without intermixed neutrophils and occasionally basophilic degeneration of associated collagen fibers (PNGD). • Intralymphatic histiocytosis shows the presence of bland histiocytes within lymphatic vessels. Differential Diagnosis • Deep granuloma annulare may share the palisaded granulomatous inflammation of rheumatoid nodules but generally is associated with mucin and not fibrin deposition. • Infection, particularly with atypical mycobacteria, can present with firm

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subcutaneous nodules on the extremities and with palisaded granulomatous inflammation on skin biopsy. Special stains for microorganisms and/or tissue cultures may be required to exclude infection. • Though rare, epithelioid sarcoma may resemble rheumatoid nodules with palisaded epithelioid cells that surround areas of geographic necrosis. The neoplastic cells of epithelioid cells are keratin-positive and INI-1-negative, thereby differentiating them from the histiocytes of rheumatoid nodule. • Intralymphatic histiocytosis may resemble other intravascular processes microscopically, such as cutaneous metastases or intravascular B-cell lymphoma. In these cases, special stains may be required to determine the identity of intralymphatic histiocytosis.

Takeaway Essentials Clinical Relevant Pearls • Symmetric hand arthralgias sparing the distal interphalangeal joints may represent rheumatoid arthritis. • Dermatologic manifestations of RA include rheumatoid papules/nodules or, less ­frequently, reactive granulomatous dermatoses or intralymphatic histiocytosis. • Pathology Interpretation Pearls • The presence of fibrinoid-rich deep dermal to subcutaneous granulomas raises the possibility of rheumatoid nodules. • Reactive granulomatous dermatitis can have two histologic patterns, IGD (resembling GA) and PNGD.

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Mixed Connective Tissue Disease Etiology and/or Pathogenesis Mixed connective tissue disease (MCTD) is a generalized connective tissue disorder in which anti-U1-RNP autoantibodies are present, along with features of SLE, systemic sclerosis, and/ or polymyositis. Antinuclear antibodies are also almost always observed. Occasionally, MCTD can be induced by medications. MCTD is not to be confused with undifferentiated connective tissue disease, in which a patient may have features of connective tissue diseases but that cannot be definitively classified otherwise.

Clinical Presentation Most patients with MCTD do have dermatologic manifestations. Perhaps the most characteristic change is edema of the hands. Other cutaneous features include Raynaud’s phenomenon, sclerodactyly, acral vasculitis, and calcinosis cutis. Extracutaneous manifestations may involve a destructive arthritis resembling that observed in rheumatoid arthritis; sicca symptoms; myositis; cardiac, pulmonary, renal, and central nervous system; and hematologic abnormalities.

Prognosis or Clinical Course Often, the clinical features of MCTD take several years to fully declare themselves, and disease can be quite heterogeneous. Prognosis is dependent on the pattern, extent, and severity of organ involvement.

Histopathology Histopathologic features correlate with the clinical morphology.

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Differential Diagnosis Patients with MCTD may have clinical features of various other connective tissue diseases which they may mimic as the disease evolves. Histopathology of skin lesions associated with MCTD overlaps considerably with features of LE, DM, or other autoimmune connective tissue diseases. Specifically, MCTD may show LCV, calcinosis cutis, and interface dermatitis. The presence of edema may support a diagnosis of MCTD in the appropriate clinical setting. However, definitive diagnosis requires clinical and serologic correlation. It is important to be aware of the dermatologic manifestations of MCTD so as not to inadvertently assign a definitive diagnosis of LE, DM, or other connective tissue disease based on cutaneous histopathologic findings alone.

J. S. Lehman and A. G. Bridges

Takeaway Essentials Clinical Relevant Pearls • MCTD is a specific form of connective tissue disease that is characterized by circulating anti-U1-RNP autoantibodies and systemic symptoms. • Hand edema is fairly specific to MCTD in the appropriate clinical setting, though a number of other cutaneous findings can be observed.

Relapsing Polychondritis Etiology and/or Pathogenesis Relapsing polychondritis is a multisystem disorder associated with autoantibodies against collagen II, a constituent of cartilage ( [63]).

Summary Clinical Presentation • Frequent features include Raynaud’s phenomenon, destructive arthritis, and involvement by a constellation of other organs. • Hand edema is fairly characteristic of MCTD. • The presence of circulating anti-U1RNP autoantibodies is required for diagnosis of MCTD. Histologic Features • Changes of interface dermatitis, edema, leukocytoclastic vasculitis, calcinosis cutis, or other cutaneous stigmata of MCTD can be seen on histopathology. Differential Diagnosis • Rheumatoid arthritis • Lupus erythematosus

Clinical Presentation Relapsing polychondritis may present initially with erythema and tenderness of cartilaginous areas, such as the pinnae and/or nasal cartilage, and tends to have a recurrent course (Fig. 11.63). After several flares over time, cartilage degeneration can lead to ear and saddle nose deformity. The most serious complication of relapsing polychondritis is collapse of the upper airway from laryngeal, tracheal, or bronchial involvement. The conjunctiva, heart, and joints may also be involved. When accompanied by mouth and genital ulcers, relapsing polychondritis may be part of the rare MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome ( [64]).

Prognosis or Clinical Course Patients with relapsing polychondritis can be classified into various groups, associated with different

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dermatitis nodularis chronicus helicis, a common condition involving the development of tenderness and/or ulceration following chronic and repetitive pressure against the ear (as with sleeping). With this entity, biopsy can show cartilage necrosis and associated reparative changes. However, it would be unusual to see organized lichenoid lymphocytic inflammation with this process. If the inflammation is mixed, infection or reactive lymphoid hyperplasia could be considered. Atypia of the lymphocytes may prompt a panel of immunohistochemistry stains to exclude NK/T-cell lymphoma, other malignant T-cell processes, or a B-cell lymphoma. If vasculitis or granulomas are noted, it may be prudent to recommend evaluation of serum ANCA antibodies to evaluate for an ANCA-associated vasculitic process such as granulomatosis with polyangiitis ( [65, 66]).

Summary Fig. 11.63  Relapsing polychondritis, showing erythema and deformity of the associated pinna

prognoses: R subgroup (respiratory involvement), A subgroup (auricular involvement), and O subgroup (overlap) ( [65]). Those in the R subgroup frequently had a progressive clinical course, while those in the A subgroup tended to have arthritis, conjunctivitis, and cardiac and nervous system involvement.

Histopathology In active lesions of relapsing polychondritis, a lichenoid lymphocytic infiltrate can be seen at the dermal-chondral junction with variable degrees of cartilage necrosis.

Differential Diagnosis The microscopic differential diagnosis of relapsing polychondritis includes chondro-

Clinical Presentation • Inflammation or deformity of the pinnae and/or nose. • Systemic features may include respiratory stridor if respiratory cartilage is affected. Histologic Features • Cartilage necrosis with an accompanying lichenoid lymphocytic infiltrate is the histopathologic hallmark of relapsing polychondritis. Differential Diagnosis • Chondrodermatitis nodularis chronicus helicis may also show cartilaginous necrosis, though a lichenoid lymphocytic infiltrate adjacent to the cartilage should not be observed. • The presence of a mixed infiltrate with cartilaginous necrosis should prompt evaluation for infection.

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Takeaway Essentials Clinical Relevant Pearls • If relapsing polychondritis is suspected, the patient requires careful examination of the upper airway, as airway collapse is a serious complication of this condition. Pathology Interpretation Pearls • Consider this diagnosis in lesions showing cartilage necrosis of the pinna or nose, in the appropriate clinical setting.

Autoinflammatory Conditions Etiology and/or Pathogenesis Autoinflammatory conditions represent a collection of systemic diseases due to alterations in the inflammasome. When they involve the skin, they can impart urticarial eruptions, neutrophilic dermatoses, or granulomatous dermal infiltrates and may represent a major clue to the diagnosis ([67]).

Fig. 11.64  Fixed urticarial lesion in a patient with adult-­ onset Still’s disease

Clinical Presentation One of the most common autoinflammatory conditions is adult-onset Still’s disease (AOSD). AOSD is a condition that presents with symmetric arthralgias, malaise, periodic high fevers, and evanescent eruption. The classic skin eruption in AOSD is transitory salmon-colored urticarial papules that accompany constitutional symptoms (Fig. 11.64). Other dermatologic manifestations, such as persistent papules and plaques and generalized or flagellate erythema, have been reported ( [68]). Patients typically have markedly elevated serum inflammatory markers, such as ferritin. Schnitzler syndrome, a distinct autoinflammatory condition, is characterized by bone pain and an urticarial skin eruption, in combination with

Fig. 11.65 Urticarial dermatosis in a patient with Schnitzler syndrome. These lesions were fixed and were associated with a burning sensation. Pruritus was absent

a monoclonal gammopathy. Unlike conventional urticaria, skin lesions of Schnitzler syndrome may be fixed and non-pruritic (Fig.  11.65). Patients may also have accompanying malaise, confusion, and other constitutional symptoms.

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Fig. 11.66  Histopathologic changes in adult-onset Still’s disease can include those of neutrophilic urticaria with overlying dyskeratosis of keratinocytes (×100, left; ×200, right)

Prognosis or Clinical Course

Differential Diagnosis

Patients with autoinflammatory conditions tend to have a chronic course. Treatments directed against interleukin-1 may be uniquely effective in this category of disorders, and rapid therapeutic response to these agents can be confirmatory for the diagnosis. AOSD may be associated with a higher rate of malignancy, particularly breast cancer and lymphoma ( [68]).

The skin findings of autoinflammatory diseases overlap with those of chronic urticaria from other causes, such as allergic urticaria, urticarial pemphigoid, or early urticarial vasculitis. In these entities, the superficial dermal infiltrate is composed of lymphocytes with scattered eosinophils. Dermal edema can be seen as well as epidermal spongiosis. The absence of pruritus and the fixed nature of skin lesions, in combination with constitutional symptoms, are also a clue to neutrophilic urticarial dermatosis, a category within which autoinflammatory conditions are represented.

Histopathology Skin biopsy findings in autoinflammatory conditions include those of neutrophilic urticaria. Specifically, specimens often show mixed superficial dermal perivascular inflammation with neutrophils, intravascular neutrophils, dermal edema, and, often, neutrophilic epitheliotropism, the latter being relatively specific for neutrophilic urticarial dermatosis (Fig.  11.66) ( [69]). An additional feature increasing diagnostic specificity for AOSD is the concomitant presence of epidermal dyskeratosis overlying the changes of neutrophilic urticaria.

Summary Clinical Presentation • Periodic or fixed, non-pruritic urticarial lesions in combination with arthralgias, periodic high fever, and other constitutional symptoms, with elevated inflammatory markers (AOSD)

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• Neutrophilic urticarial dermatosis with bone pain, monoclonal gammopathy, and other constitutional symptoms (Schnitzler syndrome) Histologic Features • Perivascular mixed inflammation with neutrophils, intravascular neutrophils, dermal edema, and neutrophilic epitheliotropism. • Epidermal dyskeratosis may be seen in the persistent lesions of AOSD. Differential Diagnosis • Chronic urticaria can also show intravascular and perivascular neutrophils. However, the presence of neutrophilic epitheliotropism may suggest the presence of a neutrophilic urticarial dermatosis, as may be seen in autoinflammatory conditions, for example. • Urticarial vasculitis also can be associated with intravascular and perivascular neutrophils, though the presence of hemorrhage and fibrinoid changes of vessel walls favor urticarial vasculitis over a neutrophilic urticarial dermatosis.

J. S. Lehman and A. G. Bridges

Takeaway Essentials Clinical Relevant Pearls • If constitutional symptoms accompany an urticarial skin eruption and/or if urticarial lesions are fixed and non-pruritic, consider auto-inflammatory conditions. Pathology Interpretation Pearls • If neutrophils are prominent in urticarial tissue reaction, consider neutrophilic urticaria, and evaluate the patient for an underlying systemic disorder. • If neutrophilic epitheliotropism is observed, consider neutrophilic urticarial dermatosis. • If epidermal dyskeratosis overlies changes of neutrophilic urticaria, consider AOSD. • Neutrophilic urticaria can be seen as an underlying systemic disorder, especially CTD such as LE (which tends not to have eosinophils) or Sjogren syndrome (which may have eosinophils).

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Case Studies Case 1 Clinical History A 63-year-old woman with interstitial lung disease presented with tender ulcerating papules on the fingertips and flexural hand (Fig. 11.67). Microscopic description Histopathology from a representative, non-ulcerated lesion showed subtle vacuolar interface changes (Fig. 11.68a, b).

Fig. 11.67  Painful, hyperkeratotic papules on the distal fingers and overlying joints

a

b

Fig. 11.68 (a, b) Subtle changes of vacuolar interface inflammation, with mild hydropic changes at the dermal-­epidermal junction (×100, ×400)

Diagnosis MDA5-positive dermatomyositis. Discussion MDA5-positive dermatomyositis tends to present with tender, ulcerating papules on the hands and elbows. Recognition of seropositivity for MDA5 is important so as to screen closely for interstitial lung disease, a frequently associated comorbidity of this subtype. As injury to dermal blood vessels has been observed with this subtype, the dermatopathologist may be able to alert the clinician to this diagnostic possibility.

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Case 2 Clinical History A 50-year-old woman presented with recurrent fevers, a persistent rash (Fig. 11.69), myalgias, and leukocytosis. Microscopic description Histopathology showed a mild perivascular infiltrate with scattered neutrophils, intravascular neutrophils, dermal edema, and focal epidermal dyskeratosis (Fig. 11.70). Difficult to see in the H&E picture.

Fig. 11.69  Flagellate erythema on the back of a patient with new constitutional symptoms

(continued)

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Fig. 11.70  Dyskeratotic keratinocytes overlying changes of urticarial tissue reaction (×100)

Diagnosis Adult-Onset Still’s Disease Discussion AOSD is classically associated with an evanescent salmon-colored urticarial eruption, which shows a corresponding neutrophilic urticarial tissue reaction on skin biopsy. Recently, there has been increased recognition of atypical cutaneous manifestations of this condition, such as the persistent papules and plaques of AOSD. In this entity, there may also be epidermal dyskeratosis overlying the changes of neutrophilic u­ rticaria. Flagellate erythema has also been observed in this entity.

Case 3 Clinical History A 49-year-old man with systemic lupus erythematosus developed a non-­pruritic urticarial eruption on the trunk and extremities (Fig. 11.71). Microscopic description Histopathology revealed the presence of perivascular and interstitial neutrophils, mild leukocytoclasis with limited erythrocyte extravasation, and dermal edema (Fig. 11.72). On DIF, perivas-

Fig. 11.71  Fixed annular petechial lesions in a patient with lupus nephritis

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Fig. 11.72 Brisk perivascular and interstitial mixed inflammation with neutrophils and karyorrhectic debris, with surrounding dermal edema (×100)

Fig. 11.73  Granular deposition of IgM along the basement membrane zone and around superficial dermal blood vessels in a skin biopsy submitted for direct immunofluorescence from a patient with hypocomplementemic urticarial vasculitis

cular granular deposition was observed around vessel walls with IgM and C3, and perivascular homogeneous deposition was observed around vessel walls with fibrinogen (Fig. 11.73). IgM and C3 also showed strong granular deposition along the basement membrane zone (lupus band).

Diagnosis Hypocomplementemic Urticarial Vasculitis Discussion Urticarial vasculitis typically presents with non-pruritic light-pink papules and plaques that resemble urticaria. However, individual lesions tend to last for longer than 24 hours at a time, and the lesions can become hemorrhagic. Hypocomplementemia may accompany urticarial vasculitis, and when it does, neutrophils tend to be more prominent on skin biopsy than eosinophils. Moreover, patients generally have an associated autoimmune diathesis, with lupus being overrepresented.

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Concha JSS, Werth VP. Alopecias in lupus erythema- 28. Cardinali C, Caproni M, Fabbri P. The composition of tosus. Lupus Sci Med. 2018;5(1):e000291. the lupus band test (LBT) on the sun-protected non-­ 15. Brinster NK, Nunley J, Pariser R, Horvath lesional (SPNL) skin in patients with cutaneous lupus B.  Nonbullous neutrophilic lupus erythematosus: a erythematosus (CLE). Lupus. 1999;8(9):755–60. newly recognized variant of cutaneous lupus erythe- 29. Fung MA, Sharon VR, Ratnarathorn M, Konia TH, matosus. J Am Acad Dermatol. 2012;66(1):92–7. Barr KL, Mirmirani P.  Elastin staining patterns in

496 primary cicatricial alopecia. J Am Acad Dermatol. 2013;69(5):776–82. 30. George SM, Taylor MR, Farrant PB. Psoriatic alopecia. Clin Exp Dermatol. 2015;40(7):717–21. 31. LeBlanc RE, Tavallaee M, Kim YH, Kim J.  Useful parameters for distinguishing subcutaneous panniculitis-­ like T-cell lymphoma from lupus erythematosus panniculitis. Am J Surg Pathol. 2016;40(6):745–54. 32. Verdelli A, Antiga E, Bonciolini V, Bonciani D, Volpi W, Caproni M.  Drug induction in connective tissue diseases. G Ital Dermatol Venereol. 2014;149(5):573–80. 33. Seidler AM, Gottlieb AB.  Dermatomyositis induced by drug therapy: a review of case reports. J Am Acad Dermatol. 2008;59(5):872–80. 34. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344–7. 35. Bailey EE, Fiorentino DF. Amyopathic dermatomyositis: definitions, diagnosis, and management. Curr Rheumatol Rep. 2014;16(12):465. 36. Bendewald MJ, Wetter DA, Li X, Davis MD.  Incidence of dermatomyositis and clinically amyopathic dermatomyositis: a population-based study in Olmsted County. Minnesota Arch Dermatol. 2010;146(1):26–30. 37. Sontheimer RD.  Cutaneous features of classic dermatomyositis and amyopathic dermatomyositis. Curr Opin Rheumatol. 1999;11(6):475–82. 38. Mainetti C, Terziroli Beretta-Piccoli B, Selmi C.  Cutaneous manifestations of dermatomyositis: a comprehensive review. Clin Rev Allergy Immunol. 2017;53(3):337–56. 39. Daly ML, Gordon PA, Creamer D. Cutaneous features of dermatomyositis associated with myositis-specific antibodies. Br J Dermatol. 2017;176(6):1662–5. 40. Di Rollo D, Abeni D, Tracanna M, Capo A, Amerio P.  Cancer risk in dermatomyositis: a systematic review of the literature. G Ital Dermatol Venereol. 2014;149(5):525–37. 41. Fiorentino D, Chung L, Zwerner J, Rosen A, Casciola-Rosen L. The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study. J Am Acad Dermatol. 2011;65(1):25–34. 42. Magro CM, Crowson AN.  The immunofluores cent profile of dermatomyositis: a comparative study with lupus erythematosus. J Cutan Pathol. 1997;24(9):543–52. 43. Ferreli C, Gasparini G, Parodi A, Cozzani E, Rongioletti F, Atzori L.  Cutaneous manifestations of scleroderma and scleroderma-like disorders: a comprehensive review. Clin Rev Allergy Immunol. 2017;53(3):306–36. 44. Fett N, Werth VP. Update on morphea: part I. epidemiology, clinical presentation, and pathogenesis. J Am Acad Dermatol. 2011;64(2):217–28. quiz 29-30 45. Fruchter R, Kurtzman DJB, Mazori DR, Wright NA, Patel M, Vleugels RA, et  al. Characteristics and treatment of postirradiation morphea: a retro-

J. S. Lehman and A. G. Bridges spective multicenter analysis. J Am Acad Dermatol. 2017;76(1):19–21. 46. Trattner A, David M, Sandbank M.  Bullous mor phea: a distinct entity? Am J Dermatopathol. 1994;16(4):414–7. 47. Khelifa E, Masouye I, Pham HC, Parmentier L, Borradori L.  Linear sclerodermic lupus erythematosus, a distinct variant of linear morphea and chronic cutaneous lupus erythematous. Int J Dermatol. 2011;50(12):1491–5. 48. Preliminary criteria for the classification of sys temic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23(5):581–590. 49. Shah AA, Wigley FM, Hummers LK. Telangiectases in scleroderma: a potential clinical marker of pulmonary arterial hypertension. J Rheumatol. 2010;37(1):98–104. 50. Leitenberger JJ, Cayce RL, Haley RW, Adams-Huet B, Bergstresser PR, Jacobe HT. Distinct autoimmune syndromes in morphea: a review of 245 adult and pediatric cases. Arch Dermatol. 2009;145(5):545–50. 51. Yang S, Draznin M, Fung MA.  The “line sign” is a rapid and efficient diagnostic “test” for morphea: clinicopathological study of 73 cases. Am J Dermatopathol. 2018;40(12):873–8. 52. Perez-Chua TA, Kisel YG, Chang KH, Bhawan J. Morphea and its variants and the “floating sign”-an additional finding in morphea. Am J Dermatopathol. 2014;36(6):500–5. 53. Onajin O, Wieland CN, Peters MS, Lohse CM, Lehman JS.  Clinicopathologic and immunophenotypic features of eosinophilic fasciitis and morphea profunda: a comparative study of 27 cases. J Am Acad Dermatol. 2018;78(1):121–8. 54. Generali E, Costanzo A, Mainetti C, Selmi C.  Cutaneous and mucosal manifestations of Sjogren’s syndrome. Clin Rev Allergy Immunol. 2017;53(3):357–70. 55. Haridas V, Shetty P, Dsouza LC, Dinesh US, Haridas K, Bargale A.  Pyoderma gangrenosum in Sjogren’s syndrome and its successful treatment with topical application of etanercept. Int J Rheum Dis. 2017;20(5):657–9. 56. Schulze-Koops H, Kalden JR.  The balance of Th1/ Th2 cytokines in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2001;15(5):677–91. 57. Lora V, Cerroni L, Cota C.  Skin manifestations of rheumatoid arthritis. G Ital Dermatol Venereol. 2018;153(2):243–55. 58. Tilstra JS, Lienesch DW.  Rheumatoid Nodules. Dermatol Clin. 2015;33(3):361–71. 59. Requena L, El-Shabrawi-Caelen L, Walsh SN, Segura S, Ziemer M, Hurt MA, et al. Intralymphatic histiocytosis. A clinicopathologic study of 16 cases. Am J Dermatopathol. 2009;31(2):140–51. 60. Lynch JM, Barrett TL.  Collagenolytic (necrobiotic) granulomas: part II--the ‘red’ granulomas. J Cutan Pathol. 2004;31(6):409–18.

11  Autoimmune Connective Tissue Diseases 61. Kumar B, Singh N, Rahnama-Moghadam S, Wanat KA, Ijdo JW, Werth VP.  Multicentric reticulohistiocytosis: a multicenter case series and review of literature. J Clin Rheumatol: Pract Rep Rheumatic Musculoskeletal Dis. 2018;24(1):45–9. 62. Jurado SA, Alvin GK, Selim MA, Pipkin CA, Kress D, Jamora MJ, et al. Fibroblastic rheumatism: a report of 4 cases with potential therapeutic implications. J Am Acad Dermatol. 2012;66(6):959–65. 63. Foidart JM, Abe S, Martin GR, Zizic TM, Barnett EV, Lawley TJ, et  al. Antibodies to type II collagen in relapsing polychondritis. N Engl J Med. 1978;299(22):1203–7. 64. Orme RL, Nordlund JJ, Barich L, Brown T.  The MAGIC syndrome (mouth and genital ulcers with inflamed cartilage). Arch Dermatol. 1990;126(7):940–4. 65. Shimizu J, Yamano Y, Kawahata K, Suzuki N.  Relapsing polychondritis patients were divided into three subgroups: patients with respiratory involvement (R subgroup), patients with auricular

497 involvement (A subgroup), and overlapping patients with both involvements (O subgroup), and each group had distinctive clinical characteristics. Medicine (Baltimore). 2018;97(42):e12837. 66. Schreiber BE, Twigg S, Marais J, Keat AC.  Saddle-­ nose deformities in the rheumatology clinic. Ear Nose Throat J. 2014;93(4–5):E45–7. 67. Moreira A, Torres B, Peruzzo J, Mota A, Eyerich K, Ring J.  Skin symptoms as diagnostic clue for autoinflammatory diseases. An Bras Dermatol. 2017;92(1):72–80. 68. Sun NZ, Brezinski EA, Berliner J, Haemel A, Connolly MK, Gensler L, et  al. Updates in adult-­ onset still disease: atypical cutaneous manifestations and associations with delayed malignancy. J Am Acad Dermatol. 2015;73(2):294–303. 69. Broekaert SM, Boer-Auer A, Kerl K, Herrgott I, Schulz X, Bonsmann G, et  al. Neutrophilic epitheliotropism is a histopathological clue to neutrophilic urticarial dermatosis. Am J Dermatopathol. 2016;38(1):39–49.

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Panniculitis Mark C. Mochel, Mariangela E. A. Marques, and Mai P. Hoang

Contents Introduction

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Septal Panniculitis Erythema Nodosum Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

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Sclerosing Septal and Lobular Panniculitides Morphea and Scleroderma Associated Panniculitis/Eosinophilic Fasciitis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Postirradiation Pseudosclerodermatous Panniculitis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Lipodermatosclerosis (Sclerosing Panniculitis) Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

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M. C. Mochel (*) Departments of Pathology and Dermatology, Virginia Commonwealth University Health System, Richmond, VA, USA e-mail: [email protected]

M. P. Hoang Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA e-mail: [email protected]

M. E. A. Marques Department of Pathology, Medical School of São Paulo State University, Botucatu, Brazil e-mail: [email protected] © Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_12

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Lobular Panniculitis and Mixed Lobular/Septal Panniculitis Neutrophil-Predominant Nodular Vasculitis/Erythema Induratum Infectious Panniculitis Neutrophilic Lobular Panniculitis Associated with Rheumatoid Arthritis Pancreatic Panniculitis Alpha-1-Antitrypsin Deficiency Associated Panniculitis Lobular Panniculitis Associated with BRAF Inhibitor Lymphocyte-Predominant Lupus Panniculitis Dermatomyositis Panniculitis Cold Panniculitis Subcutaneous Panniculitis-Like T-Cell Lymphoma Macrophage/Histiocytic-Predominant Traumatic and Factitious Panniculitis Subcutaneous Fat Necrosis of the Newborn Lipoatrophy/Lipodystrophy Histopathology

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Depositional Panniculitides Crystal-Storing Histiocytosis

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Case Studies Case 1 Clinical History Microscopic Description Diagnosis Discussion Case 2 Clinical History Microscopic Description Diagnosis Discussion Case 3 Clinical History Microscopic Description Diagnosis Discussion Case 4 Clinical History Microscopic Description Diagnosis Discussion Case 5 Clinical History Microscopic Description Diagnosis Discussion

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References

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Introduction Panniculitis encompasses a variety of conditions with overlapping clinical features. Distinctive histopathologic findings, paired with appropriate clinical features, allow for specific diagnosis in most cases. Classic organizing principles applied to the histopathologic differential diagnosis of panniculitis include [1] distinction of mostly septal versus mostly lobular panniculitis, [2] p­ resence or absence of vasculitis, and [3] composition of the inflammatory infiltrate [1–4] (Table  12.1). Careful assessment of these general features and other more specific features, Table 12.1  Classification of panniculitis Septal panniculitis Erythema nodosum Sclerosing septal and lobular panniculitides Morphea profunda/scleroderma/eosinophilic fasciitis Postirradiation pseudosclerodermatous panniculitis Lipodermatosclerosis (sclerosing panniculitis) Lobular or mixed septal/lobular panniculitis Neutrophil-predominant  Erythema induratum/nodular vasculitis  Infectious panniculitis  Neutrophilic lobular panniculitis associated with rheumatoid arthritis  Pancreatic panniculitis  Alpha-1-antitrypsin deficiency-associated panniculitis  Lobular panniculitis associated with BRAF inhibitor Lymphocyte-predominant  Lupus panniculitis  Dermatomyositis panniculitis  Cold panniculitis  Subcutaneous panniculitis-like lymphoma Macrophage/histiocytic-predominant  Factitial and traumatic panniculitis  Subcutaneous fat necrosis of the newborn Lipoatrophy/lipodystrophy Depositional panniculitides Calciphylaxis Gouty panniculitis Cutaneous oxalosis Crystal-storing histiocytosis

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as discussed in this chapter, can guide a specific diagnosis. As an illustration of this principle, in one classic study, two authors evaluated 30 cases originally diagnosed as Weber-Christian disease, now widely rejected as a specific diagnostic entity and reclassified many cases into more specific diagnoses, including erythema nodosum, phlebitis, factitial panniculitis, traumatic panniculitis, and lymphoproliferative disorders [5]. For the purposes of this chapter, diseases with significant inflammation or sclerosis of the panniculus will be considered. Inflammatory conditions with alterations mostly limited to vascular structures, such as leukocytoclastic vasculitis, superficial thrombophlebitis, and polyarteritis nodosa, are discussed in Chap. 7.

Septal Panniculitis Erythema Nodosum Erythema nodosum (EN) is a relatively common panniculitis. Though idiopathic in half of the cases, EN may be associated with various conditions, including infections (especially poststreptococcal, primary tuberculosis), systemic diseases (Crohn’s disease, ulcerative colitis, Behcet disease, and sarcoidosis), pregnancy, and drugs including antibiotics and contraceptive pills [6, 7]. EN may be the initial presentation of a malignancy as a paraneoplastic process. It has been associated with Hodgkin’s lymphoma, non-­ Hodgkin’s lymphoma, as well as solid tumors. EN-like eruptions have been recently documented to occur in association with various targeted and immunomodulatory chemotherapeutic agents, including BRAF-inhibitors [8], sorafenib [9], and inhibitors of CTLA4 and PD1 [10]. EN is considered to be a delayed-type hypersensitivity reaction with neutrophils playing an important role in the pathogenesis [11]. The incidence of EN has been estimated to be 1–5/100,000 [7, 11].

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Clinical Presentation Erythema nodosum typically affects women in the second and fourth decades, showing a threeto sevenfold female predominance [6]. Patients present acutely with tender, erythematous nodules, often located on bilateral shins (Fig. 12.1). However, involvement of the thighs, arms, face, and neck may occur [12]. There may be accompanied systemic symptoms including fever, malaise, and arthralgia.

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tal thickening with increased fibroblasts and collagen fibers. Eosinophils may be numerous [15]. In addition, the septae in either phase of the disease may contain discrete multinucleated histiocytes surrounding a central pale clefted space, a giant cell termed “Miescher’s radial granuloma” [11] (Fig.  12.4). Involvement of the fat lobules is typically restricted to fat necrosis and inflammation of the periseptal adipose tissue. Rarely, vasculitis with fibrin

 rognosis or Clinical Course P The condition is usually self-limited with resolution over 2–8  weeks without ulceration or scarring. A clinical variant termed erythema nodosum migrans is distinguished by a tendency for recurrence and peripheral expansion of lesions [6, 7, 13]. Histopathology By histopathologic examination, EN classically shows a septal panniculitis lacking vasculitis. Histologic features range from a neutrophilic panniculitis in the acute phase to a septal granulomatous and fibrosing panniculitis in the chronic phase [11–14] (Fig.  12.2). Early examples of EN demonstrate a septal neutrophilic infiltrate with septal edema [12, 14] (Fig. 12.3), while older lesions have lymphoplasmacytic infiltrates associated with sep-

Fig. 12.1  Erythema nodosum. Erythematous nodule on the anterior shin. (Courtesy of Dr. Julia Nunley, Department of Dermatology, Virginia Commonwealth University Health System, Richmond, Virginia)

Fig. 12.2  Erythema nodosum. Inflammation and expansion of subcutaneous septae with extension into septal-­ adjacent fat (×10)

Fig. 12.3  Erythema nodosum. Adjacent to septal giant cells, there is neutrophilic inflammation (×200)

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Fig. 12.4  Erythema nodosum. Septal multinucleated histiocytes with peripheral nuclei and central clefting, consistent with Miescher’s radial granuloma. Please note also scattered eosinophils, an occasional feature (×200)

deposition has been reported in early erythema nodosum, although this should be considered an exceptional occurrence [14].

Differential Diagnosis The clinical differential diagnosis includes erythema induratum, nodular vasculitis, cutaneous polyarteritis nodosa, and cutaneous lymphoma which can present as painful and erythematous subcutaneous nodules. Weight loss, fever, and age of onset over 50 years are some helpful clinical features in distinguishing paraneoplastic EN from conventional EN. Paired with an appropriate clinical appearance, the septal predominance of the infiltrate, either neutrophilic or lymphoplasmacytic with granulomas, and lack of vasculitis support a diagnosis of EN over other entities discussed in this chapter. Conditions which may rarely enter the differential diagnosis of septal panniculitis with granulomas include the palisading granulomatous conditions such as necrobiosis lipoidica (NL), subcutaneous granuloma annulare (GA), rheumatoid nodules, and necrobiotic xanthogranuloma (NXG) [1, 2]. In addition to the presence of characteristic dermal features of these diseases, discussed elsewhere (see Chap. 5), the palisading nature of the granulo-

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matous infiltrate, collagen alteration, and deposition of mucin in subcutaneous GA, fibrin in rheumatoid nodule, and cholesterol crystals in NXG should enable the pathologist to render the appropriate diagnosis. Also present in the differential diagnosis of septal panniculitis are various vasculitic processes, including leukocytoclastic vasculitis and polyarteritis nodosa, affecting small- and medium-sized vessels, respectively. The presence of vasculitis and the limited septal alterations beyond vasculitis distinguish these entities from EN.  Lymphocytic vasculitis and foci of leukocytoclastic vasculitis would be seen in some EN cases associated with Behcet disease in contrast to their absence in conventional EN [16].

Summary Clinical Presentation • Tender and erythematous nodules on bilateral shins. • The thighs, arms, face, and neck may be involved. Histologic Features • Acute: septal neutrophilic infiltrate and edema • Established lesion: septal granulomatous and fibrosing panniculitis • Chronic: septal thickening by fibrosis and lymphoplasmacytic infiltrate Differential Diagnosis • Neutrophilic phase: infection, early pancreatic panniculitis, subcutaneous Sweet’s syndrome • Granulomatous phase: necrobiosis lipoidica, subcutaneous granuloma annulare, necrobiotic xanthogranuloma • Chronic sclerosing phase: morphea, postirradiation pseudosclerodermatous panniculitis

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Takeaway Essentials Clinical Relevant Pearls • Among many other clinical associations, erythema nodosum may be a paraneoplastic process. Pathology Interpretation Pearls • The histopathologic differential diagnosis of erythema nodosum varies with the phase of the lesion. • Neutrophilic lobular panniculitis, small vessel vasculitis, and medium vessel vasculitis may rarely be seen in erythema nodosum.

 clerosing Septal and Lobular S Panniculitides

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down subcutaneous tissue, a variant termed morphea profunda.

Clinical Presentation Morphea profunda is often present in the initial stages of morphea and systemic sclerosis. The sclerodermic lesion often follows a three-phase course: edema, hardening, and atrophy. Deep morphea involves the subcutaneous tissue, fascia, and skeletal muscle. Deep and painful subcutaneous nodules characterize the early inflammatory phase. Developed lesions present as hyperpigmented, illdefined, and mildly inflamed sclerotic plaques. Deep atrophic scars are seen in the chronic phase [17].  rognosis or Clinical Course P Deep atrophic scars may result in cosmetic disfigurement and even functional impairment, with inhibited mobility, limb length discrepancy, and joint contractures [17].

Morphea and Scleroderma Associated Panniculitis/Eosinophilic Fasciitis

Histopathology The main histologic changes of morphea profunda are noted in the subcutaneous tissue and fascia with dermal involvement limited to deep reticular collagen. Lymphocytic lobular panniculitis is seen in the early phase which progresses to subcutaneous septal and deep dermal sclerosis [17]. Thickened and hyalinized collagen bundles in the deep dermis and subcutaneous septae, perivascular and interstitial lymphocytic infiltrates, and focal dermal mucin deposition are noted [18]. Increased number of elastic fibers forming clumps may be seen [18]. Reactive lymphoid follicles and aggregates of plasma cells may also be seen. Lipomembranous (membranocystic) fat necrosis is sometimes present [19]. In a small number of cases, eosinophils may be prominent within the inflammatory infiltrate [18, 20].

Systemic sclerosis (scleroderma) is a generalized disease that affects the connective tissue of not only the skin but also internal organs including the lungs, heart, kidneys, and gastrointestinal tract. The pathologic features may be attributable to autoantibody production and alterations of the microvasculature, resulting in massive collagen deposition. It often affects females in the third to fifth decades of life. Morphea, the localized form of scleroderma, may present as deep- and bound-­

Differential Diagnosis In contrast to conventional morphea, morphea profunda exhibits a deeper involvement of the subcutaneous tissue, fascia, and muscle. Clinical examination and immunologic studies are needed to distinguish morphea from systemic sclerosis. Eosinophilic fasciitis may represent severe variant of morphea [18, 21]. Eosinophilic fasciitis is a rare fibrosing disorder affecting bilateral extremities. While both eosinophilic fasciitis and systemic

Connective tissue panniculitides, such as lupus panniculitis, are predominantly lobular panniculitides, although a mixed lobular and septal pattern can be seen. Disorders of the panniculus with prominent sclerosis include morphea profunda, eosinophilic fasciitis, eosinophilic panniculitis, dermatomyositis panniculitis, postirradiation pseudosclerodermatous panniculitis, and lipodermatosclerosis. Of note, the late phases of other panniculitides discussed in this chapter, including erythema nodosum, may show predominantly sclerotic changes.

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sclerosis present as induration of the extremities, eosinophilic fasciitis is not associated with extracutaneous symptoms, joint contractures, or Raynaud phenomenon [22]. Biopsies of eosinophilic fasciitis show fascial thickening with fibrosis and infiltrates of lymphocytes, eosinophils, plasma cells, and histiocytes (Fig. 12.5). The underlying muscle may be involved by inflammation with fibrosis and muscle fiber degeneration (Fig. 12.6).

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While both nephrogenic systemic fibrosis and morphea profunda show thickened subcutaneous septae, nephrogenic systemic fibrosis also shows hypercellularity of the dermis and subcutaneous septae with increased dendritic cells, which are CD34-positive. Scleromyxedema, in contrast to morphea profunda, exhibits diffuse mucin deposition with proliferation of fibroblasts. The fibrosis of sclerodermoid chronic graft-versus-host disease (GVHD) can extend to the subcutaneous fat; however, sclerodermoid GVHD shows epidermal atrophy and lacks the prominent inflammatory infiltrate typical of morphea profunda.

Summary Clinical Presentation • Early inflammatory phase: deep and painful subcutaneous nodules • Chronic phase: deep atrophic scars Histologic Features • Thickened and hyalinized collagen bundles in the deep dermis and subcutaneous septae • Perivascular and interstitial infiltrate of lymphocytes and focal dermal mucin deposition

Fig. 12.5  Eosinophilic fasciitis. There is expansion of fibrous septae with collagen, fibroblasts, and inflammatory cells (×20)

Differential Diagnosis • Early lobular lymphocytic phase: lupus panniculitis, panniculitis of dermatomyositis • Late sclerotic phase: postirradiation pseudosclerodermatous panniculitis, eosinophilic fasciitis, nephrogenic systemic fibrosis, scleromyxedema, and chronic graft-versus-host disease

Takeaway Essentials

Fig. 12.6  Eosinophilic fasciitis. There is involvement of underlying skeletal muscle (×200)

Clinical Relevant Pearls • It is not possible to distinguish morphea from systemic sclerosis based solely on histologic findings. Clinical pathologic correlation is essential.

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• Accurate and timely diagnosis is important in treating the early inflammatory phase. Pathology Interpretation Pearls • Morphea profunda involves the subcutaneous tissue, fascia, and muscle and exhibits a denser inflammatory infiltrate in comparison to conventional morphea.

Postirradiation Pseudosclerodermatous Panniculitis Winkelmann et  al. reported in 1993 a series of four patients who developed erythematous and indurated plaques on irradiated skin 1–6 months after treatment for breast cancer and introduced the term “pseudosclerodermatous panniculitis” [23]. Since then, additional cases have been reported after radiation therapy for breast carcinoma as well as for soft tissue sarcoma [24, 25]. The entity is likely underrecognized, as skin biopsies are often prompted only by suspicion for metastatic disease.

involution can be observed in some cases [23, 24]. Although vasculitis is not seen, fibrosis of the vascular wall may be present, especially lesions developing years after radiation therapy [24].

Differential Diagnosis The histopathological differential diagnosis includes postirradiation morphea, morphea profunda, eosinophilic fasciitis, and lupus panniculitis. Postirradiation morphea typically affects mainly the dermis [28]. A septal panniculitis characterized by septal sclerosis and hyalinization and lymphoplasmacytic infiltrate is seen in this condition. In contrast to eosinophilic fasciitis, inflammation of fascia and presence of eosinophils are not seen typically in postirradiation pseudosclerodermatous panniculitis. Cases with prominent lymphocytic inflammation may raise the differential diagnosis of lupus panniculitis, which can be distinguished by the presence of predominantly centrilobular lymphocytes, lymphoid follicles, hyaline fat necrosis, and, often, dermal mucin deposition.

Summary

Clinical Presentation An indurated and erythematous plaque at the site of radiation therapy appears months to several years after treatment [23–25].

Clinical Presentation • An indurated and erythematous plaque at site of radiation therapy months or years after therapy

 rognosis or Clinical Course P Lesions may resolve either spontaneously [26] or with systemic corticosteroids [27]. Some persist despite treatment [24].

Histologic Features • Thickened and sclerotic subcutaneous septae. • An infiltrate of foamy histiocytes, lymphocytes, and plasma cells with necrotic adipocytes and lipophagic granulomas at the periphery of the subcutaneous lobules. • Features of radiation dermatitis can be seen in some cases.

Histopathology The subcutaneous septae are thickened and sclerotic. An infiltrate of foamy histiocytes, occasional lymphocytes and plasma cells, necrotic adipocytes, and lipophagic granulomas (small aggregates of foamy histiocytes around necrotic adipocytes) is seen at the periphery of the subcutaneous lobules. Features of radiation dermatitis such as epidermal atrophy, vascular proliferation with telangiectasia and mural hyalinization, fibrosis with atypical fibroblasts, and adnexal

Differential Diagnosis • Postirradiation morphea • Morphea profunda • Lupus panniculitis

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Takeaway Essentials Clinical Relevant Pearls • The lesion can develop months or even years after radiation therapy. Pathology Interpretation Pearls • The main findings are confined to the subcutaneous septae and lobules.

Lipodermatosclerosis (Sclerosing Panniculitis) In 1955 Huriez and colleagues first recognized this entity and designated it “hypodermitis sclerodermiformis” [29]. Currently, hypodermitis sclerodermiformis, sclerosing panniculitis, and lipodermatosclerosis are viewed as the same entity, with lipodermatosclerosis as the preferred term in the United States and United Kingdom. Lipodermatosclerosis is part of the spectrum of venous stasis that eventuates in cutaneous ulceration. The CEAP classification system on chronic venous disease has been proposed by an international consensus committee: class 0, no visible evidence of venous disease; class I, telangiectasias or reticular veins; class II, superficial varicose veins without edema; class III, superficial varicose veins with edema; class IV, cutaneous changes (4a, pigmentation or eczema; 4b, lipodermatosclerosis); class V, healed ulcer; and class VI, active venous ulcer [29]. Obesity and systemic hypertension are associated risk factors. Approximately 20% of patients with lipodermatosclerosis and venous ulcers have low levels of proteins S and C [30]. The underlying mechanism is likely due to fibrinolytic abnormalities leading to microthrombosis of the capillaries which result in microinfarction, tissue necrosis, and subsequently formation of scar tissue by stimulation of transforming growth factor beta 1 [31].

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Clinical Presentation The majority of patients were middle-aged in most series. Bilateral involvement (45%), discrete plaque (51%), erythema (71%), hyperpigmentation (59%), concomitant edema (71%), varicosities (57%), and ulceration (13%) have been reported [32]. There are two phases: acute and chronic. Acutely, patients present with extremely painful, red to purple, poorly demarcated, and indurated plaques on lower legs. Over the course of months, the chronic phase develops as hardening and contracted skin in the lower third of the patient’s leg. This induration and hyperpigmentation of the lower legs result in an “inverted champagne bottle” appearance (Fig. 12.7). When pain or other symptoms occur in chronic phase, the patient may have developed the “acute on chronic” form of lipodermatosclerosis.

Fig. 12.7  Lipodermatosclerosis. There is patchy erythema and mild hyperpigmentation of the lower legs with significant atrophy, more pronounced distally, rendering an “inverted champagne bottle” appearance. (Courtesy of Dr. Julia Nunley, Department of Dermatology, Virginia Commonwealth University Health System, Richmond, Virginia)

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 rognosis or Clinical Course P Ulceration develops in approximately 13% of the cases [32]. Histopathology In a series of 13 cases, Alegre et al. reported septal fibrosis and lipomembranous changes of the subcutaneous lobules [33] (Figs. 12.8, 12.9, and 12.10). Jorizzo et  al. [34] proposed early, intermediate, and advanced subcutaneous categories. A lymphocytic infiltrate within subcutaneous septae and areas of necrosis are seen in the early lesions. Thickened fibrotic subcutaneous septae and hyalinized fat sclerosis are observed in the intermediate lesions. Marked sclerosis of the panniculus, fibroplasia, atrophy, and thick-walled

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vessels are noted in the advanced cases. Calcium deposition is common. Huang et al. [35] subdivided their 17 studied cases into acute (less than a month), subacute (between a month and a year), and chronic (more than 1 year). Extravasated erythrocytes, ischemic fat necrosis, and hyalinization of fat cells are noted in the acute lesions. Membranocystic fat necrosis, septal fibrosis, and background stasis dermatitis are noted in the subacute lesions. Advanced stasis changes and septal fibroplasia are noted in the chronic lesions. Lipomembranous change of the subcutaneous fat may also be seen in various chronic panniculitides, including calciphylaxis [33, 36]. In a retrospective review of 341 panniculitis

Figs. 12.8 and 12.9  Lipodermatosclerosis. There is edema and mild fibrosis of the subcutaneous septae, and the subcutaneous fat appears altered (×20, ×40)

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Histologic Features • Acute: extravasated erythrocytes, ischemic fat necrosis, and hyalinization of fat cells • Subacute: membranocystic fat necrosis, septal fibrosis, and background venous stasis • Chronic: advanced stasis changes and septal fibroplasia

Fig. 12.10  Lipodermatosclerosis. The fat shows lipomembranous change with pale pink fibrillary edges and increased hyalinized material between adipocytes and extravascular calcification (×200)

specimens, Diaz-Cascajo et  al. [37] detected lipomembranous fat necrosis in 30 cases, 10 of which (30%) were lipodermatosclerosis cases. It has been speculated that the degeneration/necrosis of lipofuscin-­laden macrophages results in pseudomembranes of the subcutaneous fat.

Differential Diagnosis The acute phase of lipodermatosclerosis is often misdiagnosed clinically as cellulitis, morphea, or erythema nodosum. Erythema nodosum typically would not exhibit venous stasis and membranocystic fat necrosis [35]. In addition, a septal granulomatous infiltrate would be seen in EN.

Summary Clinical Presentation • A fibrosing septal-lobular panniculitis associated with venous stasis • Acute: extremely painful, red to purple, poorly demarcated, and indurated plaques on lower legs • Chronic: hardening and contracted skin in the lower third of the patient’s leg

Differential Diagnosis • Erythema nodosum • Morphea

Takeaway Essentials Clinical Relevant Pearls • Well-demarcated, indurated, and very painful “cellulitis” of the legs should raise consideration for lipodermatosclerosis. • A biopsy should be taken at the edge of the tender, erythematous, and indurated plaque. Pathology Interpretation Pearls • Lipomembranous change of the subcutaneous fat may also be seen in other panniculitis including morphea profunda and calciphylaxis.

 obular Panniculitis and Mixed L Lobular/Septal Panniculitis Lobular panniculitides show a greater diversity of morphologies than the septal disorders. While the presence or absence of vasculitis and inflammatory cell composition provides important diagnostic information, the patterns of fat necrosis are often the most distinctive features of a ­particular lobular panniculitis. As noted by Chan in an excellent review article [14], the pat-

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tern of fat alteration may often assist in making specific diagnoses of panniculitis: saponified basophilic adipocytes with preservation of cell outlines (ghost cells) indicate pancreatic panniculitis; grungy, basophilic necrosis suggests infectious panniculitis; floating fat suggests anti-alpha-­ 1-antitrypsin antibody syndrome; and hyaline sclerosis of fat supports lupus panniculitis.

Neutrophil-Predominant Nodular Vasculitis/Erythema Induratum Nodular vasculitis (NV) is a lobular panniculitis with associated vasculitis. In the most classic form of the disease, erythema induratum (EI), the disease is associated with tuberculosis, thereby representing a tuberculid [38]. The term nodular vasculitis is typically used for those cases of vasculitic and inflammatory panniculitis without associated tuberculosis. Some, however, use the terms NV and EI interchangeably, as they likely represent the same clinicopathologic entity with variable etiology [38]. Tuberculosis is the most frequently identified causative agent. In one study, Mycobacterium tuberculosis DNA was detected by polymerase chain reaction in 77% of 74 skin biopsies from 65 patients [39]. In addition to the classic mycobacterial association with EI, nodular vasculitis can be associated with systemic lupus erythematosus [40], Crohn’s disease [41], and etanercept therapy [42]. In countries with low prevalence of tuberculosis, nodular vasculitis could represent a reactive process to cold, obesity, chronic venous insufficiency, or thrombophlebitis [38]. Clinical Presentation Chronic, tender, erythematous to violaceous, and occasionally ulcerated subcutaneous nodules and plaques develop on the posterior lower extremities of middle-aged [43] (Fig.  12.11). Uncommonly, the condition may affect men and may localize to atypical sites, including the upper extremities [38].

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Fig. 12.11  Nodular vasculitis. Erythematous nodules involving the posterior lower legs. There were also nodules in the shins, knee, and arms. (Courtesy of Dr. Julia Nunley, Department of Dermatology, Virginia Commonwealth University Health System, Richmond, Virginia)

 rognosis or Clinical Course P The patients often experience an intermittent course prior to diagnosis. Recurrent episodes often occur during winter months over years or even decades [38]. The lesions of EI/NV may ulcerate and scar. Resolution of skin lesions with antituberculous therapy was observed in patients with EI [43]. No relapses were observed at a mean follow-up of 21 months [43]. Histopathology Classic cases of NV/EI combine a predominantly lobular panniculitis with associated vasculitis. The lobular inflammation is neutrophilic in early lesions and granulomatous in more developed lesions [38, 43, 44] (Figs.  12.12, 12.13, and 12.14). Septae may be inflamed and fibrotic, although most inflammatory cells involve the lobules. The panniculitis and associated vasculitis may be either focal (only one artery or small vessel affected) or diffuse (several blood vessels of different sizes in the septae and lobules affected) [44]. Regardless of the stage of the lesion, there is typically fat necrosis and vasculitis. There is often extensive fat necrosis of variably coagulative/ischemic type or caseous type with nuclear debris and surrounding granulomatous inflammation [44]. The vasculitis can be neutrophilic, granulomatous, or lymphocytic depending on the stage of the disease. In a detailed study of 101 skin biopsies from 86 patients with the diagnosis of nodular vasculitis, Segura et  al. [38] found vasculitis affecting septal vessels (mostly veins and occa-

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Fig. 12.14  Nodular vasculitis. Foci of apparent small vessels are effaced by granulomatous and neutrophilic inflammation, consistent with vasculitis (×200)

perhaps not essential in the appropriate clinical context. The vasculitis is characterized by neutrophilic and lymphohistiocytic infiltrates of ­vascular walls associated with fibrin deposition and often fibrinoid necrosis and thrombosis.

Fig. 12.12  Nodular vasculitis. The biopsy shows lobular and septal panniculitis (×10)

Fig. 12.13  Nodular vasculitis. There is granulomatous and mixed inflammation in the lobules and septae (×40)

sionally arteries) and/or lobular venules in 90% of clinicopathologically designated cases of NV/EI after serial sectioning of tissue blocks; this study thereby supported the concept that vasculitis is an important diagnostic feature of NV/EI, although

Differential Diagnosis Polyarteritis nodosa may mimic NV, although the former lacks significant panniculitis beyond the affected vessel [45]. The primary location of the vasculitis in the panniculus separates nodular vasculitis from granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. Superficial thrombophlebitis may also enter the differential diagnosis, although panniculitis is also limited in this condition. Leukocytoclastic vasculitis, including the rare immunoreactive manifestations of lepromatous leprosy, erythema nodosum leprosum, and Lucio’s phenomenon, may present as vasculitis of small subcutaneous blood vessels; however, these processes usually show a dermal predominance of findings [2]. Some infectious panniculitides, such as disseminated acanthamoebiasis, have been reported to show neutrophilic lobular panniculitis with vasculitis, but infectious panniculitis often shows dermal inflammation and subcutaneous grungy necrosis which would not be typical for nodular vasculitis [46]. Exclusion of infection may require careful evaluation of histochemical stains paired with close clinical correlation and microbiological studies.

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Summary Clinical Presentation • A predominantly lobular panniculitis with vasculitis presenting as tender, erythematous nodules on the posterior lower extremity • Often demonstrates ulceration, scarring, and recurrence Histologic Features • Acute: predominantly lobular neutrophilic inflammation with fat necrosis and vasculitis. • Chronic: septolobular granulomatous panniculitis with variable degrees of necrosis and vasculitis. • The vasculitis can be neutrophilic, granulomatous, or lymphocytic depending on the stage of the disease. Differential Diagnosis • Cutaneous polyarteritis nodosa • Granulomatosis with polyangiitis • Eosinophilic granulomatosis with polyangiitis • Leukocytoclastic vasculitides, including erythema nodosum leprosum and Lucio’s phenomenon • Infectious panniculitides

Takeaway Essentials Clinical Relevant Pearls • Painful, recurring nodules on the calves of a middle-aged woman should prompt consideration of nodular vasculitis. Pathology Interpretation Pearls • Cases of lobular panniculitis with neutrophils, granulomas, and fat necrosis should prompt a careful search, and possibly serial sectioning, for diagnostic features of vasculitis, particularly involving the center of the fat lobules.

Infectious Panniculitis Infectious agents, ranging from bacteria and mycobacteria to fungi and parasites, may involve the subcutis, prompting biopsy for suspected panniculitis (see Chap. 13). Clinical Presentation In the largest clinicopathologic study of infectious panniculitis evaluated by biopsy, lesions presented as painful, subcutaneous nodules, typically located on the extremities [46]. Infectious panniculitis may be secondary to local inoculation, superficial extension of deeper infection, or systemic infection [47]. While immunocompetent patients tend to present with localized infections secondary to inoculating trauma sustained weeks before presentation, immunosuppressed hosts often present with widely distributed subcutaneous nodules on the extremities and trunk, sometimes in a sporotrichoid pattern [47].  rognosis or Clinical Course P The prognosis and course depend on the infectious organism, host immune status, and efficacy of therapy. Histopathology While the histologic appearance of infectious panniculitis may vary greatly according to the causative organism, some features common to the various infectious panniculitides have been described. Epidermal alterations are common, including acanthosis, spongiosis, and parakeratosis [46]. The dermis is usually involved, in particular, showing edema, perivascular neutrophils, and vascular dilatation. The involvement of the panniculus is typically mixed septal and lobular with predominantly neutrophilic infiltrates, grungy basophilic necrosis, sweat gland necrosis, and hemorrhage (Figs.  12.15 and 12.16) [46]. While primary infections may show heavier involvement of the superficial dermis, secondary infections from disseminated organisms may show greater involvement of the deep dermis and subcutis. Vasculitis and thrombosis may be seen [48]. Foci of granulation tissue may be present [49]. Mycobacterial and fungal infections are associated typically with granulomatous inflammation. Depending on the inflammatory

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pattern and clinical suspicion, histochemical stains, including GMS, Ziehl-Neelsen, Fite, and Gram stains, may help to identify individual microorganisms.

Fig. 12.15  Infectious panniculitis. The biopsy shows a lobular panniculitis with involvement of adjacent septae (×20)

Differential Diagnosis Given the involvement of the lobular panniculus by neutrophil-rich infiltrates, other neutrophilic panniculitides enter the histologic differential diagnosis, including rheumatoid arthritis-­ associated neutrophilic panniculitis, pancreatic panniculitis, alpha-1-antitrypsin-associated panniculitis, and, in cases with vasculitis, nodular vasculitis/erythema induratum [14]. Features which distinguish infectious panniculitis from other neutrophilic panniculitides include the common presence of epidermal alterations, including acanthosis and spongiosis, dermal edema with neutrophils, and grungy basophilic necrosis [46]. The necrotic zones of infectious panniculitis contain fragmented, stringy, basophilic debris, distinct from other forms of fat necrosis, such as the saponification of pancreatic panniculitis or the hyaline fat necrosis of lupus panniculitis. Ultimately, a confident diagnosis of infectious panniculitis relies on identification of the causative organism, either through histochemical stains or through isolation by culture. An intriguing possibility to consider in culture-­negative cases is an id reaction to a distant infection, which may manifest as a neutrophilic panniculitis, thereby mimicking infectious panniculitis [50]. Chan has noted that the panniculitic bacterid conceptually overlaps with nodular vasculitis/erythema induratum, as both represent lobular panniculitic inflammatory reactions to distant infections [14].

Summary

Fig. 12.16  Infectious panniculitis. The infiltrate is predominantly neutrophilic and associated with karyorrhexis and smudgy basophilic debris (×200)

Clinical Presentation • Panniculitis secondary to infectious process with indistinct clinical features. • Painful subcutaneous nodules typically located on the extremities.

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Histologic Features • Typically a mixed lobular and septal neutrophilic panniculitis with grungy necrosis. • Vasculitis and thrombosis may be seen. Differential Diagnosis • An id reaction to a distant infection • Pancreatic panniculitis • Subcutaneous Sweet’s syndrome • Alpha-1-antitrypsin deficiency panniculitis • Neutrophilic panniculitis of rheumatoid arthritis • Nodular vasculitis/erythema induratum

Takeaway Essentials Clinical Relevant Pearls • Close correlation with tissue culture results essential for evaluation of infectious panniculitis. Pathology Interpretation Pearls • In a lobular and septal panniculitis rich in neutrophils, grungy necrosis and extensive epidermal and dermal alterations should prompt consideration of infectious panniculitis.

 eutrophilic Lobular Panniculitis N Associated with Rheumatoid Arthritis Rheumatoid arthritis (RA) is a systemic autoimmune disorder. Cutaneous manifestations of RA include rheumatoid nodule, rheumatoid neutrophilic dermatitis, pyoderma gangrenosum, palisaded neutrophilic granulomatous dermatitis, and rheumatoid vasculitis. Clinical Presentation A neutrophilic lobular panniculitis rarely may affect middle-aged women with rheumatoid

arthritis and presents as indurated, tender, and red nodules on the legs [51]. Lesions may ulcerate and express liquefied fat. Neutrophilic panniculitis in an infant with juvenile rheumatoid arthritis has been reported [52].  rognosis or Clinical Course P Reported cases have shown improvement with immunosuppressive therapies [51]. However, long-term follow-up is limited, with scant documentation of recurrence or persistence. Histopathology There is a neutrophilic infiltrate affecting the lobular panniculus. The neutrophils may show prominent karyorrhexis [51, 53]. Overlying leukocytoclastic vasculitis, affecting the dermis, may be present. Neutrophilic infiltrates may be associated with granuloma formation with central necrosis and peripheral lipomembranous fat necrosis [51]. The biopsy from a case of neutrophilic panniculitis of infancy in juvenile rheumatoid arthritis described a deep dermal and lobular panniculitis neutrophilic infiltrate without necrosis or vasculitis [52]. Differential Diagnosis The histologic changes raise a differential diagnosis of other neutrophilic panniculitides, including early erythema nodosum, which shows a distinctive septal predominance, pancreatic panniculitis, distinguished by the presence of saponified fat necrosis, and alpha1-antypsin deficiency panniculitis, which may show distinct neutrophilic infiltrates splaying deep dermal collagen fibers. Infectious panniculitis may overlap clinically and histologically with the neutrophilic lobular panniculitis of RA, as demonstrated by reports of disseminated histoplasmosis presenting as lobular neutrophilic panniculitis in patients with rheumatoid arthritis treated with various immunosuppressive agents [54]. Detection of microorganisms by special stains, including those for fungi and mycobacteria, or ­microbiological culture, is essential for the diagnosis of infectious panniculitis.

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Summary Clinical Presentation • Tender subcutaneous nodules on the legs of patients with rheumatoid arthritis Histologic Features • Neutrophilic infiltration of the lobular panniculus with associated leukocytoclasis. • Necrosis may be present, as may dermal leukocytoclastic vasculitis, necrotizing granulomas, and lipomembranous fat necrosis. Differential Diagnosis • Early erythema nodosum • Pancreatic panniculitis • Alpha-1-antitrypsin panniculitis • Infectious panniculitis • Subcutaneous Sweet’s syndrome

Takeaway Essentials Clinical Relevant Pearls • Diagnosis of this panniculitis depends on the associated clinical history of rheumatoid arthritis Pathology Interpretation Pearls • Strongly consider infectious panniculitis, particularly in the setting of aggressive immunosuppressive therapy, order relevant special stains, and recommend consideration of tissue culture. • Biopsies of papules and nodules from patients with rheumatoid arthritis may show a variety of non-panniculitis pathology, including interstitial granulomatous inflammation, neutrophilic dermatitis, and leukocytoclastic vasculitis.

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Pancreatic Panniculitis Pancreatic panniculitis is characterized by necrosis of fat at distant skin sites due to underlying pancreatic disease, including acute or chronic panniculitis secondary to alcohol, cholelithiasis, and pancreatic calculi, or pancreatic neoplasms, including adenocarcinoma and acinar cell carcinoma. Its incidence is approximately 2–3% of patients with pancreatic diseases [55]. The pathogenesis is likely attributable to tissue damage via released pancreatic enzymes including lipase, phosphorylase, trypsin, and amylase. Clinical Presentation Pancreatic panniculitis presents as tender, erythematous nodules of the lower extremity in patients with pancreatitis or pancreatic tumors (Fig. 12.17). Skin lesions, rather than abdominal pain, may be the presenting sign of underlying acute pancreatitis, and pancreatic panniculitis can precede pancreatitis by days to weeks [56, 57]. Rarely the patients with pancreatic panniculitis may have high pancreatic lipase serum levels yet without any evidence of pancreatic disease [55]. A case with typical clinical and histopathologic appearances of pancreatic panniculitis, but without confirmed pancreatic disease, even at autopsy, has been reported [58]. Ill-defined, painful, erythematous, and edematous nodules are noted most commonly on the lower extremities, especially the ankles and knees

Fig. 12.17  Pancreatic Panniculitis. Erythematous nodules on the lower extremity of a patient with acute pancreatitis

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[56]. Lesions often involve the ankles [56, 57]. Involvement of the trunk and forearms may also occur, and patients with diffuse lesions may show a predominance on dependent surfaces [56]. The lesions can be individual or multiple. An associated arthritis is concomitant in many affected patients, either monoarticular or oligoarticular [56]. The arthritis is usually symmetric and involves the small joints of the hands, wrists, and feet. Medullary fat necrosis of the bone, pulmonary infiltrates, and mesenteric thrombosis has also been reported [55].  rognosis or Clinical Course P The clinical course is dependent on the resolution of the underlying pancreatic disease. The lesions can spontaneously regress as the pancreatic inflammation subsides or ulcerate and drain brownish and viscous substance from liquefaction necrosis of adipocytes. They often resolve with lipoatrophy and hypopigmentation after several weeks [56]. On the contrary, panniculitis associated with pancreatic carcinoma shows a more generalized distribution, tendency to ulcerate, and chronic recurring course [56]. Schmid’s triad is an association of panniculitis, polyarthritis, and eosinophilia in a patient with pancreatic tumor and portends a poor prognosis [55]. In pancreatitis, panniculitis, and polyarthritis (PPP syndrome), the arthritis follows a chronic course in 45% of the patient [59]. Disseminated fat necrosis is a rare and often fatal manifestation with extensive involvement of subcutaneous tissue, joints, and medullary bone. Histopathology Pancreatic panniculitis is a predominantly lobular panniculitis with extensive fat necrosis with saponification (Figs.  12.18 and 12.19). In the acute lesions, neutrophilic lobular and septal panniculitis are seen [56]. Foci of coagulative fat necrosis characterized by anucleate and necrotic adipocytes (or “ghost” adipocytes) with basophilic cytoplasm are present. Homogeneous or granular basophilic material within the cytoplasm representing calcium is seen. In addition to saponification, outright dystrophic calcifica-

Fig. 12.18 Pancreatic panniculitis. Inflammation and basophilic alteration of the lobular panniculus (×20)

Fig. 12.19  Pancreatic panniculitis. Fat necrosis with preserved basophilic cell outlines, consistent with saponified fat necrosis (“ghost cells”) (×400)

tion may occur. A mixed inflammatory infiltrate is seen at the periphery of the necrotic tissue. Chronic lesions may show a lobular panniculi-

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tis with granulomatous inflammation including ­multinucleated giant cells, lymphocytes, foamy macrophages, and hemosiderin. In the end stage, the septae may be thickened and fibrotic, and lipoatrophy would be seen. Differential Diagnosis While other neutrophilic lobular panniculitides such as erythema nodosum, erythema induratum, alpha-1-antitrypsin panniculitis, and lupus panniculitis may enter the differential diagnosis, the presence of ghost adipocytes and saponification of the subcutaneous tissue are highly distinctive [14]. A biopsy from the site of interferon-beta injections, an agent therapeutic for multiple sclerosis, may yield histologic features closely reminiscent of pancreatic panniculitis, including neutrophilic infiltrates and basophilic necrosis of adipocytes with preserved cell outlines [60]. Clinical correlation may be required.

Summary Clinical Presentation • Erythematous nodules usually on the lower extremities, often involving the ankles, and associated with pancreatic disease Histologic Features • Coagulative necrosis of the fat lobules with ghost adipocytes • Saponification of the subcutaneous fat  with subsequent dystrophic calcification • Acute: neutrophilic lobular panniculitis with ghost adipocytes • Chronic: granulomatous lobular panniculitis with ghost adipocytes Differential Diagnosis • Infectious panniculitis • Interferon-beta injection site panniculitis

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Takeaway Essentials Clinical Relevant Pearls • The lesions often involve the ankles. • Lesions associated with pancreatic carcinoma tend to be more generalized and prone to ulceration. • The diagnosis of pancreatic disease may occur before, during, or subsequent to the appearance of panniculitis. Pathology Interpretation Pearls • The pattern of basophilic fat necrosis is the most specific feature.

Alpha-1-Antitrypsin Deficiency Associated Panniculitis Alpha-1-antitrypsin deficiency is an autosomal codominant disease with more than 150 identified alleles. Its incidence is approximately 1 per 2000–5000 individuals in Europe and 1 in 5000– 7000  in the United States, Canada, Australia, and New Zealand [61]. Alpha-1-antitrypsin, an acute phase reactant produced in the liver and, to a lesser degree, in the lung, inhibits a number of serine protease such as elastase, chymotrypsin, and trypsin. Among other proposed pathogenic mechanisms, disinhibition of these serine proteases may lead to tissue injury [62]. Clinical Presentation The condition manifests with chronic obstructive pulmonary disease, liver disease resulting in cirrhosis, and panniculitis. Uninhibited elastase destroys the alveolar septae and causes panacinar emphysema of the lower lobes of lung. Dyspnea, cough, and wheezing are the clinical symptoms. Accumulation of polymerized alpha1-­antitrypsin in hepatocytes results in liver disease manifesting as prolonged jaundice or liver failure in childhood and cirrhosis or hepatocellular carcinoma in adults. The phenotypes of alpha1-antitrypsin deficiency are classified by the migration pattern of the protein on gel electro-

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phoresis: Z = very slow, S = slow, M = medium, and F  =  fast. Patients who are homozygous for the Z allele have severe deficiency. Although a less common manifestation of the condition, alpha-1-antitrypsin deficiency may present with panniculitis. Affecting men and women equally, the panniculitis commonly occurs in the third and sixth decades. Recurrent erythematous subcutaneous nodules are seen on the lower trunk and proximal extremities. The developed lesions are fluctuant and progress to “punched-out” ulcerations which drain an oily substance [63].  rognosis or Clinical Course P This panniculitis often resolves with atrophic scarring or post-inflammatory hyperpigmentation following anti-inflammatory therapy paired with alpha-1-antitrypsin infusions. However, some cases show persistence and recurrence [63, 64]. Histopathology The lobular panniculus contains discrete zones of dense neutrophilic inflammation associated with fat necrosis, bordering zones of normal fat [62, 64]. The septal panniculus is also often involved. Histiocytic inflammation with giant cells and occasionally granulomas may be focally present [62–64]. Dystrophic calcification may be present. Inflammation and hemorrhage are noted at the periphery; however, vasculitis is not seen. A case report of an early lesion of alpha-1-antitrypsin deficiency panniculitis showed interstitial infiltrates of neutrophils in the deep reticular dermis and superficial subcutaneous lobules and septae, with separation of collagen fibers, termed a “splaying” pattern [65]. Extensive collagenolysis and elastolysis causing the subcutaneous lobule to detach from the adjacent reticular dermis and subcutaneous septae, also known as “floating fat,” are characteristic histologic feature [66]. Lymphocytic infiltrates and scattered eosinophils may be present. Ulceration, a common clinical feature, may be seen. Otherwise, there are limited epidermal changes. The der-

mis often contains a perivascular lymphocytic infiltrate [64]. Differential Diagnosis The differential diagnosis includes panniculitis due to infections, factitial panniculitis, and erythema induratum. Clinically, spontaneous ulceration with oily discharge favors alpha-1-antitrypsin deficiency over other types of panniculitis. Floating fat and splaying of dermal collagen are characteristic histologic features favoring alpha-­ 1-­ antitrypsin deficiency, while grungy necrosis, foreign material, and vasculitis are not expected, as they would be for infectious panniculitis, factitial panniculitis, and erythema nodosum, respectively. Ulcerated cases may resemble pyoderma gangrenosum, requiring clinicopathologic correlation. Infectious panniculitis also enters the differential diagnosis, given the presence of neutrophilic inflammation and fat necrosis. Special stains and correlation with culture results are recommended.

Summary Clinical Presentation • Recurrent erythematous subcutaneous nodules are seen on the lower trunk and proximal extremities. • “Punched-out” ulceration draining oily substance which heals with atrophic scarring or post-inflammatory hyperpigmentation. Histologic Features • Neutrophilic lobular panniculitis with fat necrosis and variable histiocytic inflammation • No vasculitis Differential Diagnosis • Infectious panniculitis • Pyoderma gangrenosum • Factitial panniculitis • Erythema induratum

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Takeaway Essentials Clinical Relevant Pearls • Spontaneous ulceration with oily discharge is characteristic of alpha-1-­ antitrypsin deficiency. • In cases of suspected alpha-1-­antitrypsin deficiency panniculitis, inquire about personal or family history of emphysema and chronic liver disease. • Confirmatory serum alpha-1-antitrypsin levels and assessment of the SERPINA1 allele status are required for definitive diagnosis. Pathology Interpretation Pearls • The zones of lobular neutrophilic inflammation with fat necrosis are often delineated from zones of normal, spared fat – characteristic “floating fat.” • Early lesions may show interstitial neutrophilic infiltrates in the deep dermis and superficial subcutaneous fat.

 obular Panniculitis Associated L with BRAF Inhibitor A neutrophilic lobular panniculitis may arise in patients receiving BRAF inhibitor (BRAFi) therapy, including vemurafenib, dabrafenib, and combination of dabrafenib and trametinib for melanoma and other BRAF-mutant malignancies. A recent phase 2 trial of dabrafenib and trametinib (MEK inhibitor) documented panniculitis in 12% of patients [67]. Clinical Presentation The cutaneous lesions occur most often during the first 8–26  weeks of therapy [68, 69]. They present as tender erythematous nodules of the lower legs and also sometimes the upper extremities; however, bilateral upper extremities, abdomen, back, and buttocks can also be

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affected [68]. There is a strong female predominance [69–71]. There may be associated fever and arthralgias.  rognosis or Clinical Course P Many cases of BRAFi-associated panniculitis resolve, even without interrupting BRAFi therapy [70]. Some cases, however, show a chronic relapsing course, which can usually be managed without interruption of BRAFi therapy [68]. Histopathology BRAFi-associated panniculitis shows variably dense neutrophilic infiltrates restricted to the lobular panniculus or involving both the lobular and septal panniculus [68–71]. The biopsies taken 1–2 months after the initiation of BRAF inhibitor showed a predominantly neutrophilic lobular panniculitis, sometimes with peripheral lymphocytic inflammation, while those taken 3  months or later showed a mild lymphocytic lobular panniculitis [68]. Hyaline necrosis, lymphoid aggregates, or vascular damage are not seen, although focal small vessel vasculitis has been rarely reported [68]. A rare case has been reported containing necrotizing granulomas [72]. Histiocytoid myeloid cells may be seen within this lobular neutrophilic panniculitis raising the possibility of myeloid leukemia cutis [73]. Differential Diagnosis Other neutrophilic panniculitides without significant vasculitis or necrosis enter the histologic differential diagnosis, including subcutaneous Sweet’s syndrome. There have also been reports of neutrophilic lobular panniculitis associated with granulocyte colony stimulating factor [74] and all-trans retinoic acid therapy [75]. All of these diagnoses ultimately rely on recognizing the characteristic histologic findings in the appropriate clinical context. Special stains and correlation with culture results should be considered to evaluate for the possibility of infectious panniculitis.

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Summary Clinical Presentation • Tender and erythematous nodules on bilateral lower extremities. • The course can be either resolving or chronic recurring, although usually the BRAF inhibitory therapy is not interrupted. Histologic Features • Neutrophilic infiltrates involving predominantly the lobular panniculus, occasionally with lymphocytic infiltrates at the periphery Differential Diagnosis • Erythema nodosum • Drug-induced neutrophilic lobular panniculitis • Alpha-1-antitrypsin deficiency • Subcutaneous Sweet’s syndrome • Infectious panniculitis

Takeaway Essentials Clinical Relevant Pearls • There may be associated fever and arthralgias. • Lesions may appear anywhere from days to more than a year after starting therapy. Pathology Interpretation Pearls • Diagnosis relies on close clinical correlation. • Vasculitis and necrosis are generally absent. • Necrotizing granulomas or histiocytoid myeloid cells can rarely be seen.

Lymphocyte-Predominant Lupus Panniculitis Lupus panniculitis, also known as lupus profundus, is a rare lobular panniculitis considered a subtype of chronic cutaneous lupus erythematosus. This condition may occur in patients with other manifestations of cutaneous or systemic lupus erythematosus or may present independently. While the etiology remains unknown, some have proposed a partial deficiency of C4 as a contributing factor [76]. Clinical Presentation Lupus panniculitis shows a female predominance and occurs mostly among middle-aged patients [77]. Painful and deep subcutaneous nodules or plaques with overlying hyperpigmentation are seen on the proximal extremities, shoulders, buttocks, trunk, breast, face, and scalp. The face is often affected in children. Involvement of the lower extremities is not typically seen. Lesions may show surface changes of cutaneous lupus erythematosus, ranging from poikiloderma to hyperkeratosis with follicular plugging, or may be surfaced by unremarkable skin [77]. Ulceration may occur. Some lesions may be associated with preceding trauma. Uncommonly, the breast (lupus mastitis), parotid gland, and periocular tissue are affected [78].  rognosis or Clinical Course P Lupus panniculitis usually has a chronic recurring course. Older lesions tend to show atrophy, which may be extensive (Fig.  12.20). While most cases occur independently of systemic lupus erythematosus, systemic manifestations may present before, during, or subsequently to panniculitis [79]. Those meeting criteria for SLE in association with this panniculitis have been noted to have a relatively indolent lupus course, relative to typical SLE. Histopathology In lupus panniculitis, the lobules are infiltrated by lymphocytes, usually with associated plasma cells and often with lymphoid follicles forming germinal centers [77] (Fig. 12.21). The fat shows

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Fig. 12.22  Lupus panniculitis. Fat necrosis with sharply preserved eosinophilic cell borders, consistent with eosinophilic fat necrosis

Fig. 12.20  Lupus panniculitis. Erythematous nodules on the right forearm, in addition to late atrophic lesions on the upper arm and chest. (Courtesy of Dr. Julia Nunley, Department of Dermatology, Virginia Commonwealth University Health System, Richmond, Virginia)

Fig. 12.21  Lupus panniculitis. Predominantly lobular panniculitis composed of lymphocytes with adjacent eosinophilic alteration of fat (×40)

hyaline fat necrosis, a distinctive alteration with hypereosinophilic fibers between and surrounding largely necrotic adipocytes (Fig.  12.22). Necrotic foci may be associated with neutrophils and nuclear debris [80]. The septae are often thickened and sclerotic. Less common features include calcium deposits, mucin, and vascular alterations including hyalinization, calcification, and thrombosis [80, 81]. Epidermal alterations

typical for cutaneous lupus erythematosus (ranging from acute SLE to chronic DLE) are seen in nearly half of cases and include vacuolar alteration of the basal epidermis with patchy lichenoid lymphocytic infiltrates, epidermal atrophy, hyperkeratosis, follicular plugging, and basement membrane thickening [80]. Dermal changes include superficial and deep perivascular lymphocytic infiltrates, mucin, and calcium deposits. Direct immunofluorescence studies usually show reactants, often granular IgM and occasionally C3, at the epidermal basement membrane (Sánchez 1981) [64]. Differential Diagnosis In addition to the characteristic subcutaneous features of lupus panniculitis, the classic epidermal and dermal changes of cutaneous lupus erythematosus may assist in this specific diagnosis. For those cases without these features, though, the differential diagnoses for lupus panniculitis include dermatomyositis panniculitis, cold panniculitis, subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and early morphea profunda. As demonstrated recently by Santos-Briz et  al. [82] in a series of dermatomyositis panniculitis, biopsies show lymphocytic infiltrates of the lobular panniculus which may be associated with hyaline fat necrosis, thereby closely mimicking lupus panniculitis. In these cases, close clinicopathologic correlation is necessary for specific diagnosis.

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Biopsies of cold panniculitis show lymphocytic infiltrates in the dermis, with perivascular and perieccrine aggregation, extending into the lobular panniculus [83–85]. There may be associated mucin, and even vacuolar alteration of the basal epidermis, mimicking lupus panniculitis [84]. However, in addition to the distinct clinical scenario of cold panniculitis, the changes are centered at the dermal-subcutaneous junction, and hyaline fat necrosis is not seen. SPTCL may pose a challenging differential diagnosis. Features favoring SPTCL include rimming of adipocytes by atypical lymphocytes with enlarged nuclei with irregular contours, ­karyorrhexis of the cellular infiltrate, predominance of CD8 positive T-cells among those in the panniculus, and high Ki-67 proliferation index [86]. Lymphocytic panniculitis with scattered plasma cells and lymphoid follicles is more in keeping with lupus panniculitis. Lupus panniculitis may have changes of interface dermatitis, dermal perivascular and periadnexal lymphocytic inflammation, and mucin, indicative of cutaneous lupus. Clusters of plasmacytoid dendritic cells, which can be highlighted by CD123 immunohistochemistry, favor lupus panniculitis over SPTCL [87]. A high Ki-67 index among periadipocytic lymphocytes favors a diagnosis of SPTCL [88]. There may be cases with overlapping features, requiring close follow-up and careful clinicopathologic correlation. It has been postulated that lupus panniculitis and SPTCL likely represent two ends of a disease spectrum [86, 89]. Magro et al. [86] has proposed terms such as “subcutaneous lymphoid dyscrasias” and “indeterminate lymphocytic lobular panniculitis” for cases that are not diagnostic of lupus panniculitis nor SPTCL. Bosisio and colleagues [89] reported a series of 11 patients with biopsies simultaneously showing features of SPTCL in some zones and features of lupus panniculitis in other zones. Of note, while lymphoid follicles with germinal centers are most characteristic of lupus panniculitis, this feature has been reported in rare cases of deep morphea, erythema induratum, and erythema nodosum [90].

Summary Clinical Presentation • Painful and deep subcutaneous nodules or plaques with overlying hyperpigmentation. • Involving the proximal extremities, shoulders, buttocks, trunk, breast, face, and scalp. • A minority of cases are associated with systemic lupus erythematosus. Histologic Features • Lobular panniculitis composed of lymphocytes with plasma cells and often lymphoid follicles with germinal centers • Hyaline sclerosis of fat lobules Differential Diagnosis • Dermatomyositis panniculitis • Cold panniculitis • Subcutaneous panniculitis-like T-cell lymphoma • Early morphea profunda

Takeaway Essentials Clinical Relevant Pearls • Distinct from other panniculitides, as it does not involve the lower legs. • Evaluation for other features of cutaneous or systemic lupus erythematosus is indicated. Pathology Interpretation Pearls • In the absence of classic epidermal and dermal changes of cutaneous lupus erythematosus, the characteristic features of lupus panniculitis should prompt additional consideration of dermatomyositis panniculitis and SPTCL.

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Dermatomyositis Panniculitis Panniculitis, presenting as a manifestation of dermatomyositis (DM), was first reported in 1924 by Weber and Gray [91]. These lesions may be clinically underdiagnosed. While imaging studies demonstrated subcutaneous edema of the thighs and buttocks in the majority of patients with juvenile dermatomyositis, clinically evident panniculitis is not common [92]. The pathogenesis of this panniculitis is not known at this time. Clinical Presentation The panniculitis can occur before, during, or after the diagnosis of dermatomyositis, with reports documenting panniculitis from 14  months prior to 5  years after the diagnosis of dermatomyositis [93]. Pediatric cases have been reported [92]. Proximal muscle weakness often precedes the diagnosis of panniculitis [82]. A majority of cases affect women. The condition presents as painful nodules or plaques on the buttocks, arms, thighs, and abdomen [93]. Asymmetric and multifocal lipoatrophy without induration can uncommonly be seen. Calcification can be seen late in the disease without preceding signs and symptoms of panniculitis.  rognosis or Clinical Course P The panniculitis associated with dermatomyositis does not resolve spontaneously but does respond to treatment of dermatomyositis. The course of panniculitis and myositis appears to parallel each other in most reported cases [94]. Although panniculitis is rarely the initial manifestation of DM with anti-MDA5 antibody, Labrador-Horrillo et  al. reported 35.7% of DM patients with panniculitis have anti-MDA5 antibody [95]. Histopathology In a histologic review of 55 skin biopsies of dermatomyositis, Janis and Winkelmann [94] found changes of panniculitis in 9% of the studied cases. A lobular panniculitis with lymphoplasmacytic infiltrate surrounding necrotic adipocytes, fat necrosis, and fibrosis is typical [82]. Variable features include septal sclerosis, lymphoid follicles,

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and karyorrhexis of the infiltrate [82]. Classic epidermal and dermal features of dermatomyositis are often present – dermal mucin is present in a majority of cases in one large series, and vacuolar interface changes were present in a minority [82]. Subcutaneous vessels exhibit endothelial swelling but without definitive features of vasculitis. Dystrophic calcification and vasculitis may be seen [93]. Direct immunofluorescence studies typically show nonspecific perivascular IgM, C3, and fibrinogen deposition [96]. Differential Diagnosis Lupus panniculitis and dermatomyositis panniculitis have overlapping features, and clinical correlation is required for specific diagnosis. As noted above, many of the characteristic features of lupus panniculitis, including hyalinized fat necrosis, lymphoid follicles, and plasma cells, may be seen in dermatomyositis panniculitis. The same features which distinguish lupus panniculitis from subcutaneous panniculitis-like T-cell lymphoma may be utilized to distinguish dermatomyositis panniculitis from this lymphoma. For further discussion of the differential diagnosis with lymphoma, please refer to the sections for lupus panniculitis and subcutaneous panniculitis-­ like T-cell lymphoma.

Summary Clinical Presentation • Painful nodules or plaques on the buttocks, arms, thighs, and abdomen Histologic Features • A lobular panniculitis with lymphoplasmacytic infiltrate surrounding necrotic adipocytes, fat necrosis, and fibrosis Differential Diagnosis • Lupus panniculitis • Subcutaneous panniculitis-like T-cell lymphoma

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Takeaway Essentials Clinical Relevant Pearls • Correlation with the clinical findings and laboratory studies is essential to diagnose panniculitis of dermatomyositis. • The course of panniculitis parallels that of myositis. Pathology Interpretation Pearls • The panniculitis of dermatomyositis may flawlessly mimic lupus panniculitis.

Cold Panniculitis Cold panniculitis typically occurs in infants and young children, a correlation potentially related to the higher freezing point of infant’s fat which contains a higher saturated fat content than that of adults [84]. The causes in children include exposure to freezing air temperature, use of ice packs to induce hypothermia, and sucking on popsicles (popsicle panniculitis) [97]. In adults, cold panniculitis affecting the thighs of equestrians who ride in prolonged periods in cold weather and due to the use of cold packs has been reported [83, 84, 98]. Clinical Presentation Erythematous and indurated plaques appear 2–3 days after cold exposure in infants and young children. It commonly occurs on the cheeks of neonates [97]. In cold panniculitis of equestrians, erythematous and pruritic papules develop on the superior and lateral aspects of one or both thighs. Lesions progress to indurated and tender plaques [84].  rognosis or Clinical Course P Individual lesions are self-limited, and avoidance of the cold stimulus prevents recurrence. The lesions spontaneously resolve after 2  weeks. Post-inflammatory hyperpigmentation may persist. In cold panniculitis of equestrians, the lesions resolve within 3  weeks; however,

new lesions tend to appear with re-exposure. The symptom severity correlates with younger age, smoking, tight-riding clothes, and prolonged riding times [84]. Histopathology There are dermal perivascular and perieccrine lymphocytic infiltrates with extension into the subcutaneous fat lobules [83–85]. There is a mild vacuolar alteration seen at the dermal-epidermal junction and an infiltrate of histiocytes, lymphocytes, neutrophils, and monocytes in the first day. Necrosis of adipocytes is noted after 2–3  days [99]. Reports have also shown dermal mucin and subtle vacuolar alteration of the basal epidermis, mimicking lupus erythematosus [84, 85]. The changes in the panniculus are largely confined to the dermal-subcutaneous junction and upper subcutaneous fat. Differential Diagnosis The clinical differential diagnosis includes sclerema neonatorum which occurs during the neonatal period up to 4 months of age. However, sclerema neonatorum affects the lower extremities of sick neonates, spreading upward, and is often fatal. Furthermore, the pathology for these conditions is entirely dissimilar, with sclerema neonatorum showing eosinophilic crystals with scant inflammation on biopsy of the panniculus. The lymphocytic infiltration of the lobules seen in cold panniculitis may mimic lupus ­panniculitis. In cold panniculitis, the subcutaneous changes are more restricted to the superficial subcutis, particularly the dermal-subcutaneous border. In addition, the characteristic feature of lupus panniculitis, hyaline fat necrosis, is not present in cold panniculitis. The histologic skin changes of cold panniculitis may also mimic those of systemic lupus erythematosus or subacute cutaneous lupus erythematosus, and these possibilities  should be considered clinically. As Stewart notes in a report of equestrian panniculitis, the condition may in some cases be analogous to those cases of pernio associated with lupus erythematosus, so-called chilblains lupus [85]. While perniosis affects the dermis and cold pan-

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niculitis affects the subcutaneous tissue, there are overlapping histopathologic features, and the two entities might represent ends of the same disease spectrum. Clusters of CD123+ plasmacytoid dendritic cells, as described in lupus erythematosus, can be seen within the inflammatory infiltrate.

Summary Clinical Presentation • Erythematous and indurated plaques appear 2–3  days after cold exposure, commonly on the cheeks of neonates Histologic Features • Necrosis of adipocytes • An infiltrate of histiocytes, lymphocytes, and neutrophils at the deep dermis and subcutaneous tissue junction • Dermal perivascular and perieccrine lymphocytic infiltrates which also extend into the upper subcutaneous fat lobules • Often a subtle vacuolar alteration of the basal epidermis Differential Diagnosis • Sclerema neonatorum • Cutaneous lupus erythematosus, including lupus panniculitis • Perniosis

Takeaway Essentials Clinical Relevant Pearls • In children, inquire about cold exposures including popsicles and ice packs. In adulthood, inquire about cold exposures, such as outdoor horseback riding activities. • Spontaneous resolution usually occurs within 2 weeks.

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Pathology Interpretation Pearls • May closely mimic cutaneous lupus erythematosus, a possibility which may need to be included in the histologic differential diagnosis and evaluated clinically

Subcutaneous Panniculitis-Like T-Cell Lymphoma Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a lymphoma which primarily involves the subcutis, mimicking panniculitides [100]. Previously, cases were classified as either alpha/ beta or gamma/delta phenotype: the alpha/beta lymphomas are CD4- CD8+ CD56- and associated with an indolent course, while gamma/delta lymphomas are CD4- CD8- CD56+ and associated with a poor prognosis. Based on different immunophenotypic, genetic, and clinical profiles, in 2005 the World Health Organization-­European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphoma designated the cases with gamma/ delta phenotype as cutaneous gamma/delta T-cell lymphoma, excluding them from the SPTCL group [101]. Associations between SPTL and autoimmune disorders such as systemic lupus erythematosus, juvenile rheumatoid arthritis, diabetes mellitus, and Sjogren syndrome have been reported [102]. Clinical Presentation There is a female predominance and a wide age distribution with median age of 36 [102]. The patients often have associated systemic symptoms, such as fever, and present with subcutaneous nodules and/or plaques mainly on the lower extremities before generalizing [102, 103]. In cases from Korea, the trunk is the predominant site [104]. Subcutaneous nodules of SPTCL tend to appear on the arms, legs, and trunk. Lesions may resolve with atrophy.  rognosis or Clinical Course P SPTCL has an excellent prognosis with a 5-year disease-specific survival rate of 85.7%

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[105]. Extracutaneous spread of disease is rare. Hemophagocytic syndrome, uncommonly associated with SPTCL and more commonly associated with cutaneous gamma-delta T-cell lymphoma, correlates with a poor prognosis [102]. Histopathology SPTCL is characterized by lobular infiltrates of lymphocytes with limited involvement of the septal panniculus. The lymphocytes often line the perimeters of adipocytes, a pattern termed “rimming” [86, 100, 102]. The lymphocytes are small to medium in size, with admixed larger lymphocytes with enlarged nuclei with irregular nuclear contours. The lymphocytes usually demonstrate karyorrhexis, and associated fat necrosis is a common feature. By immunohistochemistry, the infiltrates of SPTCL demonstrate a cytotoxic T-cell phenotype, CD3+ CD4- CD8+, with expression of cytotoxic markers, including perforin, granzyme­B, and TIA-1 [102]. CD30 and CD56 are negative. Beta-F1, a marker of the alpha-beta T-cell receptor, stains most cases, although this marker does not reliably stain all cases. The presence of T-cell clonality as demonstrated by T-cell receptor gene rearrangement has varied from 50% to 80% in reported series [106, 107]. Differential Diagnosis The two main differential diagnostic entities are lupus panniculitis, discussed in a previous section above, and other lymphomas involving the subcutaneous fat. An extensive differential diagnosis for lymphoma presenting as panniculitis is beyond the scope of this chapter, and excellent review articles cover of this topic [108]. Cutaneous gamma-delta T-cell lymphoma will be discussed here. The infiltrates of cutaneous gamma-delta T-cell lymphoma (CGDTCL) tend to involve the epidermis and dermis and are often associated with overlying ulceration, features not seen in SPTCL [108]. Angiocentric infiltrates with necrosis are common. Immunohistochemical demonstration of the appropriate immunophenotype, negative for CD4 and CD8 and positive for gamma-delta T-cell receptor and often CD56,

supports this diagnosis over SPTCL.  Finally, expression of immunohistochemistry for TCR gamma/delta and negativity for Beta-F1 confirms the diagnosis of CGDTCL. It has been postulated that lupus panniculitis and SPTCL represent two ends of a disease spectrum [86, 89]. Magro et al. proposed terms such as “subcutaneous lymphoid dyscrasia” and “indeterminate lymphocytic lobular panniculitis” for cases with features intermediate between lupus panniculitis and SPTCL [86]. Bosisio and colleagues [89] reported a series of 11 patients with features of both SPTCL and lupus panniculitis in the same skin biopsy. Rarely, SPTCL may present in patients with lupus erythematosus [102]. Features more characteristic of lupus panniculitis include dermal mucin deposition, lymphoid follicles with reactive germinal centers, hyaline fat necrosis, and CD123+ plasmacytoid dendritic cells. On the other hand, atypical CD8+ lymphoid cells rimming the adipocytes favor SPTCL.  High Ki-67 staining in the atypical CD8+ T-cells would favor SPTCL over lupus panniculitis [109].

Summary Clinical Presentation • The patients typically have fevers. • Subcutaneous nodules and/or plaques mainly on the lower extremities of young females. Histologic Features • Lobular infiltrates of lymphocytes with rimming of adipocytes. • Lymphocytes are small to medium in size with admixed larger lymphocytes and have nuclei with irregular nuclear contours. • Immunophenotype: CD3+, CD4-, CD8+, cytotoxic proteins+ (perforin, granzyme-B, and TIA-1), CD30-, CD56-, Beta-F1+, and TCR gamma/ delta

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Differential Diagnosis • Lupus panniculitis • Cutaneous gamma-delta T-cell lymphoma • Various other lymphomas which may involve the panniculus (peripheral T-cell lymphoma, tumor stage mycosis fungoides, anaplastic large cell lymphoma)

Takeaway Essentials Clinical Relevant Pearls • If ulcerated lesions present, strongly consider cutaneous gamma-delta T-cell lymphoma. • Look for evidence of hemophagocytic syndrome. Pathology Interpretation Pearls • Prominent adipocyte rimming of lymphocytes with enlarged irregular nuclei, karyorrhexis of lymphoid cells, predominance of CD8+ T-cells, and high Ki-67 among rimming lymphocytes favor SPTCL over lupus panniculitis. • The presence of hyaline fat necrosis, lymphoid follicles, scattered plasma cells, epidermal and dermal changes of lupus erythematosus, and clusters of CD123+ plasmacytoid dendritic cells favors lupus panniculitis over SPTCL.

Macrophage/ Histiocytic-Predominant  raumatic and Factitious Panniculitis T External sources of injury, ranging from traumatic, physical (hot/cold), and chemical agents to injected material, may induce panniculitis [2]. The term “factitial panniculitis” has been used in cases where the injuries are intentionally and surreptitiously self-inflicted, typically for

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concealed or subconscious gain. Subcutaneous injection of mineral or vegetable oils induces a subcutaneous foreign body reaction  – paraffinoma or sclerosing lipogranuloma [49, 110]. Clinical Presentation The clinical presentation is highly variable. Factitial panniculitis is more likely to occur in females and typically occurs in regions reachable by hands such as buttocks and thighs in patients with a history of psychiatric disorder or drug addiction. The lesions can be solitary or multiple and may have a bizarre pattern. Zones of repeated trauma may show sharp angulation, and foci of blunt trauma may appear ecchymotic. Contaminated injections may induce a suppurative panniculitis, wherein the subcutaneous nodules often ulcerate and expel liquefied, purulent material. Cases may resolve with zones of atrophy.  rognosis or Clinical Course P The prognosis depends on the discontinuation of the inciting agent and resolution of secondary infections. The severity of factitial panniculitis correlates with that of the underlying psychiatric illness. Histopathology Traumatic and factitial panniculitis appears as lobular panniculitis with infiltration of neutrophils in the early phase and granulomatous inflammation with fibrosis and foreign body giant cells in the later phase [2, 49]. Early traumatic lesions may also show hemorrhage and granulation tissue with hemosiderin, indicative of organizing hematoma [111]. In cases of suspected injected material, search for material via polarized light and phase contrast (lowering the condenser] should be pursued. Injection of mineral oil, usually for attempted cosmetic augmentation, induces a panniculitis with lymphohistiocytic inflammation, including foreign body giant cells, associated with clear cystic spaces, possibly containing translucent material that survived processing [112]. Eventually, the inflammation is replaced by diffuse dermal and subcutaneous sclerosis, with collagen outlining small, round, and clear spaces

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Fig. 12.24  Sclerosing lipogranuloma. The sclerosis surrounding small, round, clear spaces imparts a “Swiss cheese” appearance. There are occasional foamy macrophages (×200)

Fig. 12.23  Sclerosing lipogranuloma. There is inflammation and fibrosis of the lobular and septal panniculus (×20)

rendering a “Swiss cheese” appearance, a pattern designated sclerosing lipogranuloma [113]. Silicone injections may show a similar sclerosing lipogranuloma pattern, with translucent material in the cystic spaces and vacuolated macrophages [114] (Figs. 12.23 and 12.24). Reactions to fillers composed of polymethyl methacrylate microspheres appear on biopsy as diffuse dermal and subcutaneous granulomatous inflammation with uniform round clear spaces containing translucent material apparent on phase contrast microscopy [114].

Differential Diagnosis The acute neutrophilic phase and late granulomatous phases of traumatic and factitial panniculitis may resemble infectious panniculitis. Furthermore, the lesions of factitial panniculitis may become secondarily infected. The specific diagnosis of traumatic or factitial panniculitis relies on either compatible clinical history or identification of a particular foreign material. A search for microorganisms via special stains is essential in either diagnosis given the differential diagnosis or possibility of superinfection.

Summary Clinical Presentation • A panniculitis secondary to an external agent, either traumatic or injected, with clinical presentation dependent on the site of injection and material injected. • Self-induced factitial panniculitis typically occurs in regions reachable by hands such as buttocks and thighs.

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Histologic Features • Acute: neutrophilic lobular panniculitis containing eosinophils • Chronic: lymphohistiocytic lobular panniculitis with foreign body giant cells and fibrosis • Foreign material in some cases Differential Diagnosis • Infectious panniculitis • Pancreatic fat necrosis

Takeaway Essentials Clinical Relevant Pearls • The shapes of the lesions are often sharply angulated in repeated trauma or ecchymotic in blunt trauma. • Factitial panniculitis typically occurs in females and may ulcerate and drain liquefied fat. • Inquire about any use of cosmetic agents, such as fillers. Pathology Interpretation Pearls • Lobular panniculitis with foreign body giant cells should prompt a search for foreign material via polarized light and phase contrast microscopy, as well as special stains for microorganisms.

 ubcutaneous Fat Necrosis S of the Newborn Subcutaneous fat necrosis of the newborn (SFNN) is a rare disorder affecting full-term and post-term (42  weeks and beyond) infants within the first 6  weeks of life [115]. SFN typically occurs in neonates with complicated deliveries with perinatal asphyxia and hypothermia. Other associations include meconium aspiration, hypoxemia, obstetric trauma, maternal preeclampsia, and diabetes mellitus [116].

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The pathogenesis may be attributable to neonatal distress causing interference of circulation to the adipose tissue resulting in a hypoxic and hypothermic environment; this neonatal fat, which has a higher melting point due to its higher saturated to unsaturated fatty acid ratio, more easily crystallizes in the setting of hypothermia. Clinical Presentation Subcutaneous fat necrosis of the newborn (SFNN) presents as firm subcutaneous nodules, frequently erythematous or violaceous and often involving on the back, buttocks, thighs, arms, and cheeks [115] (Fig. 12.25). Lesions typically appear in the first week of life, although some appear up to a month later.  rognosis or Clinical Course P Although SCFN is self-limiting and the lesions spontaneously resolve within weeks to months, the patients must be monitored for occasional complications such as local tissue breakdown, hypoglycemia, anemia, thrombocytopenia, hypertriglyceridemia, and hypercalcemia [115, 117]. Hypercalcemia, seen in 63% of cases, can be associated with seizures, renal failure, and sudden cardiac death [115, 117].

Fig. 12.25  Subcutaneous fat necrosis of the newborn. Erythematous nodules on a neonate’s back, with recent biopsy site. (Courtesy of Dr. Julia Nunley, Department of Dermatology, Virginia Commonwealth University Health System, Richmond, Virginia)

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Histopathology A lobular panniculitis is seen containing foci of fat necrosis and dense inflammatory infiltrate composed of lymphocytes, histiocytes, and granulomas (Fig.  12.26). Radially arranged needle-­ shaped clefts are commonly seen within the cytoplasm of adipocytes, histiocytes, and ­multinucleated giant cells [116, 118] (Fig. 12.27). These triglyceride crystals are doubly birefringent under polarized light microscopy. Eosinophilic granules released from surrounding degranulating eosinophils may be seen [118]. In rare instances, a prominent infiltrate of neutro-

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Fig. 12.27  Subcutaneous fat necrosis of the newborn. Within the giant cells and lobular panniculus, there are abundant radially arranged eosinophilic crystals (×200)

phils is seen in the subcutaneous lobules raising the suspicion for cutaneous i­nfection [119]. Differential Diagnosis The primary clinicopathologic differential diagnosis is sclerema neonatorum, which presents as diffuse hardening of the skin in preterm neonates in the first week of life with severe illness and is associated with a poor prognosis. Diffuse white to yellowish, woody induration of skin and subcutaneous tissue hinders feeding and respiration, resulting in death in 75% [120]. While both conditions show radially oriented crystals, in contrast to the dense inflammation seen in SFN, sclerema neonatorum is associated with scant inflammation in association with the crystals [120]. Cold panniculitis, which may also occur in neonates, often presents as symmetric indurated nodules and plaques with overlying erythema within 1–2 days after exposure. These lesions can be reproduced with repeated cold exposure, and they are confined to the exposed areas [83–85]. A panniculitis with crystals may also be seen in the setting of corticosteroid withdrawal, most often in children. Post-steroid panniculitis has overlapping histopathologic features with SFN, with needle-shaped crystals within adipocytes, Fig. 12.26  Subcutaneous fat necrosis of the newborn. There is a lobular panniculitis (×20)

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and clinical correlation is required to make the distinction [121]. Llamas-Velasco and Requena reported a case of panniculitis with radially oriented crystals at the site of etanercept injection [122]. There has also been a case reported of thrombotic vasculopathy with a clinically livedoid pattern with small radially arrayed pale crystals in the subcutaneous fat [123].

Summary Clinical Presentation • Firm, erythematous, or violaceous subcutaneous nodules and plaques are seen on the back, buttocks, thighs, arms, and cheeks. • Subcutaneous erythematous nodules, often involving the trunk and arms, developing in the first week of life. • Often associated hypercalcemia. Histologic Features • A lobular panniculitis containing foci of fat necrosis and dense inflammatory infiltrate • Radially arranged needle-shaped clefts commonly seen within the cytoplasm of adipocytes, histiocytes, and multinucleated giant cells • Dense lymphohistiocytic inflammation of the lobular panniculus with foreign body giant cells and crystals arranged in radial arrays • Variable-associated eosinophils and neutrophils Differential Diagnosis • Sclerema neonatorum • Post-steroid panniculitis • Cold panniculitis • Rare drug reactions, both local (etanercept) and livedoid (gemcitabine)

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Takeaway Essentials Clinical Relevant Pearls • Close observation for hypercalcemia, which may result in organ damage, is recommended. • Outside of the typical clinical scenario for SFN, inquire about recent steroid withdrawal. Pathology Interpretation Pearls • Eosinophilic granules and prominent infiltrate of neutrophils may be seen. • Dense-associated inflammation distinguishes the condition from sclerema neonatorum which shows sparse inflammation.

Lipoatrophy/Lipodystrophy Lipoatrophy is defined as the post-inflammatory loss of adipose tissue, while lipodystrophy designates a noninflammatory loss of adipose tissue [2]. The late phases of various panniculitides, including lupus panniculitis and traumatic panniculitis, may show lipoatrophy. Injection sites of insulin, corticosteroids, and other medications may also cause localized lipoatrophy. Lipodystrophies encompass a spectrum of congenital and acquired syndromes of subcutaneous adipose tissue loss. The types of lipodystrophy are classified based on onset and affected areas: acquired, inherited (congenital or familial), generalized, and partial. Generalized lipodystrophy denotes near-total loss of subcutaneous tissue, while partial lipodystrophy denotes selective loss of adipose tissue. Antiretroviral therapy-­induced lipodystrophy in HIV patients and drug-induced localized lipodystrophy are more common than the inherited and acquired forms. The exact metabolic mechanism is unknown [124]. Acquired generalized lipodystrophy is also known as Lawrence syndrome or Lawrence-Seip

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syndrome. The patients are born with normal fat distribution but later develop subcutaneous fat loss of the face, arms, and legs during childhood or adolescence. The patients can also experience metabolic complications such as insulin resistance, high metabolic rate, and high lipid levels [125]. Acquired partial lipodystrophy, also known as Barraquer-Simons syndrome, cephalothoracic lipodystrophy, and progressive lipodystrophy, is a rare disease. A gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face and neck spreads to the upper extremities, chest, and abdomen in a “cephalocaudal” sequence (Figs. 12.28). The median age of onset is 7 years. The disease exhibits an association with autoimmune diseases, especially systemic lupus erythematosus and dermatomyositis [126]. Congenital generalized lipodystrophy or Berardinelli-Seip syndrome is a rare autosomal recessive disease characterized by absence of subcutaneous fat, insulin resistance, and muscular hypertrophy. Starting in early childhood, the patients experience accelerated linear growth, rapid bone aging, and excessive appetite. Acanthosis nigricans presents in the neck, trunk, and groin. Other complications include cirrhosis, muscle hypertrophy, splenomegaly, hirsutism, and hypertriglyceridemia [127]. Familial partial lipodystrophy or Kobberling-­ Dunnigan syndrome is a rare genetic disorder that affects females more than males. There is

Fig. 12.28  Acquired lipoatrophy. Loss of adipose tissue throughout the upper chest, shoulders, and neck. (Courtesy of Dr. Julia Nunley, Department of Dermatology, Virginia Commonwealth University Health System, Richmond, Virginia)

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loss of subcutaneous fat in the upper and lower extremities [128]. Biopsies from lipoatrophy show lobular lymphocytic infiltrates in the early phase [129]. Of note, early lesions of lipoatrophy may represent the late phase of an inflammatory panniculitis, such as lupus panniculitis. In the later phases, the biopsies show small adipocytes with small cytoplasm and eccentric nuclei, resembling embryonic fat cells, within shrunken lobules [130] (Figs. 12.29 and 12.30).

Histopathology Biopsies from patients with partial and generalized lipodystrophy are typically noninflammatory, with total or near-total loss of adipose tissue.

Fig. 12.29 Lipoatrophy. At first glance, this biopsy appears to be superficial to the fat (×20)

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Fig. 12.30  Lipoatrophy. However, upon closer examination, the fat is atrophic with reduction in quantity and size of adipocytes with mild sclerosis (×200)

However, rare reports describe an early inflammatory phase with lymphohistiocytic inflammation and giant cells [129, 131].

Depositional Panniculitides Depositional panniculitides, other than subcutaneous fat necrosis of the newborn which is discussed above, are briefly reviewed here. Calciphylaxis is a disease of calcium deposition, usually seen in the context of chronic kidney failure. Patients present with violaceous nodules on dependent, fat-rich zones such as the hips and buttocks which ulcerate (Fig. 12.31). On histologic examination, calciphylaxis shows calcium deposition within blood vessel walls and in the extravascular dermis and lobular and septal panniculitis [36, 132] (Figs.  12.32 and 12.33). Eccrine glands may show calcium deposition. Panniculitis may affect the lobules and the septae, and there may be ulceration. Special stains for calcium, including Von Kossa and Alizarin red, may assist in identifying calcium deposits. Gout may also involve the subcutaneous tissue, inducing a predominantly lobular panniculitis with aggregates of palely eosinophilic needle-like crystals with surrounding histiocytic inflammation, sometimes with neutrophils [133]. Oxalosis, a condition of calcium oxalate crystal tissue deposition, may be either a mani-

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Fig. 12.31  Calciphylaxis. Ulceration of the thigh with jagged edges and central eschar

festation of an inherited enzymatic defect or an acquired condition secondary to toxic ingestion or metabolic disruption. Primary oxalosis, the more likely oxalosis to cause cutaneous lesions, typically presents as livedo reticularis or acral cyanosis, while secondary oxalosis presents with acral papules [134, 135]. Biopsies of cutaneous oxalosis show deposition of yellow-brown crystals in dermis and subcutaneous tissues with involvement of vascular lumina (Fig.  12.34). These crystals are needle-shaped to rectangular and are polarizable (Fig. 12.35).

Crystal-Storing Histiocytosis Crystal-storing histiocytosis is a rare disease in which histiocytes contain intracytoplasmic crystals. The condition is associated with monoclonal gammopathies, particularly involving kappa light chain, including multiple myeloma, lymphoplasmacytic lymphoma, and monoclonal gammopathy of undetermined significance [136]. The disease can be either localized, commonly affecting the head and neck especially the eye or orbit, or generalized, affecting the bone marrow, liver, spleen, or lymph nodes. Rare cases can affect the skin [137]. The patients present with facial and eyelid swelling and indurated plaque on the neck and back or bilateral eyelid swelling [137]. Biopsies of crystal-storing histiocytosis reveal diffuse dermal and subcutaneous infiltrate of xanthomatous macrophages with cytoplasm containing eosinophilic crystalline

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Figs. 12.32 and 12.33 Calciphylaxis. Lobular inflammation with fat necrosis, foamy macrophages, and chunky to finely stippled calcifications of small blood vessels (×20, ×200)

Figs. 12.34 and 12.35  Oxalosis. Intravascular and perivascular aggregates of pale, brown, rhomboidal crystals in the superficial subcutaneous fat which are polarizable (×200, ×200, polarized light)

materials is seen in either the dermis or subcutaneous tissue [137]. These crystals are negative with periodic acid-­Schiff (PAS) stain and not birefringent with polarized light microscopy. Immunohistochemistry for the particular immunoglobulin is positive, although these stains are often difficult to interpret due to the diffuse presence of immunoglobulin in inflamed skin. Ultrastructurally, the hexagonal,

rhomboid, or needle-shaped crystals are membrane bound and electron dense [136]. The histopathologic differential diagnosis of a histiocytic infiltrate includes granular cell tumor, histiocytic neoplasm such as xanthogranuloma, storage disease such as Gaucher’s disease, and malakoplakia. However, none of the above entities exhibit the characteristic intracytoplasmic crystals of crystal-storing histiocytosis.

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Case Studies Case 1 Clinical History A 38-year-old Brazilian woman who has lived in rural areas and worked in the fields sought medical attention for a fever and generalized fatigue lasting 4 days and the appearance of erythematous malar plaques (Fig. 12.36) and painful erythematous nodules on her lower extremities (Fig.  12.37) and wrists. The clinical differential diagnosis included sarcoidosis, lupus erythematosus, and erythema nodosum leprosum. Skin biopsies were performed from her lower limbs. Microscopic Description Histologic sections show an intense inflammatory infiltrate of the dermis and subcutaneous septae (Fig. 12.38). The infiltrate is comprised of lymphocytes, neutrophils, and foamy macrophages (Fig. 12.39). Perineurial inflammatory infiltrate is seen (Fig. 12.40). Fite stain demonstrates fragmented acid-fast bacilli (Fig. 12.41).

Fig. 12.36  Case 1. Erythematous plaque on the malar cheek

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Fig. 12.37  Case 1. Erythematous and indurated nodules on both lower extremities

(continued)

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Fig. 12.38  Case 1. Intense inflammatory infiltrate of the dermis and subcutis, mainly septal panniculitis (×40)

Fig. 12.39  Case 1. Septal panniculitis and venulitis with polymorphonuclear neutrophils and foamy grayish macrophages (×100)

(continued)

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Fig. 12.40  Case 1. Lymphocytes and macrophages surrounding a dermal nerve (×400)

Fig. 12.41  Case 1. Fragmented acid-fast bacilli are identified on Fite stain (×600)

Diagnosis Erythema nodosum leprosum. Discussion The patient was diagnosed and treated as multibacillary leprosy in an outpatient clinic. Type II leprosy reaction, classically referred to as erythema nodosum leprosum, occurs secondary to immunological reaction to multibacillary leprosy (see Chap. 13). The symptoms of systemic toxicity of erythema nodosum leprosum reactions are attributed to high levels of circulating tumor necrosis factor-α. The reaction is widespread and accompanied by fever, malaise, and leukocytosis [138]. It is characterized by painful nodules on bilateral lower extremities and follows a recurrent course. Histologically, a lymphohistiocytic infiltrate is centered around small granulomas in the subcutaneous tissue. Other types of inflammatory cells including eosinophils, plasma cells, and mast cells are seen. Features of vasculitis can only be seen in a quarter of the cases. Acid-fast bacilli (AFB) are seen in lesions taken from untreated patients, whereas granular or fragmented AFB, as illustrated in this case, are seen in patients undergoing therapy [139]. The histologic differential includes Lucio phenomenon, nodular vasculitis, and deep fungal infection.

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Case 2 Clinical History A 57-year-old woman presented with a history of chronic diarrhea and weight loss for 6 months. She experienced sweating and occasional tremors. She also had cutaneous nodules in the perineal region and buttocks that appeared 3  months ago and recently increased in size (Fig.  12.42). A biopsy of a lesion in the gluteal region was performed. Microscopic Description Histologic sections demonstrate a lobular panniculitis at scanning magnification (Fig. 12.43). At higher magnification an epithelioid granulomatous process comprising of numerous giant cells and abundant eosinophils surrounding Schistosoma mansoni eggs is seen (Figs. 12.44 and 12.45).

Fig. 12.42  Case 2. A skin nodule with raised edges is seen

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Fig. 12.43  Case 2. A lobular panniculitis is noted at scanning magnification (×20)

Fig. 12.44  Case 2. A granulomatous infiltrate containing numerous giant cells and abundant eosinophils (×40)

(continued)

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Fig. 12.45  Case 2. Intracytoplasmic Schistosoma mansoni egg is seen (×400)

Diagnosis Schistosomiasis. Discussion Schistosomiasis is caused by trematode parasites of the genus Schistosoma. Schistosoma haematobium, Schistosoma mansoni, and Schistosoma japonicum are the three main species that infect human hosts (see Chap. 13). While S. haematobium live within the veins of the pelvis and urinary bladder, S. mansoni live in mesenteric veins/venules of the large intestine, and S. japonicum live within portal veins of the small intestine [140]. Cutaneous involvement is rare and may be asymptomatic [141]. Histologic sections of tissue biopsies can show either a granulomatous inflammatory infiltrate with prominent eosinophils surrounding viable eggs (as noted in the current case) or fibrosis with minimal inflammatory infiltrate around nonviable or calcified eggs [142]. The eggs of S. haematobium have terminal spines, while those of S. mansoni have lateral spines.

Case 3 Clinical History A 65-year-old man presented with erythematous and nodular plaque on his left shoulder (Fig. 12.46). A biopsy was performed. Microscopic Description A lymphoid infiltrate involves the lobular panniculus (Fig. 12.47). These lymphoid cells infiltrate the fat with rimming of adipocytes. The lymphocytes have enlarged and hyperchromatic nuclei with irregular nuclear contours (Figs. 12.48 and 12.49). By immunohistochemistry, the lymphoid cells lining the panniculus are CD3+ and CD8+ (Figs. 12.50 and 12.51), consistent with cytotoxic T-cells. These cells also express Beta-F1, and CD4 highlights a small number of admixed lymphocytes (not shown). (continued)

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Fig. 12.46  Case 3. An erythematous and nodular plaque on the patient’s left shoulder

Fig. 12.47  Case 3. Lymphoid infiltrate involving the lobular panniculus (×20)

(continued)

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Figs. 12.48 and 12.49  Case 3. Rimming of adipocytes by lymphocytes with enlarged hyperchromatic nuclei with irregular nuclear contours (×200, ×400)

Fig. 12.50  Case 3. CD3 immunohistochemistry highlights the lymphoid cells surrounding the adipocytes (×200)

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Fig. 12.51  Case 3. CD8 immunohistochemistry reveals these periadipose lymphocytes to be predominantly CD8+ T-cells (×200)

Diagnosis Atypical lymphoid infiltrate involving the panniculus, consistent with subcutaneous panniculitis-­ like T-cell lymphoma. Of note, a T-cell receptor gene rearrangement study was positive for a T-cell clone in this biopsy. Discussion While lupus panniculitis was considered in the histologic differential diagnosis, the histopathologic features of adipocyte rimming by lymphocytes with enlarged, hyperchromatic, irregular nuclei, shown to be mostly restricted to CD8+ T-cells by immunohistochemistry, support a diagnosis of subcutaneous panniculitis-like T-cell lymphoma. In this case, the positive T-cell clonality study further supports the diagnosis of SPTCL.  In the differential diagnosis between SPTCL and lupus panniculitis, features tending to favor lupus panniculitis include prominent hyaline fat necrosis, plasma cells, plasmacytoid dendritic cells demonstrated by CD123 immunohistochemistry, low Ki-67 positivity among periadipocytic lymphocytes, and epidermal and dermal changes of classic cutaneous lupus erythematosus.

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Case 4 Clinical History A 28-year-old woman presents with deeply situated nodules on her right forearm (Figs. 12.52 and 12.53). Microscopic Description The biopsy reveals a subcutaneous infiltrate, composed almost entirely of granulomas (Figs. 12.54 and 12.55). The granulomas are compact, discrete, non-necrotizing, and associated with scant to minimal lymphocytic inflammation. GMS, Ziehl-Neelsen, and Fite stains are negative for microorganisms.

Figs. 12.52 and 12.53  Case 4. Deeply situated nodules on the patient’s forearm

Figs. 12.54 and 12.55  Case 4. Subcutaneous involvement by discrete, non-necrotizing granulomas with scant associated lymphocytic inflammation

(continued)

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Diagnosis Subcutaneous sarcoidosis (Darier-Roussy variant of sarcoidosis). Discussion While various entities may produce a granulomatous panniculitis, including erythema nodosum, fungal or mycobacterial infectious panniculitis, and palisading granulomatous disorders, the presence of discrete, non-necrotizing granulomas with scant associated inflammation is most suggestive of sarcoidosis. The Darier-Roussy variant of sarcoidosis presents with deep nodules on the trunk or extremities. The forearms are often involved and typically show a linear arrangement of nodules [143]. One series found this presentation of sarcoidosis to be associated frequently with concurrent erythema nodosum [143]. Lung involvement by sarcoidosis is often associated as is eye involvement [144].

Case 5 Clinical History A 25-year-old woman presented for foreign body removal from her lower back after a motor vehicle collision. The patient then developed an erythematous blanching nontender macular and nodular rash over bilateral thighs and buttocks without draining (Figs. 12.56 and 12.57). She had received a cosmetic procedure to her buttocks a year ago in the Dominican Republic. The patient thought an “autologous fat transfer” was performed; however, she was not certain as she did not speak the native language (Spanish) of those who performed the procedure. Computed tomography showed multiple soft tissue densities in bilateral thighs and buttocks suspected to be silicone granulomas. Microscopic Description Histologic sections show an infiltrate of foamy histiocytes and occasional foreign body giant cells in the dermis and subcutaneous tissue (Fig. 12.58). Vacuolated histiocytes with clear and bubbly cytoplasm are seen infiltrating the dermis (Fig. 12.59 and 12.60). Polarized light microscopic examination is negative for birefringent foreign materials. Special stains for microorganisms including fungi and acid-fast bacilli are negative. (continued)

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Figs. 12.56 and 12.57  Case 5. An erythematous blanching nontender macular and nodular rash over the thigh and buttock. (Courtesy of Daniel Michael

O’Connor MD, Dermatology, Massachusetts General Hospital, Boston, MA, USA)

Fig. 12.58  Case 5. An infiltrate of histiocytes and occasional foreign body giant cells is seen in the dermis and subcutaneous tissue (×20)

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Figs. 12.59 and 12.60  Case 5. Foamy histiocytes with vacuolated cytoplasm infiltrating the dermis (×100, ×400)

Diagnosis Silicone granuloma. Discussion Soft tissue augmentation of the lips, hips, and buttocks with liquid silicone, polydimethylsiloxane, can cause various side effects. Hydrophobic liquid silicone disperses in the dermis causing a foreign body reaction [145]. This granulomatous response can lead to disfigurement. The onset of this granulomatous reaction may be months or years after injection, and the course follows exacerbation and remission. Erythema, ecchymosis, and edema may be present, and hypersensitivity reactions may occur. Serious complications include granulomatous reaction, product migration, cellulitis, disfigurement, embolism, and even death [146]. Several theories have been proposed regarding the development of reactions to silicone injections, including the use of impure industrial grade silicone, improper technique, large volume injection, administration by an untrained non-­physician, and exuberant immune response. Granulomas may extend beyond the site of silicone injection possibly due to immunologic cross-reaction [147]. Although the differential diagnosis includes a localized hypersensitivity reaction, the distribution over the buttocks, hips, and proximal thighs with sparing of the remainder of the body would be unusual. This case illustrates an inflammatory and granulomatous reaction at and near sites of prior cosmetic silicone injections.

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12 Panniculitis 68. Choy B, Chou S, Anforth R, Fernandez-Penas P.  Panniculitis in patients treated with BRAF inhibitors: a case series. Am J Dermatopathol. 2014;36(6):493–7. 69. Kim GH, Levy A, Compoginis G.  Neutrophilic panniculitis developing after treatment of metastatic melanoma with vemurafenib. J Cutan Pathol. 2013;40(7):667–9. 70. Vazquez-Osorio I, Sanchez-Aguilar MD, Garcia-­ Rodino S, Suarez-Penaranda JM, Aliste C, Vazquez-­ Veiga H.  Vemurafenib-induced neutrophilic panniculitis: a new case and review of the literature. Am J Dermatopathol. 2016;38(7):e93–6. 71. Ferreira J, Toda-Brito H, Moura MC, Sachse MF, Costa-Rosa J.  BRAFi-associated panniculitis  – an emerging side effect with a variable histological picture: report of two cases and review of the literature. J Cutan Pathol. 2017;44(3):307–9. 72. Ramani NS, Curry JL, Kapil J, Rapini RP, Tetzlaff MT, Prieto VG, et  al. Panniculitis with necrotizing granulomata in a patient on BRAF inhibitor (dabrafenib) therapy for metastatic melanoma. Am J Dermatopathol. 2015;37(8):e96–9. 73. Richarz NA, Puig L, Perez N, Cuadra-Urteaga J, Elez E, Fernandez-Figueras MG.  Vemurafenbi-­ induced histiocytoid neutrophilic panniculitis simulating myeloid leukaemic cutis. . Cancer Biol Ther 2019;20(3):237–9. 74. Hasegawa M, Sato S, Nakada M, Nitta H, Shirasaki H, Kasahara K, et al. Sweet’s syndrome associated with granulocyte colony-stimulating factor. Eur J Dermatol. 1998;8(7):503–5. 75. Jagdeo J, Campbell R, Long T, Muglia J, Telang G, Robinson-Bostom L.  Sweet’s syndrome--like neutrophilic lobular panniculitis associated with all-­ trans-­retinoic acid chemotherapy in a patient with acute promyelocytic leukemia. J Am Acad Dermatol. 2007;56(4):690–3. 76. Nousari HC, Kimyai-Asadi A, Provost TT.  Generalized lupus erythematosus profundus in a patient with genetic partial deficiency of C4. J Am Acad Dermatol. 1999;41(2 Pt 2):362–4. 77. Winkelmann RK.  Panniculitis in connective tissue disease. Arch Dermatol. 1983;119(4):336–44. 78. Fraga J, Garcia-Diez A.  Lupus erythematosus panniculitis. Dermatol Clin. 2008;26(4):453–63. vi 79. Watanabe T, Tsuchida T. Lupus erythematosus profundus: a cutaneous marker for a distinct clinical subset? Br J Dermatol. 1996;134(1):123–5. 80. Sanchez NP, Peters MS, Winkelmann RK. The histopathology of lupus erythematosus panniculitis. J Am Acad Dermatol. 1981;5(6):673–80. 81. Winkelmann RK.  Panniculitis and systemic lupus erythematosus. JAMA. 1970;211(3):472–5. 82. Santos-Briz A, Calle A, Linos K, Semans B, Carlson A, Sangueza OP, et al. Dermatomyositis panniculitis: a clinicopathological and immunohistochemical study of 18 cases. J Eur Acad Dermatol Venereol; 2018;32(8):1352–9.

551 83. Beacham BE, Cooper PH, Buchanan CS, Weary PE.  Equestrian cold panniculitis in women. Arch Dermatol. 1980;116(9):1025–7. 84. West SE, McCalmont TH, North JP.  Ice-pack dermatosis: a cold-induced dermatitis with similarities to cold panniculitis and perniosis that histopathologically resembles lupus. JAMA Dermatol. 2013;149(11):1314–8. 85. Stewart CL, Adler DJ, Jacobson A, Brod BA, Shinohara MM, Seykora JT, et al. Equestrian perniosis: a report of 2 cases and a review of the literature. Am J Dermatopathol. 2013;35(2):237–40. 86. Magro CM, Crowson AN, Kovatich AJ, Burns F. Lupus profundus, indeterminate lymphocytic lobular panniculitis and subcutaneous T-cell lymphoma: a spectrum of subcuticular T-cell lymphoid dyscrasia. J Cutan Pathol. 2001;28(5):235–47. 87. Liau JY, Chuang SS, Chu CY, Ku WH, Tsai JH, Shih TF.  The presence of clusters of plasmacytoid dendritic cells is a helpful feature for differentiating lupus panniculitis from subcutaneous panniculitis-like T-cell lymphoma. Histopathology. 2013;62(7):1057–66. 88. Sitthinamsuwan P, Pattanaprichakul P, Treetipsatit J, Pongpruttipan T, Sukpanichnant S, Pincus LB, et al. Subcutaneous panniculitis-like T-cell lymphoma versus lupus erythematosus panniculitis: distinction by means of the periadipocytic cell proliferation index. Am J Dermatopathol. 2018;40(8):567–74. 89. Bosisio F, Boi S, Caputo V, Chiarelli C, Oliver F, Ricci R, et  al. Lobular panniculitic infiltrates with overlapping histopathologic features of lupus panniculitis (lupus profundus) and subcutaneous T-cell lymphoma: a conceptual and practical dilemma. Am J Surg Pathol. 2015;39(2):206–11. 90. Harris RB, Duncan SC, Ecker RI, Winkelmann RK. Lymphoid follicles in subcutaneous inflammatory disease. Arch Dermatol. 1979;115(4):442–3. 91. Weber FP, Gray AMH.  Chronic relapsing polydermatomyositis with predominant involvement of the subcutaneous fat (panniculitis). Br J Dermatol. 1924;36:544–60. 92. Salman A, Kasapcopur O, Ergun T, Durmus Ucar AN, Demirkesen C. Panniculitis in juvenile dermatomyositis: report of a case and review of the published work. J Dermatol. 2016;43(8):951–3. 93. Solans R, Cortes J, Selva A, Garcia-Patos V, Jimenez FJ, Pascual C, et al. Panniculitis: a cutaneous manifestation of dermatomyositis. J Am Acad Dermatol. 2002;46(5 Suppl):S148–50. 94. Janis JF, Winkelmann RK.  Histopathology of the skin in dermatomyositis. A histopathologic study of 55 cases. Arch Dermatol. 1968;97(6):640–50. 95. Labrador-Horrillo M, Martinez MA, Selva-­ O’Callaghan A, Trallero-Araguas E, Balada E, Vilardell-Tarres M, et  al. Anti-MDA5 antibodies in a large Mediterranean population of adults with dermatomyositis. J Immunol Res. 2014;2014:290797.

552 96. Fusade T, Belanyi P, Joly P, Thomine E, Mihout MF, Lauret P. Subcutaneous changes in dermatomyositis. Br J Dermatol. 1993;128(4):451–3. 97. Ter Poorten JC, Hebert AA, Ilkiw R. Cold panniculitis in a neonate. J Am Acad Dermatol. 1995;33(2 Pt 2):383–5. 98. Kluger N, Marty L, Bourseau-Quetier C, Blum M, Camus M.  Perniosis/cold panniculitis in French equestrians: four cases. Int J Dermatol. 2016;55(12):e618–e20. 99. Duncan WC, Freeman RG, Heaton CL.  Cold panniculitis. Arch Dermatol. 1966;94(6):722–4. 100. Kumar S, Krenacs L, Medeiros J, Elenitoba-Johnson KS, Greiner TC, Sorbara L, et al. Subcutaneous panniculitic T-cell lymphoma is a tumor of cytotoxic T lymphocytes. Hum Pathol. 1998;29(4):397–403. 101. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et  al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105(10):3768–85. 102. Willemze R, Jansen PM, Cerroni L, Berti E, Santucci M, Assaf C, et  al. Subcutaneous panniculitis-­ like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases. Blood. 2008;111(2):838–45. 103. Kong YY, Dai B, Kong JC, Zhou XY, Lu HF, Shen L, et  al. Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathologic, immunophenotypic, and molecular study of 22 Asian cases according to WHO-EORTC classification. Am J Surg Pathol. 2008;32(10):1495–502. 104. Lee DW, Yang JH, Lee SM, Won CH, Chang S, Lee MW, et  al. Subcutaneous panniculitislike T-cell lymphoma: a clinical and pathologic study of 14 korean patients. Ann Dermatol. 2011;23(3):329–37. 105. Lopez-Lerma I, Penate Y, Gallardo F, Marti RM, Mitxelena J, Bielsa I, et  al. Subcutaneous panniculitis-­ like T-cell lymphoma: clinical features, therapeutic approach, and outcome in a case series of 16 patients. J Am Acad Dermatol. 2018;79(5):892–8. 106. Hoque SR, Child FJ, Whittaker SJ, Ferreira S, Orchard G, Jenner K, et  al. Subcutaneous panniculitis-­like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients. Br J Dermatol. 2003;148(3):516–25. 107. Massone C, Chott A, Metze D, Kerl K, Citarella L, Vale E, et  al. Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Am J Surg Pathol. 2004;28(6):719–35. 108. Willemze R.  Cutaneous lymphomas with a panniculitic presentation. Semin Diagn Pathol. 2017;34(1):36–43. 109. LeBlanc RE, Tavallaee M, Kim YH, Kim J. Useful parameters for distinguishing subcutaneous panniculitis-­ like T-cell lymphoma from lupus

M. C. Mochel et al. erythematosus panniculitis. Am J Surg Pathol. 2016;40(6):745–54. 110. Sanmartin O, Requena C, Requena L. Factitial panniculitis. Dermatol Clin. 2008;26(4):519–27, viii 111. Winkelmann RK, Barker SM. Factitial traumatic panniculitis. J Am Acad Dermatol. 1985;13(6):988–94. 112. Klein JA, Cole G, Barr RJ, Bartlow G, Fulwider C.  Paraffinomas of the scalp. Arch Dermatol. 1985;121(3):382–5. 113. Oertel YC, Johnson FB. Sclerosing lipogranuloma of male genitalia. Review of 23 cases. Arch Pathol Lab Med. 1977;101(6):321–6. 114. Requena C, Izquierdo MJ, Navarro M, Martinez A, Vilata JJ, Botella R, et al. Adverse reactions to injectable aesthetic microimplants. Am J Dermatopathol. 2001;23(3):197–202. 115. Del Pozzo-Magana BR, Ho N.  Subcutaneous fat necrosis of the newborn: a 20-year retrospective study. Pediatr Dermatol. 2016;33(6):e353–e5. 116. Muzy G, Mayor SAS, Lellis RF.  Subcutaneous fat necrosis of the newborn: clinical and histopathological correlation. An Bras Dermatol. 2018;93(3):412–4. 117. Stefanko NS, Drolet BA. Subcutaneous fat necrosis of the newborn and associated hypercalcemia: a systematic review of the literature. Pediatr Dermatol. 2019;36(1):24–30. 118. Tajirian A, Ross R, Zeikus P, Robinson-Bostom L.  Subcutaneous fat necrosis of the newborn with eosinophilic granules. J Cutan Pathol. 2007;34(7):588–90. 119. Ricardo-Gonzalez RR, Lin JR, Mathes EF, McCalmont TH, Pincus LB.  Neutrophil-rich subcutaneous fat necrosis of the newborn: a potential mimic of infection. J Am Acad Dermatol. 2016;75(1):177–85 e17. 120. Zeb A, Darmstadt GL.  Sclerema neonatorum: a review of nomenclature, clinical presentation, histological features, differential diagnoses and management. J Perinatol. 2008;28(7):453–60. 121. Kwon EJ, Emanuel PO, Gribetz CH, Mudgil AV, Phelps RG. Poststeroid panniculitis. J Cutan Pathol. 2007;34(Suppl 1):64–7. 122. Llamas-Velasco M, Requena L.  Panniculitis with crystals induced by etanercept subcutaneous injection. J Cutan Pathol. 2015;42(6):413–5. 123. Mir-Bonafe JM, Roman-Curto C, Santos-Briz A, Canueto J, Fernandez-Lopez E, Unamuno P.  Gemcitabine-associated livedoid thrombotic microangiopathy with associated sclerema neonatorum-­ like microscopic changes. J Cutan Pathol. 2012;39(7):707–11. 124. Garg A.  Acquired and inherited lipodystrophies. N Engl J Med. 2004;350(12):1220–34. 125. Billings JK, Milgraum SS, Gupta AK, Headington JT, Rasmussen JE. Lipoatrophic panniculitis: a possible autoimmune inflammatory disease of fat. Report of three cases. Arch Dermatol. 1987;123(12):1662–6. 126. Misra A, Peethambaram A, Garg A.  Clinical features and metabolic and autoimmune derangements

12 Panniculitis in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore). 2004;83(1):18–34. 127. Gomes KB, Pardini VC, Fernandes AP.  Clinical and molecular aspects of Berardinelli-Seip Congenital Lipodystrophy (BSCL). Clin Chim Acta. 2009;402(1–2):1–6. 128. Herbst KL, Tannock LR, Deeb SS, Purnell JQ, Brunzell JD, Chait A.  Kobberling type of familial partial lipodystrophy: an underrecognized syndrome. Diabetes Care. 2003;26(6):1819–24. 129. Peters MS, Winkelmann RK. Localized lipoatrophy (atrophic connective tissue disease panniculitis). Arch Dermatol. 1980;116(12):1363–8. 130. Dahl PR, Zalla MJ, Winkelmann RK.  Localized involutional lipoatrophy: a clinicopathologic study of 16 patients. J Am Acad Dermatol. 1996;35(4):523–8. 131. Tsuji T, Kosaka K, Terao J. Localized lipodystrophy with panniculitis: light and electron microscopic studies. J Cutan Pathol. 1989;16(6):359–64. 132. Essary LR, Wick MR. Cutaneous calciphylaxis. An underrecognized clinicopathologic entity. Am J Clin Pathol. 2000;113(2):280–7. 133. LeBoit PE, Schneider S. Gout presenting as lobular panniculitis. Am J Dermatopathol. 1987;9(4):334–8. 134. Shih HA, Kao DM, Elenitsas R, Leyden JJ. Livedo reticularis, ulcers, and peripheral gangrene: cutaneous manifestations of primary hyperoxaluria. Arch Dermatol. 2000;136(10):1272–4. 135. Blackmon JA, Jeffy BG, Malone JC, Knable AL Jr. Oxalosis involving the skin: case report and literature review. Arch Dermatol. 2011;147(11):1302–5. 136. Dogan S, Barnes L, Cruz-Vetrano WP.  Crystal-­ storing histiocytosis: report of a case, review of the literature (80 cases) and a proposed classification. Head Neck Pathol. 2012;6(1):111–20.

553 137. Li JJ, Henderson C.  Cutaneous crystal storing histiocytosis: a report of two cases. J Cutan Pathol. 2015;42(2):136–43. 138. Sarno EN, Grau GE, Vieira LM, Nery JA.  Serum levels of tumor necrosis factor–alpha and interleukin-­1 beta during leprosy reactional states. Clin Exp Immunol. 1991;84(1):103–8. 139. Massone C, Belachew WA, Schettini A.  Histopathology of the lepromatous skin biopsy. Clin Dermatol. 2015;33(1):38–45. 140. Colley DG, Bustinduy AL, Secor WE, King CH.  Human schistosomiasis. Lancet. 2014;383(9936):2253–64. 141. Barsoum RS, Esmat G, El-Baz T.  Human schistosomiasis: clinical perspective. Review. J Adv Res. 2013;4(5):433–44. 142. Poggensee G, Feldmeier H.  Female genital schistosomiasis: facts and hypotheses. Acta Trop. 2001;79(3):193–210. 143. Marcoval J, Mana J, Moreno A, Peyri J. Subcutaneous sarcoidosis--clinicopathological study of 10 cases. Br J Dermatol. 2005;153(4):790–4. 144. Ando M, Miyazaki E, Hatano Y, Nishio S, Torigoe C, Yamasue M, et  al. Subcutaneous sarcoidosis: a clinical analysis of nine patients. Clin Rheumatol. 2016;35(9):2277–81. 145. Altmeyer MD, Anderson LL, Wang AR.  Silicone migration and granuloma formation. J Cosmet Dermatol. 2009;8(2):92–7. 146. Park ME, Curreri AT, Taylor GA, Burris K. Silicone granulomas, a growing problem? J Clin Aesthet Dermatol. 2016;9(5):48–51. 147. Zappi E, Barnett JG, Zappi M, Barnett CR.  The long-term host response to liquid silicone injected during soft tissue augmentation procedures: a microscopic appraisal. Dermatol Surg. 2007;33(Suppl 2):S186–92.

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13

Mai P. Hoang, Toru Ogawa, and Mariangela E. A. Marques

Contents Introduction

 558

Bacterial Infection Impetigo Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Staphylococcal Scalded Skin Syndrome Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Toxic Shock Syndrome Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Erythrasma Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Erysipelas and Cellulitis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 558  558  559  559  559  559  560  560  560  561  561  562  562  562  563  563  563  563  563  564  564  564  565  565  565  566

M. P. Hoang (*) Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA e-mail: [email protected] T. Ogawa Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

M. E. A. Marques Department of Pathology, Medical School of São Paulo State University, Botucatu, Brazil e-mail: [email protected]

© Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_13

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M. P. Hoang et al.

556 Necrotizing Fasciitis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Ecthyma Gangrenosum Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Cat-Scratch Disease Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Bacillary Angiomatosis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 567  567  568  568  568  569  569  569  569  570  570  571  571  571  571  572  572  572  573  573

Mycobacterial Infection Cutaneous Tuberculosis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Atypical Mycobacteria Clinical Presentation and Histopathology Prognosis or Clinical Course Differential Diagnosis Leprosy Clinical Presentation Prognosis and Clinical Course Histopathology Differential Diagnosis Gonorrhea Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Granuloma Inguinale (Donovanosis) Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Chancroid Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Lymphogranuloma Venereum Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 574  574  575  575  576  576  576  577  578  579  579  580  582  583  585  586  586  586  586  586  587  587  587  587  587  588  588  588  588  588  589  589  589  590  590

Spirochete Infection Syphilis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 590  590  590  591  591  592

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557

Lyme Disease Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 592  593  593  593  594

Protozoal Infection Leishmaniasis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Toxoplasmosis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 595  595  595  596  596  596  597  597  598  598  598

Amebic Infections Cutaneous amebiasis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Cutaneous Acanthamebiasis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Cutaneous Balamuthia mandrillaris Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 599  599  599  599  599  599  600  600  600  600  600  000  601  601  601  602

Infestation Scabies Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Tungiasis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Onchocerciasis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Cutaneous Larva Migrans Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Schistosomiasis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis Cysticercosis Clinical Presentation Prognosis or Clinical Course

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558 Histopathology Differential Diagnosis

 612  612

Case Studies Case 1 Clinical history Microscopic description Diagnosis Discussion Case 2 Clinical history Microscopic description Diagnosis Discussion Case 3 Clinical history Microscopic description Diagnosis Discussion

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References

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Introduction The clinical manifestation of skin infection can vary greatly, and the infection can rarely disseminate beyond the skin resulting in a fatal outcome. A skin biopsy provides histologic clues as well as being useful in detecting fastidious or slow-­ growing organisms such as mycobacteria with ancillary stains. Examination of smear or touch preparation can also provide a rapid diagnosis. All could result in a timely recognition of a cutaneous infection which is important for treatment decision since definitive identification of the organisms by culture can take a long time. A wide range of bacteria including mycobacteria and spirochetes can affect the skin and subcutaneous tissue. The clinical presentations include impetigo, erythrasma, erysipelas, cellulitis, necrotizing fasciitis, and ecthyma gangrenosum. The mycobacterial infection can be tuberculous, non-tuberculous, or atypical mycobacteria and leprosy. The sexually transmitted bacterial infections discussed in this chapter are gonorrhea, granuloma inguinale, chancroid, and lymphogranuloma venereum. The spirochete infection includes syphilis caused by Treponema pallidum and Lyme disease caused by Borrelia burgdorferi. The protozoal diseases include leishmaniasis and toxoplasmosis. The majority of amebic infections in human are due to Entamoeba histo-

lytica. Other species of Entamoeba are nonpathogenic. Cutaneous infection by free-living amebae includes Acanthamoeba spp. and Balamuthia mandrillaris. Infestation by scabies, tungiasis, onchocerciasis, cutaneous larva migrans, schistosomiasis, and cysticercosis will also be discussed.

Bacterial Infection Impetigo This disease can be subdivided into impetigo contagiosa (non-bullous impetigo, impetigo simplex, or common impetigo) and bullous impetigo. Impetigo contagiosa accounts for about 70% of cases and bullous impetigo 30% of cases [1]. Impetigo can be a primary or secondary infection at sites of trauma, arthropod bites, herpetic lesions, or eczema. Both variants of impetigo are caused by Staphylococcus aureus. Group A β-hemolytic streptococcus is also the important pathogen for impetigo contagiosa. In some cases, both bacteria coexist. Impetigo contagiosa and bullous impetigo are caused by exfoliative toxins which attack the desmosomal protein desmoglein 1. Exfoliative toxin genes have been reported to be detected in 100% of S. aureus isolates from bullous impetigo and from 57% of isolates from

13  Infection: Bacteria, Spirochetes, Protozoa, and Infestation

impetigo contagiosa [2]. It is thought that nasal carriers of S. aureus are the risk of developing impetigo. The lesions of impetigo spread rapidly via direct person-­to-person contact.

Clinical Presentation Impetigo contagiosa typically occurs in the patients of preschool-age children, but also in adults, especially immunocompromised host. It is very uncommon in children under 2 years of age. Initially small erythema and pustules are present, often on the face and extremities, and then developing into erosions, 1–2 cm, and typical honeycolored (golden yellow) crusts (Fig. 13.1) [1]. On the other hand, bullous impetigo commonly occurs in the intertriginous areas of children aged 2–5  years [3]. Bullous impetigo is caused by S. aureus phage group II (80%), phage type 71 (60% of cases). Other phage types include IIIA, IIIC, and 55. S. aureus produces exfoliative toxins which hydrolyze desmoglein1 present at the granular layer of the epidermis. Localized blisters are seen in bullous impetigo due to exfoliative toxin A, whereas they are widespread caused by exfoliative toxin B in staphylococcal scalded skin syndrome (SSSS). Bae et  al. [4] reported a case of bullous impetigo with enormous bulla developing into SSSS. The favorite sites of bullous impetigo are the face, neck, axillae, trunk, buttocks, extremities, and perineum. Vesicles develop into flaccid bullae with subtle or no surrounding erythema, and shallow erosions are seen. Coalescence of ruptured vesicles can impart a polycyclic appearance. Systemic

Fig. 13.1  Impetigo. Erythema with associated erosion and crusts seen on trunk and upper extremity

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symptoms such as fever, diarrhea, and weakness can uncommonly be seen [1].

 rognosis or Clinical Course P Impetigo is a benign and self-limited process. The lesions of both impetigo contagiosa and bullous impetigo typically heal without scar within 2–3 weeks. Poststreptococcal glomerulonephritis is a rare yet serious complication. Histopathology Impetigo is essentially a clinical diagnosis and cultures are helpful. A skin biopsy is rarely necessary. Both impetigo contagiosa and bullous impetigo have similar histologic features. A subcorneal blister containing neutrophils and Gram-­ positive cocci is characteristic (Fig.  13.2). An infiltrate of neutrophils and lymphocytes is seen in the upper dermis. After the vesicle (pustule, bulla) ruptures, erosion and crust can be seen. In the early stage of impetigo contagiosa, only subcorneal neutrophils may be seen, whereas in the established stage, inflammatory crust containing serum and neutrophils is present. A few acantholytic cells can sometimes be identified especially in bullous impetigo; however, acantholysis is never prominent. Differential Diagnosis The histologic differential diagnosis includes pemphigus foliaceus, IgA pemphigus, staphylococcal scalded skin syndrome, sub­

Fig. 13.2  Impetigo. A subcorneal blister containing neutrophils and bacterial forms is seen. There is an underlying mixed dermal infiltrate of lymphocytes, histiocytes, and neutrophils (×100)

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corneal pustular dermatosis, pustular psoriasis, dermatophytosis, and acute generalized exanthematous pustulosis (AGEP). Direct immunofluorescence (DIF) studies would help excluding pemphigus foliaceus and IgA pemphigus (see Chap. 9). Gram stain would highlight Gram-­ positive cocci in impetigo.

Summary Clinical Presentation • Non-bullous impetigo or impetigo contagiosa: honey-colored crusts on the face and extremities of mainly children • Bullous impetigo: vesicle, flaccid bulla, and shallow erosion in intertriginous areas Histologic Features • Subcorneal blister containing neutrophils and Gram-positive cocci Differential Diagnosis • Pemphigus foliaceus, IgA pemphigus, SSSS, subcorneal pustular dermatosis, pustular psoriasis, dermatophytosis, and acute generalized exanthematous pustulosis

Takeaway Essentials Clinical Relevant Pearls • Impetigo contagiosa typically occurs in the patients of preschool-age children, but also in adults, especially immunocompromised host. • Bullous impetigo commonly occurs in the intertriginous areas of children aged 2–5 years. Pathology Interpretation Pearls • Focal acantholysis can be seen in bullous impetigo.

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 taphylococcal Scalded Skin S Syndrome Staphylococcal scalded skin syndrome (SSSS), also known as Ritter disease, is a potentially life-­ threatening condition. It is caused by the secretion of the exfoliative exotoxin (exfoliative toxins A and B) produced by S. aureus phage group II, especially type 71. However, phage types IIIA, IIIB, IIIC, and 55 have also been reported [5]. Exfoliative exotoxins and serine proteases are produced from infections at distant site and disseminated to the skin via hematogenous spread. The exotoxins cleave desmoglein 1, a cell-cell adhesion molecule expressed by keratinocytes at the granular layer, inducing the splitting of the desmosomes of these keratinocytes. As a result, blisters are formed within the granular layer right below the stratum corneum. Although prior study indicating that the incidence peaked in summer and autumn in children [6], a recent study reported that there were no seasonal differences of SSSS occurrence [7].

Clinical Presentation SSSS is usually seen in infants and children younger than 6  years due to immature immune system and ineffective toxic clearance by the kidneys. The disease rarely affects adults, especially in the setting of chronic renal insufficiency and immunosuppression such as AIDS, diabetes mellitus, and malignancy. The favorite sites are face, neck, and trunk. The patients can have a prodrome of fever and malaise. Initially skin tenderness and erythema of flexural skin and periorificial skin are seen and then spread diffusely with erosions (Figs.  13.3 and 13.4). The mucosa is generally spared. The blisters appear with pressure to the non-blistered skin. This phenomenon is known as the Nikolsky sign. There are bullae filled with fluid; however, bacteria cannot be detected. The source of infection is not typically known.  rognosis or Clinical Course P In children spontaneous clearing typically occurs within several days and healing without scarring within 14  days. Significant skin sloughing can cause temperature dysregulation, dehydration,

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Figs. 13.3 and 13.4  Staphylococcal scalded skin syndrome. Flexural erythema with superficial erosion

and susceptibility to secondary infection. Sepsis and pneumonia are the most feared complications. While mortality is less than 4% in children, it is much worse for adults ranging from 40% to 63% despite antibiotic therapy [6]. It was reported that inhospital mortality from SSSS was 1.3% for all age categories, 0.31% for patients younger than 17 years, and 4.3% for adults [8].

Histopathology Epidermal vesiculation is seen at the level of the granular layer (Fig. 13.5). Acantholytic cells and occasional neutrophils may be present in the blisters; however, there are typically no inflammatory cells within the blisters. A sparse and mixed inflammatory infiltrate is seen in the dermis. Gram stain and DIF examination are negative in SSSS. Differential Diagnosis Gram stain and DIF are helpful in distinguishing SSSS from others in the differential diagnoses. Clinically, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and pemphigus foliaceus can resemble SSSS. While the mucosa is not involved in SSSS, the patients of both SJS and TEN typically have prominent mucosal involvement. Histopathologically, only the stratum corneum and the granular layer of the epidermis become detached in SSSS; however, the entire epidermis, often exhibiting full-­thickness necrosis, is detached in SJS/TEN.  Other clinical differential diagnoses include toxic shock syndrome, Kawasaki disease,

Fig. 13.5  Staphylococcal scalded skin syndrome. A blister is noted at the granular layer of the epidermis. There is only a sparse infiltrate of lymphocytes around the superficial dermal blood vessels (×100)

and scarlet fever. Toxic shock syndrome would present with a generalized non-bullous eruption and hypotension. A polymorphous eruption is seen in Kawasaki disease in addition to fever, conjunctival injection, prominent mucous membrane involvement, and cervical lymphadenopathy. A diffuse sandpaper-­like and non-bullous eruption associated with bacterial pharyngitis, tender anterior cervical lymphadenopathy, and strawberry tongue is present in scarlet fever. Bullous impetigo and pemphigus foliaceus are the main histologic differential diagnoses for SSSS, since both exhibit subcorneal blister. In bullous impetigo, an infiltrate of prominent neutrophils is seen, and Gram stain often

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demonstrates bacterial forms within the blister space. S. aureus, mainly phage group 2, produce exfoliative toxins specific for desmoglein 1 restricted to the infected area. A blister is formed at the site of infection but not at other body sites. Nikolsky sign is absent. While negative in SSSS, DIF studies would demonstrate intercellular IgG and C3 deposition within the epidermis in pemphigus foliaceus.

Summary Clinical Presentation • Diffuse erythema, erosions, bullae, and absence of mucosal involvement. • The favorite sites are the face, neck, and trunk. • Positive Nikolsky sign. Histologic Features • Subcorneal blister at the granular layer Differential Diagnosis • Bullous impetigo • Pemphigus foliaceus • Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)

Takeaway Essentials Clinical Relevant Pearls • Staphylococcal scalded skin syndrome is seen mainly in infants and children younger than 6 years. • While typically spontaneously resolved in children, the mortality of staphylococcal scalded skin syndrome can reach 40–60% in adults. Pathology Interpretation Pearls • Minimal acantholysis in contrast to bullous impetigo

Toxic Shock Syndrome Toxic shock syndrome is a potentially lethal disease mediated by a toxin produced by phage group I of staphylococci. Initially reported in pediatric patients, an association with tampon use and S. aureus was subsequently reported in women [9]. Recurrent menstrual toxic shock syndrome has been reported in a third of patients with previous toxic shock syndrome. Colonization by toxigenic strains of S. aureus and absence of neutralizing antibody have been thought to be the risk factors [10]. The incidence of toxic shock syndrome has markedly declined since its initial description and is approximately 0.5 case per 100,000 population [11]. The exotoxins of S. aureus and group A Streptococcus perform as superantigens and mediate an immune response that potentially can cause multiorgan failure [11]. The massive cytokine production brings on fever, skin rash, capillary leak, and resultant hypotension. Tst1(toxic shock syndrome toxin-1) superantigen is associated with the majority of menstrual cases [11].

Clinical Presentation In addition to menstruating women and children, toxic shock syndrome can affect men and non-­menstruating women. The patients initially present with fever, headache, sore throat, and diarrhea and rapidly progress to multiorgan dysfunction characterized by hypotension, erythroderma, acute renal failure, hepatic abnormalities, and confusion [9]. A diffuse, blanching, macular, and erythematous eruption is seen, but might be attributed to high fever. Many patients complain of skin or muscle pain upon touch.  rognosis or Clinical Course P The cutaneous symptoms tend to resolve as fine desquamation, especially on the palms and soles, within 1–2 weeks [9]. Skin peeling may occur as sheets, and some patients may experience hair and nail loss. The disease is potentially lethal if not timely diagnosed [12].

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Histopathology A skin biopsy can exhibit epidermal spongiosis and necrosis. Features of leukocytoclastic vasculitis can be seen in the dermis [12]. Differential Diagnosis The differential diagnosis includes scarlet fever, Kawasaki disease, and Rocky Mountain spotted fever.

Summary Clinical Presentation • The patient initially presents with fever, headache, sore throat, and diarrhea and rapidly progresses to multiorgan dysfunction. • A diffuse, blanching, macular, and erythematous eruption Histologic Features • A skin biopsy can exhibit epidermal spongiosis and necrosis. • Features of leukocytoclastic vasculitis can be present.

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Clinical Presentation The typical clinical presentation is pink-brown patches with scales seen in the inguinal, interdigital, intergluteal, and crural folds, as well as the inframammary areas (Fig. 13.6). Rarely erythrasma can involve the vulvar mucosa [14]. The lesion is usually asymptomatic; however, it can occasionally be pruritic. The skin is often as thin as cigarette paper. The typical lesion is well defined, but the widespread rash of erythrasma is also reported [15]. As unusual clinical findings, the lesions can involve the non-intertriginous areas as well. Using a Wood’s lamp, a coral-red fluorescence can be identified by coproporphyrin III produced by this Gram-positive bacterium.  rognosis or Clinical Course P Erythrasma is a chronic infection and can remain asymptomatic for years. Rarely this disease may develop into cellulitis or bacteremia [16].

Differential Diagnosis • Scarlet fever • Kawasaki disease • Rocky Mountain spotted fever

Takeaway Essentials Clinical Relevant Pearls • The disease is potentially lethal if not timely diagnosed.

Erythrasma Erythrasma is caused by Gram-positive diphtheroid bacterium, mainly Corynebacterium minutissimum, and can be seen at any age. Obesity, diabetes, elderly individuals, warm and moist environment, and immunosuppression are important predisposing factors for this disease [13].

Fig. 13.6  Erythrasma. Pink-brown patches with scales in the axillary area

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Histopathology Corynebacterium bacilli are present in the stratum corneum (Fig. 13.7). Gram stain highlights this organism within the stratum corneum, and the organism can be detected by PAS and GMS stains (Fig. 13.8). Acanthosis, parakeratosis, and hypergranulosis may be seen. There is sometimes a superficial perivascular lymphocytic infiltration. Differential Diagnosis Dermatophytosis and cutaneous candidiasis are the main differential diagnoses. There are some reports of mixed infection with erythrasma coexist with dermatophytes in the toe webs [17]. Seborrheic dermatitis and inverse psoriasis should also be considered.

Summary Clinical Presentation • Asymptomatic, well-defined, pink-­ brown patches with scales in the intertriginous areas • A coral-red fluorescence by Wood’s lamp Histologic Features • Filamentous Corynebacterium bacilli in the stratum corneum • Acanthosis, parakeratosis, hypergranulosis, and superficial perivascular lymphocytic infiltrate Differential Diagnosis • Dermatophytosis • Cutaneous candidiasis • Seborrheic dermatitis • Inverse psoriasis

Takeaway Essentials Clinical Relevant Pearls • Direct KOH examination would be helpful to exclude dermatophytosis. Fig. 13.7  Erythrasma. Bacteria are seen within the compact orthokeratosis (×400)

Pathology Interpretation Pearls • Known as an “invisible dermatosis” since the skin histologic section appears unremarkable • In addition to Gram stain, PAS and GMS stains also highlight the bacilli within the stratum corneum.

Erysipelas and Cellulitis

Fig. 13.8  Erythrasma. Gram stain highlights the bacterial forms within the stratum corneum (×400)

Cellulitis is an acute, deep dermal, and subcutaneous bacterial infection often due to skin disruption by toe web space bacteria, fungal foot infection, or venous stasis ulceration. There are more than 650,000 hospital admissions due to cellulitis per year in the United States [18].

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Cellulitis has been reported to account for 10% of the infectious disease-associated hospitalizations in the United States [18]. Erysipelas is a superficial variant of cellulitis. Trauma to the skin is important to consider in both cellulitis and erysipelas. Risk factors include diabetes mellitus, lymphedema, and chronic alcoholism. The diagnosis is usually made by the clinical presentation. Erysipelas is caused mainly by β-hemolytic streptococci (groups A, B, C, G, and F) and S. aureus including MRSA. Cellulitis can be caused by any bacteria, most often by S. aureus or group A streptococci; however, microbiology cultures are typically negative. A bacterial diagnosis was documented in only 16% of 808 adult and pediatric cellulitis patients with skin biopsy [19]. S. aureus and S. pyogenes were the responsible agents in 51% and 27%, respectively. Positive blood cultures for bacteria were noted in 7.9% of 1578 patients in a series by Gunderson et al. [20][2012]: S. pyogenes (19%), S. aureus (14%), other beta-hemolytic streptococci (38%), and Gram-negative organisms (28%).

Clinical Presentation Cellulitis most commonly affect the lower extremities [18]. A tender, painful, and poorly demarcated erythematous patch or plaque with swelling and warmth is characteristic (Fig. 13.9). In the severe cases, vesicles, bullae, pustules, and necrosis may be present. The patients may also have fever, chills, malaise, and nausea. Erysipelas typically involves face and lower extremity of men more than women who are 65 years or older (Fig. 13.10) [21].  rognosis or Clinical Course P In some cases of erysipelas, there is the tendency to recur periodically. The walls of the lymphatic vessel show fibrotic thickening in the recurring cases. Histopathology Cellulitis tends to affect deeper tissue than erysipelas (Figs.  13.11 and 13.12). The infiltration of the inflammatory cells is seen in the deep dermis mainly and often extends into the subcutis

Fig. 13.9  Cellulitis. A poorly demarcated erythematous plaque with swelling

Fig. 13.10  Erysipelas involves the lower lip and perioral region

(Fig.  13.13). Neutrophils are prominent in the early stage, and the infiltration of the lymphocytes and histiocytes is present in the late stage. The dermis shows marked edema. The dilatation of the lymphatic vessels and capillary vessels is

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Figs. 13.11 and 13.12  Cellulitis. An infiltrate of neutrophils is noted in the subcutaneous lobules in cellulitis (×40, ×100)

Histologic Features • Dermal edema, dilatation of lymphatic spaces, and dense infiltrate of neutrophils Differential Diagnosis • Stasis dermatitis • Lipodermatosclerosis • Superficial thrombophlebitis • Deep venous thrombosis

Fig. 13.13  Superficial dermal neutrophilic infiltrate seen in erysipelas (×200)

identified in the dermis as well. Dermal-epidermal separation can be often seen. Gram stain is helpful to identify the organisms.

Differential Diagnosis The differential diagnoses of cellulitis of the lower extremity include stasis dermatitis, lipodermatosclerosis, superficial thrombophlebitis, and deep venous thrombosis.

Summary Clinical Presentation • Erythematous patch and plaque, pain, swelling, and warmth • Fever, chills, malaise, and nausea

Takeaway Essentials Clinical Relevant Pearls • Erysipelas is a superficial variant of cellulitis. • Cellulitis is an acute and diffuse inflammation in the dermis and/or subcutaneous tissue. • Trauma, diabetes mellitus, lymphedema, and alcoholism are risk factors for both cellulitis and erysipelas. Pathology Interpretation Pearls • Cellulitis affects deeper tissue than erysipelas. • An infiltrate of neutrophils is seen in the early stage, whereas infiltrate of lymphocytes and histiocytes is present in the late stage.

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Necrotizing Fasciitis Necrotizing fasciitis is a life-threatening bacterial infection with characteristic rapid spreading necrosis of subcutaneous tissue and superficial fascia. The agents of this disease are frequently polymicrobial, a combination of aerobic and anaerobic bacteria which contributes to its rapid course and fatality. Initially recognized to be caused by β-hemolytic streptococci, other organisms including Staphylococcus spp., Enterococcus spp., Pseudomonas spp., Proteus spp., Vibrio vulnificus have been reported [22]. Currently, there are three recognized types of necrotizing fasciitis: type I, a mixed infection; type II, due to either S. aureus or GAS; and type III, after an injury due to Vibrio spp. The risk factors are older age, diabetes mellitus, immunosuppression, as well as chronic diseases such as hypertension, peripheral vascular disease, renal failure, obesity, alcoholism, and malignancy [23].

Clinical Presentation Necrotizing fasciitis mainly affects adults, especially the middle-aged patients; however, children can rarely be affected [24]. This disease typically occurs within a day or two after trauma or surgery. The extremities, especially lower extremities, are preferentially affected, followed by the head and trunk (Figs.  13.14

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and 13.15). However, any part of the body can be affected. Localized symptoms include pain, hard edema, and erythema. Ecchymoses, necrosis, hemorrhagic blisters, and purulent secretion can also be seen [24]. The early clinical features are swelling, pain, and erythema resembling cellulitis; however, these features are nonspecific resulting in misdiagnosis in three-fourth of the patients [25]. Helpful early clinical features include out of proportion pain, failure to improve despite broad-­ spectrum antibiotics, presence of bullous skin lesions, and presence of gas in the soft tissue on plain X-ray [25]. Within 36  hours, the color of the lesion changes from reddish to violaceous. Subsequently vesicles, bullae and hemorrhagic bullae may be formed. Late signs include skin crepitus, necrosis, and anesthesia. The patients may become extremely toxic with high fever (toxic shock-like syndrome). Systemic symptoms include fever, vomiting, hypotension, and hyporexia. The exposure of muscle and tendons may be seen in the severe cases. When progressive and necrotizing infection involves the penis, scrotum, and perineum, the term Fournier gangrene is used. This variant of necrotizing fasciitis, caused by polymicrobial infections, is typically found in elderly men, diabetic patients, and immunosuppressed males. Fournier gangrene is associated with a high mortality rate of 20–40% [26].

Figs. 13.14 and 13.15  Necrotizing fasciitis. Hard edema, erythema, ecchymoses, necrosis, and hemorrhagic blisters noted on hand

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 rognosis or Clinical Course P The presence of severe pain suggests a deeper component of necrotizing fasciitis. If not treated by wide surgical debridement, the course of this disease can be fatal with mortality ranges from 20% to 60%. Infection of the head and neck is associated with high mortality [22]. Death is usually a result of septic shock associated with bacterial infection, disseminated intravascular coagulation, or multiple organ failure. Histopathology The necrosis extending from the epidermis to upper subcutis and deep tissue necrosis is characteristic for this disease (Fig.  13.16). Thrombotic vasculopathy, vasculitis, or edematous change can be seen. Hyaline necrosis of sweat glands has also been reported. A Gram stain readily highlights the bacteria between the collagen bundles. An infiltrate of histiocytes can be seen between the muscle fibers in chronic stages. Bakleh et  al. [27] showed that histologic findings may correlate with clinical outcome with patients whose biopsies show minimal neutrophils and abundant bacteria on Gram stain exhibiting higher m ­ ortality than those showing marked infiltrate of neutrophils and absent bacteria.

Differential Diagnosis It is difficult to differentiate the early lesion of necrotizing fasciitis from erysipelas and cellulitis since pain, tenderness, and swelling are the only clinical symptoms. However, blisters are seldom seen in erysipelas or cellulitis. Indistinct margins of tissue involvement and pain extending beyond the involved area are features of necrotizing fasciitis. Erysipelas involves the more superficial layers of the skin. While the necrosis is limited to the dermis and superficial subcutis in cellulitis, necrosis extends to the fascia in necrotizing fasciitis. Pyoderma gangrenosum and necrotizing Sweet syndrome are also in the differential diagnoses [28]. However, pathergy can be associated with both entities in contrast to necrotizing fasciitis. In addition, fungal necrotizing fasciitis, viral and parasitic myositis, pyomyositis, and gas gangrene should be excluded.

Summary Clinical Presentation • Edematous erythema with warmth and pain in early lesion. • Bluish patch, vesicles, bullae, and hemorrhagic bullae. • The most favorite site is the extremities, especially lower extremities, but the lesion can occur anywhere. Histologic Features • Necrosis extending from the epidermis to upper subcutis and superficial fascia. • Vasculitis, edema, thrombosis, and hyaline necrosis of sweat glands can be seen.

Fig. 13.16  Necrotizing fasciitis. Necrosis and acute inflammation involving the fascia (×40)

Differential Diagnosis • Erysipelas • Cellulitis • Clostridial myonecrosis with muscle involvement • Pyoderma gangrenosum and Sweet-like neutrophilic dermatoses

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Takeaway Essentials Clinical Relevant Pearls • Helpful early clinical features include out of proportion pain, failure to improve despite broad-spectrum antibiotics, presence of bullous skin lesions, and presence of gas in the soft tissue on plain X-ray. • Early diagnosis and timely intervention are crucial in reducing morbidity and mortality. Pathology Interpretation Pearls • Presence of microorganisms within involved skin and fascia and absence of muscle involvement

Ecthyma Gangrenosum Ecthyma gangrenosum is a severe variant of ecthyma that is typically caused by Pseudomonas aeruginosa or Pseudomonas cepacia septicemia. Pseudomonas spp. are Gram-negative, aerobic, and coccobacillus bacteria. In a series of 167 cases of ecthyma gangrenosum by Vaiman et al. [29], Pseudomonas aeruginosa was detected in 123 cases (73.65%). Other bacteria including Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Morganella morganii, Staphylococcus aureus, Corynebacterium diphtheriae, some fungi (Aspergillus, Fusarium, Candida), and others can also be the etiologic agent [29]. Ecthyma gangrenosum is mainly seen in immunosuppressed patients with AIDS, diabetes mellitus, connective tissue diseases, severe burns, organ transplant, and malignancy. It can rarely occur in the immunocompetent individuals without neutropenia and septicemia [30].

Clinical Presentation Multiple cutaneous lesions occur via hematogenous spread of bacteria, while solitary lesion is due to direct inoculation. Sources of infection include gastroenteritis, pneumonia, otitis media,

Fig. 13.17  Ecthyma gangrenosum. Necrotic ulceration with overlying eschar and surrounding erythema on a finger

urinary tract infection, prosthetic valve endocarditis, and appendiceal abscess. Invasion of the venules by etiological bacteria results in vascular thrombosis and subsequent tissue edema and epidermal detachment. The buttocks, anogenital area, and extremities are the favorite sites of involvement; however, the face and trunk can be affected. Erythematous to purpuric patches or macules are seen initially. The lesion then ­develops into hemorrhagic vesicles and bullae, to necrotic ulceration with overlying eschar and surrounding erythema (Fig. 13.17). A scar would be formed after the skin lesion heals. Fever and hypotension may be observed as well. Blood cultures and skin biopsy for histopathologic examination and cultures are needed for accurate diagnosis.

 rognosis or Clinical Course P Neutropenia is a common risk factor with many children with Pseudomonas sepsis having profound neutropenia. In the study by Vaiman et al. [29], sepsis was documented in 72/123 cases (58.5%). Ecthyma gangrenosum in healthy patients has been reported to have a higher mortality rate [31]. Histopathology Ulceration, necrosis of the epidermis and upper dermis, and underlying necrotizing vasculitis with vascular thrombosis are characteristic for this disease (Fig.  13.18) [32]. The vasculopathy is either pauci-inflammatory or with sparse

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Summary Clinical Presentation • The skin lesion can be either single or multiple. • Commonly affecting the buttocks, anogenital area, or extremities. • Erythematous to purpuric patches or macules that progress into hemorrhagic vesicles, bullae, and necrotic ulceration. Fig. 13.18  Ecthyma gangrenosum. Extensive dermal necrosis and vascular thrombosis (×100)

Histologic Features • Ulceration, necrosis of the epidermis and upper dermis, and underlying necrotizing vasculitis with vascular thrombosis • Organisms can be seen in the dermis, especially within the media and adventitia of blood vessels. Differential Diagnosis • Ecthyma • Thrombotic vasculopathy

Fig. 13.19  Ecthyma gangrenosum. Fibrin thrombus seen within a medium-sized vessel with minimal surrounding inflammatory infiltrate, consistent with a pauci-­ inflammatory vasculopathy (×600)

lymphocytes and neutrophils. The dermal infiltrate is variable with a mixture of histiocytes, lymphocytes, and neutrophils in the majority. Organisms, Gram-negative rods in the setting of Pseudomonas, can be seen in the dermis, especially within the media and adventitia of blood vessels (Fig. 13.19).

Differential Diagnosis The differential diagnosis for ecthyma gangrenosum includes ecthyma and various thrombotic vasculopathy such as warfarin-induced skin necrosis, cocaine-induced skin necrosis, disseminated intravascular coagulation, and septic emboli (see Chap. 8).

Takeaway Essentials Clinical Relevant Pearls • Ecthyma gangrenosum can be the initial manifestation of primary immunodeficiency. • It can rarely occur in the immunocompetent individuals without neutropenia and septicemia. Pathology Interpretation Pearls • Paucicellular thrombotic vasculopathy with numerous bacterial forms within the blood vessel walls

Cat-Scratch Disease Cat-scratch disease (CSD) is caused by Bartonella henselae which is a Gram-negative

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bacillus. Most patients have a history of animal contact (especially cats). Bacteremic cats with Bartonella henselae in their saliva transmit the bacteria to humans via bite or scratching. The cat fleas, Ctenocephalides felis, are responsible for transmitting the disease from cat to cat as well as to human [33]. In a retrospective analysis of CSD patients (25% body surface area) within the first 2  weeks after transplant and corresponding with a rise in the circulating absolute neutrophil count (neutrophil engraftment) [31]. Viral exanthems often present with a morbilliform eruption on the trunk and proximal extremities. Clinical history, including recent drug exposure, as well as the presence or absence of evidence of viral infection can aid in making the diagnosis. Whereas most morbilliform drug reactions exhibit eosinophils, viral exanthems are associated with extravasated erythrocytes in the upper dermis and/or epidermis. Exceptionally, a morbilliform viral exanthem will show viral cytopathic changes of cytomegalovirus (CMV) in a lesional skin biopsy [21].

15  Drug Reactions

Summary Clinical Presentation • Erythematous, maculopapular eruption involving the trunk with variable involvement of upper and lower extremities • Pruritus • Onset typically 1–3 weeks after starting a new medication • Antibiotics most commonly implicated • Absence of viral prodrome or recent hematopoietic transplant Histologic Features • Interface dermatitis (vacuolar > lichenoid), typical but not required • Superficial dermal perivascular lymphocytes, may extend to the deep dermis • Dermal eosinophils, typical but not required • Neutrophils, variable Clinical and Histologic Differential Diagnosis • Acute graft-versus-host disease • Engraftment syndrome • Eruption of lymphocyte recovery • Morbilliform chemotherapy reaction • Morbilliform viral exanthem • Morbilliform viral infection (e.g., CMV, HHV-6)

Takeaway Essentials Morbilliform/exanthematous drug eruptions represent one of the most commonly encountered drug reactions and are usually recognized clinically. Common causes include antibiotics, allopurinol, and anticonvulsants (Table 15.1). Skin biopsy may be helpful in confirming the presence of a consistent histologic appearance and also providing clues that favor or disfavor a

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drug reaction relative to the differential diagnosis of morbilliform GVHD or morbilliform viral exanthem. Clinical Relevant Pearls • Morbilliform or maculopapular eruptions typically arise within 1–3  weeks after starting a new medication and usually (but not always) resolve within days to a week of discontinuing the offending drug. • Typically involve the trunk with occasional extension to extremities. Pathology Interpretation Pearls • Interface dermatitis, often with eosinophils. • Clinical correlation is required to establish the diagnosis of morbilliform drug reaction.

 RESS (Drug Reaction D with Eosinophilia and Systemic Symptoms) Etiology and/or Pathogenesis DRESS (drug reaction with eosinophilia and systemic symptoms) is associated with significant systemic involvement, morbidity, and potential mortality. Prior terms include “druginduced hypersensitivity syndrome (DIHS),” “hypersensitivity syndrome,” and “anticonvulsant hypersensitivity syndrome.” In a series from Portugal, DRESS was the second most common form of drug reaction after morbilliform/ exanthematous drug eruptions, with a significant proportion of cases exhibiting overlapping DRESS-­morbilliform features that did not fulfill RegiSCAR criteria for a diagnosis of “probable” or “definite” DRESS [32]. Over 70 drugs have been implicated in DRESS, most commonly anticonvulsants and antibiotics [33, 34] (Table  15.2). Allopurinol accounted for one third of the 60 cases from Taiwan reported by Chen and coworkers [35].

704 Table 15.2  Drugs associated with DRESS [33, 34] Antiepileptics (e.g., carbamazepine, lamotrigine, phenobarbital, phenytoin, oxcarbazepine, gabapentin, olanzapine, valproate) Abacavir Antibiotics (e.g., amoxicillin, ampicillin, azithromycin, boceprevir, cefepime, cefixime, dapsone, ethambutol, isoniazid, levofloxacin, minocycline, nevirapine, piperacillin/tazobactam, pyrazinamide, rifampin, streptomycin, trimethoprim-sulfamethoxazole, sulfasalazine, vancomycin, zidovudine) Allopurinol Amitriptyline Antipyretics/analgesics (e.g., aspirin, diclofenac, celecoxib, ibuprofen) Atenolol Atorvastatin Bupropion Captopril Chinese herbal medicines Chlorambucil Chlorpropamide Clopidogrel Codeine Colchicine Cotrimoxazole Dapsone Diltiazem Glipizide Hydroxychloroquine Imatinib Levetiracetam Losartan Metformin Methotrexate Mexiletine Olanzapine Omeprazole Phenylbutazone Quinine Rosuvastatin Simvastatin Sorafenib Spironolactone Strontium ranelate Vemurafenib Vismodegib Zonisamide

Both a patient’s immune phenotype and ability to clear toxic metabolites contribute to the immune activation that leads to the development of DRESS. Ultimately, T-cell activation results in

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tissue damage. Activation of Th2 cells and generation of IL-5 is responsible for the prominent eosinophilia [36]. Alterations in the metabolism of certain drugs have been linked to the development of DRESS. The development of DRESS in response to anticonvulsants has been linked to an inability to clear toxic arene oxide metabolites. For this reason, patients who develop DRESS in response to an aromatic anticonvulsant (phenytoin, carbamazepine, or phenobarbital) should avoid all other aromatic anticonvulsants. Sulfonamide hypersensitivity reaction has been attributed to the generation of hydroxylamine metabolites, which leads to the generation of haptens and subsequent T-cell activation. Once immune-activating metabolites have been formed, a patient’s MHC haplotype and the presence of certain HLA molecules may allow for better binding of these haptens and peptides generated from drug breakdown. As such, several HLA molecules have been linked to a higher risk of developing DRESS in response to certain drugs [36]. HLAB∗5701 in HIV-positive Caucasian populations has been linked to the development of DRESS in response to abacavir. In fact, abacavir has been demonstrated to bind to the peptidebinding groove of this HLA molecule, where it can be presented to T cells [36, 37]. Similarly, Southeast Asian patients with HLA-­ B∗1502 and European patients with HLA-­B∗3101 are more likely to develop DRESS to carbamazepine [36, 38]. By screening for HLA phenotype prior to administering carbamazepine, and avoiding administration of carbamazepine to HLA-B∗1502-positive Taiwanese patients, the incidence of severe drug reactions including SJS, TEN, and DRESS decreased in this population, highlighting the link between immune phenotype and susceptibility [36, 39]. DRESS has additionally been associated with reactivation of latent viruses, including HHV-6, HHV-7, EBV, CMV, and even HSV [36]. HHV-6 DNA has been detected in skin and blood samples from patients with DRESS [40]. It is not clear if viral reactivation is causative or merely an epiphenomenon of DRESS [40].

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Clinical Presentation As a delayed hypersensitivity reaction, DRESS typically occurs 7–14 days after exposure but can occur up to 3 months after exposure to the o­ ffending drug. The timeline may be shorter if the patient has previous exposure to the medication. The typical presentation is fever, a morbilliform rash that may be folliculocentric initially, lymphadenopathy, and facial edema. Systemic symptoms can be quite severe, the most common of which is hepatitis. Additional systemic findings can include pneumonitis, as well as renal and cardiac involvement [36]. Blood abnormalities include eosinophilia and the presence of atypical lymphocytes and can include lymphocytopenia or lymphocytosis.

Prognosis or Clinical Course The most often employed diagnostic criteria for DRESS were developed by the European Registry of Severe Cutaneous Adverse Reactions to Drugs Collection of Biological Samples (RegiSCAR) [41]. RegiSCAR criteria include (1) skin eruption; (2) fever (>38.5 °C); (3) lymphadenopathy at least two sites, >1  cm; (4) involvement of at least one internal organ; (5) circulating atypical lymphocytes; (6) blood eosinophilia (>10% or 700/μL); and (7) negative laboratory tests for ANA, blood culture, and HAV/HBV/HSV/chlamydia/mycoplasma serology. If the patient meets a

Fig. 15.3 Azithromycin-induced drug eruption with eosinophilia and systemic symptoms (DRESS). (a) Patchy lichenoid interface dermatitis. (b) Eosinophils (short

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less than two criteria, the diagnosis of DRESS is not made. 2–3 criteria are considered “possible” DRESS, 4–5 are considered “probable,” and > 5 is considered definite DRESS [41]. In a series of 30 cases from Taiwan, high peripheral eosinophilia and significant comorbid disease were poor prognostic factors with septic shock, gastrointestinal bleeding, or acute renal failure associated with fatal outcome [42]. If a patient is diagnosed with DRESS with internal organ involvement, they are most often treated with 1  mg/kg of corticosteroids. Full recovery is achieved in 90% of patients [36, 43]. Given the immune activation that occurs with the onset of DRESS, autoimmunity, including diabetes, thyroiditis, and autoimmune hemolytic anemia, can be long-term sequelae of DRESS [44].

Histopathology Compatible with the spectrum of clinical morphology in DRESS, the histopathologic spectrum in DRESS is broad and variable (Fig. 15.3). Beyond non-specific dermal perivascular lymphocytes, there are no other requisite least common denominators. Overall, interface changes are most characteristic (Fig. 15.3), often resembling erythema multiforme with prominent single and clustered necrotic (apoptotic or dyskeratotic) keratinocytes and junctional vacuolar alteration; in one study, the presence of severe epidermal b

arrow) and necrotic keratinocytes (long arrow) are typical but not required

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dyskeratosis correlated with the presence and severity of renal or hepatic impairment [33, 45]. Spongiosis and dermal eosinophils are also usually present, although in one series from the United Kingdom, spongiosis, not interface, was the most pattern and eosinophils were present in only a minority of cases [33]. Papillary dermal edema, neutrophils, extravasated erythrocytes, and atypical lymphocytes may be seen [46]. Neutrophilic or lymphocytic vasculitis or denser lymphomatoid patterns have been documented in a minority of cases [42]. Emperipolesis has been reported [8].

Differential Diagnosis As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug. The most common histologic pattern in DRESS is that of an acute interface reaction with prominent dyskeratosis resembling erythema multiforme, but a broad range of clinical and histologic appearances is possible, and no specific histopathologic features are required.

Summary Clinical Presentation • Onset may be delayed several weeks or months after exposure • Facial edema • Variable: urticarial, morbilliform, erythema multiforme-like, exfoliative erythroderma Histologic Features • Interface (most common) dermatitis with prominent necrotic/apoptotic keratinocytes. • Eosinophils and spongiosis (usually mild) usually present.

Differential Diagnosis • Other forms of drug reaction (morbilliform) • Other forms of interface dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)

Takeaway Essentials DRESS encompasses a spectrum of combined cutaneous and systemic hypersensitivity with potential roles for HLA subtype and viral reactivation. Diagnosis should be referable to RegiSCAR criteria. Skin biopsy is not required but may show a range of compatible histologic features. Of note, an absence of lesional eosinophils does not exclude this diagnosis. Clinically Relevant Pearls • Drug reaction with systemic involvement defined by a RegiSCAR score of 4 or higher (“probable” or “definite”) • Facial edema and variable urticarial, follicular, morbilliform, erythema multiforme-­ like, or exfoliative involvement Pathology Interpretation Pearls • Most common: interface changes with prominent necrotic/dyskeratotic keratinocytes and eosinophils. • Variable: spongiosis (usually mild), papillary dermal edema, atypical lymphocytes. • Uncommon: vasculitis. • Absence of eosinophils does not exclude.

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 erum Sickness/Serum Sickness-­ S Like Drug Reaction Etiology and/or Pathogenesis For historical reference, serum sickness (SS) is considered a self-limited type III (immune complex) hypersensitivity induced by the injection of protein or serum and associated with a localized skin reaction accompanied by constitutional symptoms of fever, arthralgia, proteinuria, and variable evidence of vasculitis. In the original cases reported by von Pirquet and Shick, the reaction was induced by the subcutaneous injection of horse serum containing diphtheria antitoxin [47]. Nowadays, reports are related to biologics such as rituximab [48]. Serum sickness-­like drug reactions (SSLDR) are regarded as nonprotein, nonimmune complex mediated and will be the focus of the discussion herein; vasculitis involving the skin or other organs has not been documented to date [47].

Clinical Presentation In SSLDR, an urticarial eruption is the most common morphology followed by morbilliform reactions and purpura (Fig. 15.4). Other symptoms include malaise, fatigue, and conjunctival hyperemia. The presence of circulating serum immune complexes is also common with a decline in serum complement levels (C3 and C4). About two thirds of patients experience proteinuria, but renal failure is uncommon [47]. Leukocytosis, elevated inflammatory markers, and high immunoglobulin levels have also been reported in SSLDR [48]. Similarly, SSLDR may appear urticarial, morbilliform, and/or purpuric, with arthralgia/myalgia and fever 1–3  weeks following drug exposure (Fig.  15.4) [47]. Internal organ involvement and lymphadenopathy are not features of SSLDR.  SSLDR also does not form immune complexes, although the pathogenesis of medication-­induced SSLDR is not well

Fig. 15.4  Cefprozil-induced serum sickness-like drug eruption in a young boy presenting with urticarial papules and plaques on the hands and arms. Biopsy was not required but would be expected to show the appearances of an urticarial hypersensitivity reaction with dermal perivascular neutrophils and variable eosinophils, without vasculitis and with, at most, minimal spongiosis. Neutrophilic epitheliotropism, particularly perieccrine, may be seen [47]

understood. Typically, the drugs are nonprotein based. The clinical differential diagnoses of annular and urticarial erythema, especially those with dusky or ecchymotic central components, are urticaria multiforme, urticarial vasculitis, eosinophilic annular erythema, neutrophilic dermatosis, Still disease, and Schnitzler syndrome.

Prognosis or Clinical Course Like most drug reactions, SSLDR is self-limited and resolves upon withdrawal of the offending agent.

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Histopathology In two cases reported by Nguyen and Miller, SSLDR was characterized by a neutrophilic urticarial reaction pattern consisting of a dermal neutrophil predominant infiltrate with involvement of adnexal epithelium (neutrophilic epitheliotropism), particularly eccrine glands, and basophilic nuclear debris, but without vasculitis. Lymphocytes, eosinophils, and basophilic interstitial debris (regarded as reflecting neutrophil degranulation) were also present; the only epidermal alteration was mild spongiosis in one case [47].

Differential Diagnosis As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of an instigating drug. A neutrophilic urticarial reaction pattern may also be seen in connective tissue disorders such as lupus erythematosus (LE) (non-bullous) and systemic juvenile idiopathic arthritis (Still disease), adult onset Still disease, or autoinflammatory syndromes such as cryopyrin-associated periodic syndrome. Neutrophilic epitheliotropism has been highlighted in association with Schnitzler syndrome [49]. If epithelial changes are absent, then urticaria itself may be possible, pending clinical correlation. Most entities potentially within the clinical differential diagnosis can be excluded by skin biopsy: presence of overt interface changes in urticarial erythema multiforme (EM), presence of nuclear “dust” and vascular fibrin in urticarial vasculitis, absence of neutrophils and presence of plasma cells and eosinophils in erythema migrans, and predominant eosinophils in eosinophilic cellulitis (Wells syndrome) or eosinophilic annular erythema. If no underlying drug or systemic association is identified, classification as an idiopathic urticarial dermatitis, urticarial hypersensitivity reaction, or dermal hypersensitivity reaction may be an appropriate provisional diagnosis [50–52].

Summary Clinical Presentation • SSLDR present as urticarial, annular, morbilliform, and/or purpuric plaques in conjunction with fever and arthralgia but no additional organ involvement. • 7–21 days after exposure to the offending drug. Histologic Features • Perivascular and interstitial dermatitis with prominent neutrophils. • Neutrophilic epitheliotropism (neutrophils associated with adnexal structures, especially eccrine glands) • Basophilic nuclear debris consistent with degranulated neutrophils • Sparse eosinophils • Epidermal spongiosis minimal or absent Clinical and Histologic Differential Diagnosis • Clinical: urticarial erythema multiforme, urticarial vasculitis, eosinophilic annular erythema, juvenile rheumatoid arthritis (Still disease), Schnitzler syndrome • Histologic: neutrophilic urticaria, neutrophilic connective tissue disease (lupus, Still disease), neutrophilic autoinflammatory disease (Schnitzler syndrome, cryopyrin-associated), urticarial vasculitis

Takeaway Essentials SSLDR is a rare but distinctive and recently more fully characterized urticarial drug reaction that exhibits histologic features within the spectrum of the neutrophilic urticarial dermatoses, characterized by a neutrophil-predominant interstitial

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infiltrate with neutrophilic epitheliotropism involving eccrine sweat glands and minimal or absent epidermal changes. Documented causes include bupropion and cefazolin. Clinical Relevant Pearls • Urticarial, annular, morbilliform, and/ or purpuric eruption with arthralgia may suggest the diagnosis. Pathology Interpretation Pearls • Neutrophilic urticarial dermatosis with neutrophilic epitheliotropism. • Clinical correlation is required to establish a serum sickness-like drug reaction.

 hototoxic and Photoallergic Drug P Reaction Etiology and/or Pathogenesis Photodistributed cutaneous drug reactions are common, representing 8% of cutaneous drug reactions in a series from Norway [53]. Phototoxic and photoallergic reactions are two distinct mechanisms associated with photodistributed skin reactions, due to the interaction between a medication and metabolite [54]. Reactions associated with systemic or topical medications (“photocontact”) may occur. Greater than 300 drugs have been implicated as being photosensitizing medications, though it is often difficult to establish a definitive relationship between the drug and the reaction [54, 55]. The most commonly implicated families of drugs include antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), antihypertensive medications, and psychiatric medications [54]. Phototoxic reactions are generally considered to be significantly more common than photoallergic reactions, but it is uncertain the extent to which this holds, if at all, for photodrug reactions or photodistributed eruptions that are biopsied. It can be difficult to clinically distinguish between phototoxic and

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photoallergic reactions, though some patterns may be helpful. Diagnosis is often made based on history, clinical exam, photopatch testing, and histopathology. In general, photosensitivity occurs when a drug or drug metabolite acts as a chromophore, absorbing light at a particular wavelength (the absorption spectrum), and causes a response at a particular wavelength (the action spectrum) [56]. UVA is responsible for most photoallergic reactions, while both UVA and UVB can lead to phototoxic eruptions, though visible light has been associated with photosensitivity as well. Photoallergic reactions represent a type IV hypersensitivity reaction and therefore require prior sensitization to the medication or metabolite, while phototoxic reactions do not [54, 57]. In this setting, a hapten or antigen is created through interaction of the medication with sunlight, which can be presented on MHC molecules to T cells, resulting in activation. As such, cross-­ reactivity can occur between drugs with molecularly similar metabolites. The reaction itself will occur 24–36  hours after subsequent drug exposure [54]. As discussed below, the clinical picture resembles an eczematous dermatitis [55]. Many drugs are implicated in both phototoxic and photoallergic reactions. The most commonly implicated drugs in photoallergic reactions include sunscreen (photoallergic contact dermatitis) and NSAIDs. Within sunscreens, p-aminobenzoic acid (PABA), benzophenones, cinnamates, salicylates, and octocrylene can produce a photoallergic reaction [54]. Additional photoallergens include dapsone, pirfenidone, and sulfonylureas. Photosensitivity from hydrochlorothiazide, phenothiazines, and ketoprofen may be phototoxic or photoallergic. Phototoxicity requires no prior sensitization and is therefore thought to be more common. In theory, anyone exposed to the medication and the appropriate wavelength of light can develop a phototoxic reaction [56]. Phototoxic drug reactions are predictable, stereotypic, and usually acute onset (minutes to hours) [54]. Clinically, they tend to resemble a sunburn [55]. There is a dose-dependent effect of the interaction between a component of the phototoxic drug

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and the action spectrum of visible or ultraviolet light. The pathogenesis involves the creation of reactive oxygen species such as singlet oxygen, superoxide anion, and hydrogen peroxide and resultant host response. Phototoxic medications include tetracycline, doxycycline, furosemide, isotretinoin, acitretin, psoralens, sulfonamides, and aminolevulinic acid. Other forms of drug-induced photosensitivity include lichenoid drug reactions and pseudoporphyria; both are reviewed in separate sections.

Clinical Presentation Photoallergic drug reactions occur 24–36  hours after subsequent (not first) encounter with the offending drug, while phototoxic reactions can be immediate and do not require prior sensitization [54]. Photoallergic reactions result from immune cell activation, resulting in cutaneous inflammation that resembles eczematous dermatitis. The reaction is most often photodistributed, though systematization may occur [56] (see section “Case Vignettes”). Acute reactions present with erythema and vesiculation (corresponding to the spongiosis seen on histology), and most often will resolve upon discontinuation of the offending medication. Persistent reactions can evolve into lichenification [56]. The primary symptom is itch, though pain can be seen as well. In contrast, phototoxic reactions occur immediately after photoexposure to viable skin cells that have taken up the offending drug. They often present as an exaggerated sunburn, and the primary symptom is pain or burning, though itch may be seen as well. Post-inflammatory pigmentary changes are more commonly associated with phototoxic reactions than photoallergic reactions.

Prognosis or Clinical Course Both photoallergic and phototoxic reactions tend to resolve with discontinuation of the

offending medication. Rarely, photoallergic reaction can persist and resemble chronic actinic dermatitis [56], though the primary driver of inflammation in these cases may be actinic damage itself.

Histopathology Phototoxic and photoallergic drug reactions are usually associated with epidermal changes ranging from subtle/absent to prominent. Ballooning degeneration of superficial epidermal keratinocytes associated with intracellular edema characterizes severe phototoxic reactions. A broad zone of confluent superficial epidermal necrosis, especially if also involving the stratum corneum or associated with erosion or ulcer, also suggests a severe irritant. Individual necrotic/ apoptotic keratinocytes may be present mostly above the basal layer and may be designated “dyskeratotic” “sunburn cells,” implying photoinduction rather than the lymphocyte-mediated apoptosis characteristic of interface dermatitis. The epidermal changes in photoallergic dermatitis are primarily spongiotic with limited, if any, superimposed interface changes. The dermal perivascular lymphocytic component may extend into the reticular dermis, and eosinophils are typically present. Papillary dermal edema may be present (see “Case Vignettes”). In some examples of suspected photoallergic or phototoxic dermatitis, epidermal changes may be minimal or absent [58]. Junctional Melan A-positive pseudomelanocytic cysts were reported in a case of lichenoid phototoxic dermatitis [59]. Lichenoid drug reactions are discussed in the following section.

Differential Diagnosis As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug. All forms of cutaneous LE (acute, subacute, chronic) may be photodistributed but have distinctive

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clinical and histologic features. Lupus usually shows primary interface changes accompanied by perivascular and periadnexal lymphocytes, often moderately dense and “bottom heavy” with plasma cells and rare/absent eosinophils, and variably increased interstitial mucin, basement membrane thickening, and/or jagged rete ridges. Polymorphous light eruption (PMLE) typically presents with a chronic history of seasonal flares and, microscopically, typically exhibits a superficial and deep perivascular lymphocytic infiltrate with minimal/absent epidermal changes. Actinic prurigo is a seasonal photodermatitis accompanied by conjunctivitis and cheilitis and microscopically exhibits psoriasiform spongiotic epidermal changes associated with relatively dense and deep dermal lymphocytic infiltrates often accompanied by lymphoid follicles and eosinophils.

Summary Clinical Presentation • Photodistributed erythematous macules, patches, and/or plaques. • Phototoxic dermatitis often resembles an exaggerated sunburn with edema, crust, and desquamation. • Photoallergic dermatitis typically spongiotic/eczematous dermatitis and more likely to extend beyond exposed areas. • Acute lesions may be crusted, necrotic, or vesiculobullous. • Chronic lesions may be lichenified and hyperpigmented. Histologic Features • Spongiosis with necrotic keratinocytes (phototoxic) and/or eosinophils (photoallergic). • Variable lichenoid component. • Dermal perivascular lymphocytes may extend into the deep dermis. • Papillary dermal edema, variable.

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Differential Diagnosis • Clinical: photocontact dermatitis (e.g., phytophotodermatitis), non-drug photodermatitis (e.g., chronic actinic dermatitis), lupus erythematosus, drug-induced lupus, PMLE • Histologic: photocontact dermatitis (e.g., phytophotodermatitis), non-drug photodermatitis, actinic prurigo, lichenoid drug reaction, fixed drug reaction

Takeaway Essentials Drug-induced photodermatitis may be phototoxic or photoallergic. The histologic differential diagnosis includes spongiotic/ eczematous dermatitis and may be expanded to include actinic prurigo or a spongiotic expression of PMLE. The clinical differential diagnosis of LE can be excluded by histology. Clinical Relevant Pearls • May resemble an exaggerated sunburn (phototoxic) or eczematous dermatitis (photoallergic) Pathology Interpretation Pearls • Clinical correlation is required to establish a photodrug reaction.

Lichenoid Drug Eruption Etiology and/or Pathogenesis Lichenoid drug reactions, or drug-induced lichen planus, are common but generally less common than morbilliform drug reactions or urticaria. However, in one series from Egypt, lichenoid drug reactions were slightly more common than morbilliform drug reactions [60]. The clinical and histologic features may be similar to lichen

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planus, which may make diagnosis of drug reaction difficult. Additionally, patients may be taking multiple medications at the time of the cutaneous reaction, so it is often difficult to definitively attribute the eruption to a particular drug [61]. While many drugs have been associated with lichenoid reactions, the most commonly reported are angiotensin-converting enzyme (ACE) inhibitors, thiazide diuretics, beta-blockers, antimalarials, gold salts, statins, and penicillamine. Lichenoid drug reactions secondary to targeted biologic therapies are a major emerging reaction discussed in Chap. 16 [62, 63]. Lichenoid photodermatitis has also been associated with demeclocycline and diltiazem. Many other drugs have been documented in case reports. Oral lichenoid drug reactions can be associated with an even greater variety of agents such as talcum powder or tonic water; however, the strength of association in oral lichenoid drug reactions is often weak [64]. The length of time from initial drug exposure to cutaneous drug reaction is highly variable and may be several months to several years. The mean latent period is approximately 12  months [61]. The average latent period for beta-blockers is 3–6  months, while the average for ACE inhibitors is 12 months [61]. For penicillamine, the latent period has been reported to be up to 3 years [65]. The pathophysiology is not completely understood, though immune cell activation, likely involving both CD4+ (Th1) and CD8+ cytotoxic T cells and plasmacytoid dendritic cells, may result in destruction of basal keratinocytes. Junctional Melan A-positive pseudomelanocytic cysts were reported in a case of lichenoid phototoxic dermatitis [59].

Clinical Presentation The clinical presentation resembles lichen planus, though there may be subtle differences. As opposed to lichen planus, lichenoid drug reactions may be less monomorphic and may have eczematous, psoriasiform, or desquamative components [61, 65, 66]. Papules and plaques can be generalized but may localize to the extensor

extremities or dorsal hands [65], thus sometimes sparing the sites classically seen in lichen planus such as flexor surfaces, mucous membranes, and groin [65] (Fig. 15.5a). Wickham’s striae may be absent [65].

Prognosis or Clinical Course As with the latent period leading up to the cutaneous eruption, time to resolution can be variable. Identification and withdrawal of the offending agent are key. Symptoms such as pruritus can be managed with topical, oral, or intramuscular corticosteroids. The period until resolution has been reported as several weeks to over 12 months [65].

Histopathology Lichenoid drug reactions present as a lichenoid interface dermatitis (Fig. 15.5b), frequently with one or more typical epidermal changes of lichen planus (including hypertrophic lichen planus), including compact orthokeratosis, irregular acanthosis with jagged or sawtoothshaped rete ridges and overlying wedge-shaped hypergranulosis, and necrotic (apoptotic) keratinocytes along the dermal-­epidermal junction associated with flattened basilar keratinocytes (basilar squamatization or premature terminal differentiation) and foci of subepidermal separation (Fig. 15.5c) [67–69]. LeBoit and coworkers reported that photodistributed (versus nonphotodistributed) lichenoid drug eruptions seldom exhibited any features that differed from idiopathic lichen planus [70]. When distinguishing features are present in lichenoid drug reactions, these typically include parakeratosis (focal or diffuse) that tends to be present. In one study focusing on the thickness and configuration of the stratum corneum in the differential diagnosis of dermatoses, compact and diffuse (nonfocal) parakeratosis was seen in 50% of lichenoid drug reactions, and the stratum corneum tended to be thinner in lichenoid drug reactions compared to lichen planus [71]. As in lichen planus, cytoid

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a

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b

c

d

Fig. 15.5  Lichenoid drug eruption. (a) Lichenoid papules on the chest in a case of omeprazole-induced lichenoid drug reaction reported by Brauer and colleagues [65]. (Reproduced with permission, Barbara Burrall, Editor-in-­chief, Dermatology Online Journal). (b) Band-like lymphocytic infiltrate in the papillary dermis. (c) Compact orthokeratosis, hypergranulosis,

and jagged “sawtooth” rete ridges with basilar squamatization are lichen planus-­like features. (d) Single necrotic keratinocytes in the superficial epidermis suggest a lichenoid drug eruption [66, 67]. Other lichenoid drug reactions may show more prominent parakeratosis and/or crust, features usually not seen in lichen planus

bodies (Civatte bodies, colloid bodies), eosinophilic globules that represent immunoglobulincoated necrotic keratinocytes (usually IgM and/ or IgA on direct immunofluorescence), may be present along or immediately below the junction. Necrotic keratinocytes in the superficial epidermis (stratum corneum and stratum granulosum) have been associated with lichenoid drug reactions [66] (Fig. 15.5d). Eosinophils may be prominent or absent. Neutrophils and/or plasma cells may be seen [67]. As per drug reactions in general, deep dermal perivascular and/or periadnexal extension of the host response is typical but not required.

Differential Diagnosis As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug [66]. While some examples of lichenoid drug eruption will be histologically indistinguishable from lichen planus, histologic features that suggest lichenoid drug eruption include parakeratosis (focal or diffuse), superficial necrotic keratinocytes, prominent eosinophils, mixed lichenoid and spongiotic patterns, mixed lichenoid and granulomatous patterns, deep dermal extension of the inflammatory infiltrate, and

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prominent eosinophils. Plasma cells may also be present [67, 68]. In addition to lichen planus, multiple lichenoid keratoses (lichen planuslike keratosis) must be clinically excluded [72]. Lichenoid drug reactions may exhibit overlapping features with acute, subacute, or chronic cutaneous lupus erythematosus (LE); differentiating features include the presence of moderately dense and “bottom heavy” perivascular and periadnexal lymphocytic infiltrates with basement membrane thickening and increased interstitial mucin in the reticular dermis in LE.  Eosinophils are consistently rare/absent in LE where they would be expected in a lichenoid drug reaction. In other words, to the extent that eosinophils are prominent, lichenoid drug eruption would be favored over LE; rare/absent eosinophils would be non-specific in this differential diagnosis.

Summary Clinical Presentation • Lichenoid drug eruptions may resemble lichen planus but may differ in morphology and/or distribution. Histologic Features • Lichenoid (band-like) lymphocytic infiltrate in the papillary dermis. • Compared to lichen planus: deep dermal perivascular extension of the lymphocytic infiltrate, parakeratosis (especially if confluent), superficial necrotic keratinocytes. • Eosinophils usually present and are often prominent but not required. Clinical and Histologic Differential Diagnosis • Lichen planus (all variants: hypertrophic, atrophic, lichen planus pemphigoides) • Other forms of lichenoid dermatitis (e.g., lupus erythematosus)

• Other forms of drug reaction (e.g., fixed drug, DRESS) • Lichenoid (lichen planus-like) keratosis, e.g., multiple

Takeaway Essentials Lichenoid drug eruptions are comparable in frequency to morbilliform drug eruptions in some populations. In addition to the clinical history, clinical and/or histologic features tend to diverge from classic lichen planus with superimposed psoriasiform and/or eczematous features and nonclassic distributions clinically, as well as several clues histologically as detailed in this section. Clinical Relevant Pearls • Eczematous or psoriasiform features may be superimposed upon a lichenoid eruption. • Distribution may be generalized or favor photo-exposed extensor surfaces. • Oral involvement variable. Pathology Interpretation Pearls • Clinical correlation is required to establish the diagnosis of lichenoid drug eruption. • Features favoring lichenoid drug over idiopathic lichen planus include parakeratosis, superficial necrotic keratinocytes, or prominent eosinophils or plasma cells.

Fixed Drug Eruption Etiology and/or Pathogenesis Fixed drug eruption (FDE) has been classified as a type IVc delayed hypersensitivity reaction associated with a persistent residual population of intraepidermal CD8 memory T cells mediating a

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recurrent host response in a fixed location [73– 76]. Upon activation by antigen, intraepidermal CD8+ T cells replicate and release immunological mediators; upon subsequent exposure, their response is more vigorous and rapid as memory T cells [77]. These intraepidermal CD8+ cells release interferon gamma, granzyme B, and perforin. Recruitment of CD4+ T cells and neutrophils damages surrounding tissues (keratinocyte and melanocytes). Once resolved, these CD8+ T cells remain within the epidermis. If stimulated again by the same offending drug, they migrate upward in the epidermis and release inflammatory mediators again [77]. Various human leukocyte antigen (HLA) haplotypes have been correlated with FDE.  Numerous medications have been associated with FDE, with cotrimoxazole (trimethoprim-sulfamethoxazole), nonsteroidal anti-inflammatory drugs, and paracetamol (acetaminophen) being reported most commonly in published series [78–80]. Over 60 drugs have been implicated in FDE (Table  15.3). FDE outnumbered morbilliform reactions in some hospital-based reports from Africa and India [82, 83]. Table 15.3  Drugs associated with fixed drug eruption [76, 78, 79, 81] Acetaminophen (paracetamol) Achiote dye Acyclovir Albendazole Allopurinol Amoxicillin Aspirin Atenolol Azithromycin Barbiturates Belladonna Bromhexine Capecitabine Cefixime Cefotaxime Ceftazidime Cefuroxime Cetirizine Chlorhexidine (mouth wash) Chlorthalidone Ciprofloxacin Clindamycin Cotrimoxazole (trimethoprim-sulfamethoxazole)

715 Table 15.3 (continued) Cyclosporine Dicloxacillin Doxycycline Entecavir Ethanol (alcoholic beverage) Erythromycin Fluconazole Food additives (e.g., tartrazine) Fulvestrant Furosemide Griseofulvin Ibuprofen Influenza vaccine Ivermectin Hydralazine Hydrochlorothiazide Levocetirizine Loratadine Lorazepam Metamizole Nonsteroidal anti-inflammatory (e.g., aceclofenac, acemetacin, acyclovir, dapsone, dexketoprofen, diclofenac, etodolac, etoricoxib, flurbiprofen, griseofulvin, ibuprofen, indomethacin, loxoprofen, meloxicam, mesalazine, naproxen, nimesulide, ornidazole, piroxicam, tinidazole) Mefenamic acid Mesna Metamizole Metformin Mycophenolate Norfloxacin Nystatin Olanzapine Olopatadine ophthalmic solution Ondansetron Oral contraceptives Ornidazole Paracetamol (acetaminophen) Phenazone Pheniramine maleate Piperacillin/tazobactam Phenylbutazone Progesterone Pseudoephedrine Ropinirole Quinine (tonic water) Sildenafil citrate Sitagliptin Sunitinib Tadalafil Tetracycline

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Clinical Presentation Fixed drug eruption (FDE) often involves the genitals, face (especially lips), trunk, and hands (Fig.  15.6a). Typically, it is a well-defined, circular, often hyperpigmenting plaque recurrent as one or a few lesions in same locations after ingestion of a drug. “Fixed” means that if the same drug is taken again, recurrence happens in the same location. It can occur rapidly as early as 30 minutes or days after ingestion of the offending drug [76]. The lesions may be pruritic. Bullae and subsequent erosions occur more rarely. Satellite lesions may be seen and sometimes can be confluent. One study of FDE demonstrated greater than five lesions in up to half of the cases [78]. Rarely, FDE may happen within skin trauma sites, such as burns or bites. FDE presentations can be so unusual that, often, primary care physicians fail to recognize it. Unusual presentations include nonpigmenting FDE, which resolve without pigmentation and generalized bullous FDE which may appear similarly to Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) [78, 84, 85].

is predominantly neutrophilic [86, 87]. Purpuric FDE with associated vasculitis has been reported [88]. With recurrent flares, melanophages tend to become increasingly prominent, especially in dark complexed patients.

Differential Diagnosis As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug. In the clinical context of a solitary lesion, other types of drug reaction are less likely. If multiple or generalized lesions are present, greater emphasis on the clinical morphology will be required. If only mild perivascular lymphohistiocytic ­infiltrates with melanophages are present, without neutrophils or eosinophils, idiopathic macular pigmentation may be considered [89]. In the urgent or hospital setting, generalized FDE may be clinically confused with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), in which case histopathology may be decisive. Prominent eosinophils and melanophages typify generalized FDE, whereas both are typically rare or absent in SJS/TEN [84, 90].

Prognosis or Clinical Course FDE resolves within days upon discontinuation of the offending drug. The hyperpigmentation is long lasting once the acuteness resolves although some patients may present with no active inflammation.

Histopathology FDE typically presents as interface dermatitis (vacuolar or lichenoid), often with deep dermal perivascular extension of the predominantly lymphocytic host response (Fig. 15.6b). Superimposed spongiosis may be present and occasionally may predominate over interface changes. Papillary dermal edema may be prominent, especially in early or bullous lesions (Fig. 15.6c–e). The typical host response is lymphohistiocytic with eosinophils and/or neutrophils. Occasionally, the infiltrate

Summary Clinical Presentation • Solitary round/ovoid erythematous and/ or hyperpigmented plaque recurring at the anatomic site following administration of the same drug (or same drug class) • Face (lip) and genitalia commonly affected • Generalized and bullous variants more likely encountered in the hospital setting Histologic Features • Interface dermatitis (vacuolar or lichenoid) with deep dermal perivascular extension of inflammation

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Fig. 15.6  Fixed drug eruption. (a) A solitary erythematous plaque on the face is typical. (b) Variable spongiotic and interface changes are expected. (c) Eosinophils and papillary dermal edema are typical but not required. (d) Bullous fixed drug eruption (FDE). Superficial and deep dermal perivascular dermatitis with eosinophils, melano-

phages, and subepidermal blister secondary to confluent epidermal necrosis, similar to toxic epidermal necrolysis (TEN) but associated with a prominent inflammatory host response in bullous FDE. (e) The subepidermal blister roof exhibits orthokeratosis yet is partly reepithelialized, consistent with the acute and episodic nature of the eruption

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• Eosinophils and/or neutrophils • Melanophages increasingly prominent with repeat episodes • Papillary dermal edema, variable • Spongiosis, variable Differential Diagnosis • Clinical: solitary (contact dermatitis), generalized, SDRIFE, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) • Histologic: other forms of drug reaction, including DRESS, lichenoid, morbilliform/exanthematous, photoallergic

Takeaway Essentials FDE is a clinically distinct variant of drug reaction that is often suspected clinically, without need for a biopsy. In the hospital setting, generalized FDE is more likely to be biopsied, as the clinical differential diagnosis may include symmetric drugrelated intertriginous and flexural exanthema (SDRIFE), SJS, or TEN.  Interface dermatitis with variable edema, neutrophils, eosinophils, and/or melanophages are typical features. Melanophages may not be prominent in fair-complexed patients or nonpigmented FDE. Clinical Relevant Pearls • Generalized FDE may clinically resemble SJS/TEN. Pathology Interpretation Pearls • Interface dermatitis with variable spongiosis. • Eosinophils, neutrophils, and/or melanophages are usually present. • Clinical correlation is required to establish the diagnosis of fixed drug eruptions.

Bullous Drug Reactions Drug-Induced Linear IgA Disease  tiology and/or Pathogenesis E Linear IgA disease (LAD) is an autoimmune blistering disorder defined by the presence of linear deposition of IgA along the dermalepidermal junction (DEJ). LAD may be druginduced, infection-induced, or idiopathic. The most common causes of drug-induced LAD are antibiotics, classically vancomycin [91]. In a French cohort of 69 drug-induced LAD patients (1985–2017), vancomycin was responsible for 57% of cases [91]. Lithium, cefamandole, captopril, diclofenac, enoxaparin, minocycline, vibramycin, and cefuroxime have additionally been reported [91–93]. As with autoimmune LAD, circulating antibodies to the 97kD (most common) and 120kD fragments of the bullous pemphigoid antigen BP180 (BPAg2) localize to the lamina lucida and are considered pathogenic. However, unlike idiopathic LAD, circulating antibodies are found in only a minority of patients with drug-induced LAD [92, 93]. In drug-induced LAD, it is likely that medications or medication metabolites act as hapten or antigen. As such, first exposure will likely be asymptomatic, with drug-induced LAD occurring upon subsequent exposure. Other antigens targets include BPAg1 (230kd), BPAg2, laminin 332 (in IgG/ IgA dermatosis), and sublamina densa type VII collagen (anchoring fibril). Vancomycinassociated cases have been associated with type VII collagen as the antigen. Interestingly, many patients with drug-induced LAD have underlying infection at the time of the cutaneous eruption, indicating that immune activation may be multifactorial. Pediatric linear IgA disease (also known as chronic bullous disease of childhood) is generally not drug-induced. Clinical Presentation Reactions most commonly appear 4–14  days after the second exposure to the offending

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Fig. 15.7  Linear IgA disease. (a) Annular or circinate collection of tense blisters forming a “crown of jewels” is the classic appearance. (b) The subepidermal blister is associated with a neutrophil predominant host response, but eosinophils may be present and even predominate in

foci away from the blister edge. Perilesional direct immunofluorescence testing is required and demonstrates strong and continuous linear deposition of IgA along the dermal-­epidermal junctional of intact perilesional skin, usually as the sole immunoreactant (see Fig. 15.24d)

drug, though delayed responses, up to 3  weeks after drug withdrawal, have been reported [93]. Clinical findings in both LAD and drug-induced LAD are heterogeneous, though drug-induced LAD tends to be more severe than LAD and can even mimic toxic epidermal necrolysis (TEN) [91]. The Nikolsky sign can be positive. Tense polycyclic arciform bullae in a “cluster of jewels” pattern are often seen, and these may arise from an urticarial base [93] (Fig.  15.7a). Additional reported presentations include a dermatitis herpetiformis – like presentation with pruritic papulovesicles [93]. Approximately 42% of patients with drug-induced LAD have mucous membrane involvement [91].

tures include a neutrophil-predominant infiltrate within and around a subepidermal cleft (Fig.  15.7b). Eosinophils may be present and may even predominate in foci, but neutrophils should predominate over eosinophils at the blister edge. Neutrophils may collect within dermal papillae creating papillary dermal microabscesses (most typical of dermatitis herpetiformis) (Fig. 15.8). As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug. There is no acantholysis or vasculitis.

 rognosis or Clinical Course P While patients with autoimmune LAD may have a relapsing or chronic course, most cases of drug-­induced LAD resolve with withdrawal of offending drug. Treatment options include topical steroids, systemic steroids, dapsone, intravenous immunoglobulin, colchicine, and cyclosporine [91]. Histopathology The expected findings in LAD are the same whether drug-induced or not. Typical fea-

Differential Diagnosis The clinical differential diagnosis of LAD mostly includes other subepidermal immunobullous disorders such as bullous pemphigoid, cicatricial pemphigoid, or bullous LE, but also pemphigus or TEN.  The histologic differential diagnosis for a subepidermal blister with mostly neutrophils includes other forms of neutrophilic drug reaction as well as other neutrophilic immunobullous disorders, particularly dermatitis herpetiformis, but also bullous pemphigoid, cicatricial (mucous membrane) pemphigoid, bullous LE, and epidermolysis bullosa acquisita. Superficial fibrosis/

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Summary Clinical Presentation • Onset 4–14  days after the subsequent exposure to the offending drug • Tense polycyclic arciform bullae in a “cluster of jewels” pattern • Toxic epidermal necrolysis (TEN)-like presentation (Fig. 15.24)

Fig. 15.8  Linear IgA disease. In early lesions, a blister has not yet formed, but inflammatory cells aggregate near the dermal-epidermal junction. Neutrophils aggregating within dermal papillae (papillary dermal microabscess) are indistinguishable from the classical appearance of dermatitis herpetiformis. The H&E differential diagnosis includes other immunobullous disorders. Eosinophils are often admixed with neutrophils but do not predominate in linear IgA disease

scar characterizes cicatricial pemphigoid. In some cases, leukocytoclastic vasculitis involving postcapillary venules in the upper dermis can be associated with secondary neutrophilic infiltrates along and/or above the dermalepidermal junction that might be mistaken for LAD if the underlying vasculitis is not appreciated. Direct immunofluorescence (DIF) findings readily distinguish linear IgA disease from all other immunobullous disorders and vasculitis, typically with continuous, linear deposition of IgA along the dermal-epidermal junction as the sole finding. Papillary dermal microabscesses in LAD represent a shared H&E feature with dermatitis herpetiformis, but only LAD exhibits linear IgA deposition at the DEJ, whereas dermatitis herpetiformis exhibits granular IgA deposition (+/− C3, fibrinogen, or other immunoglobulins) at the DEJ accentuated within the DEJ and papillary dermal tips. Bullous pemphigoid occasionally exhibits linear IgA deposition but in concert with C3 and/or IgG, whereas in LAD, IgA is the sole reactant.

Histologic Features • Subepidermal cleft associated with a neutrophil-predominant host response • Linear deposition of IgA (exclusively) along the dermal-epidermal junction on direct immunofluorescence (DIF) of perilesional skin Differential Diagnosis • Clinical: bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, bullous lupus erythematosus, epidermolysis bullosa acquisita, TEN • Histologic: bullous pemphigoid, dermatitis herpetiformis, bullous lupus erythematosus, epidermolysis bullosa acquisita, secondary epidermal changes in leukocytoclastic vasculitis

Takeaway Essentials Linear IgA disease is usually drug-­ induced, most classically vancomycin. In the hospital setting, clinical presentations resembling TEN may be encountered. Perilesional DIF testing is required to establish the diagnosis and is both sensitive and specific for the diagnosis of LAD. Clinical Relevant Pearls • Consider TEN-like LAD in the hospital setting.

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Pathology Interpretation Pearls • Perilesional DIF testing is required to establish the diagnosis of LAD. • Clinical correlation is required to establish drug-induced LAD.

Drug-Induced Bullous Pemphigoid  tiology and/or Pathogenesis E Drug-induced bullous pemphigoid (BP) is associated with autoantibodies directed against the same antigen targets seen in spontaneous cases, including the 230 kD protein. More than 50 drugs have been identified in drug-induced BP [94]. Furosemide, penicillamine, and spironolactone are commonly implicated [95, 96]. Although ACE inhibitors are more commonly implicated in drug-induced pemphigus foliaceus, lisinopril-­ induced BP has been reported. Drug-induced BP has more recently been recognized in the context of patients with diabetes on dipeptidyl peptidase-­4 inhibitors (DPP4i) and patients receiving immune checkpoint inhibitors directed against programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) [97]. Patients with DPP4i-associated drug-induced BP tend to have more mucosal involvement and lower eosinophil counts than patients with diabetes and BP without DPP-4 inhibitors [98]. Vildagliptin appears to be most commonly implicated [99, 100]. Clinical Presentation Drug-induced BP typically presents as per idiopathic bullous pemphigoid with tense bullae and a negative Nikolsky sign in a generalized distribution on the trunk, extremities, or face. Localized pemphigoid, often on the legs (pretibial pemphigoid) or hands and/or feet (dyshidrosiform pemphigoid), has generally not been attributed to drugs, although a case of pembrolizumab-­ induced pretibial pemphigoid was recently reported. The perilesional skin may be non-­ inflamed, erythematous, or urticarial. Pruritus can be severe. Mucosal involvement is typically mild or absent altogether. Marked peripheral eosinophilia can be found in drug-

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induced BP [94]. Atypical features can include erythema multiforme-like target lesions on the palms and soles or a positive Nikolsky sign.

 rognosis or Clinical Course P As there are no specific tests to differentiate drug-­induced BP from idiopathic BP, the diagnosis is primarily based on correlation with the medication history. On average, patients with drug-­induced BP are younger than those with idiopathic BP. Two clinical courses are observed in drug-­induced BP: drug-induced BP “proper” that resolves promptly after discontinuing the drug and “drug-triggered” BP that persists as per classic BP after cessation of the drug, e.g., furosemide [94]. Histopathology The expected findings in BP are the same whether drug-induced or not. Typical features include a subepidermal blister with numerous eosinophils within a predominantly lymphocytic host response in the upper dermis. In paucicellular lesions, eosinophils may be rare. Neutrophils are variably present. In early/prebullous urticarial lesions, BP manifests as spongiotic dermatitis with eosinophils present along the dermal-­epidermal junction and/or within the epidermis (eosinophilic spongiosis) (Fig. 15.9). Late or established blisters show variable reepithelization across the subepidermal blister floor, creating the false impression of a suprabasilar or more superficial intraepidermal blister (Fig.  15.10). In contrast to pemphigus, the keratinocytes lining the reepithelializing blister floor are not acantholytic; in contrast, they are flattened or “squamatized” similar in profile to the keratinocytes of the stratum granulosum and as typically seen in the basilar epidermis of stereotypical wound healing reactions as well as lichen planus. In the appropriate clinical and histologic context, the diagnosis of BP is confirmed by the presence of strong, continuous, linear deposition of C3 +/− IgG along the dermal-epidermal junction on perilesional DIF.  A “n”-serrated DIF pattern has been reported to specifically distinguish EBA from BP (EBA shows a “u”-serrated pattern) [101, 102].

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a

Fig. 15.9  Bullous pemphigoid, urticarial or prebullous stage. There are no specific histologic differences between drug-induced and idiopathic pemphigoid. (a) In urticarial pemphigoid, the panoramic view shows only sparse superficial and mid-perivascular dermatitis without significant epidermal alteration or deep dermal involvement. (b) Eosinophils aggregate at the dermal-epidermal junc-

a

b

tion with variable associated spongiosis, including eosinophilic spongiosis. Clefting between the stratum corneum and stratum granulosum is a common laboratory processing artifact that is non-specific. The diagnosis is usually confirmed by demonstrating continuous, linear deposition of C3 along the dermal-epidermal junction of perilesional skin on direct immunofluorescence (DIF) testing

b

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Fig. 15.10  Bullous pemphigoid, partly reepithelialized. (a) At scanning magnification, significant portions of the blister appear intraepidermal rather than subepidermal. (b) The “active” edge of the blister reveals the true or pri-

mary subepidermal cleavage plane. (c) Flattened keratinocytes of varying thickness across the blister floor indicate reepithelialization when well-established lesions are sampled

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Differential Diagnosis As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm an instigating drug. Serologic studies may also be helpful in cases where DIF results are equivocal. If neutrophils are present, LAD, cicatricial pemphigoid, and bullous LE should be considered. The infiltrate in LAD is typically neutrophil-predominant, with strong and continuous perilesional deposition of IgA (only) on DIF testing. Cicatricial pemphigoid (mucous membrane pemphigoid) has a predilection for involvement mucosal sites, including the oral cavity and/or conjunctiva; microscopically, inflammation may be relatively sparse, and established lesions exhibit fibrosis of the papillary dermis or superficial submucosa. Bullous LE usually arises in patients with a preexisting history of systemic LE; microscopically, an atrophic interface dermatitis involving adnexal epithelium is typically present, and DIF testing usually shows either a positive lupus band or linear deposition at the basement membrane zone targeting anchoring fibrils (type VII collagen) with localization to the subepidermal blister floor in salt-split DIF testing, as per epidermolysis bullosa acquisita (EBA). Inflammation is also typically scant in EBA. If surface crust and eosinophils are prominent, scabies may be considered. Deep dermal or subcutaneous extension of the inflammatory infiltrate is not typical of BP and would suggest other forms of bullous drug or non-drug bullous hypersensitivity reaction (e.g., arthropod bite, bullous Wells syndrome). If lichen planustype epidermal hyperplasia is present, lichen planus pemphigoides may be considered.

Summary Clinical Presentation • Tense blisters, usually generalized, on the trunk, extremities, and face. • Pre-bullous lesions are often urticarial. Histologic Features • Subepidermal vesiculobullous dermatitis containing lymphocaytes and many eosinophils.

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• Early or urticarial lesions show eosinophilic spongiosis or perivascular dermatitis with eosinophils aggregating at the dermal-epidermal junction. • Linear deposition of C3 +/− IgG with variably evident “n”-serrated pattern along the dermal-­epidermal junction on DIF. • Immunopositivity localizes to the blister roof in perilesional salt-split DIF testing. Differential Diagnosis • Clinical: non-pemphigoid bullous drug reactions, cicatricial pemphigoid, bullous lupus erythematosus, epidermolysis bullosa acquisita, pemphigus, bullous scabies, bullous tinea • Histologic: non-pemphigoid bullous drug reactions, cicatricial pemphigoid, bullous lupus erythematosus, epidermolysis bullosa acquisita, lichen planus pemphigoides, bullous arthropod bite reaction, bullous scabies, bullous allergic contact dermatitis, bullous Wells syndrome (eosinophilic cellulitis)

Takeaway Essentials Drug-induced BP resembles idiopathic bullous pemphigoid both clinically and histologically. Perilesional DIF testing is required to confirm BP. Clinical correlation is required to establish drug-­induced BP. Clinical Relevant Pearls • Bullous pemphigoid is the most common immunobullous disorder • Patients with drug-induced BP may be younger, usually have generalized rather than localized lesions, and may display atypical features including targetoid lesions or a positive Nikolsky sign. • Some cases of drug-induced BP resolve promptly upon drug withdrawal, whereas other cases persist as per idiopathic BP.

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Pathology Interpretation Pearls • Perilesional DIF testing is required to establish the diagnosis of BP. • Clinical correlation is required to establish drug-induced BP.

 rug-Induced Epidermolysis Bullosa D Acquisita  tiology and/or Pathogenesis E Epidermolysis bullosa acquisita (EBA) is a rare subepidermal autoimmune blistering disease that is often idiopathic but may be drug-induced. Antibodies to type VII collagen are pathogenic and result in mucocutaneous blistering, as this anchoring fibril helps link the epidermis to the dermis [103–105]. There are two major forms of EBA: mechanobullous, which results in blisters and scarring on trauma-prone areas, and inflammatory, which resembles other autoimmune blistering diseases such as BP [103]. Drug-induced EBA has overlap with other drug-induced blistering diseases and is reported to occur most commonly with antibiotics, including vancomycin [104]. Other medications reported to cause drug-induced EBA include furosemide, sulfonamides, penicillamine, and gentamicin [104–106]. UV light and contact allergy to metal have also been implicated as t­riggers for EBA [105]. The reaction may take months or years after initiation of the drug to occur [106].

been reported to subside over the course of months, whether or not the offending drug was continued [106].

Histopathology The expected findings in EBA are the same whether drug-induced or not. Typical features include a subepidermal blister with scant inflammatory cells. Neutrophils, eosinophils, and/or superficial papillary dermal fibrosis may be present. In the appropriate clinical and histologic context, the diagnosis of EBA is confirmed by the presence of strong, continuous, and linear deposition of IgG +/− IgA and/or C3 along the DEJ on perilesional DIF. A “u”-serrated DIF pattern has been reported to specifically distinguish EBA from BP (BP shows an “n”-serrated pattern) [101, 102]. Perilesional salt-split DIF testing demonstrates localization of immunoreactants to the floor of the salt-induced subepidermal (lamina lucida) split (Fig. 15.11b, c). Indirect immunofluorescence shows circulating autoantibodies to anchoring fibrils (collagen VII) [105].

Differential Diagnosis As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm an instigating drug. EBA is among the rarest of immunobullous disorders; perilesional salt-split DIF testing and serologic studies may be needed to confirm the diagnosis. If eosinophils are present, prior probability favors BP. If neutrophils are present, LAD, cicatricial pemphigoid, or bullous LE should be considered. The infiltrate Clinical Presentation in LAD is typically neutrophil-predominant, with Mechanobullous EBA presents with non-­ strong and continuous perilesional deposition of inflammatory skin fragility, vesicles, bullae, IgA (only) on DIF testing. Cicatricial pemphigoid and erosions that heal with milia-like scars and (mucous membrane pemphigoid) has a predileccan result in cicatricial alopecia and nail dystro- tion for involvement mucosal sites, including phy (Fig.  15.11) [105]. This occurs in areas of the oral cavity and/or conjunctiva; microscopitrauma, such as over elbows, knees, hands, and cally, inflammation may be relatively sparse, and feet. In contrast, inflammatory variants of EBA established lesions exhibit fibrosis of the papilcan mimic other inflammatory autoimmune bul- lary dermis or superficial submucosa. Bullous lous diseases, such as BP, linear IgA bullous dis- LE usually arises in patients with a preexistease, or cicatricial pemphigoid [105]. ing history of systemic LE; microscopically, an atrophic interface dermatitis involving adnexal Prognosis or Clinical Course epithelium is typically present, and DIF testing While there is limited data in the literature usually shows either a positive lupus band or linregarding drug-induced EBA, the reaction has ear deposition at the basement membrane zone

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b

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Fig. 15.11  Epidermolysis bullosa acquisita (EBA). There are no specific histologic differences between drug-­induced and idiopathic EBA. (a) Tense, non-inflammatory blisters with associated scarring and dyspigmentation. Sites of trauma are most susceptible. (b, c) Perilesional direct immunofluorescence (DIF) testing typically shows continuous, linear deposi-

tion of IgG along the dermal-­ epidermal junction with a variably evident u-serrated pattern. Perilesional salt-split DIF testing induces a cell-poor subepidermal split within the lamina lucida. In EBA, IgG localizes to the blister floor, indicative of the sublamina densa location of the anchoring fibrils (type VII collagen) (b, H&E, salt-­split; c, IgG)

targeting anchoring fibrils (type VII collagen) with localization to the subepidermal blister floor in salt-­split DIF testing. If the dorsal hands are involved, porphyria and pseudoporphyria should be considered. Histologic features of porphyria/ pseudoporphyria include preserved dermal papillae (festooning), the presence of PAS-positive caterpillar bodies within the epidermal blister roof (see drug-induced pseudoporphyria), and highlighting of both the dermal-epidermal junction and superficial dermal vessels on DIF testing. Bullous lichen planus (LP) usually arises

within preexisting classic LP lesions and is associated with the typical histologic features of LP with secondary subepidermal blister formation secondary to prominent interface changes, i.e., progression of subclinical Max-Joseph spaces into a clinically evident blister; on DIF testing, cytoid bodies highlighted by immunoglobulin(s) and “shaggy” linear deposition of fibrinogen may be seen at the dermal-epidermal junction in bullous LP, but, with the exception of lichen planus pemphigoides, no linear deposition of C3 or immunoglobulins at the junction.

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Summary

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Clinical Relevant Pearls • Non-inflammatory blisters and milia at Clinical Presentation sites of trauma are characteristic. • Mechanobullous/classic: non-­ Pathology Interpretation Pearls inflammatory skin fragility with vesi• Clinical correlation, perilesional salt-­split cles, bullae, and erosions that heal with DIF testing, and/or serologic studies are milia-like scars at sites of trauma. required to establish drug-induced EBA. • Inflammatory: may resemble any subepidermal immunobullous disorder, most commonly bullous pemphigoid, but also linear IgA disease, cicatricial Drug-Induced Pemphigus pemphigoid, or Brunsting-Perry pemphigoid. Etiology and/or Pathogenesis • Oral involvement is common. Drug-induced pemphigus may mimic any of the variants of idiopathic pemphigus, although Histologic Features desmoglein 1-associated pemphigus foliaceus • Subepidermal blister with sparse host and desmoglein 3-associated pemphigus vulresponse (“cell poor”). garis are the most commonly encountered pat• Perilesional DIF: linear deposition of terns. Circulating antibodies are less frequently IgG +/− C3 with variably evident “u”detected in drug-induced pemphigus compared serrated pattern along the dermal-epito idiopathic cases [8]. Different mechanisms dermal junction. of action have been associated with different • Immunopositivity localizes to the blister classes of inciting drugs including thiol (sulffloor in perilesional salt-split DIF hydryl group)-, phenol-, or amide-containing testing. drugs. Thiol drugs inhibit enzymes that unify keratinocytes and activate enzymes that sepaDifferential Diagnosis rate keratinocytes. Some thiol-containing drugs may do so via autoantibody formation. • Clinical and histologic: non-EBA bulWhile there is significant overlap, pemphilous drug reactions, cicatricial pemphigus foliaceus has been reported to be more goid, bullous lupus erythematosus, often associated with thiol (captopril, bucilepidermolysis bullosa acquisita, porlamine, d-penicillamine, cetapril, tiopronin), phyria cutanea tarda, pseudoporphyria, whereas pemphigus vulgaris is associated with venous stasis bulla, bullosis diabeticonon-thiol drugs such as sulfasalazine [107]. rum, and bullous lichen planus Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers represent a major category [108]. Captopril was implicated in one case of pemphigus vegetans Takeaway Essentials in which lesional skin contained CharcotLeyden crystals [109]. Erdosteine was impliEBA is among the rarest of immunocated in one case of drug-induced pemphigus bullous disorders. Perilesional salt-split herpetiformis [110]. Other drugs include DIF testing and serologic studies may be imatinib. Fludarabine has been reported as required to establish the diagnosis and rule a trigger in chronic lymphocytic leukemia out drug-induced linear IgA disease or BP. (CLL)-associated paraneoplastic pemphigus.

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Phenol drugs could stimulate keratinocytes to release proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and IL-1, which can cause acantholysis. Heroin, a phenol drug associated with pemphigus, was first described in 1978. Subsequently, nasofacial pemphigus vegetans has been associated with intranasal cocaine and heroin use [111, 112]. Most examples of drug-induced pemphigus arise within a few weeks of starting the offending drug. A notable exception is the several months delayed onset associated with penicillamine-­ induced pemphigus.

Clinical Presentation The clinical presentation often differs from idiopathic pemphigus vulgaris. Drug-induced pemphigus vulgaris more often resembles pemphigus foliaceus or pemphigus herpetiformis, so the term “pemphigus-like syndrome” often appears more appropriate for this condition [113].  rognosis or Clinical Course P If pemphigus is induced by a thiol drug and lacks cell surface antibodies, at least 50% of patients will see an improvement on discontinuation. If the patient with drug-induced pemphigus has cell surface autoantibodies, the course is more chronic and often similar to pemphigus vulgaris [114]. Histopathology There are no established differences in the histopathologic features of drug-induced versus idiopathic cases of pemphigus. The diagnostic changes affect both epidermis and adnexal epithelium and sometimes may be centered upon hair follicles or sweat ducts. Drug-induced pemphigus vulgaris shows suprabasilar acantholysis creating a tombstone-like row of acantholytic basal layer keratinocytes comprising the blister floor (see Chap. 9). Eosinophils and/or neutrophils are typically present within the host response. Drug-induced pemphigus foliaceus (PF) is characterized by superficial acantholysis and dyskeratotic granular keratinocytes centered upon the stratum granulosum and its junction with the stratum spinosum (see Chap. 9). Rare cases of drug-induced pemphigus erythematosus resemble PF but also exhibit interface dermatitis. In early lesions of pemphigus, the appearances

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may merely show eosinophilic spongiosis or neutrophilic spongiosis without overt acantholysis.

Differential Diagnosis As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug. In paraneoplastic pemphigus, acantholysis is usually accompanied by interface changes and additional basement membrane deposition on perilesional DIF testing. The exfoliative toxins in bullous impetigo and staphylococcal scalded skin syndrome (SSSS) target pemphigus foliaceus-­ associated desmoglein 1 and thus create the same cleavage plane with associated superficial acantholysis. In bullous impetigo, Gram-positive cocci can be identified within the blister. In SSSS, in addition to the distinctive clinical setting, lesional pathogens and the inflammatory host response are both lacking. Benign familial ­pemphigus (Hailey-Hailey disease) is associated with more variable and full thickness acantholysis; in contrast, pemphigus usually exhibits either a suprabasilar or intragranular cleavage plane. Acantholytic dyskeratosis is an epidermal reaction pattern seen in transient acantholytic dermatosis (Grover disease) and keratosis follicularis (Darier disease) where suprabasilar acantholysis resembling pemphigus vulgaris may be seen; in contrast to pemphigus, there are overlying dyskeratotic keratinocytes exhibiting round (“corps ronds”) or flat (“grains”) profile, and DIF is essentially negative.

Summary Clinical Presentation • Flaccid blisters and superficial erosions characterize all forms of pemphigus. • Oral involvement expected in pemphigus vulgaris. Histologic Features • Pemphigus vulgaris: intraepithelial acantholysis centered upon the suprabasilar zone creating a tombstone appearance of the epithelial blister floor.

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• Pemphigus foliaceus: superficial acantholysis centered upon the granular layer with dyskeratotic granular keratinocytes in the epidermis and follicular epithelium. • Host response contains lymphocytes, eosinophils, and often neutrophils and/ or plasma cells. • Intercellular (cell surface) epidermal IgG and/or C3 deposition on perilesional DIF. Differential Diagnosis • Clinical: non-drug-induced pemphigus, non-pemphigus bullous drug reactions, benign familial pemphigus (Hailey-­ Hailey disease), bullous impetigo, bullous lupus erythematosus • Histologic: non-drug-induced pemphigus, bullous impetigo, staphylococcal scalded skin syndrome, benign familial pemphigus (Hailey-Hailey disease), transient acantholytic dermatosis (Grover disease), keratosis follicularis (Darier disease)

Takeaway Essentials In all clinical and histologic variants, the diagnosis of drug-­ induced pemphigus requires clinical correlation combined with histologic, immunofluorescent, and/or serologic confirmation of the pemphigus group of diseases. Certain classes of drugs are more likely to induce pemphigus foliaceus, whereas others tend to induce pemphigus vulgaris. Clinical Relevant Pearls • Drug-induced pemphigus is not readily distinguishable from idiopathic pemphigus on clinical morphology, only by clinical history.

M. A. Fung et al.

Pathology Interpretation Pearls • Perilesional DIF testing is required to establish the diagnosis of pemphigus. • Clinical correlation is required to establish drug-induced pemphigus.

Drug-Induced Pseudoporphyria  tiology and/or Pathogenesis E Pseudoporphyria is a photodistributed phototoxic reaction with clinical and histologic features virtually identical to porphyria cutanea tarda (PCT) but with normal urine, stool, and blood porphyrin levels [115]. Pseudoporphyria can be drug-­ induced, but has also been reported to occur in the setting of renal disease, excess sun exposure, or UVA light such as through tanning bed use [115]. Over two dozen medications have been implicated as causes of drug-induced pseudoporphyria, including NSAIDs such as naproxen, nabumetone, oxaprozin, ketoprofen, mefenamic acid, and diflunisal; antibiotics such as nalidixic acid and tetracycline; diuretics such as chlorthalidone, bumetanide, furosemide, torsemide, and hydrochlorothiazide/triamterene; retinoids such as isotretinoin and etretinate; and other medications including cyclosporine, finasteride, 5-­ fluorouracil, carisoprodol/aspirin, diclofenac, metformin, pyridoxine, amiodarone, chlorophyll, supplements, country mallow, flutamide, dapsone, gold, imatinib, and voriconazole [115, 116]. PCT occurs after exposure to light in the Soret band (400–410  nm); however, pseudoporphyria is more associated with UVA light, through either direct UVA damage or UVA effect on a medication and subsequent generation of reactive oxygen species [115]. Interestingly, many of the drugs that can cause drug-induced pseudoporphyria may increase sensitivity to UVA, including retinoids, NSAIDs, and nalidixic acid [115]. There is some evidence that pseudoporphyria associated with renal disease may be partially due to inadequate clearance of photosensitive medications such as diuretics [115]. It is likely

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that both immune activation from medications or metabolites of medications and reactive oxygen species from UVA result in the clinical features of drug-induced pseudoporphyria.

Clinical Presentation Drug-induced pseudoporphyria can be clinically quite similar to PCT or pseudoporphyria associated with other causes. Patients present with photodistributed skin fragility, vesicles, bullae, milia, and scars on the dorsal hands with variable involvement of the photo-exposed arms and face, particularly the ears or nose (Fig. 15.12a). Photoonycholysis may be present. In contrast to PCT, hypertrichosis, sclerodermoid changes, and dystrophic calcification are only rarely found [115]. Porphyrin levels are normal by definition.  rognosis or Clinical Course P Drug-induced pseudoporphyria should resolve promptly upon cessation of the offending agent. The cornerstones of treatment are withdrawal of the offending drug and sun protection, particularly against UVA light. Histopathology Consistent with the typical lesional distribution in pseudoporphyria, biopsies are usually obtained from the dorsal hands or extensor forearms of the skin with severe solar elastosis and characterized by a subepidermal blister with sparse inflammaa

Fig. 15.12  Pseudoporphyria. (a) Crust, scarring, and milia on the dorsal hands. (Courtesy Summer Youker MD, Sacramento, CA, USA). (b) Pseudoporphyria and por-

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tion and variable hemorrhage. The blister floor is composed of preserved dermal papillae (festooning) (Fig.  15.12b) [117]. Papillary dermal vessels may be thickened and hyalinized. Caterpillar bodies are often present; these are somewhat linear or elongated collections of PAS-positive segments or globules within the middle of the epidermal blister roof that ultrastructurally are composed of degenerating keratinocytes, colloid bodies, basement membrane material, and associated collagen [118]. In one study, caterpillar bodies were 98% specific for PCT [119]. PAS-­ negative caterpillar body-like clusters have also been documented in PCT as well as a broader spectrum of disorders, including pseudoporphyria, bullous pemphigoid, and hereditary and acquired epidermolysis bullosa [119]. DIF may show deposition of IgG, IgM, and C3 within and around thickened papillary dermal vessels (doughnut-shaped pattern) or be negative [117].

Differential Diagnosis As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug. There are no established qualitative differences in the histopathologic features of drug-induced versus idiopathic cases of pseudoporphyria or between pseudoporphyria from any of the true porphyrias; however, quantitative differences appear to exist, in that one or more of the b

phyria cutanea tarda appear the same on H&E, with a subepidermal blister, festooning, and minimal inflammation. Caterpillar bodies may be present within the blister roof

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expected histopathologic and DIF findings in pseudoporphyria are more likely to be absent or less prominent compared to the true porphyrias. For example, solar elastosis and/or any one or more of the typical features described above may be absent in pseudoporphyria [116]. Ramdial and Naidoo suggested that the presence of eosinophils can favor pseudoporphyria over porphyria [120].

Summary Clinical Presentation • Tense non-inflammatory blisters on the photo-exposed dorsal hands, extensor forearms, face. • Blisters heal with milia and scarring. Histologic Features • Subepidermal blister, cell-poor. • Preserved dermal papillae (festooning). • Caterpillar bodies (PAS/PASD positive) within the blister roof. • Biopsy typically obtained from acral skin, except solar elastosis, is not required. Differential Diagnosis • Porphyria cutanea tarda • Phototoxic dermatitis • Bullous pemphigoid • Epidermolysis bullosa acquisita

Takeaway Essentials Clinical Relevant Pearls • Correlation of clinical features with lesional histopathology can confirm the differential diagnosis of pseudoporphyria versus porphyria cutanea tarda. • Correlation with laboratory porphyrin studies is required to exclude true porphyria.

M. A. Fung et al.

• Clinical history alone is necessary and sufficient to identify the etiologic drug. Pathology Interpretation Pearls • Histopathologic and DIF findings can confirm the differential diagnosis of pseudoporphyria versus porphyria, but clinical correlation and laboratory porphyrin studies are required to establish the diagnosis of drug-induced pseudoporphyria.

 cute Generalized Exanthematous A Pustulosis (AGEP) Etiology and/or Pathogenesis Acute generalized exanthematous pustulosis (AGEP) is a severe and rare (1–5 per million) eruption. Historical names include toxic pustuloderma, pustular drug rash, and pustular psoriasiform eruption with leukocytosis. AGEP is drug-induced in the vast majority of cases (90%) including antibiotics (65%), mainly macrolides (24%) and beta-lactams (22%), but also cephalosporins, quinolones, tetracyclines, and other antibiotics including antimycotics (terbinafine, ketoconazole, fluconazole), pristinamycin, and antimalarials [121–123]. Most non-drug causes are various infections. Other drugs involved include calcium channel blockers (diltiazem), carbamazepine, NSAIDs, and acetaminophen (paracetamol). Contrast media such as iodinated nonionic contrast dye can rarely cause AGEP; a case of AGEP induced by mercury exposure from a broken thermometer has also been reported [123]. AGEP has been viewed as a type IV delayed hypersensitivity reaction with mixed Th1-Th2 but predominant Th1 cytokine expression profile [123]. Patch testing may provoke local similar morphology which supports that the immune system is implicated. The sensitivity of patch testing has been reported to be approximately 50% of AGEP cases [124].

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Clinical Presentation

Table 15.4 Diagnostic criteria for acute generalized exanthematous pustulosis (AGEP) [122]

AGEP starts by acute onset of fever and widespread pinpoint non-follicular sterile pustules arising on a background of edema and erythema with variable burning or itching (Fig.  15.13a, b). In most patients, the eruption develops on the face and/or large intertriginous areas (inguinal, axillar, and sub-mammary areas) within 24 to 48  hours of drug exposure (usually antibiotics), disseminates rapidly, and resolves after discontinuation of the causative agent. Vesicles, purpura (especially on the lower extremities), and atypical targets can be seen. An edematous erythema of the face may be present. AGEP localized to the face has been reported. The EuroSCAR study group published an AGEP diagnostic validation score (Table 15.4 [122]). Mucous membranes may be involved in 25%, usually limited to oral mucosa. Leukocytosis can occur in 80% which is mostly caused by a neutrophilia above 7000 mm3. Mild eosinophilia may be present in about a third of the cases. Systemic symptoms are not uncommon, but objective internal organ involvement is uncommon. Mild renal impairment occurs in approximately 30% of cases. Lymphadenopathy and a mild elevation of liver enzymes may be present, but internal organ involvement is exceptional in AGEP. AGEP can be a life-threatening disease in 5%, mainly in patients with poor general health [124].

a

Morphology Pustules  Typicala  Compatibleb  Insufficientc Erythema  Typical  Compatible  Insufficient Distribution/pattern  Typical  Compatible  Insufficient Postpustular desquamation  Yes  No/insufficient Course Mucosal involvement  Yes  No Acute onset (≤10 d)  Yes  No Resolution ≤15 days  Yes  No Fever ≥38 °C  Yes  No Neutrophils ≥7000/mm3  Yes  No

+2 +1 0 +2 +1 0 +2 +1 0 +1 +0

−2 0 0 −2 0 −4 +1 0 +1 0 (continued)

b

Fig. 15.13  Acute generalized exanthematous pustulosis (AGEP). (a) Innumerable tiny white pustules are usually present on the face, trunk, and skin folds. (b) The eruption may extend to involve upper and lower extremities

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Prognosis or Clinical Course

Table 15.4 (continued) Histology Other disease Not representative/no histology Exocytosis of neutrophils Subcorneal and/or intraepidermal non-­ spongiform or NOS pustule(s) with papillary edema or subcorneal and/or intraepidermal spongiform or NOS pustule(s) without papillary edema (NOS = not otherwise specified) Spongiform subcorneal and/or intraepidermal pustule(s) with papillary edema

−10 0 +1 +2

+3

Reproduced with permission from John Wiley & Sons Ltd Interpretation: ≤0: no AGEP, 1–4: possible, 5–7: probable, 8–12: definite. Remarks: Patients are not included in the study, if only localized pustules are reported, the pustular rash already lasts longer than 3  weeks or a clear alternative diagnosis has been made by a dermatologist a Typical: typical morphology as described in the “clinical features” section b Compatible: not typical, but not strongly suggestive of other disease c lnsufficient: lesions cannot be judged (mostly because of late stage of the disease or poor quality of pictures)

a

Fig. 15.14  Vancomycin-induced acute generalized exanthematous pustulosis (AGEP). Clinical correlation is required to identify the causative drug. (a) Inflammation is centered in the upper dermis. (b) Subcorneal neutro-

AGEP is self-limited once the causative agent is discontinued. AGEP resolves within 4–10  days and is often followed by desquamation. The EuroSCAR group reported two different patterns in relation to clinical disease onset: AGEP secondary to antibiotics usually occurred within 1  day, whereas, for all other drugs, the median time to onset was 11 days [121].

Histopathology AGEP is characterized by a superficial dermal inflammatory host response with basket-weave orthokeratosis with non-follicle-based subcorneal and/or intraepidermal neutrophilic spongiform pustules and papillary dermal edema (Fig. 15.14b, c). EuroSCAR diagnostic criteria place greater diagnostic weight for spongiform pustules (over

b

philic pustules. Deeper intraepidermal spongiform pustules, interface changes, papillary dermal edema, and eosinophils are also typical features

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non-spongiform pustules) and presence of papillary dermal edema. Variable features include limited interface changes (junctional vacuolar alteration and single necrotic keratinocytes) and eosinophils, as may be seen in any drug reaction.

Differential Diagnosis The histologic differential diagnosis for acute pustular eruptions includes follicular and non-­ follicular eruptions. Follicular eruptions such as bacterial folliculitis or steroid acne can be readily excluded by their predilection for hair follicles. Streptococcal pharyngitis-associated pustulosis acuta generalisata contrasts clinically both by the presence of pharyngitis and absence of a drug history. Pustular psoriasis and subcorneal pustular dermatosis (Sneddon-Wilkinson disease) should be distinguished primarily on clinical grounds, with psoriasis more likely to be associated with acral involvement and a family history of psoriasis; in contrast, Sneddon-Wilkinson disease characteristically presents as chronic, recurrent crops of flaccid, pea-sized superficial pustules and unique disease associations including paraproteinemia or pyoderma gangrenosum. However, AGEP usually shows features that support a drug etiology including superimposed interface changes and eosinophils. Vyas and coworkers conducted a detailed comparison of AGEP and pustular psoriasis [125]. They demonstrated a significant association between AGEP and the presence of eosinophils, although single necrotic keratinocytes as well as eosinophils were seen in both diseases, and sparse dermal eosinophils are a well-documented finding in psoriasis [126–128]. There was a tendency for AGEP to exhibit both subcorneal and deeper intraepidermal pustules, whereas pustular psoriasis showed mostly subcorneal pustules. In contrast to AGEP, pustular psoriasis showed increased intraepidermal and perivascular CD123+ plasmacytoid dendritic cells and MxA expression [125]. As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug.

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Summary Clinical Presentation • Acute, symmetrical eruption of numerous (hundreds of) small non-follicular pustules on the trunk and extremities with predilection for skin folds • Variable facial edema and erythema • Rapid 24–48-hour onset following antibiotics; several days following non-­ antibiotic triggers Histologic Features • Basket-weave orthokeratosis • Subcorneal and/or intraepidermal neutrophilic pustules, usually with associated spongiosis (spongiform pustule) • Papillary dermal edema, often marked • Eosinophils and single necrotic keratinocytes commonly present • No predilection for hair follicles or eccrine ducts Clinical and Histologic Differential Diagnosis • Other drug reactions (e.g., pustular DRESS), generalized pustular psoriasis, subcorneal pustular dermatosis (Sneddon-­Wilkinson disease), pustulosis acuta generalisata, impetigo, follicular disorders such as steroid acne, bacterial folliculitis, pustular vasculitis, miliaria

Takeaway Essentials A biopsy demonstrating neutrophilic pustules is required to support the diagnosis of AGEP.  AGEP may sometimes exhibit limited overlapping features with DRESS, with EuroSCAR and RegiSCAR criteria serving to facilitate distinction between these disorders.

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Clinical Relevant Pearls • Antibiotic reactions usually occur within 24–28  hours, whereas non-­ antibiotic triggers usually being several days later. • Infection and psoriatic flare must be excluded. Pathology Interpretation Pearls • The presence of intraepidermal pustules (not only subcorneal pustules), interface changes, eosinophils, and papillary dermal edema favors AGEP over pustular psoriasis. • Clinical correlation is required to establish the diagnosis of AGEP.

 DRIFE (Symmetric Drug-Related S Intertriginous and Flexural Exanthema) Etiology and/or Pathogenesis SDRIFE is a clinically distinct systemic allergic contact dermatitis that has been regarded as a form of delayed (type IV) hypersensitivity, although a component of immune-complex (type III) hypersensitivity has also been considered. Using nickel sensitivity as the prototypical example, both antigen-presenting and direct drug-T-­ cell receptor binding have been proposed. Other causes of systemic contact dermatitis associated with contact allergens, most commonly nickel or topical antibiotics, are encompassed by other terms including baboon syndrome [129, 130], whereas SDRIFE represents the same clinical presentation in the absence of known contact sensitization. Antibiotics appear to be the most common causes of SDRIFE, but a diversity of anecdotal cases have been reported, well over 40 drugs to date (Table 15.5).

Clinical Presentation The term “baboon syndrome” was coined to describe a symmetrical erythematous exan-

M. A. Fung et al. Table 15.5  Drugs associated with symmetric drug-­related intertriginous and flexural exanthema (SDRIFE) [131] Allopurinol Antibiotics (e.g., ampicillin, amoxicillin, cefepime, ceftriaxone, cefuroxime, cephalexin, clindamycin, erythromycin, ketoconazole, penicillin, terbinafine, trimethoprim-sulfamethoxazole) Berberine Chemotherapy and targeted anticancer therapies Cimetidine Cinchocaine Deflazacort Etonogestrel/ethinyl estradiol vaginal ring 5-Fluorouracil Heparin Hydroxyurea Hydroxyzine IVIg Mefenamic acid Mercury Metronidazole Mitomycin C Naproxen Nefopam Nickel Nystatin Oxycodone Paracetamol Pristinamycin Pseudoephedrine Radiocontrast media (iodinated) Ranitidine Salicylate Secnidazole Tacrolimus Telmisartan-hydrochlorothiazide Tetracaine Valacyclovir Zoledronic acid

thema involving the gluteal folds resembling the red buttocks displayed by female baboon (Fig. 15.15a). V-shaped erythema of inguinal and perigenital skin and other flexural regions may also occur following the systemic absorption of a contact allergen (nickel, mercury, or ampicillin) in a sensitized individual. The noncontact allergic variant of baboon syndrome is known as symmetrical drug-related intertriginous and flexural exanthema (SDRIFE). Diagnostic criteria were published by Häusermann and coworkers in 2004 (Table 15.6) [131].

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a

735

b

c

Fig. 15.15  Probable cefepime-induced SDRIFE (symmetric drug-related intertriginous and flexural exanthema). (a) Acute onset of symmetrical erythema centered upon skin folds. (b) Scanning view shows a sparse superTable 15.6  Criteria proposed for symmetric drug-related intertriginous and flexural exanthema (SDRIFE) [131] Criteria 1

2

3 4 5

Description Exposure to a systemically administered drug, first or repeated doses (contact allergens excluded) Sharply demarcated erythema of the gluteal/ perianal area and/or V-shaped erythema of the inguinal/perigenital area Involvement of at least one other intertriginous/flexural fold Symmetry of affected areas Absence of systemic symptoms and signs

ficial and deep perivascular and interstitial dermatitis. (c) Epidermal spongiosis with sparse eosinophils within the predominantly lymphocytic dermal infiltrate

Prognosis or Clinical Course SDRIFE is a benign, self-limited eruption that is not usually associated with constitutional symptoms. SDRIFE resolves within days upon discontinuation of the offending drug.

Histopathology Many, if not most, patients diagnosed with SDRIFE do not receive a skin biopsy. The range

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of histopathologic features reported in the ­literature is broad, but the most common features include a superficial perivascular lymphocytic infiltrate with variable eosinophils and/ or neutrophils [131]. Spongiosis is perhaps the most typical epidermal alteration, but interface changes or no apparent epidermal changes have also been reported (Fig.  15.15b, c). Dermal edema may be present. In rare patients, including one of the cases from the original report of baboon syndrome, leukocytoclastic vasculitis has been reported [129].

Differential Diagnosis The clinical presentation of SDRIFE is highly distinctive such that biopsy is often not mandated. Generalized fixed drug eruption may resemble SDRIFE.  SDRIFE must also be distinguished clinically from toxic erythema of chemotherapy [132]. Histologically, the differential diagnosis includes other forms of spongiotic/eczematous dermatitis, including contact dermatitis or an Id reaction. The presence of interface changes or papillary dermal edema may serve as clues to the possibility of a drug reaction. As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug.

Summary Clinical Presentation • Symmetrical, sharply demarcated erythematous eruption favoring major skin folds (e.g., baboon syndrome) • No systemic symptoms Histologic Features • Perivascular dermatitis, usually with spongiosis or, less commonly, interface changes • Eosinophils typical but not required • Vasculitis unusual but possible

Differential Diagnosis • Generalized fixed drug eruption • Toxic erythema of chemotherapy • Spongiotic/eczematous dermatitis (nummular, allergic contact, atopic, Id reaction) • Intertrigo

Takeaway Essentials SDRIFE is a clinically distinctive eruption that may not require biopsy. As a form of systemic allergic contact dermatitis, spongiotic dermatitis with eosinophils is typical, but there may also be interface changes or no epidermal changes at all. Clinical Relevant Pearls • Well-demarcated symmetrical eruption involving major skin folds is highly distinctive. Pathology Interpretation Pearls • Spongiotic dermatitis with eosinophils. • Variable dermal edema. • Interface or vasculitic features have been documented. • Clinical correlation is required to establish the diagnosis of SDRIFE.

Drug-Induced Hyperpigmentation Etiology and/or Pathogenesis Drug-induced pigmentation (DIP) is a commonly observed adverse effect, estimated to account for a 10–20% of patients with acquired pigmentation, with chemotherapeutic and targeted biologic therapies accounting for pigmentary changes of the skin, hair, or nails in approximately 20% of hospitalized patients in one study of 8052 patients [133, 134]. The pathogenesis of druginduced pigmentation varies by drug. Moreover,

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some drugs are associated with multiple types of pigmentation, each with different clinical and histologic features and pathogenesis. Some drugs cause pigmentation by inducing increased melanin synthesis, whereas other drugs cause pigmentation as a post-inflammatory phenomenon (e.g., diltiazem, minocycline-one variant). Some pigmentation represents a drug-hemosiderin complex (e.g., minocycline-­one variant, antimalarials). Lipofuscin synthesis has been implicated in amiodarone- and clofazimine-­induced pigmentation. In a murine model, a soluble, free base form of clofazimine has also been demonstrated in the subcutaneous fat. Numerous drugs causing pigmentary issues include alkylating/cytotoxic agents (Table  15.7), analgesics, antiarrhythmics, anticoagulants, antiepileptics, antimalarials, antimicrobials, antiretrovirals, metals, prostaglandin analogs, and psychotropic agents, among others. Delayed onset of pigmentation and coexisting Table 15.7  Examples of cytotoxic agents and particular pigmentation patterns Intravenous 5-fluorouracil

Bleomycin

Cyclophosphamide, ifosfamide

Daunorubicin, doxorubicin

Hydroxyurea

Pemetrexed

Diffuse palmar pigmentation, transverse pigmented bands over interphalangeal joints, and pigmented macules on the palms, soles, nails, and oral mucosa Erythematous linear streaks evolving into typical flagellate pigmentation Nails: diffuse black pigmentation, slate-gray to black longitudinal streaks, or dark-gray pigmentation located proximally with overlying transverse bands Photodistributed Nails: transverse and longitudinally pigmented bands and nail bed pigmentation Diffuse black-brown pigmentation of the dorsal portion of the phalangeal creases, palms, soles Tongue and buccal mucosa: black pigmentation Nail: longitudinal, transverse or diffuse melanonychia. Blue discoloration of the lunula Spares the oral mucosa

polypharmacy render the identification sometimes difficult. The existence of at least a dozen classes of drugs in this group precludes comprehensive discussion of all drug-induced hyperpigmentation, but the reader is referred to recent comprehensive reviews of this topic [133, 135].

Clinical Presentation Drug-induced pigmentation (DIP) occurs insidiously and worsens over the course of months to years. A distribution pattern is a common feature of DIP such as sun-exposed areas, mucous membranes, or other specific locations. Colors seen may not always be very specific, but certain drugs may have certain hues. Minocycline is p­ robably the best-known inducer of pigmentation. Up to 15% of patients may get drug-induced pigmentation secondary to minocycline. Several risk factors for minocycline-induced pigmentation include prolonged duration of treatment, cumulative doses >50  g, cutaneous alterations secondary to inflammation (acne scars), or cumulative photodamage. There are three wellestablished clinical patterns of minocycline pigmentation (Table  15.8), with additional variants also reported, including localization to the lower lip (possible fixed drug eruption) and calcium-­ containing pigment within acne scars [133, 137– 139]. Hyperpigmentation of preexisting scars is perhaps the best known pattern of minocycline pigmentation (Fig.  15.16). Dyschromia related to minocycline may also involve mucous membranes, including the conjunctiva, oral mucosa, tongue, and gingiva [133]. Amiodarone-induced hyperpigmentation is often photodistributed with blue-gray or purple discoloration. Commonly affected areas include the face, nose, and ears usually at least 6 months of therapy [133], but the cornea is often the first noticed and may be found with yellow-brown granular pigmentation secondary to formation of lipofuscin [140] (Fig. 15.17). Amiodarone pigmentation is also associated with higher treatment dosing of ≥400–800  mg/ day. Resolution of pigmentation is possible but may last for up to 1  year. Diltiazem pigmentation is associated with the extended-­release form

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738 Table 15.8  Minocycline-induced pigmentation Pattern 1. Within sites of prior inflammation, e.g., acne scars [136]

Clinical features Blue-black macules or patches

2. Photo-exposed, e.g., anterior legs

Localized of diffuse hyperpigmentation

3. Muddy skin syndrome

Generalized, symmetrical blue-brown-gray, photo-accentuated

Pathology Minocycline or degradation product possibly chelated to iron-containing pigment Dermal-­subcutaneous perivascular and periadnexal pigment within macrophages (siderophages), dendritic cells, or extracellular Variant: Calcium-­ containing melanin deposits [137] Minocycline or oxidation product possibly chelated to iron Increased melanin in the epidermal basal layer and papillary dermis (melanophages)

a

Melanin Negative

Hemosiderin Positive

Positive

Positive

Positive

Negative

b

Fig. 15.16  Minocycline pigmentation. (a) Brown-blue-­gray pigmentation within acne scars. (b) Yellow-brown pigment within histiocytes in the reticular dermis. In this variant of minocycline pigmentation, the pigment is positive for hemosiderin but negative for melanin [136]

and is photodistributed, reticulated, and bluegray to dark brown. Pigmentation induced by cytotoxic agents may affect the hair, nails, and mucous membranes in  local or diffuse patterns (Table  15.7). Pigmentation patterns may also be observed at sites of acute or chronic trauma where local blood flow is increased leading to drug delivery and secondary skin deposition. Imatinib mesylate, a tyrosine-kinase inhibitor, can cause

rare cases of paradoxical hyperpigmentation but more frequently hair graying and hypopigmentation, typically patchy and generalized, and is often periorbital. Sorafenib and sunitinib, also tyrosine-kinase inhibitors, induce yellow skin discoloration, but the sclera and mucous membranes are spared. Hair yellowing or graying may also be observed. Paclitaxel, a taxane, has been reported as inducing reticulate hyperpigmentation in the

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a

739

b

Fig. 15.17  Amiodarone hyperpigmentation. (a) Insidious onset of blue-gray hyperpigmented patches on the dorsal

hands is characteristic. (b) Brown pigment granules in the dermis

skin when administered. Darker skin areas tend be favored. Barbiturates can cause diffuse brown hyperpigmentation [133]. Other antiepileptics, hydantoin and phenytoin, can produce skin pigmentation similar to melasma. Antimalarials cause DIP in 25% of patients receiving either chloroquine, hydroxychloroquine, mefloquine, or mepacrine (quinacrine) for at least 4 months. Most frequently patients present with a bluish gray to dark purple hue of isolated pigmented macules coalescing into large patches on the anterior aspect of the legs and head (forehead, nose, cheeks, ears, and oral mucosa, especially the hard palate) [141]. Years later, it can be diffuse especially involving sun-exposed areas. On the nails, transverse bands or diffuse pigmentation may be observed. Cartilage of the ear and nose may also become pigmented giving a pseudo-ochronosis pattern. Hydroxychloroquine can induce pigmentation in areas of previous ecchymosis and microtrauma, especially if the patient receives concurrent oral anticoagulant or antiplatelet therapy [141]. Chloroquine can also cause hypopigmented lesions and cause hair pigment loss. Quinacrine can diffusely and uniformly cause yellowing similar in appearance to jaundice from direct tissue staining by the drug, attributable to its acridine dye composition. Resolution often occurs within 2–6 months contrary to chloroquine and hydroxychloroquine which may take much longer. Clofazimine can cause a reddish-­ blue skin discoloration within the first few weeks of use that evolves into a red-brown or violaceous-­

brown skin and conjunctiva. Dapsone can cause photo-induced hypermelanosis and blue-grayish dyschromia partially attributable to methemoglobinemia. Isoniazid can induce violaceous, lilac-­like skin discoloration that may accompany a pellagra-like coloration. When isoniazid has resulted in actual pellagra, the appearance has been described as sun-exposed symmetric, well-­ demarcated, hyperpigmented, and hyperkeratotic plaques involving the face, neck, dorsal surface of the hands, and extensor surface of the forearms and feet. Levofloxacin has been reported to be associated with a blue-gray skin pigmentation involving the dorsal surface of the hands, extensor forearms, shins, and neck. Rifampin can induce red skin and mucous membrane pigmentation (with red-orange coloring of the urine, saliva, and tear secretions), but mainly observed with medication overdose. The ­antiretroviral emtricitabine can cause dark skin pigmentation primarily on the dorsal surface and palms and soles and are typically mild. Heavy metal-­induced hyperpigmentation has decreased over the last several decades because these metals are becoming less frequently used. Gold deposition causes a blue-gray hyperpigmentation, termed chrysiasis. It may develop on sun-exposed areas and periorbital areas with sparing of mucous membranes following prolonged parenteral use. Silver salt via ingestion of colloidal silver as a food supplement may lead to a diffuse pattern of slate-gray pigmentation in sunexposed areas with some bluish discoloration of the fingernails, called argyria (Fig. 15.18a) [142].

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a

b

Fig. 15.18 Argyria. (a) Insidious onset of symmetrical palmar pigmentation. In other cases, the pigmentation can be generalized and affect mucous membranes. (b) Tiny round black pigment deposits aggregate at basement

membrane zones of adnexal epithelium and blood vessels. (Reproduced with permission, Barbara Burrall, Editor-in-­ chief, Dermatology Online Journal [142])

Pigmentation may be observed on mucous membranes, including the sclera. Among psychotropic drugs implicated in DIP, the most common offenders are the phenothiazines and tricyclic antidepressants. Chlorpromazine pigmentation occurs on sun-­exposed areas as violet or purple-gray metallic pigmentation on the face and extremities, nail beds, and eye (sclera, cornea, and lens). Sparing of facial wrinkles and mucous membranes may also be observed. Amitriptyline-induced hyperpigmentation may appear years after use, with onset in a photodistributed pattern. Desipramine and imipramine may result in a blue to slate-gray hyperpigmentation in sun-exposed areas.

ized by increased melanin, or, less commonly, hemosiderin, lipofuscin, or a combination or complex of more than one, with pigmented sequestered within macrophages in the papillary dermis +/− reticular dermis. When the hyperpigmentation is purely post-inflammatory, melanophages are confined to the upper dermis, as may be seen in diltiazem pigmentation or one variant of minocycline pigmentation (Table  15.8). When purpura plays a role, extravasated erythrocytes and hemosiderin are expected. Hemosiderin granules tend to be yellow-gold, heterogeneous in size, and relatively refractile compared to melanin. Melanin granules appear dark brown, more uniformly small in size, and non-refractile compared to hemosiderin. Drug-induced pigmentation containing both components display an intermediate appearance relative to these characteristics, as may be seen in antimalarial-induced pigmentation and one variant minocycline pigmentation (Table  15.8). Lipofuscin appears yellow-­brown, thus resembling hemosiderin more than melanin. Pigment granules are most easily identified when sequestered within macrophages and may also be present free in the dermis. If needed, the pigment can be definitively characterized with histochemical staining for melanin (Fontana-Masson) and hemosiderin (Perls or Prussian blue). Sudan Black B has been reported to be specific for lipofuscin [143]. Argyria manifests as tiny brown-

Prognosis or Clinical Course With drug cessation, the majority resolves over time, but complete disappearance is not always the rule [133].

Histopathology Any acquired pigment deposition that is beyond the usual range of post-inflammatory changes should evoke consideration of DIP. The nature of the pigment in drug-induced hyperpigmentation varies with the drug but is commonly character-

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black granules along basement membrane zones (Fig. 15.18b). The pigment granules in chrysiasis are similar to those of argyria but slightly larger and round-­ovoid, appear red-orange under polarized light, and aggregate within histiocytes, not basement membrane. Both silver and gold particles are well visualized with darkfield microscopy.

Differential Diagnosis As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug. For the histologic evaluation of acquired pigmentation, the delayed and insidious onset of the pigmentation makes it more difficult to establish a drug etiology, especially if the patient takes multiple medications. The pathologist can readily confirm the melanocytic versus ferruginous nature of the pigment with histochemical stains. Involvement of the reticular dermis is against postinflammatory hyperpigmentation and would suggest the possibility of drug-induced pigmentation.

Summary Drug-induced pigmentation is relatively common in hospitalized patients. A complete medication history is required, since clinical onset occurs months after initiation of the causative drug. Lesional biopsy can confirm the presence of pigmentation and clarify the nature and distribution of the pigmentation. Clinical Presentation • Delayed onset relative to initiation of drug. • Pigmentation may be generalized, photodistributed, or localized, but each drug has specific characteristics. Histologic Features • Epidermal hyperpigmentation: increased melanin in the stratum basale, no increase in the number of melanocytes.

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• Dermal pigmentation: increased numbers of pigment-laden histiocytes (melanin, hemosiderin, lipofuscin, or drug-pigment complex). • Argyria and chrysiasis appear as tiny dark pigment granules in characteristic distribution. Clinical and Histologic Differential Diagnosis • Post-inflammatory hyperpigmentation secondary to any spongiotic or interface dermatitis • Phytophotodermatitis • Non-drug causes of acquired hyperpigmentation

Drug-Induced Pseudolymphoma Etiology and/or Pathogenesis Drug-induced pseudolymphoma represents an inflammatory response that results in benign atypical lymphocytic infiltrates of the skin that histologically mimic either B- or T-cell lymphoma [8, 144]. Historically, the terms pseudolymphoma, lymphocytoma cutis, and ­ cutaneous lymphoid hyperplasia could be interchangeably applied to cases clinically presenting as one or a few nodules or plaques and histologically exhibiting dense nodular dermal lymphocytic infiltrates resembling primary cutaneous low-grade B-cell lymphomas such as follicular lymphoma or marginal zone lymphoma. Subsequently, more superficial and/or sparsely cellular lymphomatoid reactions histologically resembling various forms of T-cell lymphoma were documented, facilitating broad classification into classic lymphocytoma cutis (nodular pseudolymphoma) for cases associated with dense infiltrates that histologically and/or clinically resemble nodules or plaques of lymphoma cutis and T-cell patterns resembling mycosis fungoides or other forms of cutaneous T-cell lymphoma. Drugs, including DRESS (discussed separately above), perhaps

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represent the largest documented proportion within both subsets. In B-cell-type pseudolymphoma (lymphocytoma cutis), a combination of hapten-mediated type IV delayed hypersensitivity and drug-­ mediated immune dysregulation has been implicated, consistent with the fact that several months or even years may pass before the onset of the skin lesions. Reported drugs for lymphocytoma cutis include allopurinol, amiloride, carbamazepine, cyclosporine, clomipramine, diltiazem, and phenytoin (Table 15.9) [144]. Table 15.9  Drugs or externally applied material associated with pseudolymphoma [145, 146] Lymphocytoma cutis (nodular pseudolymphoma, B-cell pattern) [147] Bromocriptine Cyclosporine Etanercept Gold Leech (Hirudo medicinalis) therapy Methotrexate Phenytoin Sodium cromylate (sodium cromoglycate, cromolyn sodium) Tattoo pigment Thioridazine Drug-associated reversible T-cell dyscrasia (pseudo cutaneous T-cell lymphoma, T-cell pattern) [145] Angiotensin-converting enzyme inhibitors (e.g., benazepril, captopril, enalapril, lisinopril) Anticonvulsants (e.g., butobarbital, carbamazepine, gabapentin, methsuximide, phenobarbital, phensuximide, phenytoin, primidone, trimethadione) Antidepressants (e.g., bupropion, fluoxetine, maprotiline, sertraline) Antihistamines (e.g., cimetidine, diphenhydramine, doxepin, ranitidine) Antipsychotics (e.g., carbamazepine, chlorpromazine, thioridazine, promethazine) Beta-blockers (e.g., atenolol, labetalol) Calcium channel blockers (e.g., amlodipine, diltiazem, verapamil) Clindamycin Dapsone Decitabine Estrogen Etheric plant oil Granulocyte macrophage-colony-stimulating factor Gold (continued)

Table 15.9 (continued) Levofloxacin Menthol Mexiletine Methylphenidate Metronidazole Nickel Nitrofurantoin D-Penicillamine Penicillin Phenytoin Procainamide Progesterone Sirolimus Statins (e.g., atorvastatin, lovastatin, simvastatin) Tattoo pigment, especially red tattoo pigment Tocilizumab Ustekinumab Vancomycin

For T-cell-type pseudolymphoma, cases bearing histologic resemblance to early mycosis fungoides (pseudo mycosis fungoides) were initially documented, although drug reactions containing large CD30-positive cells associated with a diverse spectrum of clinical presentations have been increasingly reported. Magro and colleagues classify this expanding spectrum of T-cell patterns under the heading of “drug-­ associated reversible T-cell dyscrasia.” [145] Reported drugs for T-cell pattern are listed in Table  15.9. It is thought that these drugs affect lymphocytes such that they will have overzealous responses to other antigens, resulting in lymphoid hyperplasia [145]. As these effects may be cumulative over time, it may be years between initiation of the drug and onset of symptoms.

Clinical Presentation Cutaneous pseudolymphomas represent a diverse spectrum ranging from those resembling tumor-­ stage lymphoma cutis and with histologic features of lymphocytoma cutis (nodular pseudolymphoma) to a very broad spectrum of eruptions that tend to be acute and symmetrical in onset often with no clinical resemblance to lymphoma but with histologic features that mimic mycosis fungoides (MF) or an

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expanding spectrum of other forms of cutaneous T-cell lymphoma (CTCL). Idiopathic, or solitary, drug-induced lymphocytoma cutis presents as a single or small number of plaques or nodules, most often on the head or neck and generally above the waist. Rare cases of acute generalized exanthematous pustulosis or linear folliculotropic eruption have been documented [148, 149]. Generalized fixed drug eruption with features of CD8-positive T-cell lymphoma has also been documented [150]. Drug-induced pseudolymphomas that mimic CTCL present as solitary or generalized erythematous patches, plaques, or nodules, or morbilliform eruptions, most commonly correlated with anticonvulsant therapy [151]. This presentation may be recalcitrant to steroid therapy, but tends to resolve upon discontinuation of the offending drug; solitary lesions may be cured by excision [151].

Prognosis or Clinical Course As noted above, most cases of pseudolymphoma eventually resolve upon withdrawal of the offending medication. Progression to B-cell or T-cell lymphoma is extraordinarily rare.

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tive disorder (PCSMPT-LPD) is widely regarded as a variant of lymphocytoma cutis but is usually idiopathic; methotrexate- and etanercept-associated PCSMPT-LPD have been reported. T-cell patterns are diverse but generally present as superficial perivascular and/or lichenoid infiltrates with variable spongiotic and interface changes. Dermal edema and eosinophils are common features. In pseudo mycosis fungoides, lymphocyte exocytosis evokes concern for neoplastic epidermotropism, but there is an absence of Pautrier microabscess formation, overt atypia, or haloed lymphocytes (exaggerated perilymphocytic retraction artifact). Pseudo-Pautrier microabscesses containing Langerhans cells essentially represent spongiotic vesiculation characteristic of a reactive process such as a drug reaction or spongiotic/eczematous dermatitis. In a variety of other clinical settings, large CD30-positive lymphocytes may be increased in numbers, even forming small clusters of cells, evoking concern for a CD30-positive lymphoproliferative disorder. Intravascular lymphomatoid proliferations have been reported [152].

Differential Diagnosis Histopathology Lymphocytoma cutis is characterized by a dense nodular or diffuse dermal infiltrate of mostly small-medium lymphocytes with varying degrees of mild to moderate atypia. Variable features include scattered eosinophils, plasma cells, reactive lymphoid follicles, and/or foci of granulomatous inflammation. Immunohistochemistry will confirm that most cases show a mixed T- and B-cell population with a T/B ratio usually greater than 3 and a mixed population of CD4 and fewer CD8 T cells, without significant (>90%) loss of CD7. T-cell receptor gene rearrangement analysis should be negative for a clonal gene rearrangement, although positive results are possible; an identical clone is less likely to be demonstrated in multiple specimens if lymphoma is not present. A minority of cases may demonstrate a predominance of B cells. Primary cutaneous CD4-positive small-medium pleomorphic T lymphoprolifera-

As with all drug reactions, clinical correlation is required to resolve the differential diagnosis and confirm the presence of the instigating drug. In lymphocytoma cutis, the initiation of the offending drug might predate the onset of skin lesion by several months or even years. Microscopically, compared to lymphoma cutis, lymphocytoma cutis tends to be “top heavy” in its distribution within the dermis, is devoid of severe atypia or anaplastic cytology, and may contain scattered eosinophils and reactive lymphoid follicles. There should be no evidence of clonality by kappa/lambda analysis or gene rearrangement analysis. Compared to true cutaneous T-cell ­lymphoma, pseudo mycosis fungoides tends to exhibit greater spongiosis, dermal edema, and numerous eosinophils; vasculitis or subcorneal pustules have rarely been documented [148]. Often the biggest clue to the diagnosis of a lymphomatoid drug reaction is that the clinical presentation does not resemble any form of T-cell lymphoma, temporally or by clinical morphology;

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a

b

Fig. 15.19  Pseudolymphoma, T-cell pattern associated with red tattoo pigment. (a) Epidermal hyperplasia combined with a lichenoid (sparse in this example) lymphocytic infiltrate may evoke the psoriasiform lichenoid profile that typifies early mycosis fungoides. Reactive lymphocyte exocytosis in pseudolymphoma may resemble neoplastic epidermotropism. In reactive exocytosis, gener-

rather, T-cell pattern pseudolymphoma tends to present with an acute, symmetrical onset of a maculopapular or other generalized eruptions. A wide variety of clinical presentations have been reported, including AGEP, linear folliculotropic lesions, red tattoo reactions (Fig. 15.19), and generalized fixed drug eruption [148–150].

ally greater spongiosis, greater upward scatter of lymphocytes throughout the epidermis (in contrast to the basilar epidermotropism of epidermotropic T-cell lymphoma), and severe atypia or anaplastic features should not be present [153]. (b) Often the most helpful clue is that there is no clinical concern for lymphoma whatsoever! (Courtesy Philina Lamb MD, Sacramento, CA, USA)

Differential Diagnosis • Cutaneous lymphoma • Primary cutaneous lymphoproliferative disorder (CD30-positive, post-­ transplantation, CD4-positive small-­ medium pleomorphic) • Various cutaneous inflammatory disorder (pityriasis lichenoides, pigmented purpura)

Summary Clinical Presentation • Lymphocytoma cutis: solitary or small number of nodules above the waist • Often presents clinically as a “rash” that is not suggestive of lymphoma at all Histologic Features • Lichenoid, nodular, or diffuse dermal lymphocytic infiltrate • Lymphocytes mostly small-medium. No anaplastic cytology • Scattered eosinophils, frequently

Takeaway Essentials Drug-induced pseudolymphoma is a heterogeneous group of reactions that typically evoke consideration of lymphoma for the pathologist much more so than for the clinician, which often represents the single most important clue to the correct diagnosis. While B-cell lymphocytoma cutis additionally exhibits clinical overlap with lymphocytoma cutis and greater temporal dissociation

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between the initiation of the drug and onset of the skin lesions, T-cell reactions are typically acute, symmetrical, and often morbilliform and characterized histologically by spongiosis, dermal edema, and eosinophils, sometimes with increased numbers of large CD30-­positive immunoblasts. Clinical Relevant Pearls • The clinical presentation alone may bear no resemblance to any form of cutaneous lymphoma.

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Pathology Interpretation Pearls • In the absence of overt cytologic atypia, an outright diagnosis of lymphoma based on histology alone should be withheld, pending clinical correlation that is always required to establish the diagnosis of druginduced pseudolymphoma. • The absence of any clinical concern for any type of cutaneous lymphoma represents a clue to the diagnosis of pseudolymphoma.

Case Vignettes Case 1 Clinical History A 27-year-old man admitted for methicillin-­resistant Staphylococcus aureus (MRSA) abscess. Four days after starting cefazolin, he developed a morbilliform eruption consisting of faint pink macules coalescing into patches on his trunk and extremities (Fig. 15.20a). He otherwise felt well and denied upper respiratory infection or viral symptoms. Microscopic Description Histologic sections show subtle junctional vacuolar interface changes and sparse dermal perivascular lymphocytes with rare eosinophils (Fig. 15.20b, c). a

b

Fig. 15.20 (a) Morbilliform eruption with macules and papules coalescing into patches on the torso. (b) Sparse superficial and mid-perivascular dermatitis with lymphocytes and sparse eosinophils. (c) Only minimal junctional vacuolar alteration is present in this case, without overt necrotic keratinocytes

(continued)

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c

Fig. 15.20 (continued)

Diagnosis Cefazolin-induced morbilliform/exanthematous drug reaction Discussion Although not favored, the clinical differential diagnosis in this case included a viral exanthem. Although the histologic differential diagnosis also includes a viral exanthem, the presence of dermal eosinophils and absence of extravasated erythrocytes favor a drug reaction. Other cases may show more prominent interface and/or spongiotic changes or no epidermal changes at all.

Case 2 Clinical History A 67-year-old man developed folliculocentric papules and pustules 21  days after starting trimethoprim-­sulfamethoxazole therapy (Fig. 15.21a). He also noted profound facial and ear edema. Associated renal insufficiency was present. The patient did not have peripheral eosinophilia. He was treated with 1 mg/kg oral prednisone with improvement. Microscopic Description Histologic sections revealed vacuolar and lichenoid interface changes with neutrophilic pustules appearing centered within hair follicles, with scattered neutrophils and sparse eosinophils in the dermis (Fig. 15.21b, c). (continued)

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a

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b

c

Fig. 15.21 (a) Folliculocentric papules and pustules on the upper chest. (b) Vacuolar and lichenoid interface dermatitis. (c) Neutrophilic pustules with scattered neutrophils and sparse eosinophils in the dermis

Diagnosis Probable cotrimoxazole-induced DRESS (RegiSCAR score 4) Diagnostic criteria are referenced to a RegiSCAR classification scoring system for severe adverse drug reaction, in which a score of >/= 4 designates “probable” or “definite” DRESS. Discussion Peripheral eosinophilia is a major criterion for the diagnosis of DRESS but is not required for a “probable” or even “definite” diagnosis of DRESS if the RegiSCAR criteria are otherwise fulfilled. This patient had underlying immunodeficiency that may have accounted for the lack of peripheral eosinophilia. Similarly, eosinophils were not prominent in the skin biopsy and need not be present at all in lesional skin. The combined pustular and interface changes suggest a drug reaction. Clinical correlation is required to establish the diagnosis of DRESS.

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Case 3 Clinical History A 63-year-old woman presents with 3-day history of painful, burning crusted papules coalescing into plaques on the chest and arms that started hours after her 12th phototherapy (narrow band-­UVB) treatment (Fig. 15.22a). She had been on hydrochlorothiazide for many years. Microscopic Description The biopsy demonstrated superficial and deep dermal perivascular and periadnexal inflammation with marked papillary dermal edema associated with a lichenoid infiltrate with numerous neutrophils and eosinophils (Fig. 15.22b, c). The epidermis shows spongiotic vesicles. An unexpected feature in this case is the presence of follicular pustules (not shown). a

b

c

Fig. 15.22 (a) Crusted papules coalescing into plaques on the chest and arms. (b) Sparse lichenoid and superficial and deep dermal perivascular and periadnexal inflammation with marked papillary dermal edema. (c) Numerous neutrophils and eosinophils with spongiotic vesicles. In other cases, the degree of inflammation can be minimal [58]

Diagnosis Hydrochlorothiazide-induced photoallergic drug reaction Discussion At 3-month follow-up, the patient was greatly improved after discontinuing hydrochlorothiazide.

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Case 4 Clinical History A 42-year-old man admitted for evaluation and management of neurologic symptoms developed several dusky erythematous oval patches on his ankle, palm, and penile shaft 1 day after ibuprofen therapy (Fig. 15.23a). Microscopic Description Vacuolar interface dermatitis with deep dermal perieccrine extension (Fig. 15.23b, c) is seen on histologic section. a

b

c

Fig. 15.23 (a) Solitary round plaque on the penile shaft. Lesions were also present on the palm and leg. (b) Scanning magnification shows mild papillary dermal edema associated with a perivascular and interstitial infiltrate centered in the papillary dermis focally obscuring the dermal-epidermal junction consistent with vacuolar interface dermatitis. There

is sparse deep perieccrine extension. (c) Junctional vacuolar alteration with rare single necrotic keratinocytes. Pigment incontinence is minimal, compatible with an initial episode or nonpigmented variant of FDE. Eosinophils were present in the upper reticular dermis (not shown)

(continued)

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Diagnosis Ibuprofen-induced generalized fixed drug eruption Discussion The patient reported lesions recurring in the same location in the past several years but had not associated the eruption with any particular trigger. The lesions were asymptomatic and resolved weeks after cessation of ibuprofen. Patients may present with a solitary lesion after initial exposure, but subsequent exposure results in a generalized eruption [154].

Case 5 Clinical History A 55-year-old woman with widespread skin sloughing on the torso 5  days after receiving cefazolin (Fig. 15.24a). The patient also received vancomycin for 3 days that was discontinued 5 days prior when it was replaced by cefazolin. Microscopic Description Subepidermal blister with mostly neutrophils, although eosinophils predominate over neutrophils in foci away from the blister edge (Fig. 15.24b). DIF demonstrates linear deposition of IgA as the sole immunoreactant (Fig. 15.24c). a

c

b

d

Fig. 15.24 (a) Extensive skin sloughing on the torso. (Courtesy Catherine G. Manabat-Hidalgo, MD, Fresno, CA, USA). (b) Subepidermal blister with sparse super-

ficial inflammation. (c) Neutrophils predominate at the blister edge, not typical of TEN. (d) Continuous, linear deposition of IgA (only) was present

(continued)

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Diagnosis Probable cefazolin-induced linear IgA disease clinically resembling toxic epidermal necrolysis. Discussion TEN-like linear IgA disease is a good example of the clinical relevance of dermatopathology in the hospital setting. Although vancomycin is the most classic trigger of linear IgA disease, the timing in this case implicates cefazolin. The histopathology excludes TEN but is non-specific with respect to which drug was the cause.

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752 eosinophils truly absent in pityriasis lichenoides, connective tissue disease, and graft-vs.-host disease? J Cutan Pathol. 2012;39(4):413–8. 26. Weaver J, Bergfeld WF.  Quantitative analysis of eosinophils in acute graft-versus-host disease compared with drug hypersensitivity reactions. Am J Dermatopathol. 2010;32(1):31–4. 27. Kohler S, Hendrickson MR, Chao NJ, Smoller BR.  Value of skin biopsies in assessing prognosis and progression of acute graft-versus-host disease. Am J Surg Pathol. 1997;21(9):988–96. 28. Firoz BF, Lee SJ, Nghiem P, Qureshi AA.  Role of skin biopsy to confirm suspected acute graft-vs-host disease: results of decision analysis. Arch Dermatol. 2006;142(2):175–82. 29. Kuykendall TD, Smoller BR.  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(6):1081–5. 30. Chen A, Chao K, Rodriguez L, Munday W, Worswick S. Toxic epidermal necrolysis versus cutaneous Graft-Versus-Host Disease in a hematopoietic stem cell transplant recipient: the role of elafin. Leuk Lymphoma. 2018;59(9):2261–3. 31. Spitzer TR.  Engraftment syndrome: double-edged sword of hematopoietic cell transplants. Bone Marrow Transplant. 2015;50(4):469–75. 32. Pinto Gouveia M, Gameiro A, Coutinho I, Pereira N, Cardoso JC, Goncalo M. Overlap between maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms among cutaneous adverse drug reactions in a dermatology ward. Br J Dermatol. 2016;175(6):1274–83. 33. Walsh S, Diaz-Cano S, Higgins E, et al. Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? A review of clinicopathological features of 27 cases. Br J Dermatol. 2013;168(2):391–401. 34. Martinez-Cabriales SA, Rodriguez-Bolanos F, Shear NH.  Drug reaction with eosinophilia and systemic symptoms (DReSS): how far have we come? Am J Clin Dermatol. 2019;20:217–36. 35. Chen YC, Chiu HC, Chu CY.  Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases. Arch Dermatol. 2010;146(12):1373–9. 36. Musette P, Janela B. New insights into drug reaction with eosinophilia and systemic symptoms pathophysiology. Front Med. 2017;4:179. 37. Ostrov DA, Grant BJ, Pompeu YA, et  al. Drug hypersensitivity caused by alteration of the MHC-­ presented self-peptide repertoire. Proc Natl Acad Sci U S A. 2012;109(25):9959–64. 38. McCormack M, Alfirevic A, Bourgeois S, et  al. HLA-A∗3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364(12):1134–43. 39. Chen P, Lin JJ, Lu CS, et al. Carbamazepine-induced toxic effects and HLA-B∗1502 screening in Taiwan. N Engl J Med. 2011;364(12):1126–33.

M. A. Fung et al. 40. Shiohara T, Ushigome Y, Kano Y, Takahashi R. Crucial role of viral reactivation in the development of severe drug eruptions: a comprehensive review. Clin Rev Allergy Immunol. 2015;49(2):192–202. 41. Kim DH, Koh YI.  Comparison of diagnostic criteria and determination of prognostic factors for drug reaction with eosinophilia and systemic symptoms syndrome. Allergy, Asthma Immunol Res. 2014;6(3):216–21. 42. Chiou CC, Yang LC, Hung SI, et  al. Clinicopathological features and prognosis of drug rash with eosinophilia and systemic symptoms: a study of 30 cases in Taiwan. J Eur Acad Dermatol Venereol. 2008;22(9):1044–9. 43. Cacoub P, Musette P, Descamps V, et  al. The DRESS syndrome: a literature review. Am J Med. 2011;124(7):588–97. 44. Chen YC, Chang CY, Cho YT, Chiu HC, Chu CY.  Long-term sequelae of drug reaction with eosinophilia and systemic symptoms: a retrospective cohort study from Taiwan. J Am Acad Dermatol. 2013;68(3):459–65. 45. Chi MH, Hui RC, Yang CH, et al. Histopathological analysis and clinical correlation of drug reaction with eosinophilia and systemic symptoms (DRESS). Br J Dermatol. 2014;170(4):866–73. 46. Skowron F, Bensaid B, Balme B, et al. Comparative histological analysis of drug-induced maculopapular exanthema and DRESS.  J Eur Acad Dermatol Venereol. 2016;30(12):2085–90. 47. Nguyen CV, Miller DD.  Serum sickness-like drug reaction: two cases with a neutrophilic urticarial pattern. J Cutan Pathol. 2017;44(2):177–82. 48. Karmacharya P, Poudel DR, Pathak R, et  al. Rituximab-induced serum sickness: a systematic review. Semin Arthritis Rheum. 2015; 45(3):334–40. 49. Broekaert SM, Boer-Auer A, Kerl K, et  al. Neutrophilic epitheliotropism is a histopathological clue to neutrophilic urticarial dermatosis. Am J Dermatopathol. 2016;38(1):39–49. 50. Fung MA. The clinical and histopathologic spectrum of “dermal hypersensitivity reactions,” a nonspecific histologic diagnosis that is not very useful in clinical practice, and the concept of a “dermal hypersensitivity reaction pattern”. J Am Acad Dermatol. 2002;47(6):898–907. 51. Kossard S, Hamann I, Wilkinson B.  Defining urticarial dermatitis: a subset of dermal hypersensitivity reaction pattern. Arch Dermatol. 2006;142(1):29–34. 52. Hannon GR, Wetter DA, Gibson LE. Urticarial dermatitis: clinical features, diagnostic evaluation, and etiologic associations in a series of 146 patients at Mayo Clinic (2006-2012). J Am Acad Dermatol. 2014;70(2):263–8. 53. Selvaag E.  Clinical drug photosensitivity. A retrospective analysis of reports to the Norwegian Adverse Drug Reactions Committee from the years 1970-1994. Photodermatol Photoimmunol Photomed. 1997;13(1–2):21–3.

15  Drug Reactions 54. Monteiro AF, Rato M, Martins C.  Drug-induced photosensitivity: Photoallergic and phototoxic reactions. Clin Dermatol. 2016;34(5):571–81. 55. Glatz M, Hofbauer GF. Phototoxic and photoallergic cutaneous drug reactions. Chem Immunol Allergy. 2012;97:167–79. 56. Stein KR, Scheinfeld NS. Drug-induced photoallergic and phototoxic reactions. Expert Opin Drug Saf. 2007;6(4):431–43. 57. Moore DE.  Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Saf. 2002;25(5):345–72. 58. Su W, Hall BJ, Cockerell CJ. Photodermatitis with minimal inflammatory infiltrate: clinical inflammatory conditions with discordant histologic findings. Am J Dermatopathol. 2006;28(6):482–5. 59. Beltraminelli H, Shabrawi-Caelen LE, Kerl H, Cerroni L.  Melan-a-positive “pseudomelanocytic nests”: a pitfall in the histopathologic and immunohistochemical diagnosis of pigmented ­ lesions on sun-damaged skin. Am J Dermatopathol. 2009;31(3):305–8. 60. El-Nabarawy EA, Elmasry MF, El Lawindi MI, Tarek YA. An epidemiological and clinical analysis of cutaneous adverse drug reactions seen in a tertiary care outpatient Clinic in Cairo, Egypt. Acta Dermatovenerol Croat. 2018;26(3):233–42. 61. Halevy S, Shai A.  Lichenoid drug eruptions. J Am Acad Dermatol. 1993;29(2 Pt 1):249–55. 62. Tetzlaff MT, Nagarajan P, Chon S, et al. Lichenoid dermatologic toxicity from immune checkpoint blockade therapy: a detailed examination of the clinicopathologic features. Am J Dermatopathol. 2017;39(2):121–9. 63. Merk HF, Vanstreels L, Megahed M. Lichenoid drug reactions. Hautarzt. 2018;69(2):116–20. 64. Fortuna G, Aria M, Schiavo JH.  Drug-induced oral lichenoid reactions: a real clinical entity? A systematic review. Eur J Clin Pharmacol. 2017;73(12):1523–37. 65. Brauer J, Votava HJ, Meehan S, Soter NA. Lichenoid drug eruption. Dermatol Online J. 2009;15(8):13. 66. Van den Haute V, Antoine JL, Lachapelle JM. Histopathological discriminant criteria between lichenoid drug eruption and idiopathic lichen planus: retrospective study on selected samples. Dermatologica. 1989;179(1):10–3. 67. LeBoit PE.  What goes down can go up. Am J Dermatopathol. 2005;27(1):89–90. 68. Joshi R.  Interface dermatitis. Indian J Dermatol Venereol Leprol. 2013;79(3):349–59. 69. LeBoit PE.  Interface dermatitis. How specific are its histopathologic features? Arch Dermatol. 1993;129(10):1324–8. 70. West AJ, Berger TG, LeBoit PE. A comparative histopathologic study of photodistributed and nonphotodistributed lichenoid drug eruptions. J Am Acad Dermatol. 1990;23(4 Pt 1):689–93. 71. Marsch AF.  Using stratum corneum thickness and configuration to distinguish lichenoid dermatoses. Am J Dermatopathol. 2018;40(9):655–60.

753 72. Pitney L, Weedon D, Pitney M.  Multiple lichen planus-­ like keratoses: lichenoid drug eruption simulant and under-recognised cause of pruritic eruptions in the elderly. Australas J Dermatol. 2016;57(1):54–6. 73. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003;139(8):683–93. 74. Hausmann O, Schnyder B, Pichler WJ. Drug hypersensitivity reactions involving skin. Handb Exp Pharmacol. 2010;196:29–55. 75. Ozkaya E.  Fixed drug eruption: state of the art. J Dtsch Dermatol Ges. 2008;6(3):181–8. 76. Flowers H, Brodell R, Brents M, Wyatt JP.  Fixed drug eruptions: presentation, diagnosis, and management. South Med J. 2014;107(11):724–7. 77. Shiohara T, Mizukawa Y, Teraki Y. Pathophysiology of fixed drug eruption: the role of skin-­ resident T cells. Curr Opin Allergy Clin Immunol. 2002;2(4):317–23. 78. Mahboob A, Haroon TS.  Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37(11):833–8. 79. Heng YK, Yew YW, Lim DS, Lim YL.  An update of fixed drug eruptions in Singapore. J Eur Acad Dermatol Venereol. 2015;29(8):1539–44. 80. Brahimi N, Routier E, Raison-Peyron N, et  al. A three-year-analysis of fixed drug eruptions in hospital settings in France. Eur J Dermatol. 2010;20(4):461–4. 81. Sehgal VN, Srivastava G.  Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int J Dermatol. 2006;45(8):897–908. 82. Qayoom S, Bisati S, Manzoor S, Sameem F, Khan K.  Adverse cutaneous drug reactions--a clinico-­ demographic study in a tertiary care teaching hospital of the Kashmir Valley, India. Arch Iran Med. 2015;18(4):228–33. 83. Inbaraj SD, Muniappan M, Muthiah NS, Arul Amutha GJI.  Pharmacovigilance of the cutaneous drug reactions in outpatients of dermatology department at a tertiary care hospital. J Clin Diagn Res. 2012;6(10):1688–91. 84. Cho YT, Lin JW, Chen YC, et al. Generalized bullous fixed drug eruption is distinct from StevensJohnson syndrome/toxic epidermal necrolysis by immunohistopathological features. J Am Acad Dermatol. 2014;70(3):539–48. 85. Mitre V, Applebaum DS, Albahrani Y, Hsu S. Generalized bullous fixed drug eruption imitating toxic epidermal necrolysis: a case report and literature review. Dermatol Online J. 2017;23(7). 86. Suzuki S, Ho J, Rosenbaum M, Bhawan J.  Neutrophilic fixed drug eruption: a mimic of neutrophilic dermatoses. Clin Exp Dermatol. 2019;44:236–8. 87. Agnew KL, Oliver GF. Neutrophilic fixed drug eruption. Australas J Dermatol. 2001;42(3):200–2. 88. Ozkaya E, Buyukbabani N, Erbudak DE.  Image Gallery: Purpuric fixed drug eruption from ornidazole showing leukocytoclastic vasculitis. Br J Dermatol. 2017;177(4):e164.

754 89. Jang KA, Choi JH, Sung KS, Moon KC, Koh JK.  Idiopathic eruptive macular pigmentation: report of 10 cases. J Am Acad Dermatol. 2001;44(2 Suppl):351–3. 90. Lin TK, Hsu MM, Lee JY. Clinical resemblance of widespread bullous fixed drug eruption to Stevens-­ Johnson syndrome or toxic epidermal necrolysis: report of two cases. J Formos Med Assoc. 2002;101(8):572–6. 91. Garel B, Ingen-Housz-Oro S, Afriat D, et al. Drug-­ induced linear IgA bullous dermatosis: a French retrospective pharmacovigilance study of 69 cases. Br J Clin Pharmacol. 2019;85:570–9. 92. Kuechle MK, Stegemeir E, Maynard B, Gibson LE, Leiferman KM, Peters MS. Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature. J Am Acad Dermatol. 1994;30(2 Pt 1):187–92. 93. Pastuszczak M, Lipko-Godlewska S, Jaworek AK, Wojas-Pelc A. Drug-induced linear IgA bullous dermatosis after discontinuation of cefuroxime axetil treatment. J Dermatol Case Rep. 2012;6(4):117–9. 94. Stavropoulos PG, Soura E, Antoniou C.  Drug-­ induced pemphigoid: a review of the literature. J Eur Acad Dermatol Venereol. 2014;28(9):1133–40. 95. Lloyd-Lavery A, Chi CC, Wojnarowska F, Taghipour K.  The associations between bullous pemphigoid and drug use: a UK case-control study. JAMA Dermatol. 2013;149(1):58–62. 96. Bastuji-Garin S, Joly P, Picard-Dahan C, et al. Drugs associated with bullous pemphigoid. A case-control study. Arch Dermatol. 1996;132(3):272–6. 97. Siegel J, Totonchy M, Damsky W, et  al. Bullous disorders associated with anti-PD-1 and anti-PD­L1 therapy: a retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol. 2018;79(6):1081–8. 98. Varpuluoma O, Forsti AK, Jokelainen J, et al. Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case-control study. J Am Acad Dermatol. 2018;79(6):1034–8.. e1035 99. Benzaquen M, Borradori L, Berbis P, et  al. Dipeptidyl peptidase IV inhibitors, a risk factor for bullous pemphigoid: retrospective multicenter case-­ control study from France and Switzerland. J Am Acad Dermatol. 2018;78(6):1090–6. 100. Varpuluoma O, Forsti AK, Jokelainen J, et  al. Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study. J Invest Dermatol. 2018;138(7):1659–61. 101. Meijer JM, Atefi I, Diercks GFH, et  al. Serration pattern analysis for differentiating epidermolysis bullosa acquisita from other pemphigoid diseases. J Am Acad Dermatol. 2018;78(4):754–9.. e756 102. Vodegel RM, Jonkman MF, Pas HH, de Jong MC.  U-serrated immunodeposition pattern differentiates type VII collagen targeting bullous diseases

M. A. Fung et al. from other subepidermal bullous autoimmune diseases. Br J Dermatol. 2004;151(1):112–8. 103. Kasperkiewicz M, Sadik CD, Bieber K, et  al. Epidermolysis bullosa acquisita: from pathophysiology to novel therapeutic options. J Invest Dermatol. 2016;136(1):24–33. 104. Delbaldo C, Chen M, Friedli A, et al. Drug-induced epidermolysis bullosa acquisita with antibodies to type VII collagen. J Am Acad Dermatol. 2002;46(5 Suppl):S161–4. 105. Vorobyev A, Ludwig RJ, Schmidt E.  Clinical features and diagnosis of epidermolysis bullosa acquisita. Expert Rev Clin Immunol. 2017;13(2):157–69. 106. Van Joost T, Van’t Veen AJ. Drug-induced cicatricial pemphigoid and acquired epidermolysis bullosa. Clin Dermatol. 1993;11(4):521–7. 107. Yoshimura K, Ishii N, Hamada T, et  al. Clinical and immunological profiles in 17 Japanese patients with drug-induced pemphigus studied at Kurume University. Br J Dermatol. 2014;171(3):544–53. 108. Palleria C, Bennardo L, Dastoli S, et al. Angiotensin-­ converting-­ enzyme inhibitors and angiotensin II receptor blockers induced pemphigus: a case series and literature review. Dermatol Ther. 2019;32:e12748. 109. Pinto GM, Lamarao P, Vale T.  Captopril-induced pemphigus vegetans with Charcot-Leyden crystals. J Am Acad Dermatol. 1992;27(2 Pt 2):281–4. 110. Akoglu G, Yavuz SO.  Pemphigus herpetiformis-­ type drug reaction caused by erdosteine containing mucolytic in a child. Cutan Ocul Toxicol. 2017;36(3):302–4. 111. Ngo JT, Trotter MJ, Robertson LH. Pemphigus vegetans associated with intranasal cocaine abuse. J Cutan Med Surg. 2012;16(5):344–9. 112. Downie JB, Dicostanzo DP, Cohen SR. Pemphigus vegetans-Neumann variant associated with intranasal heroin abuse. J Am Acad Dermatol. 1998;39(5 Pt 2):872–5. 113. Ahronowitz I, Fox L. Severe drug-induced dermatoses. Semin Cutan Med Surg. 2014;33(1):49–58. 114. Tavakolpour S.  Pemphigus trigger factors: special focus on pemphigus vulgaris and pemphigus foliaceus. Arch Dermatol Res. 2018;310(2):95–106. 115. Green JJ, Manders SM.  Pseudoporphyria. J Am Acad Dermatol. 2001;44(1):100–8. 116. Maynard B, Peters MS.  Histologic and immunofluorescence study of cutaneous porphyrias. J Cutan Pathol. 1992;19(1):40–7. 117. Schanbacher CF, Vanness ER, Daoud MS, Tefferi A, Su WP.  Pseudoporphyria: a clinical and biochemical study of 20 patients. Mayo Clin Proc. 2001;76(5):488–92. 118. Raso DS, Greene WB, Maize JC, McGown ST, Metcalf JS. Caterpillar bodies of porphyria cutanea tarda ultrastructurally represent a unique arrangement of colloid and basement membrane bodies. Am J Dermatopathol. 1996;18(1):24–9.

15  Drug Reactions 119. Fung MA, Murphy MJ, Hoss DM, Berke A, Grant-Kels JM.  The sensitivity and specificity of "caterpillar bodies" in the differential diagnosis of subepidermal blistering disorders. Am J Dermatopathol. 2003;25(4):287–90. 120. Ramdial PK, Naidoo DK.  Drug-induced cutaneous pathology. J Clin Pathol. 2009;62(6):493–504. 121. Sidoroff A, Dunant A, Viboud C, et  al. Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR). Br J Dermatol. 2007;157(5): 989–96. 122. Sidoroff A, Halevy S, Bavinck JN, Vaillant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol. 2001;28(3):113–9. 123. Szatkowski J, Schwartz RA.  Acute generalized exanthematous pustulosis (AGEP): a review and update. J Am Acad Dermatol. 2015;73(5):843–8. 124. Sidoroff A. Acute generalized exanthematous pustulosis. Chem Immunol Allergy. 2012;97:139–48. 125. Vyas NS, Charifa A, Desman GT, McNiff JM.  Distinguishing pustular psoriasis and acute generalized exanthematous pustulosis (AGEP) on the basis of plasmacytoid dendritic cells (PDCs) and MxA protein. J Cutan Pathol. 2019;46: 317–26. 126. Chau T, Parsi KK, Ogawa T, et al. Psoriasis or not? Review of 51 clinically confirmed cases reveals an expanded histopathologic spectrum of psoriasis. J Cutan Pathol. 2017;44(12):1018–26. 127. Penn L, Brinster NK. Eosinophils among the histological features of psoriasis. Am J Dermatopathol. 2019;41:347–9. 128. Rosa G, Fernandez AP, Schneider S, Billings SD.  Eosinophils are rare in biopsy specimens of psoriasis vulgaris. J Cutan Pathol. 2017; 44(12):1027–32. 129. Andersen KE, Hjorth N, Menne T. The baboon syndrome: systemically-induced allergic contact dermatitis. Contact Dermatitis. 1984;10(2):97–100. 130. Aquino M, Rosner G. Systemic Contact Dermatitis. Clin Rev Allergy Immunol. 2019;56:9–18. 131. Hausermann P, Harr T, Bircher AJ.  Baboon syndrome resulting from systemic drugs: is there strife between SDRIFE and allergic contact dermatitis syndrome? Contact Dermatitis. 2004;51(5–6):297–310. 132. Wolf R, Tuzun Y. Baboon syndrome and toxic erythema of chemotherapy: fold (intertriginous) dermatoses. Clin Dermatol. 2015;33(4):462–5. 133. Dereure O.  Drug-induced skin pigmentation. Epidemiology, diagnosis and treatment. Am J Clin Dermatol. 2001;2(4):253–62. 134. Dai J, Belum VR, Wu S, Sibaud V, Lacouture ME.  Pigmentary changes in patients treated with targeted anticancer agents: a systematic review and meta-analysis. J Am Acad Dermatol. 2017;77(5):902–10.. e902

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Adverse Cutaneous Reactions to Chemotherapeutic Agents

16

Mai P. Hoang and Daniela Kroshinsky

Contents Introduction

 759

Chemotherapy-Induced Acral Erythema Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 760  760  760  761  761

Neutrophilic Eccrine Hidradenitis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 761  762  762  762  762

Eccrine Squamous Syringometaplasia Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 763  763  763  763  763

Tumor Necrosis Factor-α Inhibitors Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 764  765  765  765  766

M. P. Hoang (*) Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA e-mail: [email protected] D. Kroshinsky Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_16

757

M. P. Hoang and D. Kroshinsky

758 Granulocyte-Macrophage Colony-­Stimulating Factor Clinical Presentation Histopathology

 767  767  767

Epidermal Growth Factor Receptor Inhibitor Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 768  768  768  768  768

Kinase Inhibitors Multikinase Inhibitors Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 769  769  769  770  770  770

BRAF V600E Inhibitor Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 771  771  772  772  772

MEK Inhibitor Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 773  773  774  774  774

Immune Checkpoint Blockade Clinical Presentation Prognosis and/or Clinical Course Histopathology

 775  775  777  777

Other Inhibitors ALK Inhibitors Clinical Presentation Histopathology PI3K/AKT/mTOR Inhibitors Clinical Presentation Histopathology Smoothened (SMO) Inhibitors Clinical Presentation and Histopathology CD20 Inhibitors Clinical Presentation Histopathology CD25 Inhibitors Clinical Presentation Histopathology CD30 Inhibitor Clinical Presentation and Histopathology CD52 Inhibitors Clinical Presentation Interferon Clinical Presentation and Histopathology Proteasome Inhibitor/Apoptosis Inducing Clinical Presentation and Histopathology

 778  778  779  779  779  779  779  780  780  780  780  781  781  781  781  781  781  781  782  782  782  782  783

16  Adverse Cutaneous Reactions to Chemotherapeutic Agents

759

Case Studies Case 1 Clinical History Microscopic Description Diagnosis Discussion Case 2 Clinical History Microscopic Description Diagnosis Discussion Case 3 Clinical History Microscopic Description Diagnosis Discussion Case 4 Clinical History Microscopic Description Diagnosis Discussion

 784  784  784  784  784  785  785  785  785  787  787  787  787  788  789  789  790  790  790  791  791

References

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Introduction As major advancements in cancer treatment are being made, adverse effects including cutaneous ones are increased in parallel. The cutaneous adverse events result in declined quality of life as well as increased cost of health care. In a 10-year analysis of skin adverse events in 3517 patients enrolled in phase 1 trials from 2000 to 2010, more skin adverse events were noted consistently in patients treated with molecular agents in comparison to patient received cytotoxic agents. With the exception of alopecia, more frequent events were noted for maculopapular eruption, mucositis, hand-foot skin reaction, dry skin, and acneiform eruption [1]. The effect of skin adverse effects on quality of life was surveyed in 283 cancer patients in a 16-item questionnaire focusing on symptoms, emotions, and function; the authors reported

significant differences in Skindex score and emotions in patients received targeted therapy versus those received nontargeted therapy [2]. In a retrospective and prospective study of 132 adult patients by Borovicka et  al. [3] treated with one molecularly targeted agent for 1 primary cancer type, the authors reported a median of 3 clinic visits for dermatologic adverse effects with a median cost of $1920 per patient. Therefore, awareness of the spectrum of these adverse cutaneous r­eaction patterns is important since they can change the treatment strategy. In this chapter the common cutaneous adverse reactions associated with chemotherapy, tumor necrosis factor-α inhibitor, granulocyte-­ macrophage colonystimulating factor, epidermal growth factor inhibitor, kinase inhibitors, immune checkpoint blockade, and other targeted therapies will be discussed.

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Chemotherapy-Induced Acral Erythema

and soles, to burning pain. The palms and soles then become symmetrically erythematous and edematous (Figs.  16.1 and 16.2) [5]. Prominent Hand-foot, hand-foot skin (HFS) reaction, palmar-­ vesiculation resulting in bullae is associated with plantar erythrodysesthesia, chemotherapy-­cisplatin, methotrexate, and multikinase inhibiinduced acral erythema or Burgdorf reaction is tors. The hands are more frequently involved in a dose-limiting cutaneous reaction to many cyto- classic HFS.  On the contrary, the feet, not only toxic chemotherapeutic agents including 5-fluo- pressure-bearing areas but also lateral aspects and rouracil (5-FU), methotrexate, hydroxyurea, web spaces are affected in HFS associated with doxorubicin, cytarabine, and multikinase inhibi- multikinase inhibitors (Table 16.1). tors (sorafenib and sunitinib) [4, 5].

Clinical Presentation The onset of HFS is typically 2–12  days after receiving chemotherapy. The patients experienced a several-day prodrome, progressing from dysesthesia, tingling sensation of the palms

Prognosis or Clinical Course Subsequent vesiculation and ulceration result in pain and interference with daily activities. The eruption worsens with continued chemotherapy and presents increased risk of infection. While keratolytics and emollients are

Figs. 16.1 and 16.2  Hand-foot skin reaction. Erythematous and edematous lesions on palms and soles

16  Adverse Cutaneous Reactions to Chemotherapeutic Agents Table 16.1  Clinical features of classic hand-foot skin reaction versus multikinase inhibitor Onset

Location

Clinical lesions Pathogenesis

Chemotherapy 2–12 days after therapy Hands predominant

Possible sweat-­ associated toxicity

Multikinase inhibitor Sorafenib: 2nd–fourth week of therapy Sunitinib: 1–3 months Feet predominant At pressure point, lateral aspect and web spaces Thick, well-defined hyperkeratotic lesion Possible vascular mechanism

used to treat grade 1 disease, therapy cessation is often necessary for grade 3 disease. Significant improvement with healing of skin lesions is observed within weeks upon treatment cessation [6].

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• The palms and soles then become symmetrically erythematous and edematous and then develop blisters. • The feet, not only pressure-bearing areas but also lateral aspects and web spaces are affected in hand-foot skin reaction associated with multikinase inhibitors. Histologic Features • Various stages of epidermal necrotic keratinocytes resulting in epidermal necrosis and vesiculation Differential Diagnosis • Graft-versus-host disease

Takeaway Essentials Histopathology The histologic features are characterized by various stages of epidermal necrotic keratinocytes resulting in epidermal necrosis and vesiculation, vacuolar degeneration of basal aspect of the epidermis, and sparse dermal lymphocytic infiltrate [5].

Clinical Relevant Pearls • Hand-foot skin reaction is a dose-­ limiting cutaneous reaction to many cytotoxic chemotherapeutic agents. Pathology Interpretation Pearls • A superficial intraepidermal blister is seen.

Differential Diagnosis Clinically similar lesions have been reported in patients with graft-versus-host disease and neoplasia [6].

Summary Clinical Presentation • Several-day prodrome, progressing from dysesthesia, tingling sensation of the palms and soles, to burning pain.

Neutrophilic Eccrine Hidradenitis Neutrophilic eccrine hidradenitis (NEH) is a self-­limiting dermatosis associated with cytostatic chemotherapy (cytarabine or anthracyclines) most commonly for acute myelogenous leukemia, other types of leukemia, and solid tumors and with targeted therapy including epidermal growth factor receptor (EGFR) inhibitor, tyrosine kinase inhibitors, and BRAF inhibitors [7, 8]. It has been postulated that the infiltration of neutrophils into the eccrine

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Fig. 16.3  Neutrophilic eccrine hidradenitis. Multiple erythematous plaques seen on sole of foot

glands is a result of either abnormal neutrophil function or local chemotactic factors. Since both eccrine and apocrine glands can be affected, the term “neutrophilic hidradenitis” has been proposed [9]. Eccrine glands regulate the increased body temperature in the setting of physical exertion or hot environment; therefore, they are most dense on the palms and soles. One possibility of eccrine injury is direct toxicity due to the secretion of drug into sweat. Cross-reacting antibody occurs due to a shared epitope between a drug and eccrine epithelium. Reabsorption of secreted drug in the sweat may result in damage of the glandular epithelium.

Clinical Presentation Solitary or multiple erythematous plaques can be seen on the face, trunk, and extremities associated with fever and leukocytosis (Fig. 16.3).

Prognosis or Clinical Course The lesions typically resolve within 1–4 weeks.

Histopathology A variable infiltrate of neutrophils surrounds the eccrine coils and extends into the glandular epithelium (Fig.  16.4). Variable vacuolar degenera-

Fig. 16.4  Neutrophilic eccrine hidradenitis. Neutrophils are seen infiltrating the eccrine coils in the dermis (×200)

tion and necrosis of the secretory epithelium and edema within the surrounding connective tissue can be seen.

Differential Diagnosis Although the differential diagnosis includes idiopathic recurrent palmoplantar hidradenitis, the idiopathic lesions affect the soles and palms of pediatric patients rather than upper trunk and extremities in chemotherapy-related neutrophilic eccrine hidradenitis [10].

Summary Clinical Presentation • Solitary or multiple erythematous plaques can be seen on the face, trunk, and extremities associated with fever and leukocytosis. Histologic Features • A variable infiltrate of neutrophils surrounds the eccrine coils and extends into the glandular epithelium. Differential Diagnosis • Idiopathic recurrent hidradenitis

palmoplantar

16  Adverse Cutaneous Reactions to Chemotherapeutic Agents

Takeaway Essentials Clinical Relevant Pearls • Idiopathic recurrent palmoplantar hidradenitis which affects the palms and soles of pediatric patients rather than the upper trunk and extremities in chemotherapy type Pathology Interpretation Pearls • Both eccrine and apocrine glands can be affected.

Eccrine Squamous Syringometaplasia Squamous syringometaplasia is characterized by replacement of cuboidal glandular epithelium of the eccrine glands and ducts by keratinizing squamous epithelium. Eccrine squamous syringometaplasia (ESS) has been reported in association with several chemotherapeutic agents including BRAF inhibitors, tyrosine kinase inhibitors, bleomycin, cisplatin, cyclophosphamide, daunorubicin, doxorubicin, fluorouracil, methotrexate, vincristine, and others [11]. Martorell-Calatayud and colleagues [12] have proposed the term “chemotherapy-related bilateral dermatitis associated with eccrine squamous syringometaplasia” for a subset of cases presenting as bilateral eruption on intertriginous skin. While the underlying mechanism is unclear, it has been postulated that syringometaplasia is due to direct toxicity of the eccrine glands and ducts by the chemotherapeutic agents secreted in the sweat or extravasated chemotherapy [13]. Regeneration of epithelium following ischemia and necrosis is another possible mechanism. Some have postulated that the metaplasia is due to the MAPK pathway dysregulatory effect induced by BRAF inhibitors.

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Clinical Presentation An erythematous macular, papular, or vesicular eruption typically appears 2–30  days after ­initiation of chemotherapy. These lesions can be either generalized or limited to the extremities and intertriginous areas such as the neck, axillae, and groin. Cutaneous toxicity developed at site of extravasated chemotherapy has been reported [13].

Prognosis or Clinical Course The eruption would spontaneously resolve with desquamation and postinflammatory hyperpigmentation within several weeks [11]. In half of the patients, the eruption would recur upon reintroduction of the cytotoxic agent [12].

Histopathology The histologic features are characterized by replacement of cuboidal glandular epithelium of the eccrine glands and ducts by keratinizing squamous epithelium (Figs. 16.5 and 16.6). Early changes would be characterized by hyperplastic duct with prominent apoptotic cells and mitotic figures. Squamous metaplasia of the glandular epithelium within superficial and mid-dermis is noted in established lesions 3–4 days after onset of dermatitis [12].

Differential Diagnosis When the squamous metaplasia is exuberant, squamous cell carcinoma is raised in the differential diagnosis. The lobular architecture and the proximity to an eccrine ductal lumina are supportive of a metaplastic process. Eccrine squamous syringometaplasia can be seen in a variety of settings such as reactive changes adjacent to an area of chronic ulceration, scar, panniculitis,

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Figs. 16.5 and 16.6  Eccrine squamous syringometaplasia. Glandular epithelium of the eccrine duct and glands has been replaced by keratinizing squamous epithelium (×200, ×200)

or carcinoma. The clinical differential diagnosis would include acute graft-versus-host disease and neutrophilic eccrine hidradenitis.

Summary Clinical Presentation • An erythematous macular, papular, or vesicular eruption appears 2–30  days after initiation of chemotherapy. • Can be either generalized or limited to the extremities and intertriginous areas such as the neck, axillae, and groin. Histologic Features • Replacement of cuboidal glandular epithelium of the eccrine glands and ducts by keratinizing squamous epithelium Differential Diagnosis • The clinical differential diagnosis would include acute graft-versus-host disease and neutrophilic eccrine hidradenitis.

Takeaway Essentials Clinical Relevant Pearls • Eccrine squamous syringometaplasia has been reported in association with several chemotherapeutic agents including BRAF inhibitors, tyrosine kinase inhibitors, bleomycin, cisplatin, cyclophosphamide, daunorubicin, doxorubicin, fluorouracil, methotrexate, vincristine, and others. Pathology Interpretation Pearls • Eccrine squamous syringometaplasia can be seen in a variety of settings such as reactive changes adjacent to an area of chronic ulceration, scar, panniculitis, or carcinoma.

Tumor Necrosis Factor-α Inhibitors Tumor necrosis factor-α (TNF-α) is a cytokine which plays an important role in the production of proinflammatory cytokines, Langerhans cell

16  Adverse Cutaneous Reactions to Chemotherapeutic Agents

maturation, keratinocyte proliferation, increased expression of vascular endothelial growth factors, and adhesion molecules [14]. TNF-α inhibitors are known to have potent disease-modifying effects in severe inflammatory conditions such as Crohn disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, and connective tissue disease. These agents include infliximab (Remicade), a chimeric mouse/human monoclonal antibody; etanercept (Enbrel), a dimeric fusion protein comprised of human TNF-α receptor fused to the Fc fragment of the IgG1; and adalimumab (Humira), a completely humanized monoclonal antibody. A variety of cutaneous reactions have been reported in association with TNF-α inhibitors. Although the mechanism is not completely understood, it has been postulated that TNF blockade causes cytokine imbalance which subsequently results in unopposed interferon-alpha production by plasmacytoid dendritic cells [15]. Unrestrained, upregulated expression of chemokine receptors promotes infiltration of autoreactive T cells to the skin [13].

Clinical Presentation Since the initial description in 2004 there have been over 200 cases of psoriasiform eruptions associated with TNF-α inhibitor. A retrospective review showed that are possibly three patterns of TNF-α-induced dermatitis: new onset of psoriasis characterized by palmoplantar pustulosis most within the first year of treatment, worsening of pre-existing psoriasis occurring from days to years after treatment, and induction of a psoriasiform eruption (Fig. 16.7) [14]. Though not frequently biopsied, urticaria and cellulitis are the most commonly reported injection site cutaneous adverse event associated with etanercept/Enbrel. Leukocytoclastic vasculitis has been reported to develop initially in the lower extremities and then became diffuse in a series of 35 patients after receiving etanercept and infliximab therapy [16].

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Fig. 16.7  TNF-alpha inhibitor psoriasiform dermatitis. New onset of plantar pustulosis in a patient on Remicade

Isolated cases of granuloma annulare or interstitial granulomatous dermatitis, sarcoidosis, lupus erythematosus-like reaction, perniosis-like eruption, erythema nodosum, and non-scarring alopecia have been reported in association with TNF-α inhibitors [17, 18]. Eruptive nevi and multiple lentigines as even eruptive keratoacanthomas have rarely been reported [18].

Prognosis or Clinical Course A majority of patients improved with topical treatment without the need for cessation of anti-­ TNF-­α therapy. Possible loss of treatment efficacy should be considered in therapy withdrawal.

Histopathology The histology of the psoriasiform lesions can resemble those of guttate psoriasis, well-­ established psoriasis to even pustular psoriasis (Figs.  16.8 and 16.9) [19]. Mounds of

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Differential Diagnosis Clinical history is needed to distinguish psoriasis from TNF-α-induced psoriasis.

Summary

Fig. 16.8  TNF-alpha inhibitor psoriasiform dermatitis. Psoriasiform and spongiotic dermatitis with dermal eosinophils (×200)

Clinical Presentation • Tumor necrosis factor-α inhibitor therapy has been associated with new-onset psoriasis, worsening of pre-existing psoriasis, and psoriasiform eruptions. • The most common cutaneous adverse effects are plaque psoriasis and palmoplantar pustulosis. Histologic Features • Mounds of parakeratosis containing neutrophils are seen in guttate-like lesion, whereas prominent subcorneal pustules are seen in pustular psoriasis. Differential Diagnosis • Psoriasis

Fig. 16.9  TNF-alpha inhibitor psoriasiform dermatitis. Prominent subcorneal pustule is seen (×100)

p­ arakeratosis containing neutrophils are seen in guttate-like lesion, whereas prominent subcorneal pustules are seen in pustular psoriasis. The eruption can resemble lichen planus and pustular folliculitis histopathologically. The number of dermal eosinophils varies from one to numerous. The skin biopsy of an urticarial lesion associated with etanercept/Enbrel would show a perivascular dermal infiltrate of lymphocytes and eosinophils. An interstitial infiltrate as well as palisade of histiocytes would be seen in mid and deep dermis in the biopsy of granuloma annulare or interstitial granulomatous dermatitis.

Takeaway Essentials Clinical Relevant Pearls • Discontinuing TNF-α therapy would often result in psoriasis resolution. • TNF-α inhibitor-induced psoriasis can be successfully managed with skin-­ directed therapies, and treatment does not need to be ceased. Pathology Interpretation Pearls • Clinical history is needed to distinguish psoriasis from TNF-α-induced psoriasis.

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Granulocyte-Macrophage Colony-­ Stimulating Factor Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine used to stimulate the growth of hematopoietic progenitor cells in the marrow, to reduce the incidence of febrile neutropenia, and to accelerate neutrophil recovery after transplantation [20].

Clinical Presentation A number of cutaneous side effects can be observed including local reaction at injection site, diffuse non-specific maculopapular eruption, neutrophilic dermatoses such as pyoderma gangrenosum and Sweet syndrome, neutrophilic eccrine hidradenitis, leukocytoclastic vasculitis, folliculitis, and rare cases of epidermolysis bullosa acquisita [21, 22].

Histopathology Although early changes might show focal interface and spongiotic dermatitis with dermal eosinophils consistent with a hypersensitivity reaction, established changes are characterized by interstitial inflammatory infiltrate of enlarged histiocytes (Fig.  16.10) [23]. Skin biopsies of a series of eight patients with a maculopapular rash show enlarged histiocytes [24]. Mehregan et  al. [25] reported a series of 26 patients with GM-CSF cutaneous side effects including local site injection and generalized cutaneous reactions; however, only 3 had skin biopsies performed. Skin biopsies often show a mixed dermal infiltrate of neutrophils, lymphocytes, eosinophils, and enlarged dermal CD68+ macrophages [22, 25]. An interstitial granulomatous dermatitis characterized by interstitial and enlarged dermal histiocytes has been reported [23]. These atypical appearing histiocytes raise the suspicion for leukemia cutis.

Fig. 16.10  GM-CSF hypersensitivity reaction. Perivascular and interstitial inflammatory infiltrate of lymphocytes, enlarged histiocytes, and erythrocytes in the dermis (×200)

Summary Clinical Presentation • A number of cutaneous side effects can be observed including local r­ eaction at injection site, diffuse non-­specific maculopapular eruption, neutrophilic dermatoses, neutrophilic eccrine hidradenitis, leukocytoclastic vasculitis, folliculitis, and rare cases of epidermolysis bullosa acquisita. Histologic Features • Early lesion exhibits focal interface and spongiotic dermatitis. • Established lesion shows a mixed dermal infiltrate of neutrophils, lymphocytes, eosinophils, and enlarged dermal histiocytes. Differential Diagnosis • Leukemia cutis

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Takeaway Essentials Clinical Relevant Pearls • The cutaneous adverse effects can be diverse for GM-CSF. Pathology Interpretation Pearls • The dermal histiocytes are enlarged and appeared atypical.

 pidermal Growth Factor Receptor E Inhibitor The epidermal growth factor receptor (EGFR) is a member of the Erb-B receptor tyrosine kinase or human epidermal growth factor receptor (HER) family and drives cell-signaling pathways that regulate cellular proliferation, survival, and differentiation. Cetuximab, gefitinib, and erlotinib are Food and Drug Administration (FDA) approved for treatment of colorectal, non-small cell lung, head and neck, and breast carcinomas [26]. Food and Drug Administration (FDA)-approved agents include EGFR-targeted monoclonal antibodies (cetuximab/Erbitux, panitumumab/Vectibix), tyrosine kinase inhibitor (erlotinib/Tarceva, gefitinib/Iressa, afatinib/Gilotrif), and dual EGFR and HER2 kinase inhibitors (lapatinib/Tykerb). Current clinical trials are investigating the use of EGFR inhibitors in treatment of thyroid cancer, malignant gliomas, and renal cell carcinoma.

Clinical Presentation The most common dermatologic reaction of EGFR inhibitors is a papulopustular eruption occurring within days to weeks after initiating EGFR inhibitor therapy. The eruption is characterized by pruritic, erythematous, folliculocentric papules and pustules, on the skin with high density of sebaceous glands such as the scalp, face, upper chest, and back (Fig. 16.11). It affects 50–90% of the patients, is dose dependent, typically develops within 7–10  days,

Fig. 16.11  EGFR inhibitor. A widespread eruption of erythematous, folliculocentric papules, and pustules on the back. (Courtesy of Esther Freeman MD, Department of Dermatology, Massachusetts General Hospital, Boston, MA)

and gradually resolves with postinflammatory hyperpigmentation after 12–16 weeks of EGFR inhibitor therapy [27]. Patients who develop this eruption while on EGFR therapy for nonsmall cell lung cancer are more likely to have a better prognosis than those patients who do not [28]. Other adverse reactions include xerosis, photosensitivity, pruritus, paronychia, hair abnormality, oral and genital mucositis, and nail toxicity [26].

Prognosis or Clinical Course The eruption can be treated empirically and usually does not required treatment modification.

Histopathology Two histologic patterns were observed for the papular pustular rash associated with EGFR inhibitor: (1) superficial inflammatory infiltrate surrounding hyperkeratotic and dilated follicular infundibula and (2) acute folliculitis with associated ruptured of follicular epithelium (Fig. 16.12).

Differential Diagnosis The main differential diagnosis would be a staphylococcal folliculitis and bacterial superinfection

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Takeaway Essentials Clinical Relevant Pearls • The eruption can be treated empirically and usually does not require treatment modification. Pathology Interpretation Pearls • Histologic features are indistinguishable from folliculitis. Fig. 16.12  EGFR inhibitor. An acute and ruptured folliculitis noted (×40)

[29]. The distinction would rely mainly on clinical findings with bacterial superinfection affecting the extremities, abdomen, and groin. Its onset occurs at any point during EGFR inhibitor therapy in contrast to the initial 7–10  days of inhibitor-­induced acneiform eruption.

Kinase Inhibitors Cutaneous adverse reactions, inflammatory as well as neoplastic, reported in association with multikinase inhibitor, BRAF inhibitor, MEK inhibitor, and combined BRAK and MEK inhibitor are outlined in Table 16.2. [30, 31]

Multikinase Inhibitors Summary Clinical Presentation • The most common dermatologic reaction is a papulopustular eruption occurring within days to weeks after beginning EGFR inhibitor therapy. • Other adverse reactions include hair and nail changes. Histologic Features • Acute folliculitis with associated ruptured • Superficial inflammatory infiltrate surrounding hyperkeratotic and dilated follicular infundibula Differential Diagnosis • Staphylococcal folliculitis • Bacterial superinfection

Imatinib mesylate (Gleevec), the first approved inhibitor of specific protein tyrosine kinases, is the standard treatment for patients with gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia. Sorafenib tosylate, a multikinase inhibitor with broad-spectrum activity, is used in the treatment of metastatic renal cell carcinoma (RCC), unresectable hepatocellular carcinoma (HCC), imatinib- and sunitinibresistant GIST, and metastatic colorectal carcinoma [32].

Clinical Presentation Cutaneous reactions can be seen up to 93% of the patients. The most common skin adverse effect is hand-foot skin (HFS) reaction, also known as palmar-plantar erythrodysesthesia and acral erythema, seen in 48% of patients on sorafenib and 36% of patients on sunitinib [32]. These lesions present as painful bilateral erythematous lesions, often associated with

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Morbilliform drug eruption Xerosis Photosensitivity Hand-foot skin reaction Acneiform eruption/folliculitis Panniculitis Grover disease Plantar hyperkeratosis Squamous papilloma Squamous cell carcinoma Melanocytic lesions alteration Cutaneous hypopigmentation Mucosal hyperpigmentation Hair kinking Diffuse hair loss Paronychia

Multikinase inhibitor + − − + − − − + − + − − − + + +

BRAF inhibitor/ vemurafenib + + + − − + + + + + + − − + + +

blisters, on the palms and soles usually within 45  days of initiating therapy (Figs.  16.1 and 16.2) [32]. Concerning the pathogenesis, the most accepted theory is direct toxicity of chemotherapeutic agents against acral epithelium [33]. The histologic findings of apoptotic keratinocytes with satellitosis of lymphocytes led Beard et al. [34] to propose the host-versus-altered-host response. A third theory proposed by Lacouture et al. [35] suggests that inhibition of both PDGFR and VEGFR may interfere with vascular repair mechanisms and become clinically apparent in areas exposed to repeated trauma such as the palms and soles. Cutaneous reactions other than HFS reaction have been reported in association with broad-­ spectrum multikinase inhibitors. These include non-specific rash, skin discoloration, xerosis, hair color changes, alopecia, nail changes, keratoacanthoma-­type squamous cell carcinomas, and eruptive melanocytic nevi [32].

 rognosis or Clinical Course P The extent of this epidermal change appears to correlate with the duration of therapy with the multikinase inhibitor [35].

MEK inhibitor/ dabrafenib − + − − − + + + + + + + + + + −

BRAF + MEK inhibitor/ dabrafenib + trametinib − + − − + + − − − − + − − − + +

Histopathology The general histopathologic pattern of HFS reaction is an interface dermatitis with some degree of epidermal necrosis or vesiculation, as noted in some cases [32, 35]. An interface dermatitis seen on skin biopsies from seven patients with HFSR associated with sorafenib or sunitinib [35] was similarly noted in the skin biopsies from six patients in a case series by Lee et al. [32] Differential Diagnosis The HFSR associated with sorafenib shares the similarities, including palmoplantar distribution, dose dependency, and tenderness to the conventional HFSR, but differed by thick, well-defined hyperkeratotic lesions frequently affecting digit flexural locations [36].

Summary Clinical Presentation • Hand-foot skin reaction is the most common cutaneous reaction. • Others include non-specific rash, skin discoloration, xerosis, hair color changes,

16  Adverse Cutaneous Reactions to Chemotherapeutic Agents

alopecia, nail changes, keratoacanthoma-­ type squamous cell carcinomas, and eruptive melanocytic nevi. Histologic Features • Hand-foot skin reaction is characterized by an interface dermatitis with some degree of epidermal necrosis or vesiculation. Differential Diagnosis • Conventional hand-foot skin reaction

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action of the BRAF kinase by competitively bind to the ATP binding site and have demonstrated improved overall survival and progression-free survival in large clinical trials. However, cutaneous inflammatory dermatoses are common including an exanthematous rash, keratosis pilaris-like reaction, alopecia, and neutrophilic panniculitis [38, 39]. As a consequence of RAF inhibition, the paradoxical activation of MAPK pathway in wild-type BRAF cells results in squamoproliferative lesions and atypical melanocytic proliferations [39].

Clinical Presentation Takeaway Essentials Clinical Relevant Pearls • The most common skin adverse effect associated with broad-spectrum multikinase inhibitor is hand-foot skin reaction. • The hand-foot skin reaction associated with sorafenib differs from conventional HFSR by thick, well-defined hyperkeratotic lesions frequently affecting digit flexural locations. Pathology Interpretation Pearls • Epidermal necrosis resulting vesiculation

in

BRAF V600E Inhibitor BRAF is a serine/threonine kinase involved in the RAS-RAF-MEK-ERK-MAP kinase signaling pathway, which regulates the cellular response to growth signals and drives proliferation [37]. BRAF mutations are common in hairy cell leukemia, cutaneous melanomas (40–60%), thyroid carcinomas (46%), ovarian low-grade serous carcinomas (34%), and colorectal carcinomas (10%). Vemurafenib and dabrafenib selectively inhibit the BRAF V600E oncoprotein and are currently approved for the treatment of unresectable and/or metastatic melanoma. These inhibitors inhibit the

Maculopapular eruptions, seen in 15–27% of patients on BRAF inhibitors, often present during the first 2 weeks of therapy and do not associate with treatment response. They are characterized by many 2–4 mm erythematous papules coalescing into plaques [39]. Pruritus (29%), UVAinduced photosensitivity (30–57%) during the early phase of therapy, and hair and nail changes can also be seen. BRAF inhibitor therapy has also been associated with the development of tender erythematous nodules resembling erythema nodosum associated with mild arthralgias on the upper and/or lower extremities anywhere from days to weeks after initiating treatment [39]. A spectrum of squamoproliferative lesions ranging from actinic keratosis, verrucoid keratosis, to well-differentiated or invasive squamous cell carcinomas (SCC) can be seen in 49–85% of the patients [40]. Squamous cell carcinoma (SCC) is the most common malignancy associated with BRAF inhibition therapy and develops in both sunexposed and non-sun-exposed skin (Fig.  16.13). SCC can develop within days or months in approximately a quarter of patients after receiving BRAF inhibitor treatment [40]. The median time of onset is 8 weeks in v­ emurafenib and 16 weeks in dabrafenib, suggesting close monitoring during the first 6  months of treatment is important. These SCC affect the upper arm, chest, back, and/ or thigh. Increasing age has been cited as a risk factor for developing an SCC while on BRAF inhibitor therapy [40].

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Fig. 16.13  BRAF inhibitor. Squamous cell carcinoma presents as a nodule on sun-exposed skin

Fig. 16.15  BRAF inhibitor. A crateriform proliferation of atypical keratinocytes consistent with a well-­ differentiated squamous cell carcinoma (×100)

involved in the development of new or progression of existing melanocytic lesions [42].

Prognosis or Clinical Course

Fig. 16.14  BRAF inhibitor. Eruptive nevi on dorsum of foot. (Courtesy of Maria B. Alora-Palli MD, Department of Dermatology, Massachusetts General Hospital, Boston, MA)

During BRAF inhibitor therapy, existing melanocytic lesions can undergo involution or exhibit change in size and color [41]. Eruptive nevi, new nevi, as well as new primary melanomas can develop (Fig.  16.14) [41]. New or changing nevi from patients receiving BRAF inhibitors have been shown to be BRAF wild type, supportive of the hypothesis of paradoxical MAPK activation [42]. Several studies have demonstrated that the new or changing melanocytic lesions associated with BRAF inhibitor therapy are BRAF wild type [42]. A biological mechanism similar to that proposed for the development of squamous proliferative lesions while on BRAF inhibitor therapy may also be

A combination of BRAF and MEK inhibitors would improve treatment efficacy as well as decrease cutaneous toxicity.

Histopathology The squamoproliferative lesions can assume various morphology ranging from actinic keratosis to well-differentiated SCC (Fig.  16.15) [40]. Histologic examination of nevi associated with BRAF inhibitor therapy showed increased melanin pigmentation within the stratum corneum, epidermal keratinocytes, dermal melanophages, and deep HMB-45 expression (Fig. 16.16) [42].

Differential Diagnosis Clinical history is vital in recognizing the association of squamoproliferative and melanocytic lesions and BRAF inhibitor therapy.

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Takeaway Essentials Clinical Relevant Pearls • A combination of BRAF and MEK inhibitors would improve treatment efficacy as well as decrease cutaneous toxicity. Pathology Interpretation Pearls • Clinicopathologic correlation is essential in rendering the diagnosis Fig. 16.16  Nevi associated with BRAF inhibitor therapy. A proliferation of atypical melanocytes at the basal aspect of the epidermis associated with increased pigmentation noted within epidermis, stratum corneum, and superficial dermis (×200)

Summary Clinical Presentation • Maculopapular eruptions, pruritus, UVA-induced photosensitivity, and hair and nail changes can be seen. • A spectrum of squamoproliferative lesions ranging from actinic keratosis, verrucoid keratosis, to well-­differentiated or invasive squamous cell carcinomas can be seen. • Change of existing nevi, eruptive nevi, new nevi, as well as new primary melanomas can develop. Histologic Features • The squamous lesions can exhibit histologic features of actinic keratosis, verrucoid keratosis, to well-differentiated or invasive squamous cell carcinomas. • Nevi associated with BRAF inhibitor therapy show increased melanin pigmentation. • A septal and lobular panniculitis with prominent infiltrate of neutrophils. Differential Diagnosis • Acquired squamous or melanocytic lesions

MEK Inhibitor The mitogen-activated protein kinases 1 and 2 (MEK1/MEK2) are key enzymes in the RAS/ RAF/MEK/ERK pathway that regulates cellular proliferation and survival [43]. Improved survival has been reported for combining MEK inhibitors such as trametinib and BRAF inhibitors in treatment of BRAF-mutant metastatic melanomas [44]. Combinations of MEK and BRAF inhibitors were shown to have a higher frequency of folliculitis and a significantly decreased rate of cutaneous squamoproliferative lesions [30]. Patients received BRAF inhibitor monotherapy developed more frequent cutaneous adverse events and in a shorter time interval than those receiving a combination of BRAF and MEK inhibition [45]. It has been hypothesized that the paradoxical activation of MAPK pathway can be prevented with a MEK inhibitor. Cutaneous adverse effects associated with MEK inhibitor therapy include a dose-dependent morbilliform eruption, acneiform eruption, xerosis, hyperpigmentation, paronychia, alopecia, and palmar-­ plantar erythrodysesthesia [43, 46].

Clinical Presentation The cutaneous adverse events of MEK inhibitors resembles that of EGFR inhibitors [43]. This acneiform eruption involving the head and neck and upper trunk is the most common ­cutaneous adverse

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Fig. 16.18  MEK inhibitor. A suppurative folliculitis seen (×40)

Fig. 16.17  MEK inhibitor. Numerous papules and pustules are seen. (Courtesy of Daniel Sugai MD and Vladimir Ratushny MD PhD, Department of Dermatology, Massachusetts General Hospital, Boston, MA)

effect seen in association with the second generation MEK inhibitor selumetinib (Fig. 16.17) [43]. Paronychia is characterized by erythema, swelling, and ingrown nail. Xerosis and alopecia can be seen in 35% and 5% of the patients, respectively. Panniculitis can rarely be seen [47].

Prognosis or Clinical Course This eruption is typically responsive to systemic antibiotics for their anti-inflammatory properties. Discontinuation of MEK inhibitor would result in symptom improvement [43].

Histopathology The histopathology of the acneiform eruption can be either suppurative folliculitis or perifol-

liculitis (Fig. 16.18). A dense, perifollicular, and often periadnexal infiltrate of predominantly neutrophils with or without associated follicular rupture would be seen [43]. Histopathology of a dermal hypersensitivity reaction is characterized by a sparse, superficial perivascular mixed inflammatory infiltrate composed of lymphocytes, eosinophils, and with or without neutrophils.

Differential Diagnosis The main differential diagnosis is a bacterial folliculitis.

Summary Clinical Presentation • An acneiform eruption involving the head and neck and upper trunk. • Paronychia, xerosis, and alopecia can be seen. Histologic Features • Either suppurative perifolliculitis Differential Diagnosis • Bacterial folliculitis

folliculitis

or

16  Adverse Cutaneous Reactions to Chemotherapeutic Agents

Takeaway Essentials Clinical Relevant Pearls • An acneiform eruption is the most common cutaneous adverse effect seen in association with MEK inhibitor. • A combined therapy of BRAF and MEK inhibition has demonstrated fewer cutaneous adverse events and longer cutaneous adverse event-free interval than BRAF inhibitor monotherapy. Pathology Interpretation Pearls • The histopathologic features can resemble a dermal hypersensitivity reaction.

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A recent landmark trial has shown superior response to PD1 inhibitor (pembrolizumab) in comparison to CTLA-4 inhibitor (ipilimumab) in patients with metastatic melanomas [48]. However, these agents can trigger immune-­ related adverse effects that may be seen up to 49–68% whose incidence appears to be higher in patients with melanomas and renal cell carcinomas in comparison to other tumor types [49, 50]. Cutaneous adverse events are twice as frequent in patients receiving anti-CTLA4 than those receiving anti-PD1/PDL1 therapy (68% versus 38%) [49]. A more severe cutaneous side effect has been reported in combined therapy of ipilimumab and nivolimumab [49].

Clinical Presentation

Immune Checkpoint Blockade Inhibitory (checkpoint) pathways regulate tumor infiltrating lymphocytes that inhibit the tumor’s growth and limit autoimmunity which causes injury to the host. During progression, tumors have adapted to bypass immune inhibitory signal and thus block the host’s antitumor response. When PDL1 expressed on tumor cells binds to PD1 expressed on activated T-cells, an inhibition of tumor immune destruction by activated T-cells occurs. By releasing tumorspecific immune cells from inhibitory signaling, immunotherapy that targets cytotoxic T-lymphocyte-associated antigen-­ 4 (CTLA4), programmed cell death 1 (PD-­1) receptor, and its ligand (PDL1) is currently the frontline treatment of metastatic melanoma and other solid tumors. Ipilimumab and tremelimumab are fully humanized monoclonal IgG1 antibody and IgG2 antibody, respectively, that blocks CTLA-4 receptors on T-cells. Anti-PD1 antibodies include nivolumab, a fully human IgG4-kappa monoclonal antibody, and pembrolizumab, a recombinant humanized IgG4kappa monoclonal antibody. The inhibitory effects on T-cells are removed when these antibodies block the PD1-­PDL1 and PD1-PDL2 interactions.

Curry and colleagues have proposed categorizing these reactions into four groups: inflammatory, immunobullous, alteration of keratinocytes, and alteration of melanocytes (Table  16.3) [49, 50]. Clinical appearances of these lesions ranged from maculopapular, follicular, pruritic, pustular, vesicular, acneiform, to exfoliative [49]. A morbilliform drug eruption is the most common adverse cutaneous reaction reported in association with CTLA-4 blockade and can be seen up to 25% of patients (Fig. 16.19) [51]. Clinically it is characterized by generalized pruritic, minimally scaly papules or plaques diffusely involve the trunk and extremities [51]. Other less frequent adverse events include vitiligo-like melanoma-­ associated hypopigmentation [52], DRESS, SJS/ TEN, prurigo nodularis, acneiform eruption, lichenoid exanthema, pyoderma gangrenosum-­ like ulceration, radiation recall dermatitis [53], dermatitis herpetiformis, and dermatomyositis [52–54]. Adverse effects associated with anti-PD1 agents are immune related affecting the skin and thyroid and less commonly neurological, gastrointestinal, and hepatic systems. In a meta-­ analysis of 3825 patients received anti-PD1 and 556 patients received anti-PDL1, skin adverse effects were noted in 39% and 17%, respectively [49]. Pruritus and rash were reported in 45%

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776 Table 16.3  Cutaneous adverse effects in immunotherapy [49, 50] Type Inflammatory

Immunobullous Squamoproliferative

Melanocytic proliferation

Lichenoid dermatitis Acute generalized exanthematous pustulosis Dermal hypersensitivity reaction Acneiform eruption Photosensitivity reaction Stevens-Johnson syndrome/toxic epidermal necrolysis Radiation-associated dermatitis Psoriasiform dermatitis Spongiotic dermatitis Pityriasis lichenoides chronica-like dermatitis Sarcoid-like granulomatous dermatitis Vasculopathic Erythema nodosum-like panniculitis Dermatomyositis Neutrophilic dermatosis CD30-positive lymphoid reaction Drug rash with eosinophilia and systemic syndromes (DRESS) Bullous pemphigoid Dermatitis herpetiformis Grover disease Prurigo nodularis Seborrheic keratosis Actinic keratosis Squamous cell carcinoma Basal cell carcinoma Vitiligo Regression of melanocytic nevi Tumoral melanosis

Fig. 16.19  Immunotherapy. A morbilliform eruption is seen. (Courtesy of Janelle S. Nassim MD, Department of Dermatology, Massachusetts General Hospital, Boston, MA)

Anti-­ CTLA4 + + + + + + + − − − − − − + + + +

Anti-PD1/ PDL1 + + + + + + + + + + + + + − − − −

− + + + − − − − + + +

+ − + − + + + + + + −

of individuals receiving anti-PD1 and anti-PDL1 therapy [55]. Lichenoid drug eruption is the most common cutaneous side effect associated with anti-PD1/and-PDL1 therapy [50]. The mean onset of lichenoid dermatitis and bullous pemphigoid was 88 days (1–266 days) and 190 days (21–630 days), respectively [49]. Erythematous/ violaceous plaques to scaly papules/nodules are the typical presentation of the lichenoid eruption. Other reactions include psoriasiform dermatitis, spongiotic dermatitis, bullous pemphigoid, Stevens-Johnson syndrome/toxic epidermal necrolysis, Grover disease, pityriasis lichenoides chronica-like, sarcoid-like granulomatous dermatitis, and erythema nodosum-like panniculitis were also reported [50].

16  Adverse Cutaneous Reactions to Chemotherapeutic Agents

Prognosis and/or Clinical Course The low-grade adverse effects such as dermal hypersensitivity reaction and pruritus are effectively treated with topical corticosteroids and antihistamines, respectively. High-grade cutaneous adverse effects may require systemic steroid and withholding chemotherapy [49]. In a series of 16 patients, 67% were treated with systemic corticosteroids, and 19% discontinued immunotherapy due to their skin reactions [50].

Histopathology

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infiltrate can be either mixed CD4+ and CD8+ or predominantly CD4+. A subepidermal bullous dermatosis with mixed infiltrate of neutrophils and eosinophils, type IV collagen-positive blister floor, linear IgG and C3 deposition at basement membrane zone on direct immunofluorescence examination, and linear IgG and C3 deposition on the blister roof on indirect immunofluorescence examination is seen vesiculobullous lesions (Fig.  16.23) [57]. Granulomatous or sarcoid-like eruptions as well as granuloma annulare have been reported in patients receiving checkpoint inhibitors [58, 59].

A morbilliform drug eruption of anti-CTLA4 is characterized by a perivascular, predominantly CD4+ T-cell inflammatory infiltrate, and interface dermatitis with basilar vacuolization, spongiosis, and occasional dyskeratosis in more severe reactions are seen (Fig.  16.20) [51]. Histology of the lichenoid eruption associated with anti-PD1/PDL1 therapy is similar to those observed in other lichenoid reaction: hyperkeratosis, wedge-shaped hypergranulosis, epidermal acanthosis, apoptotic keratinocytes at the dermal-­ epidermal junction, dense and band-like lymphohistiocytic infiltrate within the papillary dermis, and occasional dermal eosinophils (Figs. 16.21 and 16.22) [56]. The dermal

Fig. 16.21  Nivolimumab. Intraepidermal necrotic keratinocytes and patchy band-like inflammatory infiltrate are seen consistent with an interface and lichenoid dermatitis (×100)

Fig. 16.20  Immunotherapy. Necrotic keratinocytes are seen at the dermal-epidermal junction consistent with an interface drug eruption (×200)

Fig. 16.22  Nivolimumab. Interface and lichenoid dermatitis (×200)

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Takeaway Essentials Clinical Relevant Pearls • Cutaneous adverse events are twice as frequent in patients receiving anti-­ CTLA4 than those receiving anti-PD1/ PDL1 therapy. • Dermatologic toxicities are usually mild and rarely morbid. • Early management is important to prevent treatment discontinuation. Fig. 16.23  Subepidermal bullous dermatosis in a patient on immunotherapy (×100)

Summary Clinical Presentation • The most common cutaneous side effects associated with anti-CTLA4 therapy are pruritus and self-limiting maculopapular rash. • Lichenoid dermatitis, eczema, bullous pemphigoid, and vitiligo are seen with anti-PD1/PDL1 therapy. • Lichenoid drug eruption is the most common cutaneous side effect associated with anti-PD1/and-PDL1 therapy. Histologic Features • Four groups of cutaneous reactions: Inflammatory, immunobullous, alteration of keratinocytes, and alteration of melanocytes. • Histology of the lichenoid eruption associated with anti-PD1/PDL1 therapy is similar to those observed in other lichenoid reaction. • A subepidermal bullous dermatosis with linear IgG and C3 deposition at basement membrane zone on direct immunofluorescence examination is seen vesiculobullous lesions. Differential Diagnosis • Lichenoid hypersensitivity reaction • Bullous pemphigoid

Pathology Interpretation Pearls • Histologic features of subepidermal bullous dermatoses are indistinguishable from bullous pemphigoid.

Other Inhibitors A number of inhibitors target the underlying molecular alteration of certain tumor cancer via a variety of mechanisms including chromosomal translocation involving the tyrosine kinase anaplastic lymphoma kinase (ALK) gene, the PI3K/AKT/mTOR pathway, proteasome or apoptosis inducing, and mutation of smoothened (SMO). Other inhibitors target antigens that are expressed on specific tumor cells such as CD20, CD25, CD30, and CD52. Adverse cutaneous reactions occurring in these inhibitors have been documented only in isolated case reports.

ALK Inhibitors The majority of lung carcinomas are non-small cell type and 3–5% of which harbor a chromosomal translocation involving the tyrosine kinase anaplastic lymphoma kinase (ALK) gene [60]. Crizotinib is an inhibitor of ALK, ROS1, and MET, especially for patients with non-small cell lung carcinoma with echinoderm microtubule-­ associated protein-like 4 (EMLA)/ALK translocation [61, 62]. Alectinib is a next-generation ALK inhibitor.

16  Adverse Cutaneous Reactions to Chemotherapeutic Agents

Clinical Presentation In a series of 172 patients with ALK-positive non-small cell lung carcinomas, mild adverse effects included gastrointestinal disorders (nausea, vomiting, diarrhea, or constipation), vision disorder, and pitting edema [63]. Rare cases of transformation of ALK rearrangement-positive adenocarcinoma to small-cell lung cancer have been reported as acquired resistance to alectinib [64]. Cutaneous adverse effects of ALK inhibitor are infrequent with case reports of toxic epidermal necrolysis, erythema multiforme, and erythematous and exfoliative rash on sun-exposed skin (Fig. 16.24) [65–67]. Histopathology The skin biopsy of the erythema multiforme case showed spongiosis and superficial perivascular infiltrate of lymphocytes and eosinophils in the dermis (Fig. 16.25) [65].

PI3K/AKT/mTOR Inhibitors The PI3K-AKT-mTOR signaling cascade is upregulated in a variety of malignancies. Targeted inhibition of mTOR and the PI3K-AKT-mTOR pathway impairs cell growth and proliferation which is the likely basis for the common mucocutaneous adverse effects associated with mTOR inhibition.

Fig. 16.24  ALK inhibitor. A morpheaform eruption characterized by atrophic plaque with surrounding erythema. (Courtesy of Ryan Sells MD, Department of Dermatology, Massachusetts General Hospital, Boston, MA)

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Fig. 16.25  ALK inhibitor. A sclerotic dermis with minimal inflammation consistent with morphea (×40)

Clinical Presentation Approximately half of the patients on mTOR inhibitor therapy will develop either a generalized, cutaneous morbilliform drug eruption or discrete, mucosal aphthous stomatitis [68]. Stomatitis can be seen in 44% of patients, severe (grade 3 toxicity) in 3%, and can result in dose modification or drug cessation [68]. Morbilliform, eczematoid, and acneiform eruption can develop within the first couple of weeks of therapy but can occur up to 3 months after starting treatment [69]. The eruption frequently affects the trunk, but also the extremities, neck, face and scalp. Severe pruritus, xerosis, nail toxicity (paronychia), alopecia, bullous pemphigoid, facial hypertrichosis, vasculitis, and edema are additional cutaneous adverse effects that can be observed [70–72]. Histopathology Histologically, the cutaneous eruption is characterized by epidermal spongiosis and focal interface change, underlying mixed perivascular inflammatory infiltrate containing eosinophils (Fig. 16.26) [69]. A papulopustular clinical morphology has also been described, which corresponded histologically to a suppurative folliculitis with associated eosinophils [69]. In addition, an erythematous nodular appearance has also been described, which, histologically, demonstrated superficial and deep perivascular and interstitial mixed inflammatory infiltrates with eosinophils, neutrophils, and vasculopathic changes [69].

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Fig. 16.26  PIK3 inhibitor. Superficial and deep perivascular dermatitis with rare dermal eosinophils (×100)

Histologically confirmed cases of leukocytoclastic vasculitis have also been reported [73].

Smoothened (SMO) Inhibitors Basal cell carcinoma (BCC) is the most common human cancer and the underlying pathogenesis often involves abnormal activation of hedgehog pathway signaling, by a mutation either in the tumor-suppressor gene encoding patched 1 (PTCH1) or smoothened (SMO) [74]. Vismodegib is a first-in-class FDA-approved oral smoothened receptor inhibitor for the treatment of patients with locally advanced and metastatic BCC and who are not candidates for either surgery or radiation. Sonidegib is a second inhibitor which has recently approved for the same patient group [75]. A variety of adverse effects can be observed and have been attributed to the inhibition of the hedgehog pathway.

Clinical Presentation and Histopathology Commonly observed adverse events include muscle spasms (71.7%), alopecia (63.8%), taste disturbance (55.1%), weight loss, fatigue (asthenia), nausea, loss of appetite, diarrhea, and hepatotoxicity [75]. Muscle spasms tend to affect the muscles of the lower leg and foot at night. The loss (ageusia) or distortion (dysgeusia) of taste can lead to anorexia and depression. Alopecia,

46–66% of patients, is apparent at fourth month of treatment, generally reversible, and thought to be induced by arrested transition from telogen to anagen phase by hedgehog pathway inhibitors [76]. Drug reaction with eosinophils and systemic symptoms has been reported in one patient with metastatic BCC and another with numerous recurrent BCCs treated with vismodegib [77, 78]. Few case reports have documented the squamoproliferative adverse effects associated with vismodegib treatment. Multiple epidermoid cyst and hyperkeratosis have been reported in one patient [79]. A man with Gorlin or basal cell nevus syndrome developed trichodysplasia spinulosa or virus-associated trichodysplasia after 3 months of vismodegib treatment [80]. New keratoacanthomas developing within 2 months of treatment were reported in two individuals [81]. Histopathologically, these lesions showed an atypical and endophytic squamous proliferation. Iarrobino et  al. [82] described an SCC developing following treatment of metastatic BCC with vismodegib.

CD20 Inhibitors Rituximab is a chimeric monoclonal antibody that targets the human CD20 antigen, a multimeric, and cell-surface complex antigen that is specific to B-cells [83]. Anti-CD20 antibodies such as rituximab are thought to contribute to B-cellspecific destruction through a combination of synergistic mechanisms including complement-­ dependent cytotoxicity, antibody-­ dependent cell-mediated cytotoxicity, direct antiproliferative effect, and the induction of apoptosis [83]. Rituximab is currently used to treat an array of malignancies and several inflammatory conditions, including B-cell lymphomas [83], chronic lymphocytic leukemia [84], as well as rheumatoid arthritis, systemic lupus erythematosus, pemphigus, and refractory nephrotic syndrome.

Clinical Presentation Infusion-related reactions occur at an incidence rate of up to 14%, as documented in clinical trials. The patients typically experience fever, chills, nausea, and headache [83, 85]. However,

16  Adverse Cutaneous Reactions to Chemotherapeutic Agents

more serious adverse reactions such as cytokine-­ release syndrome associated with lymphopenia, thrombocytopenia, and hepatotoxicity can occur [86]. Potentially life-threatening noninfectious pulmonary toxicity [87] and cardiac arrhythmias and acute coronary syndromes [88] have also been described in the literature. Cutaneous adverse reactions are characterized predominantly by lesion-localized urticaria [85, 89]. One hour after infusion, a pruritic, erythematous to violaceous, well-demarcated, irregularly shaped plaques develop at the site of existing or previously excised tumors [85]. The lesions spontaneously regress 1–2  hours after stopping the infusion [85].

Histopathology Histologic sections of an urticarial lesion show an interstitial infiltrate of predominant CD8+ T-cells [89]. There have been three reported cases of rituximab-induced vasculitis, and the skin biopsies of these cases demonstrated histologic features of leukocytoclastic vasculitis [90]. In addition, there are single, isolated case reports of Stevens-Johnson syndrome [91], psoriasis [92], Merkel cell carcinoma [93], and SCC [94] reported in association with rituximab therapy.

CD25 Inhibitors

781

nemia, congestive heart failure, and infections [95, 97]. Cutaneous side effects were reported in 37% of daclizumab-treated patients including allergic dermatitis (7%) and eczema (4%). They are mild to moderate in severity and often resolved over time [95, 98]. Predisposing factor to cutaneous eruption includes a history of eczema and seborrheic dermatitis [96]. Uncommon cutaneous adverse events include DRESS syndrome, leukocytoclastic vasculitis, pityriasis rubra pilaris, pustular psoriasis, and acute generalized psoriasis [97, 98].

Histopathology Histologic features of an eczematous dermatitis including spongiosis and perivascular infiltrate with rare dermal eosinophils are seen [96]. An infiltrate of CD56+ T-cells was prominent in biopsies from moderate to severe rashes [96].

CD30 Inhibitor Brentuximab vedotin is an antibody-drug conjugate that induces cell cycle arrest and apoptosis by delivering monomethyl auristatin E, an antimicrotubule agent, to CD30+ cells. It is FDA-­approved for the treatment of patients with stage II or IV Hodgkin’s lymphoma, relapsed or refractory systemic anaplastic large-cell lymphoma and CD30positive peripheral T-cell lymphomas [99–101].

Daclizumab, a humanized monoclonal antibody against the alpha subunit (CD25) of the interleukin-­ 2 receptor, is a treatment of relapsing-­ remitting multiple sclerosis and adult T-cell leukemia/lymphoma, an aggressive lymphoproliferative disorder resulting from human T-cell lymphotropic virus type 1 infection [95–97]. By enhancing bioavailability of IL2 for innate lymphoid cells, daclizumab redirects differentiation of innate lymphoid cells from proinflammatory lymphoid tissue inducer cells toward natural killer cells [96].

Clinical Presentation and Histopathology Peripheral neuropathy is a common adverse event associated with accumulated exposure to brentuximab vedotin [100]. A case report of toxic epidermal necrolysis involving greater than 90% of the body surface area was reported in a patient receiving brentuximab vedotin infusion [102]. Skin histology demonstrated epidermal necrosis, subepidermal blistering, and rare dermal eosinophils [102].

Clinical Presentation The most common side effects of daclizumab in multiple sclerosis and lymphoma patients were transiently elevated liver enzymes, hyperbilirubi-

CD52 Inhibitors Alemtuzumab (Campath-1H) is a humanized, monoclonal antibody that targets CD52, a cell-­

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surface peptide antigen expressed on normal and malignant B and T lymphocytes [103]. It is FDA-­approved for the treatment of B-cell ALL.

Clinical Presentation Adverse events associated with alemtuzumab include infusion-related rigors, fever, nausea, vomiting, and rash [103]. One-third of patients develop a rash likely due to cytokine release. Opportunistic infections, myelosuppression, cardiac toxicity, and neutropenia may also occur [103, 104]. An injection site reaction characterized by deep dermal and subcutaneous infiltrate of lymphocytes, neutrophils, and histiocytes exhibiting phagocytosis was reported in a patient being treated with subcutaneous alemtuzumab injections for Sezary syndrome [105]. Richter’s syndrome refers to the development of a second, more aggressive lymphoma in a patient with CLL.  A long-term follow-up, retrospective study of 38 patients with CLL who underwent alemtuzumab therapy found that there was an increased but not statistically significant risk of developing Richter’s syndrome in patients on alemtuzumab therapy (16%, 6/38) compared with consecutive historical controls who underwent alternative salvage therapy (12%, 9/75) [106].

Interferon Interferon, a family of secretory glycoproteins, is an immune-modulating agent that is used in the treatment of tumors, viral infections such as chronic hepatitis C, and inflammatory conditions including multiple sclerosis.

Clinical Presentation and Histopathology Local injection site reactions are very common, varied from bullous, granulomatous, embolus, and lupus like [107]. Psoriasis was one of the early cutaneous reactions developed in association with interferon treatment [108]. Eczematous drug eruptions associated with interferon often present as ill-defined clusters of coalescing, ery-

Fig. 16.27  Interferon. Eczematous dermatitis. (Courtesy of Richard Johnson MD, Department of Dermatology, Massachusetts General Hospital, Boston, MA)

Fig. 16.28  Interferon. An interface dermatitis characterized by occasional necrotic keratinocytes at the dermal-­ epidermal junction (×100)

thematous, blanchable, pruritic papules often on the extremities and trunk (Figs. 16.27 and 16.28) [109]. Sarcoidosis, alopecia, vitiligo, fixed drug eruption, lichenoid eruptions, and lupus erythematosus have been reported in association with interferon [107, 110].

Proteasome Inhibitor/Apoptosis Inducing Bortezomib (Velcade) is a proteasome inhibitor that inhibits nuclear factor kappa B signaling and induces cell death in tumor cells [111]. It is used in the treatment of multiple myeloma,

16  Adverse Cutaneous Reactions to Chemotherapeutic Agents

783

non-­ Hodgkin’s lymphoma, and mantle cell lymphoma [111].

Clinical Presentation and Histopathology The most common side effects of bortezomib include thrombocytopenia, anemia, and neutropenia [111]. Cutaneous adverse effects can be seen in 7–24% of patients [112]. A maculopapular drug eruption, small vessel vasculitis, erythema multiforme-like eruption, and drug-induced lupus erythematosus have been reported [113, 114]. Rarely, the cutaneous eruption can contain prominent CD30-positive immunoblasts mimicking a CD30+ lymphoproliferative disorder [115]. Sweet syndrome associated with bortezomib treatment has been reported, including a histiocytoid variant of Sweet syndrome characterized histopathologically by an infiltrate of mononuclear cells rather than neutrophils can be seen (Figs. 16.29 and 16.30) [116].

Fig. 16.29  Bortezomib. Multiple edematous and erythematous plaques and nodules on the patient’s face consistent with Sweet syndrome

Fig. 16.30  Bortezomib. Prominent papillary dermal edema and dense infiltrate of neutrophils, features characteristics of Sweet syndrome (×100)

Summary • ALK inhibitor: toxic epidermal necrolysis, erythema multiforme, morphea and erythematous, and exfoliative rash on sun-exposed skin • PI3K/AKT/mTOR inhibitor: morbilliform drug eruption, severe pruritus, xerosis, nail toxicity (paronychia), alopecia, bullous pemphigoid, facial hypertrichosis, vasculitis, and edema • Smoothened (SMO) inhibitor: reversible non-scarring alopecia, dysgeusia or taste disturbance, and new keratoacanthomas and squamous cell carcinomas • CD20 inhibitor: urticaria • CD25 inhibitor: allergic dermatitis, eczematous dermatitis • CD30 inhibitor: toxic epidermal necrolysis • CD52 inhibitor: drug rash, Richter’s syndrome • Interferon: psoriasis, eczematous drug eruption, sarcoidosis, alopecia, vitiligo, fixed drug eruption, lichenoid eruptions, and lupus erythematosus • Proteasome inhibitor: Sweet syndrome, maculopapular drug eruption, small vessel vasculitis, erythema multiformelike eruption, and drug-induced lupus erythematosus

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Case Studies Case 1 Clinical History A 45-year-old woman with hepatitis C and hepatocellular carcinoma on sorafenib treatment presented with bilateral and tender vesicles and bullae on her hands and feet (Figs. 16.31 and 16.32). The blisters resolved after cessation of sorafenib treatment. Microscopic Description A skin biopsy from her foot showed prominent necrotic keratinocytes within the epidermis resulting in a blister within the superficial epidermis (Fig. 16.33).

Figs. 16.31 and 16.32  Tender vesicles and bullae seen on the hand and foot

Fig. 16.33  A superficial intraepidermal blister is a result of prominent necrotic keratinocytes (×100)

Diagnosis Hand-foot skin reaction (continued)

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Discussion Hand-foot skin (HFS) reaction is also known as hand-foot reaction, palmar-plantar erythrodysesthesia, chemotherapy-induced acral erythema, or Burgdorf reaction [4, 5]. It is a dose-limiting cutaneous reaction to many cytotoxic chemotherapeutic agents and multikinase inhibitors (sorafenib and sunitinib) [4, 5]. The hands are more frequently involved in classic HFS. On the contrary, the feet, not only pressure-bearing areas but also lateral aspects and web spaces, are affected in HFS associated with multikinase inhibitors.

Case 2 Clinical History A 77-year-old woman had acute myelogenous leukemia status post decitabine treatment 1 year ago with complete remission. Recent bone marrow biopsy revealed relapsed disease. Molecular studies revealed a single-nucleotide variant of IDH1, and the patient was started on a new therapy, IDH1 inhibitor AG-120. She presented 1 month later with a pruritic diffuse morbilliform eruption (Figs. 16.34 and 16.35). Microscopic Description A skin biopsy from her forearm showed confluent parakeratosis overlying an acanthotic epidermis (Fig. 16.36). Occasional necrotic keratinocytes are noted within the epidermis (Fig. 16.37). There is an underlying perivascular and interstitial infiltrate of lymphocytes and rare eosinophils in the dermis.

Fig. 16.34  An erythematous and morbilliform eruption seen on the patient’s trunk. (Courtesy of Drs. Rebecca Hartman and Andrew Walls, Dermatology, Massachusetts General Hospital, Boston, MA)

(continued)

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Fig. 16.35 Extremities. (Courtesy of Drs. Rebecca Hartman and Andrew Walls, Dermatology, Massachusetts General Hospital, Boston, MA)

Fig. 16.36  Confluent parakeratosis and acanthotic epidermis (×100)

(continued)

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Fig. 16.37  Occasional intraepidermal necrotic keratinocytes (×200)

Diagnosis Morbilliform eruption associated with IDH1 inhibitor Discussion Several tumor types including acute myeloid leukemia (AML), glioma, cholangiocarcinoma, and chondrosarcoma harbor mutations of isocitrate dehydrogenase (IDH) 1 and 2 [ 117]. IDH1 and IDH2 mutations occur in approximately 6–10% and 9–13% of AML patients, respectively. Ivosidenib (AG-120) and enasidenib (AG-221) are oral small-molecule inhibitors of mutant IDH1 and mutant IDH2, respectively. Common adverse effects associated with ivosidenib (AG-­120) treatment include diarrhea, leukocytosis, febrile neutropenia, anemia, nausea, fatigue, dyspnea, peripheral edema, and pyrexia [117].

Case 3 Clinical History The patient is a 58-year-old man with a history of stage IIIB melanoma with positive sentinel lymph node biopsy. He has been treated with pembrolizumab when around cycle 13 he developed a diffuse bullous and maculopapular rash covering greater than 30% of his body surface area. The eruption is most extensive on his back, trunk, arms, and legs (Figs. 16.38 and 16.39). Blisters were noted in some areas. Large confluent lesions were noted in his back. The lesions are sometimes pruritic. (continued)

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Microscopic Description A skin biopsy from his left breast showed a subepidermal blister containing eosinophils (Figs. 16.40 and 16.41). Direct immunofluorescence examination demonstrates linear IgG and C3 deposition at the basement membrane zone (Fig. 16.42).

Figs. 16.38 and 16.39  A diffuse bullous and maculopapular eruption seen on the trunk and back. (Courtesy of Dr. William M. Lin, Dermatology, Massachusetts General Hospital, Boston, MA, USA)

Fig. 16.40  A skin biopsy demonstrates a subepidermal blister (×100)

(continued)

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Fig. 16.41  Eosinophils are prominent within the blister space and in the superficial dermis (×200)

Fig. 16.42  Direct immunofluorescence studies demonstrate linear C3 deposition at the base of the blister

Diagnosis Bullous pemphigoid induced by pembrolizumab Discussion In a series of five patients treated with either nivolumab or pembrolizumab, pruritic vesicles and blisters were noted on the skin during anti-­PD1 immunotherapy [57]. A subepidermal bullae with IgG and C3 linear deposition on the blister roof, similar to the case presented here, were noted. In addition, type IV collagen highlights the floor of the blister. All five patients experienced either partial or complete resolution of the cutaneous lesions after cessation of therapy and administration of corticosteroid [57].

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Case 4 Clinical History A 16-year-old female with a history of polyarticular juvenile arthritis and currently under control with infliximab. After 1 year of therapy, the patient presented with a sudden and worsening eruption of multiple flesh-colored papules on her bilateral cheeks (Fig. 16.43). Associated alopecia is not seen. The adjacent skin is unremarkable. Infliximab was discontinued, and the progression of her lesions ceased several months later. Microscopic Description Prominent mucin deposition is noted with follicular epithelium (Fig.  16.44). Immunohistochemistry demonstrates equal number of T lymphocytes labeled with CD4 and CD8 (Figs. 16.45 and 16.46).

Fig. 16.43  An eruption of multiple flesh-colored papules on the patient’s cheek. (Courtesy of Dr. Gideon Smith, Dermatology, Massachusetts General Hospital, Boston, MA, USA)

Fig. 16.44  Histologic section shows prominent mucin deposition within follicular epithelium (×100)

(continued)

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Figs. 16.45 and 16.46  CD4 and CD8 demonstrate a 1:1 ratio of the intrafollicular lymphoid infiltrate (×100, ×100)

Diagnosis Follicular mucinosis associated with infliximab (TNF-alpha inhibitor) Discussion Follicular mucinosis can be either primary or secondary which can be associated with lymphoma (mycosis fungoides), infection, and medication [118]. The association of follicular mucinosis and TNF-alpha inhibitor has previously been reported [119]. Drugs such as imatinib, oxcarbamazepine, captopril, and dextromethorphan have been reported in association with TNF-alpha inhibitor [120].

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Transplant-Related and Metastatic Malignancies

17

Rami N. Al-Rohil and Maria Angelica Selim

Contents Acute Graft-Versus-Host Disease Clinical Presentation Prognosis Histopathology Differential Diagnosis

 798  799  799  800  801

Eruption of Lymphocyte Recovery Clinical Presentation Prognosis Histopathology Differential Diagnosis

 801  802  802  802  802

Engraftment Syndrome Clinical Presentation Prognosis Histopathology Differential Diagnosis

 803  803  803  803  803

Toxic Erythema of Chemotherapy Clinical Presentation Prognosis Histopathology Differential Diagnosis

 804  804  804  804  805

Cutaneous Metastases Clinical Presentation Prognosis Histopathology

 806  806  807  807

R. N. Al-Rohil (*) · M. A. Selim Department of Pathology and Dermatology, Duke University Medical Center, Durham, NC, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_17

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R. N. Al-Rohil and M. A. Selim

798 Differential Diagnosis

 809

Leukemia Cutis Clinical Presentation Prognosis Histopathology Differential Diagnosis

 810  811  811  811  811

Intravascular Large B-Cell Lymphoma Clinical Presentation Prognosis Histopathology Differential Diagnosis

 812  812  813  813  814

Case Studies Case 1 Histopathologic Findings Diagnosis Discussion Case 2 Histopathologic Findings Diagnosis Discussion Case 3 Histopathologic Findings Diagnosis Discussion

 815  815  815  816  816  817  817  818  818  819  819  821  821

References

 822

Acute Graft-Versus-Host Disease Graft-versus-host disease (GVHD) usually results from the transplant of donor (i.e., foreign) hematopoietic stem cells into a host recipient. Hematopoietic stem cell transplantation is currently used to treat neoplastic processes (e.g., leukemia, lymphoma, myeloma, myeloproliferative disorders), immunodeficiency (e.g., severe combined immunodeficiency, chronic granulomatous disease, DiGeorge syndrome), autoimmune diseases (e.g., autoimmune lymphoproliferative syndrome, severe scleroderma), and metabolic disorders (e.g., Gaucher disease, mucopolysaccharidoses). Despite all the advances in medical care and immunosuppressive regimens utilized in stem cell transplant patients, GVHD remains a significant cause of morbidity and mortality. The most important factor that predicts the possibility of the development of GVHD is human leu-

kocyte antigen (HLA) compatibility between the recipient and donor. Other factors that can increase the risk are unrelated donor, older age of the recipient, and the source of stem cells (peripheral blood versus bone marrow) [1]. Despite the associated morbidity and mortality, the presence of GVHD has a beneficial effect of graft-versus-tumor which reduces the possibility of relapse in hematologic malignancies. GVHD was primarily classified as acute GVHD when the signs and symptoms occur within the first 100  days after transplantation while chronic for those presenting after 100 days of transplantation, independent of clinical presentation. However, with the evolving practice of transplant medicine such as conditioning regimens (use of less chemotherapy and radiation), second allogeneic stem cell transplantation, and infusion of donor lymphocytes, it became apparent that the classic onset of acute and chronic manifestations does not always follow the time-

17  Transplant-Related and Metastatic Malignancies

line, with some cases presenting with an “acute picture” beyond the 100 days window. For these reasons, GVHD has been reclassified according to the clinical and histopathologic features as classic acute GVHD, persistent/recurrent/late-­ onset acute GVHD, classic chronic GVHD, and overlap syndrome. Acute GVHD is mainly mediated by donor T cells. Pre-treatment with chemotherapy and radiation before stem cell transplant causes tissue damage and activation of host antigen-presenting cells (APC). After transplantation, donor T cells proliferate and react to primed APCs. This subsequently destroys target tissues (liver, gastrointestinal tract, thymus, skin, and mucosa) by cytotoxic T cells, natural killer cells, tumor necrosis factor, interleukins (IL-1, IL-6), and interferons [2].

Clinical Presentation The incidence of acute GVHD is roughly 35%– 50% of patients receiving stem cell transplantation. The cutaneous presentation of acute GVHD is mainly a morbilliform exanthem that appears 4–6 weeks after stem cell transplantation despite immunosuppression. It has a predilection to acral sites (dorsal hands and feet/ palms and soles), forearms, ears, and upper chest and back (Fig.  17.1). Pruritis may be present. Due to thrombocytopenia, associated hemorrhage and petechiae can occur. Other accompanying symptoms include nausea, diarrhea, abdominal pain, and altered liver function tests (transaminitis, elevated bilirubin levels). The degree of involvement of these organs is used to stage the disease (see Table 17.1).

Prognosis When patients have isolated cutaneous GVHD without any other organ involvement, the prognosis is better and can be managed with topical

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Fig. 17.1  Acute graft-versus-host disease. Morbilliform rash following hematopoietic stem cell transplant. (Courtesy of Dr. Adela Rambi G.  Cardones. Duke University Medical Center, Durham North Carolina) Table 17.1  Clinical staging system for acute graft-versus-host disease Stage Cutaneous 1 50% BSA erythematous maculopapular rash 4 Generalized erythroderma with bullae formation

Gastrointestinal Diarrhea >500 ml/day or persistent nausea Diarrhea >1000 ml/day

Bilirubin level 2–1500 ml/day

6–15 mg/ dl

Severe abdominal pain +/− ileus

>15 mg/dl

BSA body surface area

agents only (corticosteroids); however, most patients require systemic immunosuppression (prednisone, methylprednisolone) with calcineurin inhibitors (cyclosporine/ tacrolimus). This usually helps in controlling acute GVHD in 50% of patients. Patients who do not respond to corticosteroid therapy are at high risk of mortality. Stage IV acute GVHD carries a poor likelihood of survival.

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Histopathology Acute GVHD will show vacuolar interface dermatitis with sparse associated lymphocytic infiltrate. Classically there is satellite cell necrosis, in which there would be intraepidermal l­ ymphocytes associated with a dyskeratotic keratinocyte. The interface changes and dyskeratotic keratinocytes involve both epidermis and follicular epithelium.

a

There is usually a sparse superficial perivascular and interstitial lymphocytic infiltrate. Eosinophils may be present (Fig. 17.2). A histologic grading system can be used for acute GVHD: grade I displays vacuolar alteration, grade II will show vacuolar alteration and scattered dyskeratotic keratinocytes, grade III in addition to changes of grade II will display subepidermal microvesicles, and grade IV shows

b

c

d

Fig. 17.2  Acute graft-versus-host disease. Low power shows minimal inflammatory infiltrate with focal parakeratosis (a). On higher magnification, vacuolar changes with dyskeratotic keratinocytes are seen (b) in addition to

satellite cell necrosis (c). In some cases, due to concomitant chemotherapy, epidermal dysmaturation in the background can be seen along with acute GVHD (d)

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full-thickness epidermal necrosis with separation of the epidermis from the dermis. It is worth noting that the histologic grading of acute GVHD does not correlate highly with the clinical severity of GVHD.

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Differential Diagnosis • Allergic drug reaction. • Viral exanthem. • Eruption of lymphocyte recovery. • Engraftment syndrome.

Differential Diagnosis Clinically the main differential diagnosis of acute GVHD is viral exanthem, drug exanthem, eruption of lymphocyte recover, and engraftment syndrome (please see below). When there is palmoplantar involvement during the first 2–6  weeks following hematopoietic stem cell, transplant toxic erythema of chemotherapy should be considered. Unfortunately, almost all these diagnostic entities show a considerable overlap with histopathologic features of acute GVHD which makes it difficult to establish a definite diagnosis. Clinical follow-up associated clinical signs and symptoms, and additional laboratory results will help for a definitive diagnosis.

Summary Clinical Presentation • Affects patients post hematopoietic stem cell transplant. • Morbilliform exanthem that appears 4–6  weeks after stem cell transplantation despite immunosuppression. • Has predilection for acral sites (dorsal hands and feet/palms and soles), forearms, ears, and upper chest and back. Histopathology • Vacuolar interface dermatitis with associated sparse lymphocytic infiltrate. • Classically there is satellite cell necrosis (intraepidermal lymphocytes associated with a dyskeratotic keratinocyte). • Sparse superficial perivascular and interstitial lymphocytic infiltrate (eosinophils may be present).

Takeaway Essentials Clinical Relevant Pearls • Acute GVHD usually happens 4–6 weeks after stem cell transplant; if occurs earlier consider other causes for a rash before being definitive with the diagnosis. • Correlate with other clinical findings to establish the diagnosis (bilirubin level and gastrointestinal symptoms). Pathologic Interpretation Pearls • There are no definitive histologic features pathognomonic of GVHD. • Usually acute GVHD is pauci-­ inflammatory, and the amount of dyskeratotic keratinocytes is more impressive than the amount of inflammatory infiltrate. • Look for dyskeratotic keratinocytes within hair follicles. • The presence of eosinophilic infiltrate does not rule out acute GVHD.

Eruption of Lymphocyte Recovery Eruption of lymphocyte recovery was first described in 1989, in which eruption of lymphocyte recovery occurred in ten patients who developed cutaneous eruptions after receiving cytoreductive therapy without bone marrow transplant for acute myelogenous leukemia [3]. Eruption of lymphocyte recovery develops after marrow aplasia, as lymphocytes reappear in the peripheral circulation, and is often associated with a transient fever (with no evidence for an underlying infectious etiology).

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Clinical Presentation

Differential Diagnosis

Eruption of lymphocyte recovery occurs during the recovery phase of transplantations (marrow recovery is defined as an absolute neutrophil count of 1500/μL and platelet count of 50,000/μL). It occurs within 3  weeks after the start of the chemotherapy in conjunction with the earliest return of lymphocytes after the chemotherapy. Manifests as a morbilliform (erythematous maculopapular) rash affecting mostly the trunk and limbs. There is usually an associated fever (usually between 100 and 102 Fahrenheit/38–39 ° Celsius). Some patients develop purpura secondary to low platelet count.

Clinically and histopathologically, the differential diagnoses include acute GVHD, viral exanthem, drug eruption, and engraftment syndrome. The presence of fever, distribution of rash, and the identification of bone marrow recovery are good diagnostic clues. It is important to rule out infectious etiologies before rendering the diagnosis of eruption of lymphocyte recovery. From a histopathologic point of view, there are no definitive clues to distinguish eruption of lymphocyte recovery from acute GVHD, engraftment syndrome, viral exanthema, and drug eruption; the clinical setting and progression of the rash will help determine the final diagnosis.

Prognosis Eruption of lymphocyte recovery resolves spontaneously or may require potent topical corticosteroids within 3 days but may last up to 4 weeks. The rash may leave post-inflammatory hyperpigmentation. Relapse does not occur.

Histopathology Histologically, classically eruption of lymphocyte recovery shows slight basal vacuolization, mild spongiosis, and rare dyskeratotic keratinocytes in the epidermis. The dermis can show mild superficial perivascular lymphocytic infiltrate [4]. In a recent case series of 12 patients, it has been found that eruption of lymphocyte recovery histologically can mimic primary cutaneous T-cell lymphomas such as Sézary syndrome (in six patients) or CD30+ T-cell lymphoproliferative disorder, mainly lymphomatoid papulosis (in six patients). Atypia in the lymphocytes was identified in 10–50% of the lymphocytes and some cases showed CD30 positivity in the atypical lymphocytes, the cases were recognized as being eruption of lymphocyte recovery due to the typical clinical history and spontaneous resolution [5].

Summary Clinical Presentation • Occurs within 3 weeks after the start of the chemotherapy in conjunction with the earliest return of lymphocytes after the chemotherapy. • Morbilliform eruption affecting mostly the trunk and limbs. • Associated with fever (usually between 38 and 39 Celsius). Histopathology • Slight basal vacuolization, mild spongiosis, and rare dyskeratotic keratinocytes. • Mild superficial perivascular lymphocytic infiltrate. • Some cases can show atypical lymphocytic infiltrate mimicking T-cell lymphoma. Differential Diagnosis • Interface changes: acute GVHD, allergic drug reaction, viral exanthem, and engraftment syndrome. • In atypical infiltrate: CD30+ lymphoproliferative disorders and Sézary syndrome.

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Takeaway Essentials Clinical Relevant Pearls • Earlier onset than acute GVHD. • Usually has an accompanying fever with no evidence for an underlying infection. Pathologic Interpretation Pearls • Correlation with the clinical findings is always necessary to distinguish from other differential diagnoses.

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pulmonary edema is usually associated with increased levels of B-type natriuretic peptide.

Prognosis Most cases are mild and resolve spontaneously or may require steroid therapy. However, engraftment syndrome can rarely be fatal. The cause of death is usually related to respiratory dysfunction and multi-organ failure. Early detection is essential to reduce morbidity and mortality.

Histopathology

Engraftment Syndrome Engraftment syndrome is characterized by fever, skin rash, pulmonary edema, weight gain, liver, renal dysfunction, and encephalopathy. It occurs at the time of neutrophil recovery after hematopoietic stem cell transplantation. Engraftment syndrome usually occurs on between days 9 and 16 post-transplant (~4  days post granulocyte recovery). The pathophysiology is poorly understood. Multiple studies postulate that it may involve pro-inflammatory cytokines (IL-2, TNF-­ α, interferon-γ, etc.), the effect of degranulation products and system release of products of degranulation and oxidative metabolism, and secondary systemic endothelial damage resulting in multi-organ dysfunction.

Clinical Presentation The clinical manifestations include fever (≥ 100.9 Fahrenheit/38.3 ° Celsius), skin rash (≥25% of body surface area, non-specific maculopapular/erythematous), pulmonary edema (hypoxemia and radiographic diffuse infiltrates), diarrhea, weight gain (≥ 2.5% of baseline), renal dysfunction (serum creatinine ≥2 times baseline), hepatic dysfunction with jaundice (bilirubin ≥2  mg/dL or transaminase level  ≥  2 times normal), and transient encephalopathy [6]. The

The histopathologic features in engraftment syndrome can be variable. In a series of 55 patients with clinically confirmed engraftment syndrome that underwent skin biopsy: 27 showed vacuolar/ interface dermatitis with perivascular inflammation, 16 showed minimal histopathologic changes, and 12 showed epidermal dysmaturation/dyskeratosis [7].

Differential Diagnosis The top differential diagnoses from a clinical perspective for engraftment syndrome is acute and hyperacute GVHD, sepsis, pre-engraftment syndrome, viral exanthem, drug eruption, and graft rejection. Given the non-specific histopathologic findings on skin biopsy, differentiating engraftment syndrome from other potential culprits is best achieved on a clinical basis.

Summary Clinical Presentation • Usually occurs within 9–16  days post hematopoietic stem cell transplant. • Fever, skin rash (≥25% of body surface area), pulmonary edema, diarrhea,

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weight gain, renal and hepatic dysfunction, and transient encephalopathy. • Elevated B-type natriuretic peptide (occurs with pulmonary edema). • Majority of cases resolve spontaneously or may require steroid therapy. Histopathology • No specific histopathologic changes. • Can show vacuolar interface dermatitis and dysmaturation/dyskeratosis and in some cases may not show any significant histopathologic changes. Differential Diagnosis • Acute and hyperacute graft-versus-host disease. • Sepsis. • Pre-engraftment syndrome. • Drug reaction. • Viral exanthem. • Graft rejection.

Takeaway Essentials Clinical Relevant Pearls • Engraftment syndrome occurs within the first 2  weeks post hematopoietic stem cell transplant and usually has an accompanying fever, skin rash, and multi-organ dysfunction. • Majority of cases resolve spontaneously. Pathologic Interpretation Pearls • Correlation with the clinical findings is always necessary to distinguish from other differential diagnoses.

Toxic Erythema of Chemotherapy Toxic erythema of chemotherapy is an umbrella term that encompasses multiple entities that occur after the administration of chemotherapy and includes palmar-plantar erythrodysesthesia,

hand-foot syndrome, and eccrine squamous syringometaplasia. Numerous chemotherapeutic agents can cause toxic erythema of chemotherapy. The most common agents include Cytarabine, Anthracyclines, Doxorubicin, 5-Fluorouracil, Taxanes, and Methotrexate. With novel treatments being added for various malignancies, the list of offending drugs is expanding. The most accepted proposed pathophysiologic cause for toxic erythema of chemotherapy is a toxic insult to the cells of the eccrine ducts/acrosyringium and the epidermis mainly via excretion of chemotherapeutic agents via eccrine sweat glands [8].

Clinical Presentation Clinically toxic erythema of chemotherapy presents within 2 days to 3 weeks following the administration of chemotherapy. Patients present with erythematous patches/edematous plaques that can also have accompanying symptoms of pain, paresthesia, and pruritis. The areas most commonly involved are the hands, feet, and intertriginous areas (due to the high density of eccrine glands in those anatomic locations). Other areas can be involved (but less often) include elbows, knees, and ears. Petechiae and bullae formation can occur. The natural course is progression to desquamation followed by spontaneous resolution without specific therapeutic agents. Recurrence may occur if the offending agent is re-administrated.

Prognosis Toxic erythema of chemotherapy is usually self-­ limited; it may require topical treatment with triamcinolone. The prognosis is usually dependent on the underlying disease for which the patient is receiving chemotherapy for and if any systemic manifestations/adverse reactions secondary to the chemotherapy (e.g., immunosuppression, infection, etc.).

Histopathology The histopathologic features are variable and depend on the clinical form of reaction and some-

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times the type, dose, and the number of chemotherapeutic agents administered. The most common pattern is vacuolar interface dermatitis with dyskeratotic keratinocytes affecting the epidermis but can also show the involvement of adnexal structures and eccrine units. Rarely, full epidermal necrosis and blister formation can occur. The inflammation can be variable from scattered perivascular lymphocytic infiltrate to a dense lichenoid lymphocytic infiltrate. Eosinophils may or may not be present. Epidermal atrophy can be seen. Maturation arrest (also known as dysmaturation) is another useful histologic clue. The histopathologic features of dysmaturation include loss of polarity, increased intercellular spaces with prominent intercellular bridges, large nuclei with some displaying irregular contours, mitotic figures within different levels of the epidermis, and apoptosis (Fig. 17.3). Dysmaturation is seen in patients receiving high-­ dose chemotherapy or receiving multiple chemotherapeutic agents simultaneously. Eccrine squamous syringometaplasia (squamous metaplasia of the dermal sweat ducts) may be seen (Fig. 17.4) [9].

Fig. 17.3 Dysmaturation chemotherapy

in

toxic

erythema

of

Differential Diagnosis Toxic erythema of chemotherapy is important to recognize and to differentiate from another possible differential diagnosis which on clinical basis includes hypersensitivity reactions (encompassing allergic drug eruptions and contact dermatitis), GVHD (in case of hematopoietic stem cell transplant), vasculitis, and infections. From a histopathologic perspective, the differential includes GVHD (dysmaturation can be seen in patients with GVHD since they are usually receiving concurrent chemotherapy). If full epidermal necrosis occurs, then it can mimic erythema multiforme/toxic epidermal necrolysis. If there is thinning of the epidermis in a background of vacuolar interface dermatitis, it may mimic connective tissue disease; however, toxic erythema of chemotherapy will lack dermal mucin and would not show plasma cell infiltrate.

Summary Clinical Presentation • Toxic erythema of chemotherapy presents within 2 days to 3 weeks following the administration of chemotherapy. • Erythematous patches/edematous plaques most commonly involving the hands, feet, and intertriginous areas. • There can be accompanying symptoms of pain, paresthesia, and pruritis. Histopathology • The most common pattern is vacuolar interface dermatitis with dyskeratotic keratinocytes. • Epidermal dysmaturation is a helpful diagnostic clue. • Squamous metaplasia of eccrine units can be seen. Differential Diagnosis • Clinically: hypersensitivity reactions, GVHD, vasculitis, and infections. • Histologically: GVHD, erythema multiforme/toxic epidermal necrolysis (if sig-

Fig. 17.4  Eccrine squamous syringometaplasia in toxic erythema of chemotherapy

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nificant dyskeratosis is present), and connective tissue disease (if there is marked epidermal thinning with vacuolar changes).

Takeaway Essentials Clinical Relevant Pearls • Toxic erythema of chemotherapy is a clinical diagnosis that encompasses multiple entities that occur after the administration of chemotherapy. • The cutaneous manifestations of toxic erythema of chemotherapy can resemble acute GVHD; but in contrast to acute GVHD, toxic erythema of chemotherapy does not affect the gastrointestinal system nor liver function tests. Pathologic Interpretation Pearls • It should always be kept in mind that patients with acute GVHD also can show epidermal dysmaturation due to the administration of chemotherapeutic agents along with stem cell transplantation.

Cutaneous Metastases Metastatic disease to the skin is relatively rare compared to metastasis to other organ systems (lymph nodes, liver, lung, adrenals, brain, bone, intraperitoneal, etc.). Cutaneous metastases usually develop within 1–2  years after the initial diagnosis of the primary malignancy. Secondary involvement of the skin by a malignant tumor may represent a metastatic phenomenon (such as following vascular or lymphatic emboli) or occur via direct contiguous spread. The ability of malignancy to acquire metastatic potential is thought to occur via linear progression model (also known as clonal expansion) or parallel progression model. In linear progression model, it is thought that with tumor growth

and increment in size, cancer cells pass through multiple successive rounds of mutation and selection for competitive fitness, which leads to acquiring growth advantages enabling them to lose cohesiveness from the primary tumor and proliferate in distant sites. Correlation between tumor size and metastasis provides a strong argument in favor of this model. In the parallel progression model, tumors are thought to harbor aggressive clones with metastatic potential and stem cell-like properties from the beginning, and these cells can disseminate at any point during tumorigenesis regardless of tumor stage. Loss of adhesion molecules has been shown to play an important role in distant metastasis in general.

Clinical Presentation The frequency of carcinoma metastasis to the skin correlates with the type of primary carcinoma, which differs according to gender. The most common sites of involvement also differ according to gender. In females the anterior chest and abdomen are the most common locations, while the head and neck and the anterior chest are the most common locations in males. The diagnosis can be straightforward in the proper clinical setting; patient with a known history of carcinoma presenting with erythematous, firm, single, or multiple nodules that are rapidly growing overlying the site of primary carcinoma. However, there are multiple cases where the presentation is atypical requiring biopsy. Metastatic carcinoma to the skin can present as a slow-growing mass, ulcer, and sometimes mimicking a wide range of inflammatory dermatoses (contact dermatitis, erythema annulare centrifugum, erysipelas, cellulitis, zosteriform herpes simplex, etc.). Rarely, cutaneous metastases may be the presenting sign of an underlying visceral malignancy, but with the advancement of clinical care (screening, serologic, and imaging studies), the prevalence of such presentation is declining. Breast carcinoma is the most common metastatic carcinoma to the skin in females, which is mostly due to its high prevalence and for its propensity to involve the skin via direct extension or

17  Transplant-Related and Metastatic Malignancies

hematogenous/lymphatic spread. Sites of cutaneous involvement include chest, site of a previous surgical incision, back, scalp, upper extremities, abdomen, neck, lower extremities, and face. Metastatic breast carcinoma to the skin has a wide range of clinical presentations (the widest among metastatic carcinomas to the skin) including papules, nodules, peau d’orange (due to dermal edema secondary to superficial lymphatic blockage by carcinoma), purpuric/hemorrhagic lesions, vascular-like tumors (also known as carcinoma telangiectaticum), and patches/plaques of erythema affecting the anterior chest wall that are tender and warm (also known as carcinoma erysipelatoides) which can be mistaken as erysipelas or cellulitis. Another rare clinical presentation is metastasis en cuirasse located on thoracic and abdominal walls characterized by infiltrated, hard, and sclerodermoid plaque (the nomenclature is due to its resemblance to the armor of a cavalry soldier). Lung carcinoma is reported to be the most common metastatic carcinoma to the skin in males in most studies. Sites of cutaneous involvement are most commonly the chest, abdomen, scalp, upper and lower extremities, and face/ neck. Clinically they most commonly present as papules or nodules. Inflammatory form (carcinoma erysipelatoides) and metastasis en cuirasse have been reported. Metastatic renal cell carcinoma and thyroid carcinoma to the skin can be mistaken as a primary cutaneous vascular tumor given the rich vascularization of these tumors. Most cutaneous metastasis of carcinomas occur overlying the skin of the primary carcinoma; however, some have a propensity to involve certain anatomic sites; the prototypical example is “Sister Mary Joseph nodule” which presents as a periumbilical nodule most commonly secondary to metastatic gastric, colon, ovarian, or pancreatic carcinomas.

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presence of metastatic carcinoma in the skin signifies a widespread systemic disease and a high mortality rate.

Histopathology Metastatic carcinomas to the skin histopathologic features are dependent on the type of carcinoma, histomorphology, and level of differentiation. Metastatic adenocarcinoma can be in the form of glands, sheets, and single cells which sometimes can occur concomitantly. Metastatic carcinoma with gland formation within the dermis carries a very wide differential diagnosis and is not exclusive to any specific organ, but it is mostly encountered in carcinomas of breast, lung, gastrointestinal, and pancreaticobiliary origin. Metastatic breast adenocarcinoma is by far the most commonly encountered metastatic carcinoma to the skin. It most commonly presents in the form of glands (ductal carcinoma) or single cells with a single filing/linear pattern (lobular carcinoma or ductal carcinoma with lobular features). Inflammatory carcinoma of the breast and carcinoma telangiectaticum presents as carcinoma within dermal lymphatic and vascular channels, respectively (Fig. 17.5). Metastatic carcinoma with papillary morphology is another non-specific morphologic feature for a primary site of origin, but can be seen in metastatic carcinomas from colorectal, endometrial, ovarian, thyroid, lung, and gastric origin. Metastatic carcinoma in sheets can be seen in metastatic carcinoma of urothelial, adrenal, and

Prognosis The outcome of cutaneous metastases of carcinoma varies considerably depending on the type of the primary malignancy. But usually the

Fig. 17.5  Inflammatory carcinoma of the breast with carcinoma present within dermal lymphatic channels

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hepatocellular origin. Metastatic carcinoma in the form of single cells is mostly seen in metastatic gastric adenocarcinoma (signet ring cell) and metastatic lobular carcinoma of the breast. Metastatic colorectal carcinoma usually shows necrotic debris in the lumen, so-called dirty necrosis (Fig. 17.6); however, that feature can be seen in upper gastrointestinal, pancreaticobiliary, lung, ovarian, and uterine adenocarcinomas. Metastatic serous carcinoma of the ovary and papillary thyroid carcinoma can show psammomatous calcifications. Metastatic carcinoma with clear cell features is most commonly seen in clear cell renal cell carcinoma (Fig. 17.7); but clear cell features can be seen in carcinomas from thyroid, lungs, and endometrial origin. Metastatic neuroendocrine carcinoma shows small, hyperchromatic, and round nuclei with

Fig. 17.6  Dirty necrosis seen in a case of metastatic colorectal carcinoma involving the skin

a

minimal to near absent cytoplasm. Typically, these tumors show crush artifacts and incrustation of the blood vessel wall with basophilic nuclear material (Azzopardi effect). The most common metastatic neuroendocrine carcinoma is small cell carcinoma of the lung which usually requires immunohistochemical workup to confirm the primary site of origin and differentiate from other malignancies like Merkel cell carcinoma, small cell melanoma, and lymphoma. Metastatic squamous carcinoma to the skin most commonly occurs from the lung, oral cavity, larynx, esophagus, and uterine cervix. A primary cutaneous squamous cell carcinoma usually shows an epidermal connection with overlying actinic keratosis or squamous cell carcinoma in situ; usually metastatic squamous cell carcinoma is dermal/subcutaneous. But it is worth noting in many instances that primary cutaneous squamous cell carcinoma can lack overlying epidermal connection. In some instances, relying on the histopathologic features alone can be difficult to determine the primary site of origin; immunohistochemical studies are a useful adjunct when attempting to determine the primary site of origin of metastatic carcinoma to the skin. But before performing immunohistochemical studies, checking the clinical history is the most cost and time-effective approach to reach the correct diagnosis. If there b

Fig. 17.7  Metastatic renal cell carcinoma, clear cell type, involving the skin. (a) Low power examination reveals a dermal nodular deposit of atypical cells with prominent hemorrhage (b) High power examination reveal prominent gland-like structures lined by clear cells with collapsed capillaries in between the glands

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is a known history, there is no fault in performing a small panel of organ-specific immunohistochemical studies for confirmation, if the histopathologic features are doubtful. If there is no known history, then an algorithmic approach is best applied when attempting to determine the primary site of origin. If the tumor displays carcinomatous features (e.g., gland formation, intracytoplasmic mucin, keratinization), there is no necessity to perform a pankeratin. If the malignancy is poorly differentiated, a generic pankeratin stain (e.g., CAM5.2 or AE1/AE3) to determine if the metastatic tumor is carcinomatous or not can be applied, but it is important to know that pankeratin can be expressed in some sarcomas, lymphomas, and melanomas, so it is recommended to perform a battery of stains when dealing with a poorly differentiated malignancy. For carcinomas of unknown primary with glandular differentiation, a good starting point would be Keratin 7 (CK7) and Keratin 20 (CK20); performing these two stains can help point toward a primary site of origin (see Table  17.2). After performing Keratin 7 and 20; a more organ-­ specific immunohistochemical stain can be applied to help determine the primary site of origin (see Table 17.3). Table 17.2  Keratin 7 and Keratin 20 staining patterns in different carcinomas Staining pattern Keratin 7 (+) keratin 20 (−)

Keratin 7 (+) keratin 20 (+)

Keratin 7 (−) keratin 20 (+) Keratin 7 (−) keratin 20 (−)

The primary site of origin 1. Breast adenocarcinoma 2. Lung adenocarcinoma 3. Esophagus adenocarcinoma 4. Pancreaticobiliary adenocarcinoma 5. Salivary gland carcinoma 6. Esophageal adenocarcinoma 7. Female genital tract carcinoma 1. Gastric adenocarcinoma 2. Pancreaticobiliary adenocarcinoma 3. Bladder/ureter carcinoma 1. Colorectal adenocarcinoma 1. Hepatocellular carcinoma 2. Renal carcinoma (mostly clear cell type) 3. Adrenocortical carcinoma 4. Prostatic adenocarcinoma 5. Germ cell tumors

809 Table 17.3  Organ-specific immunohistochemical studies that can help in determining the primary site of origin Carcinoma subtype Immunohistochemical studies Adrenocortical Inhibin, calretinin, SF1 Breast GATA3, GCDFP-15, mammaglobin, estrogen receptor Colorectal Villin, CDX2, SATB2 Endometrial PAX8, estrogen receptor Gastric CK19, SMAD4, CDX2 Germ cell tumors SALL4 Hepatocellular Hep-par1, arginase-1 Lung TTF-1, napsin A Ovarian (serous) PAX8, WT-1 Pancreaticobiliary CK19, SMAD4, CA19.9 Prostate NKX3.1, PSA, PAP PAX8, RCC, CAIX Renal cell (clear cell) Thyroid PAX8, thyroglobulin, TTF-1 Urothelial GATA3, uroplakin, p40, p63

Metastatic squamous cell carcinoma will stain with the common squamous markers (CK5/6, p63, p40). There are no good immunohistochemical studies to determine the primary site of origin. Clinical and radiographic studies are necessary to determine the primary site of origin. Poorly differentiated squamous cell carcinoma that lacks squamous differentiation cannot be differentiated immunohistochemically from metastatic urothelial carcinoma as both stains with same immunohistochemical markers (including GATA3). Metastatic neuroendocrine carcinomas would stain with generic neuroendocrine markers (Synaptophysin, Chromogranin, CD56, NSE). It is important to note that TTF-1 is most commonly expressed in metastatic small cell carcinoma of the lung, but it can be expressed in small cell carcinomas from gastrointestinal, genitourinary (ovarian and prostate) origin, and rarely in Merkel cell carcinoma.

Differential Diagnosis The histopathologic features for metastatic carcinomas can overlap with primary cutaneous tumors (especially adnexal neoplasms). For that, obtaining clinical history in all cases is the most

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useful approach which can help in avoiding misdiagnosis. The main histopathologic features that favor cutaneous metastasis are dermal-based tumors with possible subcutaneous involvement, multifocality, and lymphovascular invasion. Features that would favor a primary cutaneous adnexal neoplasm is the presence of overlying in situ disease (epidermotropic metastatic carcinoma is extremely rare), carcinoma arising within a benign adnexal neoplasm (e.g., hidradenocarcinoma within a hidradenoma) and vascular hyalinization within the benign-appearing areas. Despite these useful histopathologic clues, they should always be used in combination with the clinical history. Immunohistochemical studies can be of utility to distinguish between primary adnexal carcinoma and metastatic adenocarcinoma. D2–40, p63/p40, and CK15 positive staining favor a primary adnexal carcinoma over metastatic adenocarcinoma [10, 11]. One of the most notorious examples is distinguishing sweat gland carcinoma occurring in an axillary site from metastatic breast carcinoma. In one study, a suggested panel of mammaglobin, p63, CK5, CK14, and CK17 was found to have a sensitivity of 100% and a specificity of 91% [12]; however, the most reliable method to distinguish in between these two is a thorough clinical and radiographic assessment.

Summary Clinical Presentation • Cutaneous metastasis usually presents as erythematous, firm, single, or multiple nodules that are rapidly growing overlying the site of primary carcinoma. • Breast carcinoma is the most common cutaneous metastasis in females. • Lung carcinoma is the most common cutaneous metastasis in males. Histopathology • Highly variable depending on the morphology and degree of differentiation of the primary malignancy.

• Usually dermal based, can extend into underlying subcutaneous tissue with lymphovascular invasion. Differential diagnosis • Primary cutaneous adnexal neoplasms (benign and malignant).

Takeaway Essentials Clinical Relevant Pearls • The diagnosis of cutaneous metastasis in most cases is straightforward, but in some instances can be challenging due to an atypical presentation (e.g., slow-­ growing, anatomic location different than primary carcinoma, etc.). Pathologic Relevant Pearls • Correlating with the clinical history and prior biopsy material (if present) is usually the most time and cost-effective method to determine the primary site of origin. • An algorithmic approach with the immunohistochemical studies performed (starting with Keratin 7 and Keratin 20) would help in pinpointing the primary site of origin in most cases. • Immunoreactivity for D2–40, p63/p40, and CK15 favors a primary adnexal carcinoma over metastatic adenocarcinoma.

Leukemia Cutis Leukemia cutis is a generic term that is used to describe cutaneous involvement by an underlying leukemic process (i.e., hematopoietic neoplastic process originating from the bone marrow). The most common subtypes of leukemia vary considerably with age. The most common leukemia in children is acute lymphoblastic leukemia (ALL). In adults, acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) are

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the most common. In the elderly, chronic lymphocytic leukemia (CLL) is the most frequent. Cutaneous involvement by ALL and CML are extremely rare. When CLL is encountered in a skin biopsy, usually the biopsy is performed for another reason (e.g., squamous cell/basal cell carcinoma) and the CLL infiltrate is a bystander. Most cases encountered in practice of leukemia cutis are mainly secondary to myelogenous leukemia and will be the main entity discussed in this chapter. Leukemia cutis secondary to myelogenous leukemia has been given other diagnostic terms including chloroma (due to the green color clinically) and granulocytic sarcoma (an obsolete term).

811

usually signifies an aggressive clinical course with a poor prognosis.

Histopathology

Cutaneous lesions show a variable degree of moderate to dense dermal infiltrate. The infiltrate commonly is nodular or diffuse with possible subcutaneous extension. The epidermis is usually spared but can sometimes show ulceration. The infiltrate tends to show cells recapitulate myeloid precursor cells in their immature stages of development. Background of red blood cell extravasation is common. The neoplastic cells show medium to large blastic infiltrate (monoblastic or myelomonocytic) with large and hyperchromatic nuclei, minimal cytoClinical Presentation plasm, and prominent nucleoli (some cells can Leukemic infiltrate into the skin occurs in 3–10% display multiple nucleoli). Mitotic figures and of AML patients . They can present as firm pap- apoptotic bodies can be seen. Most cases the ules and nodules. Usually the lesions are hemor- infiltrate stains positive with common myeloid rhagic (due to underlying thrombocytopenia). markers which include myeloperoxidase, Sometimes leukemia cutis can ulcerate. Bullous-­ CD117, CD34, CD33, CD4, CD14, and CD68. like presentation has been reported. They can But there are instances where some of these present anywhere on the body but most com- markers are lost. Reviewing flow cytometry monly affect the extremities, trunk, and head and results is helpful in selecting which immunoneck. Additionally, they have a tendency to histochemical stains to employ according to the develop on sites of trauma and scars. Gingival flow cytometry results. hyperplasia is characteristic of acute monocytic leukemia. In most patients, the cutaneous lesion occurs Differential Diagnosis concomitantly at the time of diagnosis/recurrence, but, rarely, skin involvement can be the The clinical differential diagnosis includes an first presentation with no evidence of periph- infectious process (bacterial, fungal, and mycoeral blood or bone marrow involvement, but bacterial), neutrophilic dermatosis like Sweet’s usually, these patients progress to show sys- syndrome, leukocytoclastic vasculitis, lymtemic disease. Other cutaneous manifestations phoma cutis, and drug eruptions. For that reain patients with acute myeloid leukemia are son, a biopsy is necessary to differentiate Sweet’s syndrome, pyoderma gangrenosum, between these entities. Histopathologically, the neutrophilic eccrine hidradenitis, and erythema main d­ ifferential diagnoses include blastic plasmacytoid dendritic cell neoplasm (stains posinodosum. tive with CD123, CD56, CD4, TCL-1, and CD303), diffuse large B-cell lymphoma (stains Prognosis positive with CD20, PAX-5, MUM-1), anaplastic large cell lymphoma (stains positive with The prognosis is dependent on the subtype of CD3, CD30, +/− ALK), and small round blue acute myeloid leukemia and the underlying genetic cell tumors (variable immunophenotype dependalteration. However, cutaneous involvement ing on the primary neoplasm).

R. N. Al-Rohil and M. A. Selim

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Summary Clinical Presentation • Firm papules and nodules that can be hemorrhagic. • Usually affects the trunk, extremities, and head and neck. • Prognosis is usually poor when leukemic infiltrate is identified in the skin. Histopathology • Dermal based in a diffuse or nodular distribution. • Cells are usually atypical with variation in size from medium to large. • Immunohistochemical studies usually show positivity to common myeloid markers. Differential Diagnosis • Clinically: infectious process, neutrophilic dermatosis like Sweet’s syndrome, leukocytoclastic vasculitis, lymphoma cutis, and drug eruptions. • Histopathologically: blastic plasmacytoid dendritic cell neoplasm, diffuse large B-cell lymphoma, anaplastic large cell lymphoma, and small round blue cell tumors.

Takeaway Essentials Clinical Relevant Pearls • The clinical differential diagnoses show considerable overlap in these patients, for that whenever suspected, a biopsy is necessary to confirm the diagnosis. • Cutaneous involvement by leukemia may be the first presentation preceding peripheral blood and bone marrow involvement. Pathologic Interpretation Pearls • Reviewing the flow cytometry results may be of value in selecting the immunohistochemical markers that may aid in supporting the diagnosis.

• Sometimes the infiltrate may not show overt cytologic atypia but usually will give a diffuse/nodular dermal infiltrate. • Correlation with the clinical history aids tremendously in case the immunohistochemical markers are nonconclusive.

I ntravascular Large B-Cell Lymphoma Intravascular large B-cell lymphoma (IVLBCL) – also known as angiotropic large cell lymphoma, intravascular lymphomatosis, and malignant angioendotheliomatosis – is a rare type of lymphoma where the neoplastic lymphocytes are found within the lumina of small-sized blood vessels. The malignant lymphocytes are confined into vascular spaces, and there is usually no evidence for a tumoral mass. The old diagnostic term “malignant angioendotheliomatosis” was used because it was thought to be an endothelial malignancy.

Clinical Presentation IVLBCL is a disease of elderly patients. Patients usually present with B symptoms (fever, night sweats, and weight loss) along with pancytopenia. The two most commonly involved organs are the skin and the central nervous system. Other organ systems can be involved, but never found in lymph nodes. It can rarely be found within blood vessels in the bone marrow. Given the non-­specific symptoms, most cases are diagnosed at postmortem. Two clinical forms have been described in different geographic distributions. In Western countries (also known as the classic form), symptoms are usually related to skin and central nervous system involvement. The Asian variant (also known as the hemophagocytic associated form) presents with multiorgan failure, liver and spleen involvement, pancytopenia, and hemophagocytic syndrome. Skin lesions can present as erythematous plaques and nodules with a widespread distribution.

17  Transplant-Related and Metastatic Malignancies

Hemorrhagic/vasculitis-like lesions have been described.

Prognosis IVLBCL is an aggressive disease and the prognosis is relatively similar in both clinical forms (i.e., Western and Asian). As previously mentioned, most cases are diagnosed postmortem; however, recognition of this entity has shown that with a high index of suspicion and early diagnosis may lead to improved survival [13]. a

813

Histopathology The characteristic histopathologic feature is the presence of neoplastic lymphocytes within vascular lumina. The atypical cells are usually within small-caliber vessels mostly in the subcutaneous tissue but not within large arteries and veins. The lymphocytes display large vesicular nuclei with prominent nucleoli and scanty cytoplasm. Mitotic figures are usually seen. Associated intravascular thrombi or complete occlusion with neoplastic lymphocytes are frequently evident (Fig.  17.8). Immunohistochemically, the lymphocytes are b

c

d

Fig. 17.8  Intravascular large B-cell lymphoma. Low power examination reveals multiple expanded superficial and deep dermal vascular channels (a). The vessels are packed with atypical large cells (b) displaying cytologic

atypia, mitosis, apoptosis, and fibrin thrombi (c). Immunohistochemical study with CD20 highlights the cells and shows confinement within the vascular channels

814

positive for B-cell markers (CD20, CD79a, PAX5). The lymphocytes can stain for various other markers including CD10, CD5, BCL-2, and BCL-6 in a variable pattern [14].

Differential Diagnosis Other systemic lymphomas/leukemias can show a prominent intravascular component; however, when examining a case histologically, if the infiltrate shows prominent extravascular involvement (i.e., the involvement of the dermis or subcutaneous tissue), this basically rules out IVLBCL. Intravascular pseudo-T-cell lymphoma (an unfortunate diagnostic term for a benign entity) presents as intralymphatic aggregates of blastic CD3- and CD30-positive T-cells, usually an incidental finding in biopsies performed for other reasons (nonneoplastic and neoplastic skin conditions). All reported cases of this entity have behaved in a benign fashion. Intravascular histiocytosis is another rare disease that presents with ill-defined plaques mostly affecting the extremities; some patients may have a history of rheumatoid arthritis. Histologically intravascular histiocytosis shows collection of banal appearing histiocytes within vascular lumina. There is usually an associated perivascular lymphoplasmacytic infiltrate. Immunohistochemically the histiocytes stain positive with CD68 and CD163.

Summary Clinical Presentation • IVLBCL usually affects elderly patients presenting with B symptoms. • Most commonly affected organ systems are the skin and central nervous system. • Cutaneous manifestations are usually erythematous plaques and nodules.

R. N. Al-Rohil and M. A. Selim

Histopathology • Atypical large lymphocytes within vascular channels. • Usually seen within small-caliber vessels in the subcutaneous tissue mostly. • Occlusion of vessels with fibrin thrombi or neoplastic lymphocytes can be seen. Differential Diagnosis • Other systemic lymphomas/leukemias with a prominent intravascular component. • Intravascular pseudo-T-cell lymphoma. • Intravascular histiocytosis.

Takeaway Essentials Clinical Relevant Pearls • Performing multiple biopsies from various anatomic sites (trunk, upper, and lower extremities) increases the chances of detection of IVLBCL. • Early diagnosis of these cases can help improve survival. Pathologic Interpretation Pearls • If there is prominent perivascular or dermal involvement by neoplastic lymphocytes, this rules out IVLBCL.

17  Transplant-Related and Metastatic Malignancies

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Case Studies Case 1 A 54-year-old female with a past medical history of metastatic breast carcinoma, for which she has undergone treatment with multiple chemotherapeutic agents. Despite treatment she continued to show progressive disease. A change in her chemotherapeutic regimen was implemented two weeks ago. In the past week, she started experiencing pain under her arms which subsequently progressed to show an erythematous rash (Fig.  17.9). The erythematous rash also affected her palms.

Histopathologic Findings Low power examination reveals orthohyperkeratosis with acanthosis and mild superficial inflammatory infiltrate (Fig. 17.10a and b). Closer inspection of the epidermis reveals vacuolar changes with dysmaturation of keratinocytes (Fig. 17.10c) in addition to eccrine squamous syringometaplasia (Fig. 17.10d).

Fig. 17.9  Toxic erythema of chemotherapy in the setting of receiving therapy for metastatic breast cancer

(continued)

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a

b

c

d

Fig. 17.10  Low power examination reveals orthohyperkeratosis with acanthosis and mild superficial inflammatory infiltrate (a and b). Closer inspection of

the epidermis reveals vacuolar changes with dysmaturation of keratinocytes (c) in addition to eccrine squamous syringometaplasia (d)

Diagnosis Toxic erythema of chemotherapy. Discussion Toxic erythema of chemotherapy presents within 2 days to 3 weeks following the administration of chemotherapy. Patients present with erythematous patches/edematous plaques that can also have accompanying symptoms of pain, paresthesia, and pruritis. The areas most commonly involved are the hands, feet, and intertriginous areas. The natural course is progression to desquamation followed by spontaneous resolution. The histopathologic features are variable and depend on the clinical form of reaction and sometimes the type, dose, and the number of chemotherapeutic agents administered. The most common pattern is vacuolar interface dermatitis with dyskeratotic keratinocytes affecting the epidermis but can also show involvement of adnexal structures and eccrine units. The inflammation can be variable from scattered perivascular lymphocytic infiltrate to a dense lichenoid lymphocytic infiltrate. Maturation arrest (also known as dysmaturation) is a useful histologic clue. Eccrine squamous syringometaplasia may be seen.

17  Transplant-Related and Metastatic Malignancies

817

Case 2 A 67-year-old female with a past medical history of invasive ductal carcinoma of the breast diagnosed 2 years ago. She was treated with skin-­sparing mastectomy, radiation, chemotherapy, and reconstructive implant surgery. She has been in remission, but in the past month, she started developing erythematous areas overlying her breast and previous surgical scar (Fig. 17.11).

Histopathologic Findings There is a dermal-based proliferation of cells with no overlying significant pathologic changes in the epidermis (Fig. 17.12a). Higher magnification shows the cells arranged in the form of sheets and nests (Fig. 17.12b) with areas of duct formation (Fig. 17.12c). Immunohistochemical studies have shown the tumoral cells to be immunoreactive for Keratin 7 (Fig.  17.12d) and GATA-3.

Fig. 17.11  A case of metastatic breast carcinoma to the skin

(continued)

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a

b

c

d

Fig. 17.12 Low power examination reveals a dermal-­based proliferation of cells with no overlying significant pathologic changes in the epidermis (a). Higher magnification shows the cells arranged in the

form of sheets and nests (b) with areas of duct formation (c). Immunohistochemical studies with Keratin 7 showing diffuse immunoreactivity (d)

Diagnosis Metastatic invasive ductal carcinoma of the breast. Discussion This is the classic and most common scenario encountered by dermatopathologists for metastatic carcinoma involving the skin. Usually metastatic carcinoma occurs overlying the site of previous disease within 1–2 years of primary diagnosis, manifesting as erythematous, firm, single, or multiple nodules that are rapidly growing. Histopathologically, the metastatic disease morphology is highly dependent on the primary malignancy. But in general, it is multifocal, dermal based with no epidermal connection, and tends to show lymphovascular invasion. Reviewing the clinical history is of utmost value as it may spare performing immunohistochemical studies; however, there is no (continued)

17  Transplant-Related and Metastatic Malignancies

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fault in performing a small panel of specific stains to confirm that this truly represents the primary known carcinoma given the evolving types of chemotherapeutic agents offered for different subtypes of carcinoma. Another important value of performing the biopsies is to submit the tissue for additional prognostic and molecular testing that may open the door for possible therapeutic agents.

Case 3 A 48-year-old male patient with a recently diagnosed acute myeloid (monocytic) leukemia undergoing ablation chemotherapy in preparation for allogenic stem cell transplantation. While receiving therapy, the patient started developing multiple erythematous/hemorrhagic papules and nodules on his lower extremities (Fig. 17.13).

Histopathologic Findings There is a dense and diffuse dermal infiltrate (Fig. 17.14a). On closer inspection, the infiltrate is monotonous and shows dissection-like growth through collagen bundles (Fig. 17.14b). The infiltrate is hematopoietic and formed of mostly small- to medium-sized cells displaying hyperchromatic nuclei with scant cytoplasm; some red blood cell extravasation is noted in the background (Fig.  17.14c). A panel of immunohistochemical studies was performed (Fig. 17.15); the cells show diffuse immunoreactivity for CD45 (Fig. 17.15a) but were negative for myeloperoxidase, CD117 (Fig. 17.15b), and CD34 (Fig. 17.15c). Upon review of flow cytometry results, the patient’s AML was negative for CD34 and CD117 but showed expression of CD33 (Fig. 17.15d) and CD4; immunohistochemical studies with these two markers showed diffuse, albeit weak, immunoreactivity. The infiltrate was negative for CD56, CD123, CD3, and CD20.

Fig. 17.13  A case of acute myeloid leukemia involving the skin with multiple erythematous/hemorrhagic papules and nodules on the lower extremities

(continued)

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820

a

b

c

Fig. 17.14  There is a dense and diffuse dermal infiltrate (a). On closer inspection, the infiltrate is monotonous and shows dissection-like growth through collagen bundles (b). The infiltrate is hematopoietic

and formed of mostly small- to medium-sized cells displaying hyperchromatic nuclei with scant cytoplasm; some red blood cell extravasation is noted in the background (c)

(continued)

17  Transplant-Related and Metastatic Malignancies

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a

b

c

d

Fig. 17.15  Immunohistochemical studies were performed; the cells show diffuse immunoreactivity for CD45 (a) but were negative for CD117 (b) and CD34 (c) but showed diffuse and weak expression of CD33 (d)

Diagnosis Leukemia cutis (cutaneous involvement by acute myeloid leukemia). Discussion Leukemia cutis usually presents in patients with a known history of underlying leukemia; however, rarely, it can be the first presentation for underlying leukemia or may precede the development of leukemia. The cutaneous manifestations are in the form of papules and nodules on the extremities, trunk, and head and neck. Hemorrhage in the lesions is common due to underlying thrombocytopenia. The clinical differential diagnosis includes an infectious etiology, neutrophilic dermatosis, Sweet’s syndrome, leukocytoclastic vasculitis, lymphoma cutis, and drug eruptions. For that reason, a biopsy is necessary to differentiate between these entities. On histopathology, the infiltrate is in a nodular or diffuse distribution in the dermis with accentuation around vessels and eccrine units. The infiltrate can show a variable degree of cytologic atypia but blast forms can be found. Immunohistochemically the infiltrate stains positive with generic myeloid markers in most cases (i.e., myeloperoxidase, CD117, and CD34); however, in some instances (as in this case), these markers can be negative. Reviewing the flow cytometry results may be of value to select which immunohistochemical studies to employ. Leukemia cutis usually carries a poor prognosis with rapid progression of the disease.

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References

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9. Hunjan MK, Nowsheen S, Ramos-Rodriguez AJ, Hashmi SK, Bridges AG, Lehman JS, et al. Clinical and histopathological spectrum of toxic erythema of 1. Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy chemotherapy in patients who have undergone alloPL, Cutler CS, et  al. Risk factors for acute GVHD geneic hematopoietic cell transplantation. Hematol/ and survival after hematopoietic cell transplantation. Oncol Stem Cell Ther. 2019;12(1):19–25. Blood. 2012;119(1):296–307. 10. Mahalingam M, Nguyen LP, Richards JE, Muzikansky 2. Strong Rodrigues K, Oliveira-Ribeiro C, de Abreu A, Hoang MP. The diagnostic utility of immunohistoFiuza Gomes S, Knobler R. Cutaneous graft-versus-­ chemistry in distinguishing primary skin adnexal carhost disease: diagnosis and treatment. Am J Clin cinomas from metastatic adenocarcinoma to skin: an Dermatol. 2018;19(1):33–50. immunohistochemical reappraisal using cytokeratin 3. Horn TD, Redd JV, Karp JE, Beschorner WE, Burke 15, nestin, p63, D2-40, and calretinin. Mod Pathol. PJ, Hood AF.  Cutaneous eruptions of lymphocyte 2010;23(5):713–9. recovery. Arch Dermatol. 1989;125(11):1512–7. 11. Rollins-Raval M, Chivukula M, Tseng GC, Jukic D, 4. Bauer DJ, Hood AF, Horn TD. Histologic comparison Dabbs DJ.  An immunohistochemical panel to difof autologous graft-vs-host reaction and cutaneous ferentiate metastatic breast carcinoma to skin from eruption of lymphocyte recovery. JAMA Dermatol. primary sweat gland carcinomas with a review of the 1993;129(7):855–8. literature. Arch Pathol Lab Med. 2011;135(8):975–83. 5. Hurabielle C, Sbidian E, Beltraminelli H, 12. Lee JJ, Mochel MC, Piris A, Boussahmain C, Bouchindhomme B, Chassagne-Clement C, Balme Mahalingam M, Hoang MP. P40 exhibits better speciB, et al. Eruption of lymphocyte recovery with atypificity than p63 in distinguishing primary skin adnexal cal lymphocytes mimicking a primary cutaneous carcinomas from cutaneous metastases. Hum Pathol. T-cell lymphoma: a series of 12 patients. Hum Pathol. 2014;45(5):1078–83. 2018;71:100–8. 13. Matsue K, Abe Y, Narita K, Kobayashi H, Kitadate 6. Spitzer TR.  Engraftment syndrome: double-edged A, Takeuchi M, et al. Diagnosis of intravascular large sword of hematopoietic cell transplants. Bone Marrow B-cell lymphoma: novel insights into clinicopathoTransplant. 2015;50(4):469–75. logical features from 42 patients at a single institution 7. Chang L, Frame D, Braun T, Gatza E, Hanauer DA, over 20 years. Br J Haematol. 2019;187(3):328–36. Zhao S, et  al. Engraftment syndrome after allo 14. Murase T, Yamaguchi M, Suzuki R, Okamoto M, Sato geneic hematopoietic cell transplantation predicts Y, Tamaru J, et  al. Intravascular large B-cell lympoor outcomes. Biol Blood Marrow Transplant. phoma (IVLBCL): a clinicopathologic study of 96 2014;20(9):1407–17. cases with special reference to the immunophenotypic 8. Bolognia JL, Cooper DL, Glusac EJ. Toxic erythema heterogeneity of CD5. Blood. 2007;109(2):478–85. of chemotherapy: a useful clinical term. J Am Acad Dermatol. 2008;59(3):524–9.

Human Immunodeficiency Virus (HIV)-Associated Dermatoses and Malignancy

18

Wayne Grayson

Contents Introduction

 825

Acute HIV Exanthem Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 827  827  827  827  828

HIV-Associated Papulosquamous Dermatoses HIV-Associated Seborrheic Dermatitis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis HIV-Associated Psoriasis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis HIV-Associated Pityriasis Rubra Pilaris Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis HIV-Associated Xerosis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 829  829  829  829  829  829  831  831  831  832  832  833  833  834  834  835  835  836  836  836  836

HIV-Related Pruritic Papular Dermatoses Pruritic Papular Eruption Clinical Presentation

 837  837  837

W. Grayson (*) School of Pathology, University of the Witwatersrand, Johannesburg, South Africa e-mail: [email protected] © Springer Nature Switzerland AG 2020 M. P. Hoang, M. A. Selim (eds.), Hospital-Based Dermatopathology, https://doi.org/10.1007/978-3-030-35820-4_18

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W. Grayson

824  rognosis or Clinical Course P Histopathology Differential Diagnosis HIV-Associated Eosinophilic Folliculitis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 837  837  838  839  839  839  840  840

HIV-Associated Autoimmune Vesiculobullous Dermatoses Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 841  841  841  842  842

HIV-Associated Vasculitides Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 842  843  843  843  845

HIV-Associated Photodistributed Eruptions HIV-Associated Chronic Actinic Dermatitis Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis HIV-Associated Lichenoid Photoeruptions Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis HIV-Associated Porphyria Cutanea Tarda Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 845  845  846  846  846  846  847  848  848  848  848  851  851  851  852  852

Adverse Cutaneous Drug Reactions in HIV/AIDS Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 852  853  853  854  854

HIV-Associated Lipodystrophy Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 857  857  858  858  858

HIV-/AIDS-Associated Neoplasia AIDS-Associated Kaposi Sarcoma Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

 859  859  859  859  860  861

18  Human Immunodeficiency Virus (HIV)-Associated Dermatoses and Malignancy HIV-Related Non-Hodgkin Lymphomas Clinical Presentation Prognosis or Clinical Course Histopathology Differential Diagnosis

825  862  862  863  863  866

Case Studies/Vignettes Case 1 Clinical History Microscopic Findings Diagnosis Discussion Case 2 Clinical History Microscopic Findings Diagnosis Discussion Case 3 Clinical History Microscopic Findings Diagnosis Discussion

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References

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Introduction It is estimated that 36.9 million adults and children were living with human immunodeficiency virus (HIV) infection in 2017, with a prevalence rate of around 0.8% among people aged between 15 and 49 years. Some 940,000 (670000–1,300,000) adults and children are thought to have died from the acquired immunodeficiency syndrome (AIDS) during 2017; this is a significant decline from the 2004 peak of 1.9 million (1.4–2.7 million). The worldwide decrease in AIDS-related deaths is largely attributable to improved access to antiretroviral therapy (ART), with an estimated 21.7 million (59%) of those living with HIV receiving ART in 2017. Sub-­Saharan Africa, however, continues to carry the burden of disease and is home to some 53% of the global population of people living with HIV [1, 2]. A vast majority of patients with HIV/AIDS will develop one or more cutaneous conditions

during the course of their illness. A high index of suspicion is thus required of dermatologists and dermatopathologists, especially those who practice in parts of the world where there is a high prevalence of HIV/AIDS. Although presentation with an AIDS-defining condition will automatically alert one to the possibility of underlying HIV infection, the latter should also be suspected if a common dermatosis presents with atypical clinical features, pursues an abnormal clinical course, exhibits greater clinical severity than expected, and/or is refractory to standard therapy. The spectrum of HIV-associated skin disease includes a range of noninfectious dermatoses, adverse cutaneous drug reactions, as well as certain opportunistic infections and neoplasms, some of which are AIDS-defining [3]. Cutaneous infections occurring in HIV/AIDS will not be discussed in detail in this chapter, and the reader is instead referred to the relevant chapter on infectious diseases.

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The importance of careful clinicopathologic correlation cannot be overemphasized. The basic approach to the skin biopsy in the context of HIV/AIDS entails identification of the dominant histological pattern (Table 18.1), with subsequent interpretation thereof in the context of the clinical presentation and ancillary data such as the CD4 T-cell count, a relevant pharmacological history, and the ART treatment status in particular. The latter is an important factor, as the potential occurrence of the immune reconstitution inflammatory syndrome (IRIS) in those receiving ART may be associated with a wide range of infective, noninfective, and neoplastic cutaneous manifestations (Table  18.2) [4, 5]. Gray areas, however, exist; certain lesions traditionally classified as AIDS-associated neoplasms have an infective etiology, such as Epstein-Barr virus (EBV)-driven lymphomas and Kaposi sarcoma (KS), the latter caused by human herpesvirus type 8 (HHV-­8). One must also remain cognizant of the fact that a given histologic specimen may potentially harbor more than one concurrent disease process. In some cases the findings may be subtle, with the attendant risk of a potentially lethal but treat-

Table 18.1  Major histologic patterns encountered in HIV/AIDS-related dermatopathology [3] Psoriasiform Spongiotic Lichenoid Pustular  Intraepidermal  Intradermal  Folliculocentric Vasculopathic Granulomatous Ulcerative Vesiculobullous

Verrucous/hyperkeratotic Panniculitic Proliferative  Vascular  Spindle cell  Lymphoid Mixed patterns “Normal”/“near-normal” Miscellaneous (e.g., mucinosis, xerosis, lipodystrophy, etc.)

Table 18.2  Etiologic spectrum of IRIS-associated conditions with skin manifestations Infective Viral:  CMV  HSV  VZV  MCV (incl. giant lesions)  HPV (verrucae, EDV) Fungal:  Dermatophytosis  Pityriasis versicolor   Sporothrix schenckii   Cryptococcus neoformans   Talaromyces marneffei   Histoplasma capsulatum   Emergomyces africanus  Blastomycosis  Fusariosis  Paracoccidioidomycosis Bacterial:   Mycobacterium tuberculosis   M. leprae   M. avium complex   Staphylococcus aureus  Bacillary angiomatosis  Secondary syphilis Protozoal:  Leishmaniasis Arthropod:  Crusted (Norwegian) scabies Helminthic:  Strongyloidiasis

Noninfective Seborrheic dermatitis Psoriasis Sarcoidosis Foreign body granulomatous reactions Reactive arthritis LE Alopecia universalis Acne vulgaris HIV-EF PPE Vasculitis (incl. EED) Mid-dermal elastolysis Sweet syndrome Pyoderma gangrenosum Urticaria

Neoplastic Kaposi sarcomaa Non-Hodgkin lymphomab Adapted from Nelson et al. [4] and Ramdial [5] IRIS immune reconstitution inflammatory syndrome, CMV cytomegalovirus, HSV herpes simplex virus, VZV varicella zoster virus, MCV molluscum contagiosum virus, HPV human papillomavirus, EDV epidermodysplasia verruciformis, LE lupus erythematosus, HIV-EF human immunodeficiency virus-associated eosinophilic folliculitis, PPE pruritic papular eruption, EED erythema elevatum diutinum a Caused by human herpesvirus type 8 b Including Epstein-Barr virus-driven lymphomas

18  Human Immunodeficiency Virus (HIV)-Associated Dermatoses and Malignancy

able systemic opportunistic infection inadvertently being overlooked (e.g., incidental cryptococcosis in a biopsy undertaken for confirmation of KS) [6].

Acute HIV Exanthem Symptoms and signs of seroconversion illness following acquisition of HIV infection may occur in some 95% of infected individuals and is characteristically infectious mononucleosislike. Mucocutaneous manifestations develop in 60% of these patients [7, 8]. Correlation exists between the severity of symptoms and the initial viral load [8].

Clinical Presentation The rash is generally roseola-like or maculopapular (Fig.  18.1), and in keeping with an

Fig. 18.1  Acute HIV exanthem: maculopapular eruption in a patient with symptomatic illness at the time of seroconversion. (Courtesy of Dr. Jeremy Nel, Department of Internal Medicine, Helen Joseph Hospital and the University of the Witwatersand, Johannesburg, South Africa)

827

infectious mononucleosis-like picture, it may be accompanied by malaise, fever, a sore throat, myalgia, arthralgia, and lymphadenopathy [7, 8]. The exanthem is painful and erosive in 25% of patients [7]. Palmoplantar involvement may also occur. Other potential mucocutaneous manifestations include urticaria, vesiculation, ­ genital ulceration, Stevens-Johnson syndrome (SJS), and alopecia [9].

Prognosis or Clinical Course Spontaneous resolution is the norm. The mean duration of the exanthem is in the order of 10 days [8]. A higher viral load in the plasma and greater severity of acute HIV illness in ART-naïve patients is associated with more rapid disease progression and a higher overall HIV-associated mortality [10].

Histopathology The skin biopsy findings are variable and relatively nonspecific; hence, their interpretation requires careful clinicopathologic correlation. Early lesions may reveal only a mild perivascular dermal lymphocytic infiltrate, without accompanying epidermal alterations [11, 12]. More established cases show epidermal lymphocytic exocytosis with associated keratinocyte dyskeratosis and overlying parakeratosis (Fig. 18.2). Advanced lesions may demonstrate lymphocytic vacuolar interface dermatitis, pigmentary incontinence, and spongiosis, with the latter sometimes accompanied by intraepidermal vesiculation. A more pronounced perivascular and peri-­ appendageal lymphocytic infiltrate is also seen, sometimes with simi-

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Summary Clinical Presentation • Roseola-like or maculopapular skin rash in association with other infectious mononucleosis-like symptoms and signs, in the presence of proven HIV seroconversion

Fig. 18.2  Acute HIV exanthem: lymphocytic exocytosis, mild spongiosis, scattered dyskeratotic keratinocytes, and focal parakeratosis are seen (×400)

lar involvement of hair ­follicle epithelium to that seen in the epidermis [12]. Plasma cells are absent from the infiltrate. Some authors have specifically noted a lack of perivascular erythrocyte extravasation [11]. This is likely a reflection of early lesions, as others have indeed observed features of a lymphocytic vasculopathic reaction in biopsies from wellestablished cases [3].

Histologic Features • Early lesions: only a mild perivascular dermal lymphocytic infiltrate and a relative absence of accompanying epidermal changes • Well-established lesions: associated lymphocytic vasculopathic changes and epidermal alterations, including lymphocytic vacuolar interface dermatitis, keratinocyte dyskeratosis/apoptosis, and focal spongiosis, sometimes with spongiotic vesiculation Differential Diagnosis • Other viral exanthems • Cutaneous adverse drug reaction, especially a morbilliform drug eruption

Differential Diagnosis As already stated, the histopathologic findings are not specific. Other viral exanthems may exhibit identical histologic features, and proven HIV seroconversion is critical in rendering a definitive diagnosis. Similar microscopic findings may also be encountered in a morbilliform drug eruption (MDE) in particular. Others have noted histological overlap with drug-induced chronic HIV interface dermatitis [9]. Although the identification of eosinophils amid the dermal infiltrate may serve as a useful clue to a cutaneous adverse drug reaction (ADR), their absence does not necessarily rule out a pharmacologically induced skin rash in an HIV-positive individual. Careful correlation with a detailed drug history, therefore, is essential [3].

Takeaway Essentials Clinical Relevant Pearls • A roseola-like or maculopapular skin rash with infectious mononucleosis-like clinical features should prompt investigation of the HIV status. • The occurrence of a maculopapular rash in association with oral and genital ulceration should alert one to the possibility of acute HIV infection. Pathology Interpretation Pearls • The findings are relatively nonspecific and must be interpreted in the context of the clinical presentation and HIV serology.

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HIV-Associated Papulosquamous Dermatoses HIV-Associated Seborrheic Dermatitis Seborrheic dermatitis (SD) represents the most common dermatosis affecting those living with HIV/AIDS, and has a reported prevalence ranging from 20% to 83%. SD may be a presenting feature of AIDS or predate the latter by up to 2 years [13]. Its exact pathogenesis is not fully understood, although immune dysregulation and a resultant alteration in Malassezia (formerly Pityrosporum) species and the concentration of these organisms have been hypothesized [14]. An altered cutaneous lipid profile may be encountered in HIVinfected patients [15]. There is also a production of heat shock proteins not observed among HIVnegative patients with SD or psoriasis [16].

Clinical Presentation Although the erythematous, greasy scaling lesions of usual SD are seen, HIV-associated cases tend to have more extensive disease (Fig.  18.3), with erythematous, scaly papules,

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and plaques beyond the normal seborrheic distribution (e.g., extremities, groins, axillae), more prominent psoriasiform morphology, “cradle-­ cap” scalp involvement, hyper- and hypopigmentation within the inflammatory patches and plaques, and a greater propensity to develop erythroderma [13, 14].

 rognosis or Clinical Course P SD in HIV-infected patients has a distinctive clinical appearance, with diffuse and severe skin involvement that is refractory to standard therapy, and a greater proclivity toward the development of erythroderma [14]. It is noteworthy that the CD4 T-cell count may not be necessarily low at the time of presentation. SD may be an early feature of HIV infection. In general, however, very low CD4 counts are associated with particularly severe disease and erythroderma. SD in patients with HIV/AIDS is often refractory to standard treatment, requiring prolonged courses of topical and systemic antifungal agents, as well as topical or oral corticosteroids. Treatment failure and frequent recurrence are also common. Some cases may show clinical improvement following initiation of anti-staphylococcal antimicrobial therapy [14]. A relationship with AIDS dementia has been reported [13]. Histopathology The histologic findings in the context of HIV infection generally mirror those of usual SD, including psoriasiform epidermal acanthosis, hyperkeratosis, focal parakeratosis, and lymphocytic exocytosis with associated foci of spongiosis. Additional features which may be encountered in HIV-associated SD, however, include more widespread parakeratosis (Fig. 18.4), spotty keratinocyte dyskeratosis (Fig.  18.5), a perivascular plasma cell infiltrate, and the presence of neutrophils and eosinophils amid the predominantly lymphocytic perivascular dermal inflammatory infiltrate [13, 14].

Fig. 18.3  HIV-associated seborrheic dermatitis: note the extensive lesions. (Courtesy of the Division of Dermatology, University of the Witwatersand, Johannesburg, South Africa)

Differential Diagnosis HIV-associated psoriasis constitutes the main histologic differential diagnosis. Its distinction

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kocytes (in the context of a positive drug history), and the identification of geometric parakeratosis, ­respectively [3].

Summary

Fig. 18.4  HIV-associated seborrheic dermatitis: in this example there is pronounced psoriasiform hyperplasia, accompanied by a disrupted parakeratotic scale containing serum (×40)

Fig. 18.5  HIV-associated seborrheic dermatitis: the presence of scattered dyskeratotic keratinocytes is not uncommon in this clinical setting (×400)

from HIV-associated SD may prove challenging as the former may have fewer Munro microabscesses than usual psoriasis, demonstrate somewhat irregular acanthosis and less suprapapillary thinning, and can exhibit slight spongiosis and a perivascular dermal lymphohistiocytic infiltrate [13]. Erythrodermic psoriasiform SD in HIV-­ infected patients should be distinguished from erythrodermic psoriasis, an erythrodermic cutaneous ADR, and erythrodermic pityriasis rubra pilaris (PRP). Careful clinicopathologic correlation, therefore, is essential. Useful clues to the aforementioned entities on biopsy include Munro microabscesses, dermal eosinophilic leu-

Clinical Presentation • As for usual seborrheic dermatitis but with more extensive and recalcitrant disease, a more prominent psoriasiform appearance, “cradle-cap” scalp involvement, and a greater proclivity for erythroderma Histologic Features • Psoriasiform epidermal acanthosis, patchy parakeratosis, and focal lymphocytic exocytosis and spongiosis • Features peculiar to HIV-associated seborrheic dermatitis include spotty keratinocyte dyskeratosis, plasma cells amid the perivascular dermal lymphocytic infiltrate, and a polymorphous dermal infiltrate which may also contain eosinophils and polymorphonuclear leukocytes Differential Diagnosis • HIV-associated psoriasis • If erythrodermic: erythrodermic psoriasis, erythrodermic cutaneous ADR, erythrodermic PRP

Takeaway Essentials Clinical Relevant Pearls • Seborrheic dermatitis is the commonest HIV-associated dermatosis and may be a presenting feature of undiagnosed HIV infection or AIDS. • Seborrheic dermatitis showing extensive disease and resistance to conventional therapy should alert the clinician

18  Human Immunodeficiency Virus (HIV)-Associated Dermatoses and Malignancy

to the possibility of HIV-associated disease. Pathology Interpretation Pearls • Recognition of dyskeratotic epidermal keratinocytes and a dermal contingent of plasma cells in a biopsy showing features of seborrheic dermatitis should alert one to the possibility of HIV-­ related seborrheic dermatitis.

HIV-Associated Psoriasis The prevalence of psoriasis among HIV-infected patients does not appear to exceed that of the general population (1–3%), and shows a similar clinical spectrum. HIV-related psoriasis, however, shows a greater propensity to occur with advanced immunosuppression, with CD4 T-cell counts of 1000 cells/ μL [24]. The exact pathogenesis of this papulosquamous dermatosis, which is clinically distinct from classic adult type PRP, remains unknown [25]. The alternative designations HIV-associated follicular syndrome and HIV-associated follicular occlusion triad have been proposed since it is the presence of nodulocystic follicular disease that sets this PRP type apart from classic adult PRP [26]. Direct infection of the follicular hair bulge by HIV has been hypothesized [23].

Clinical Presentation PRP type 6 may be a presenting feature of HIV infection. PRP is typified by symmetrical erythematous, hyperkeratotic follicular papules with a predilection for the extensor surfaces. Confluence ensues, with resultant erythematosquamous orange-red/salmon-colored scaly plaques (Fig. 18.9). The latter are associated with well-demarcated islands of sparing. Variable keratoderma of the palms and soles is a further

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Fig. 18.9   HIV-associated (type 6) pityriasis rubra pilaris: coalescent plaques on the trunk, accompanied by facial and scalp involvement, and plantar hyperkeratosis.

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(Courtesy of Prof. Anisa Mosam, Division of Dermatology, Nelson R. Mandela School of Medicine and University of KwaZulu-Natal, Durban, South Africa)

finding [27, 28]. Erythroderma may ensue [29]. In addition to the above, this PRP variant is characterized by a variable association with acne conglobata, hidradenitis suppurativa, and lichen spinulosus [27].

 rognosis or Clinical Course P An increased mortality has been observed in patients with CD4 counts of >500 cells/μL [25]. The condition has a poor prognosis if left untreated, but usually improves following initiation of antiretroviral therapy [24, 30]. Histopathology There is usually mild to moderate epidermal acanthosis, which may be psoriasiform. The rete ridges usually appear short and broadened. The diagnostic feature is a checkerboard pattern of so-called geometric parakeratosis, with alternating layers

Fig. 18.10  Pityriasis rubra pilaris: note the mild acanthosis and characteristic alternating (“geometric”) orthokeratosis and parakeratosis (×200)

of orthokeratosis and parakeratosis in the vertical and horizontal planes (Fig. 18.10) [3]. There is retention of the granular cell layer. A sparse

18  Human Immunodeficiency Virus (HIV)-Associated Dermatoses and Malignancy

superficial perivascular dermal lymphocytic infiltrate may be present. Follicular involvement is heralded by infundibular dilatation and hyperkeratotic follicular plugging [31]. Perifollicular mucin deposition has been reported [32].

Differential Diagnosis • HIV-associated psoriasis, seborrheic dermatitis, or xerosis • If erythrodermic: erythrodermic psoriasis, erythrodermic seborrheic dermatitis, or drug-induced erythroderma • Early lesions: other causes of seemingly “normal” skin biopsy histology (Table 18.3)

Differential Diagnosis HIV-associated psoriasis, psoriasiform SD, or xerosis might be considered in cases with established epidermal hyperplasia. Careful clinicopathologic correlation, therefore, is required. Early lesions, however, may prove diagnostically challenging in view of the subtlety of the geometric parakeratosis and an almost “normal” histologic appearance [3]. The differential diagnosis of a “normal”/“near-normal” skin biopsy in HIV-­ infected individuals is summarized in Table 18.6. Erythrodermic PRP should be distinguished from other causes of HIV-related erythroderma, including psoriasis, SD, or an ADR [29].

Takeaway Essentials Clinical Relevant Pearls • PRP type 6 may serve as a sentinel of undiagnosed HIV infection. • It is typified by its variable association with acne conglobata, hidradenitis suppurativa, and lichen spinulosus. Pathology Interpretation Pearls • Diagnosis of early lesions may prove challenging and often requires careful scrutiny of multiple serial sections.

Summary Clinical Presentation • Initial erythematous follicular papules coalescing to form orange-red scaly plaques, with characteristic islands of sparing and associated palmoplantar keratoderma • Erythroderma may ensue • Variable association with acne conglobata, hidradenitis suppurativa, and lichen spinulosus Histologic Features • Mild to moderate psoriasiform acanthosis, with short, blunt rete ridges and alternating orthokeratosis and parakeratosis in a “checkerboard” pattern • Follicular infundibular dilatation and hyperkeratosis • Minimal superficial perivascular lymphocytic infiltrate

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HIV-Associated Xerosis Xerosis (asteatotic eczema) is a common scaling dermatosis among HIV-infected individuals and may even be a presenting sign of AIDS [13]. It Table 18.3  Histopathologic differential diagnosis for the “normal” or “near-normal” skin biopsy in the setting of HIV/AIDS [3] Superficial fungal infection (tinea) Pityriasis rubra pilaris Anetoderma Very early patch stage KS Interstitial (“incomplete”) granuloma annulare Opportunistic invasive fungal infectiona With a negligible or absent host response in the face of profound immunosuppression

a

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is said to occur in as many as 37.6% of HIVpositive patients, including those who are on antiretroviral therapy [33]. There is a propensity for the condition to occur when the CD4 T-cell count is ≤400 cells/μL, and it may antedate the onset of other papulosquamous disorders in a given patient [13]. Although its exact pathogenesis is not fully understood, factors such as cutaneous microcirculatory changes, nutritional alterations, altered sweat gland or sebaceous gland activity, changes in the composition of the sweat, changes in the dermal mast cell population, decreased calcitonin gene-related peptide and substance P levels, and a diminished epidermal lipid content have all been implicated [34, 35]. These act in concert to undermine the integrity of the epidermis and its important barrier function [34].

Clinical Presentation The pruritic rash is characterized by fine, diffuse branny scaling and a predilection for the lower extremities. Discrete, thickened patches are also encountered. Associated changes of acquired ichthyosis may be seen [13].  rognosis or Clinical Course P The condition has a tendency to worsen as the CD4 T-cell count decreases [33]. It is often severely pruritic, with the pruritus disproportionate to the degree of clinically apparent xerosis. It may also be resistant to treatment with antihistamines [13]. Histopathology The histological picture is influenced by associated scratching or rubbing. In most cases there is mild acanthosis accompanied by minimal hyperkeratosis and parakeratosis. Mild, focal spongiosis may be seen. There is a sparse superficial perivascular dermal lymphocytic infiltrate. Superimposed changes of early acquired ichthyosis are observed in some cases, with compact orthokeratosis, a diminished granular cell layer, and a minimal inflammatory infiltrate [13]. The aforementioned epidermal changes have ­occasionally been reported in association with underlying KS (Fig. 18.11) [6].

Fig. 18.11  Xerosis complicated by early acquired ichthyosis: the hyperkeratosis in this biopsy from the lower leg is associated with early Kaposi sarcoma in the underlying dermis (×200)

Differential Diagnosis HIV-associated xerosis should be distinguished from irritant contact dermatitis, as well as other itchy, scaling dermatoses that may occur in patients with advanced HIV infection. These include scabies, dermatophyte infection, and nutritional deficiency [13].

Summary Clinical Presentation • Marked pruritus and diffuse, fine branny scaling • Predilection for the lower extremities • Associated features of acquired ichthyosis is some patients Histologic Features • Mild acanthosis accompanied by mild hyperkeratosis and parakeratosis • Minimal spongiosis and a mild superficial dermal perivascular lymphocytic infiltrate • Superimposed changes of acquired ichthyosis in some cases Differential Diagnosis • Irritant contact dermatitis • Other HIV-related scaling dermatoses, e.g., scabies, dermatophytosis, nutritional deficiency

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Takeaway Essentials Clinical Relevant Pearls • Xerosis may be a sentinel of undiagnosed HIV infection/AIDS. • It should be distinguished from other HIV-related scaling dermatoses. • Pathology Interpretation Pearls • The findings are mild and relatively nonspecific, but may be influenced by associated rubbing and scratching.

 IV-Related Pruritic Papular H Dermatoses Pruritic Papular Eruption Pruritic papular eruption (PPE), sometimes referred to as papulopruritic eruption, is a common dermatosis among HIV-infected individuals, with a reported prevalence ranging from 12% to 46%, depending on geographical location [33]. Although its exact etiopathogenesis is not fully understood, a hypersensitivity reaction to arthropod bites, and mosquitos in particular, seems likely. It has been proposed that PPE represents an exaggerated immune response to mosquito-­ derived antigens in a subset of susceptible individuals infected with HIV [36]. There is apparent cytokine production (IL-2, IL-12, interferon-γ, IL-5) and recruitment of eosinophilic leukocytes to the dermis in the face of a mixed Th1/ Th2 or Th0 pattern, with a decreased peripheral CD4 T-cell count and increased CD8+ T-cells in lesional skin [37, 38].

Clinical Presentation Patients present with a markedly pruritic, generally symmetrical eruption of skin-colored to erythematous papules, with a predilection for the distal extremities. More widespread involvement may ensue (Fig. 18.12), with lesions on the trunk and face. Superimposed changes related to ­excoriation, impetiginization, or nodular prurigo can occur. Associated hyperpigmentation

Fig. 18.12  Pruritic papular eruption of HIV: widespread lesions are present on this patient’s trunk. (Courtesy of Prof. Anisa Mosam, Division of Dermatology, Nelson R.  Mandela School of Medicine and University of KwaZulu-Natal, Durban, South Africa)

is a frequent finding in patients with pigmented skin [33].

 rognosis or Clinical Course P PPE has a propensity to occur in individuals with advanced HIV disease and a low CD4 T-cell count (40 °C, enlarged lymph nodes, arthralgia/ arthritis, eosinophilia >1000/μL, lymphocytosis with atypical cells, and raised liver enzymes

Characterized by numerous necrotic keratinocytes often with fullthickness epidermal necrosis and a subepidermal blister, which may contain extravasated erythrocytes. Papillary dermal melanophages are present in late lesions Variable, ranging from a spongiotic reaction to EM or TEN. Subcorneal pustulation has also been reported

Agent(s) implicated TMP/SMX Rifampicin Pyrazinamide Isoniazid Ethambutol Streptomycin Cycloserine Fluoroquinolones NVP Darunavir (rare) Etravirine (rare) TMP/SMX NVP Anti-TB (in general)

Isoniazid Rifampicin Streptomycin Pyrazinamide NVP EFV ABC Amprenavir Indinavir Raltegravir (rare) Etravirine (rare) Maraviroc (uncommon) TMP/SMX (rare)

Keywords TMP/SMX trimethoprim/sulfamethoxazole, Anti-TB antituberculous, NVP nevirapine, EFV efavirenz, EM erythema multiforme, TEN toxic epidermal necrolysis, BSA body surface area, DRESS drug hypersensitivity with eosinophilia and systemic symptoms, ABC abacavir a Reproduced with permission from S. Karger AG, Basel and adapted from Hoosen et al. [97]

Fig. 18.33  Morbilliform drug eruption: note the subtle lymphocytic exocytosis, scattered dyskeratotic keratinocytes, and mild superficial perivascular dermal lymphocytic infiltrate (×100)

Fig. 18.34  Erythema multiforme: note the dyskeratotic cells throughout the epidermis, in addition to lymphocytic exocytosis and mild spongiosis (×200)

18  Human Immunodeficiency Virus (HIV)-Associated Dermatoses and Malignancy

Fig. 18.35  Fixed drug eruption: note the confluent dyskeratosis and prominent, somewhat band-like dermal inflammatory infiltrate. An incipient subepidermal blister is visible at the edge of this field (×40)

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Fig. 18.38  Drug hypersensitivity syndrome due to abacavir: there is papillary dermal edema, patchy lymphocytic exocytosis, mild spongiosis, focal keratinocyte apoptosis, and focal parakeratosis. Although eosinophilia was noted in the peripheral blood, the dermal inflammatory infiltrate in this example was found to contain surprisingly few eosinophils (×200)

HIV-Associated Lipodystrophy

Fig. 18.36  Waning lichenoid drug eruption: the histologic picture closely resembles lichen planus (×400)

Fig. 18.37 Drug-induced leukocytoclastic vasculitis: note the prominent fibrinoid changed in relation to the dermal vessel walls, as well as the early hemorrhagic subepidermal vesiculation (×200)

HIV-infected patients on long-term ART, and those receiving nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) in particular, are at risk of developing lipodystrophy. The aforementioned term is used to describe both lipoatrophy and lipohypertrophy [102]. The alternative designation fat redistribution has gained favor and encompasses lipohypertrophy, lipoatrophy, and mixed syndromes [102, 103]. NRTIs, especially stavudine and zidovudine, inhibit mitochondrial polymerase-g, resulting in mitochondrial toxicity. PIs inhibit zinc metalloproteases such as ZMPSTE24. The latter plays an important role in the processing and maturation of prelamin A, and accumulation of toxic farnesylated prelamin A is brought about by PIs. PIs have also been implicated in the dysregulation of adipogenic transcription factors, and may also inhibit glucose transporter 4 expression, thus contributing to insulin resistance [104].

Clinical Presentation Patients typically manifest with a loss of fat from the face (Fig.  18.39), gluteal region, and

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Histopathology Biopsies are seldom performed, as the diagnosis is made largely on clinical grounds. Consequently, there are very few descriptive reports of the histopathologic features of ART-associated lipodystrophy. Cases of lipoatrophy will reveal thinning of the subcutaneous fat in the presence of morphologically normal adipocytes [105].

Differential Diagnosis

Fig. 18.39  HIV-associated lipodystrophy: the loss of fat from the malar areas is a characteristic feature. (Courtesy of Prof. Anisa Mosam, Division of Dermatology, Nelson R.  Mandela School of Medicine and University of KwaZulu-Natal, Durban, South Africa)

extremities, accompanied by increased deposition of fat around the neck, abdomen, and trunk [102]. The loss of fat from the malar region and temples imparts a pseudocachectic appearance [105]. Bilateral or unilateral breast enlargement has also been reported [103]. Risk factors for ART-­associated lipodystrophy include older age (>40 years), a greater baseline body mass index at ART initiation, undetectable HIV RNA, recent weight loss, and faster rate of weight loss [102].

Prognosis or Clinical Course The condition is associated with an increased predisposition toward cardiovascular disease. Further associations include insulin resistance, glucose intolerance, diabetes mellitus, hypertriglyceridemia, and low serum HDL levels [106].

Lipodystrophy may occur outside of the context of ART in those infected with HIV.  The spectrum includes inherited forms such as congenital generalized lipodystrophy and familial partial lipodystrophy, acquired generalized lipodystrophy related to underlying autoimmune disease, acquired partial lipodystrophy (usually encountered in children), and localized lipodystrophy as a result of insulin or corticosteroid injections [104].

Summary Clinical Presentation • History of long-term ART (NRTIs and PIs in particular) • Loss of fat from the face (especially the malar area), gluteal region, and extremities • Increased fat deposition around the neck, abdomen, and trunk Histologic Features • Diminished subcutaneous adipose tissue in cases of lipoatrophy, with morphologically normal adipocytes Differential Diagnosis • Fat redistribution due to other causes (inherited or acquired)

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Takeaway Essentials Clinical Relevant Pearls • This is not merely a cosmetically distressing condition; patients are also at risk for cardiovascular disease. • Further associations include insulin resistance, glucose intolerance, diabetes mellitus, hypertriglyceridemia, and low serum HDL levels. Pathology Interpretation Pearls • Biopsies are seldom performed since the diagnosis is essentially a clinical one.

HIV-/AIDS-Associated Neoplasia AIDS-defining malignancies include KS, certain high-grade non-Hodgkin lymphomas (NHLs), and carcinoma of the uterine cervix [107]. Although the advent of HAART and cART has seen significant reduction in the prevalence of these neoplasms, there has been an apparent increase in the incidence of non-AIDS-defining malignancies. The latter include cutaneous, anogenital, and oropharyngeal squamous cell carcinomas (SCCs), Merkel cell carcinoma (MCC), Hodgkin lymphoma, and certain visceral neoplasms, including malignancies of the lung, liver, and kidney [108, 109]. HIV infection is also associated with increased melanoma mortality [109]. Human papillomavirus (HPV) infection plays a well-recognized etiologic role in the evolution of invasive SCC and preinvasive neoplastic squamous lesions of the vulva, penis, and anus, while Merkel cell polyomavirus is implicated in MCC among HIV-infected individuals [109, 110]. Further discussion will now focus on AIDS-­associated KS and HIV-related NHLs.

AIDS-Associated Kaposi Sarcoma KS is a vascular proliferation caused by HHV-8, also known as KS herpesvirus (KSHV). Whether

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KS qualifies as a true sarcomatous neoplasm, however, remains the subject of debate [111]. HHV-8 also plays an etiologic role in other conditions, notably KSHV-associated multicentric Castleman disease, primary effusion lymphoma, and the recently described KSHV inflammatory cytokine syndrome [112]. AIDS-associated KS occurs mainly in HIV-infected people in the third to sixth decades of life, with an increased incidence among men who have sex with men, as well as intravenous drug users. In sub-Saharan Africa, however, women and children are equally affected [113]. The life cycle of HHV-8 encompasses both latent and lytic phases. Since HHV-8 infection alone is not sufficient for the evolution of KS, other factors play an important role; these include host immune dysfunction, genetic factors, and environmental factors. The reader is referred to the listed references for a more detailed account of the complex pathogenesis of KS [111, 114, 115]. Evidence has shown that KS is a predominantly multifocal disease, with a majority of cases characterized by oligoclonality, and not all lesions arising from a single clone [116, 117].

Clinical Presentation Patients may present with purplish-red cutaneous patches, plaques, and/or nodules (Fig.  18.40), which tend to parallel disease progression. There is a predilection for the lower extremities, followed by the face and genitalia. Painful lymphedema may accompany advanced KS of the lower limbs. Associated intraoral mucosal lesions are not uncommon (Fig. 18.41). Rare cases may present with verrucous or bullous lesions [111].  rognosis or Clinical Course P The AIDS Clinical Trial Group (ACTG) staging system demonstrated good correlation with survival prior to the ART era [115]. A more recent prognostic scoring system for AIDS-associated KS was subsequently proposed, and this appears to have prognostic and therapeutic relevance [115, 118]. Advanced cutaneous KS may result in considerable morbidity, particularly if accompanied by lymphedema. Visceral involvement, which can occur in the absence of concomitant cutaneous lesions, may be locally invasive and

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Fig. 18.42 AIDS-associated Kaposi sarcoma: early plaque-stage lesion showing dissection of dermal collagen by the lesional cells and the resultant creation of slit-like spaces, some of which contain erythrocytes (×400)

result in catastrophic organ dysfunction, hemorrhage, or even death in clinically advanced cases [111]. KS may be a manifestation of IRIS [4, 5].

Fig. 18.40  AIDS-associated Kaposi sarcoma: numerous purplish plaques and nodules are present on the trunk. (Courtesy of Dr. Federica Dassoni, Department of Dermatology, University of Milan, Milan, Italy)

Fig. 18.41  AIDS-associated Kaposi sarcoma: intraoral lesions, as seen in this child, are not uncommon. (Courtesy of Dr. Federica Dassoni, Department of Dermatology, University of Milan, Milan, Italy)

Histopathology The histopathologic findings correlate with the progression of the clinical lesions. Patch stage lesions show a subtle proliferation of endothelial cells and abnormal vessels. There is associated dissection of dermal collagen dissection and proclivity for the periadnexal dermis (Fig.  18.42). The so-called promontory sign, whereby native dermal vessels and/or skin adnexa demonstrate protrusion into the lumen of a dilated neoplastic vascular structure, serves as a useful diagnostic clue. Plaque stage KS lesions exhibit greater cellularity and a more prominent intradermal spindle cell proliferation, with slitlike spaces containing erythrocytes, background siderophages and plasma cells, and occasional intracellular and extracellular hyaline globules. Extension into the deep dermis and superficial subcutis may occur. The tumoral lesions which typify nodular KS show greater cellularity and are composed of intersecting fascicles of mildly atypical spindled cells. Occasional mitoses are seen. The diagnosis is confirmed by positive IHC staining of the KS nuclei with a monoclonal antibody to HHV-8 latent nuclear antigen 1 (LNA-1) (Fig.  18.43). The lesional cells also exhibit immunoreactivity for CD31

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Fig. 18.43 AIDS-­ associated Kaposi sarcoma: nodular lesion showing a more densely cellular vasoformative spindle cell proliferation, with the diagnosis confirmed by positive nuclear staining with a monoclonal antibody to HHV-8 LNA-1 (inset) (×200; HHV-8, ×400 (inset))

and p­odoplanin (D2-40) [58]. A number of uncommon histopathologic variants have been described, including anaplastic, verrucous, pyogenic granuloma-like, ecchymotic, keloidal, and glomeruloid KS [58, 111]. Although relatively rare, KS lesions in patients with AIDS may potentially harbor a coexistent opportunistic pathogen, such as Cryptococcus neoformans or Mycobacterium tuberculosis, among others [6].

Differential Diagnosis The differential diagnosis varies according to the clinicopathologic subtype. Patch stage KS lesions may be confused with interstitial GA or a mild inflammatory dermatosis. The differential diagnosis of plaque stage KS includes microvenular hemangioma, tufted angioma, targetoid hemosiderotic hemangioma, and acroangiodermatitis (“pseudo-KS”). A wide differential diagnosis exists for nodular KS and includes other vascular tumors composed of spindled cells (e.g., spindle cell hemangioma, Kaposiform hemangioendothelioma (KHE), angiosarcoma), dermatofibroma variants (i.e., cellular, aneurysmal, hemosiderotic, atypical), angiomatoid fibrous histiocytoma, spindle cell sarcomas (e.g., dermatofibrosarcoma protuberans (DFSP), leiomyosarcoma), EBV-­ associated smooth muscle tumor, spindle cell

amelanotic melanoma, dermal fasciitis, bacillary angiomatosis, or even a spindle cell pseudotumor of infective (e.g., mycobacterial) origin [3, 111]. Careful clinicopathologic correlation and the judicious application of appropriate IHC stains to confirm the presence of HHV-8 and exclude the aforementioned entities, however, should facilitate an accurate diagnosis of KS.

Summary Clinical Presentation • Purplish-red patches, plaques, or nodules. • Predilection for the lower limbs, face, and genitalia. • Concomitant oral mucosal involvement is common. Histologic Features • Intradermal vasoproliferative process • Variable cellularity, ranging from subtle in early patch stage lesions to dense and fascicular in advanced nodular KS • Associated hemosiderin deposition, hyaline globule formation, and a plasma

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cell-predominant background inflammatory infiltrate • Positive IHC staining for HHV-8 LNA-1 Differential Diagnosis • Patch stage KS: mild inflammatory dermatosis, interstitial GA • Plaque stage KS: microvenular hemangioma, tufted angioma, targetoid hemosiderotic hemangioma, acroangiodermatitis • Nodular KS: other spindle cell vascular tumors (e.g., spindle cell hemangioma, KHE), dermatofibroma variants (e.g., cellular, aneurysmal), angiomatoid fibrous histiocytoma, spindle cell sarcomas (e.g., DFSP), EBV-associated smooth muscle tumor, amelanotic spindle cell melanoma, dermal fasciitis, bacillary angiomatosis, infective spindle cell pseudotumor

Takeaway Essentials Clinical Relevant Pearls • Mucosal and visceral KS may occur in the absence of associated KS skin lesions. • Cutaneous KS may be a manifestation of IRIS. Pathology Interpretation Pearls • Histologic diagnosis of early patch stage lesions and regressed KS lesions following therapy can be particularly challenging and requires a high index of suspicion. • Some KS lesions harbor very sparse punctate nuclear signals for HHV-8, which are easily overlooked; examination of the sections under oil immersion is useful in such cases. • Always remain on the lookout for a coincidental opportunistic pathogen.

HIV-Related Non-Hodgkin Lymphomas NHL occurs with greater frequency among those living with HIV than in the general population. The vast majority of these lymphomas are of B-cell lineage and are predominantly extranodal. Among these, specific lymphoma types are regarded as AIDS-defining neoplasms. The latter include primary central nervous system lymphoma (PCNSL), primary effusion lymphoma (PEL), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBL), and plasmablastic lymphoma (PL), the latter representing a specific variant of DLBL [107]. DLBL accounts for 70–80% of cases. Cutaneous involvement is observed in only 2% of HIV-infected patients with BL [119]. PL accounts for only 2.7% of all AIDS- related lymphomas [120]. Extracavitary/ solid forms of PEL have been described, and these may rarely present with cutaneous lesions [121]. EBV plays a variable etiologic role in PCNSL, BL, DLBL, and PL, while HHV-8 and EBV are both linked to PEL [107]. Although peripheral T-cell lymphomas (PTCL), including primary cutaneous variants, are relatively uncommon among HIV-infected individuals, their incidence may be as much as 15 times greater than in the general HIV-negative population. Anaplastic large cell lymphoma (ALCL) accounts for 18–28% of HIV-associated PTCL, and although cutaneous involvement is usually secondary in the context of HIV/AIDS, cases of primary cutaneous ALCL have nevertheless been reported [122, 123]. Rare cases of mycosis fungoides (MF) have also been documented in association with underlying HIV infection [124, 125].

Clinical Presentation In general, there is a marked predilection for adult males. Primary skin lesions of AIDS-­associated BL, DLBL, and PL are relatively rare [126]. The occurrence of extensive cutaneous or subcutaneous lesions in a patient with an AIDS-­associated high-grade B-cell NHL, therefore, is more often indicative of disseminated nodal or extranodal/ visceral disease (Fig. 18.44) [127, 128]. Although PL exhibits a strong proclivity for origin in the

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Fig. 18.44  AIDS-associated diffuse large B-cell lymphoma: large, extensively ulcerated abdominal wall recurrence of a tumor which arose primarily in the abdominal cavity. (Courtesy of Dr. Jonéll Meyer, Pretoria East Hospital, Pretoria, South Africa)

Fig. 18.45  AIDS-associated plasmablastic lymphoma: unusual primary penile neoplasm. (Courtesy of the Division of Urology, Charlotte Maxeke Johannesburg Academic Hospital and the University of the Witwatersrand, Johannesburg, South Africa)

oral cavity/jaw and the gastrointestinal tract, primary skin tumors do occasionally occur and may be a presenting feature of HIV infection (Fig.  18.45) [120, 129, 130]. Cutaneous lesions of HIV-associated ALCL, either primary or secondary, usually comprise multiple nodules, which are frequently ulcerated (Fig.  18.46) [122, 123]. Extranodal involvement and an aggressive clinical course are the norm [122]. MF in HIV/AIDS appears to have the same spectrum of lesions as non-HIV-related cases (Fig. 18.47) [124].

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 rognosis or Clinical Course P Most AIDS-defining high-grade B-cell NHLs pursue an aggressive clinical course and tend to present with advanced stage disease. Although the concomitant administration of anticancer chemotherapy and ART may be complicated by increased chemotherapy-associated toxicity, a decrease in treatment efficacy, and a significant decline in the CD4 T-cell count, refinements in treatment regimens have seen an improvement in overall survival in recent years [107]. It has been suggested that a subset of HIV-associated primary cutaneous ALCLs may pursue a more aggressive clinical course [123]. Histopathology DLBL is composed of sheets of large, atypical, usually immunoblastic-type lymphoid cells, which express CD20 (Fig.  18.48). A Brazilian study of AIDS-related DLBLs revealed that a majority of tumors exhibited a germinal center (GC) immunophenotype (CD10+, BCL6+, MUM1–), while 40% revealed a non-GC profile (CD10–, BCL6–, MUM1+). This is in contrast to the findings in the series of non-HIV-related cases of DLBL [131]. The diffuse dermal and/or subcutaneous infiltrate of BL is composed of medium-sized, mitotically active lymphoid cells, which possess a round nucleus with a granular chromatin and multiple basophilic nucleoli. The scant cytoplasm is deeply basophilic and there is an abundance of apoptotic debris. The distinctive “starry-sky” appearance is imparted by an interspersed contingent of tingible body macrophages (TBM). The neoplastic cells exhibit a CD20+/ CD10+/BCL6+/MYC+/BCL2−/TdT– immunophenotype and a Ki-67 proliferation index in the order of 100%. In situ hybridization (ISH) for EBV-encoded small RNA (EBER) is positive in around 48% of cases [119, 127]. AIDS-associated PL is composed of diffuse expanses of large, mitotically active atypical lymphoid cells with abundant amphophilic cytoplasm, vesicular chromatin, prominent central nucleoli, and frequent stigmata of plasma cell differentiation (Fig.  18.49). The latter include more eccentrically placed nuclei, smaller

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Fig. 18.46  AIDS-associated anaplastic large cell lymphoma: multiple ulcerated nodular cutaneous are present with disseminated primary extranodal disease. (Courtesy

Fig. 18.47 Mycosis fungoides in an HIV-positive patient: depigmentation and poikilodermatous changes are present. (Courtesy of the Division of Dermatology, University of the Witwatersand, Johannesburg, South Africa)

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of the Division of Dermatology, University of the Witwatersand, Johannesburg, South Africa)

nucleoli, “clock-face” chromatin condensation, and paranuclear hof formation. Necrosis and apoptotic debris may be encountered, while the presence of TBM in some cases is associated with a “starry-sky” appearance. The cells of PL usually do not express pan-B-cell markers such as CD20 or PAX-5, while staining for CD45 is either weak or absent. CD79a expression, however, is often seen, and the neoplastic cells also stain positively with markers of plasmacytic differentiation such as VS38c, CD138, CD38, and IRF4/MUM1 (Fig.  18.50). EBER positivity is encountered in around 75% of cases (Fig. 18.51) [130]. ALCL is generally composed of large atypical T-cells with relatively abundant cytoplasm, one or more round, oval, or irregular nuclei and promi-

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Fig. 18.48 AIDS-­ associated diffuse large B-cell lymphoma: dense, diffuse dermal infiltrate of poorly preserved neoplastic lymphoid cells in this biopsy from the lesion depicted in Fig. 18.44 (×200), with diffuse CD20 expression (inset) (×200)

Fig. 18.49  AIDS-associated plasmablastic lymphoma: diffuse population of large neoplastic cells with amphophilic cytoplasm, slightly eccentric nuclear placement, relative nucleolar prominence, and a “clock-face” chromatin pattern (×1000)

Fig. 18.50  AIDS-associated plasmablastic lymphoma: diffuse staining of the neoplastic cells with a monoclonal antibody to the plasma cell marker, VS38c (×200)

Fig. 18.51  AIDS-associated plasmablastic lymphoma: positive nuclear expression of EBER (in situ hybridization, ×400)

nent eosinophilic nucleoli. By definition, >75% of the tumor cells express CD30 (Fig. 18.52). A majority of cases are CD4+, and there is variable loss of CD2, CD3, CD5, or CD7. In contrast to primary cutaneous ALCL, ALK immunoreactivity is usually indicative of systemic ALCL with secondary cutaneous involvement, and EMA is usually negative [132]. MF is characterized by an atypical epidermotropic T-cell lymphoid infiltrate with irregular, cerebriform nuclear contours and Pautrier microabscess formation (Fig.  18.53). A majority of cases show a CD2+/CD3+/CD4+/CD5+/CD8–/ TCRβ chain immunophenotype and loss of CD7. A CD4–/CD8+ immunophenotype, however, is encountered occasionally [133].

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Fig. 18.52 AIDS-­ associated anaplastic large cell lymphoma: dense dermal infiltrate of large atypical lymphoid cells, some reminiscent of Reed-­ Sternberg cells (×400). The neoplasm is defined by its diffuse CD30 expression (inset) (×200)

Fig. 18.53 Mycosis fungoides in HIV/AIDS: atypical epidermotropic lymphoid infiltrate with associated Pautrier microabscess formation in this biopsy from the patient with poikilodermatous skin lesions depicted in Fig. 18.47 (×1000). The neoplastic cells have a CD8+ immunophenotype (inset) (×400)

Differential Diagnosis DLBL with immunoblastic morphology may be confused with other NHLs, such as PL or ALCL. PL should not be confused with myeloma, EBV+ DLBL, or ALCL [130]. Occasionally, dense B-cell predominant pseudolymphomatous dermal lymphoid infiltrates may complicate infections such as nodular secondary syphilis or herpes simplex virus

infection. Molluscum contagiosum is sometimes associated with a dense perilesional infiltrate composed of large CD30+ T-cells, resulting in potential confusion with a CD30+ LPD [3]. Rarely, patients with HIV/AIDS may present with a benign, generally polyclonal CD8+ epidermotropic T-cell infiltrate, which possesses the capacity to resemble MF both clinically and pathologically – especially

18  Human Immunodeficiency Virus (HIV)-Associated Dermatoses and Malignancy

CD8+ variants of the latter. This condition has variably been referred to as atypical cutaneous LPD in AIDS, pseudo-Sézary syndrome with a CD8 phenotype in AIDS, and HIV-associated atypical cutaneous LPD [3, 74, 134, 135].

Summary Clinical Presentation • AIDS-defining B-cell NHLs as well as the less frequently encountered PTCL usually present with advanced stage disease and generally pursue an aggressive clinical course. • Multiple cutaneous lesions, which are frequently nodular. • Marked proclivity for adult males. Histologic Features • AIDS-defining B-cell NHLs presenting in the skin generally show morphologic and IHC features in favor of either DLBL, Burkitt lymphoma, or plasmablastic lymphoma. • Strong but variable association with EBV infection, which may be confirmed by ISH. • Although PTCL in HIV-infected subjects are considerably less common, a significant proportion may show features of ALCL. • Although rare, the presence of an atypical epidermotropic T-cell infiltrate heralds MF.

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Differential Diagnosis • DLBL: plasmablastic lymphoma, ALCL, nodular pseudolymphomatous B-cell infiltrates in response to secondary syphilis or HSV • Plasmablastic lymphoma: myeloma, DLBL, ALCL • ALCL: DLBL, plasmablastic lymphoma, Burkitt lymphoma (if “starry-­ sky” pattern present) • MF (CD4–/CD8+ variant in particular): HIV-associated atypical CD8+ cutaneous LPD

Takeaway Essentials Clinical Relevant Pearls • Although NHLs in HIV/AIDS are generally extranodal, skin involvement is usually secondary. • Unlike DLBL, Burkitt lymphoma, and plasmablastic lymphoma, PTCL are not considered AIDS-defining neoplasms. Pathology Interpretation Pearls • Beware of infection-related pseudolymphomatous dermal lymphoid infiltrates, which may simulate a B-cell NHL or even a CD30+ LPD. • Accurate diagnosis hinges on a comprehensive panel of IHC markers, ISH for EBER, and detailed clinicopathologic correlation.

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Case Studies/Vignettes Case 1 Clinical History A 60-year-old woman was admitted to hospital in a moribund state, with confusion, pyrexia, and a 3-month of widespread, progressively enlarging cutaneous ulcers. The ulcers were most pronounced on the lower limbs (Fig. 18.54). She was found to be HIV-positive, with a CD4 count of 45 cells/μL. A punch biopsy was obtained for histopathology, and swabs were referred for fungal culture and mycobacterial culture. The chest radiograph showed no pulmonary infiltrate. Her condition continued to deteriorate, and she died on the second day of hospitalization. Consent for a postmortem examination could not be obtained from her next of kin. Microscopic Findings The skin biopsy revealed florid pan-dermal acute vasculitic changes, accompanied by extensive deep dermal and superficial subcutaneous necrosis (Fig. 18.55). Intranuclear CMV inclusions were observed in the vascular endothelial cells of many of the vessels (Fig.  18.56). Present within numerous other involved blood vessel walls and amid the necrotic and inflammatory debris, however, were conspicuous numbers of large round cells that were initially presumed to represent macrophages. On further consultation and review of the sections, however, it was apparent that the latter were in fact free-living amebae, each showing a distinctive targetoid nucleus. A presumptive diagnosis of acanthamebiasis was thus made, with subsequent immunohistochemical confirmation that organisms were indeed Acanthamoeba sp. (Fig. 18.57). The PAS-stained sections also revealed rare encysted forms (Fig. 18.58).

Fig. 18.54  Multiple deep ulcers are present on the leg of this emaciated patient with advanced AIDS. (Courtesy of Dr. Nooren-Nisa Moti-Joosub, Division of Dermatology, University of the Witwatersand, Johannesburg, South Africa)

(continued)

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Fig. 18.55 Low-power photomicrograph of biopsy obtained from the skin near the edge of an ulcer. Note the extensive vasculitic changes and the presence of necrosis in the deep dermis (×40)

Fig. 18.56  Vasculitis in the presence of cytomegalovirus (CMV) inclusions within vascular endothelial nuclei (×1000). The presence of CMV was confirmed on immunohistochemical staining (inset) (×400)

(continued)

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Fig. 18.57  Necrotizing vasculitis due to vascular invasion by free-living amebae (×1000), confirmed to be Acanthamoeba species on immunohistochemistry (inset) (×200)

Fig. 18.58 Encysted Acanthamoeba organisms are present amid the necrotic cellular debris (PAS, ×1000)

(continued)

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Diagnosis Cutaneous ulceration and necrotizing vasculitis in the presence of combined Acanthamoeba infection and CMV infection Discussion CMV is the most frequently encountered co-­pathogen in histological specimens from HIV-­infected individuals. It is frequently observed in biopsies of HSV-related genital or perineal ulcers, where concomitant vasculitis is invariable. It has also been documented in association with KS, BA, mycobacterial infection, and even mucormycosis. Although the clinical significance of coincidental CMV infection is sometimes uncertain, its presence in skin biopsies should not be overlooked as it may alert the clinician to the possibility of undetected retinitis or pneumonitis [6]. It is also a potential manifestation of IRIS [5]. Acanthamoeba infection in patients with AIDS may present as ulcerated, chronic non-­ healing lesions confined to the skin. Cutaneous involvement may, however, be a presenting feature of disseminated infection from a primary source of infection elsewhere, such as the lungs. Spread to the central nervous system can ensue, resulting in potentially fatal granulomatous amebic encephalitis [136–138]. This case illustrates the importance of careful examination of biopsy material from patients with HIV/AIDS for more than one infective pathogen or pathological process.

Case 2 Clinical History The patient was a 33-year-old woman who presented with a 6-month history of a chronic 7 × 7 cm ulcer on the left posterior scalp (Fig. 18.59). There was no palpable regional lymphadenopathy. Seropositivity for HIV was detected, with a CD4 T-cell count of 88 cells/μL. A punch biopsy was obtained from indurated skin in the immediate vicinity of the ulcer edge. ART was initiated, and when seen at a scheduled 2-month follow-up visit, the ulcer was noted to have healed spontaneously (Fig. 18.60). She defaulted on her ART and was lost to clinical follow-up after relocating to another city. It was later established that she had been admitted to hospital with signs of meningitis some 5 months after the initial diagnosis. C. neoformans was detected in the cerebrospinal fluid, and she succumbed to her illness. There were no signs of recrudescence of the scalp ulcer at the time of her death. Microscopic Findings The punch biopsy revealed a pan-dermal and superficial subcutaneous cellular infiltrate comprising lymphocytes and histiocytes (Fig. 18.61). Interspersed among these were numerous large atypical lymphoid cells whose morphology closely resembled the Reed-Sternberg (RS) cells of classic Hodgkin lymphoma (Fig. 18.62). IHC studies revealed that these large atypical cells co-­expressed CD30 (Fig. 18.63) and CD15 (Fig. 18.64), but were largely CD20–. The intervening population of mature T-cells, B-lymphocytes, and histiocytes are stained with CD3, CD20, and CD68, respectively. Importantly, large atypical cells were also positive for EBV LMP1 (Fig.  18.65). PCR for an IgH gene rearrangement yielded no reaction product, while T-cell receptor gene rearrangement studies declared an oligoclonal T-cell population. Unfortunately, insufficient tissue remained for EBER ISH and DNA re-extraction for repeat IgH PCR. (continued)

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Fig. 18.59  Large ulcerated lesion on the posterior scalp of this HIV+ patient. (Courtesy of Dr. Pholile Mpofu, Johannesburg, South Africa)

Fig. 18.60  Spontaneous healing of the ulcerated lesion following initiation of HAART. (Courtesy of Dr. Pholile Mpofu, Johannesburg, South Africa)

Fig. 18.61  Low-power photomicrograph of biopsy obtained from the edge of the ulcerated scalp lesion, showing a pandermal cellular infiltrate of variable density (×25). (Case by courtesy of Dr. Charles Thatcher, Gritzman & Thatcher Inc. Anatomical Pathologists, Randburg, South Africa)

(continued)

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Fig. 18.62 Reed-Sternberg-like cell present amid a background population of lymphocytes and histiocytes (×1000). (Case by courtesy of Dr. Charles Thatcher, Gritzman & Thatcher Inc. Anatomical Pathologists, Randburg, South Africa)

Fig. 18.63  CD30 expression in the large atypical lymphoid cells (×1000). (Case by courtesy of Dr. Charles Thatcher, Gritzman & Thatcher Inc. Anatomical Pathologists, Randburg, South Africa)

(continued)

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Fig. 18.64  CD15 expression in one of the large atypical lymphoid cells (×1000). (Case by courtesy of Dr. Charles Thatcher, Gritzman & Thatcher Inc. Anatomical Pathologists, Randburg, South Africa)

Fig. 18.65   EBV LMP1 expression in one of the large atypical lymphoid cells (×1000). (Case by courtesy of Dr. Charles Thatcher, Gritzman & Thatcher Inc. Anatomical Pathologists, Randburg, South Africa)

(continued)

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Diagnosis EBV-positive mucocutaneous ulcer Discussion EBV-positive mucocutaneous ulcer is an uncommon and recently recognized entity. It has a strong association with age-related and iatrogenic immunosuppression and is typified by RS-like cells EBV+ B-cells in a mixed inflammatory background. Although the condition tends to occur in the eighth decade of life or beyond, iatrogenically immunosuppressed individuals and those with HIV infection are usually younger. Sites of involvement include the oropharyngeal region, skin, and gastrointestinal tract [139]. Only rare cases have been documented in the setting of HIV infection [140]. The transformed atypical B-cells show variable CD20 expression and have a non-GC phenotype (MUM1+, CD10–, BCL6–) and are CD30+. CD15 co-expression is observed in only half of all cases. The RS-like cells are typically LMP1+ and express EBER. There is an admixture of CD4+ and CD8+ reactive background T-cells, which are usually oligoclonal. Clonal immunoglobulin gene rearrangements are detected in