Dermatopathology, 2nd Edition

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Werner Kempf • Markus Hantschke •
Heinz Kutzner

Dermatopathology
Second Edition

123
Werner Kempf Markus Hantschke
Kempf und Pfaltz Histologische Diagnostik MVZ Dermatopathologie Friedrichshafen
Zürich, Switzerland Friedrichshafen, Baden-Württemberg, Germany
Department of Dermatology
University of Zürich
Zürich, Switzerland

Heinz Kutzner
Dermatopathologie Friedrichshafen
Friedrichshafen, Baden-Württemberg, Germany

ISBN 978-3-030-82819-6 ISBN 978-3-030-82820-2 (eBook)

https://doi.org/10.1007/978-3-030-82820-2

1st edition: © Steinkopff Verlag 2008

2nd edition: © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2022
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reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval,
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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
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This Springer imprint is published by the registered company Springer Nature Switzerland AG
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We dedicate this book to our families
Preface

The aim of this book is to provide a structured and easy approach to dermatopathology. To
ensure the clarity of the book for beginners, we have limited ourselves to the histology of the
most common and important skin diseases. Each entity is described in a structured form with
clinical description, histological features, additional examinations (special stains, immuno-
histochemistry, molecular biologic studies) and the differential diagnoses are listed with the
distinguishing features. For each disease or pattern, two representative histologic photographs
show the most important diagnostic key features highlighted with pointers. Clinicopathologic
correlation plays a central role in the diagnosis of inflammatory skin diseases in particular.
This is pointed out in the comments on the corresponding diseases.
The second edition continues the structure and organization of the book. New inflammatory
and infectious dermatoses as well as new diagnostic methods have been included. As in the
first book, we have deliberately omitted references in view of the large number of scientific
papers and widespread access to Internet-based sources of information. Our book cannot and
is not intended to replace the detailed works on dermatopathology. We dedicate the book to
our families and to our friend and co-editor Walter Burgdorf who passed away.
We hope that this book can pass on the authors’s fascination with dermatopathology to the
future generation of dermatologists and dermatopathologists.

Zürich, Switzerland Werner Kempf

Friedrichshafen, Germany Markus Hantschke
Friedrichshafen, Germany Heinz Kutzner
Summer 2021

vii
Contents

Part I Basic Principles

1 Principles of Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2 Skin Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1 Biopsy Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.2 Fixation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.3 Embedding and Sectioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3 Histopathological Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.1 Staining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.2 Immunohistochemical Stains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.3 Immunofluorescence Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.3.1 Direct Immunofluorescence . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.3.2 Indirect Immunofluorescence . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.3.3 Salt-Split Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.4 Molecular Biological Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.4.1 In Situ Hybridization (ISH) . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.4.2 Fluorescence in Situ Hybridization (FISH) . . . . . . . . . . . . . . . . 10
3.4.3 Polymerase Chain Reaction (PCR) . . . . . . . . . . . . . . . . . . . . . 10
4 Dermatopathologic Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Part II Inflammatory and Infectious Dermatoses

5 Epidermis: Spongiosis, Acanthosis and Hyperparakeratosis . . . . . . . . . . . . . . 15
5.1 Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
5.2 Prurigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
5.3 Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.4 Pustular Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.5 Pityriasis Rosea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5.6 Cutaneous Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.7 Human Papilloma Virus-Associated Acanthopapillomas: Verruca
Vulgaris and Condyloma Acuminatum . . . . . . . . . . . . . . . . . . . . ...... 28
5.8 Molluscum Contagiosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...... 30
5.9 Parapoxvirus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...... 32
6 Epidermis Acantholysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
6.1 Darier Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
6.2 Hailey-Hailey Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
6.3 Herpes Virus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
7 Bullous Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
7.1 Pemphigus Foliaceus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
7.2 Pemphigus Vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

ix
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7.3 Bullous Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

7.4 Dermatitis Herpetiformis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
7.5 Porphyria Cutanea Tarda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
8 Interface Dermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
8.1 Erythema Multiforme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
8.2 Pityriasis Lichenoides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
8.3 Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
8.4 Lichen Sclerosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
8.5 Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
8.6 Pigmented Purpuric Dermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
8.7 Incontinentia Pigmenti . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
9 Dermis Vascular Disorders . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . 65
9.1 Leukocytoclastic Vasculitis . . . . . . . . . . . . ........... . . . . . . . . . . . 65
9.2 Granuloma Faciale and Erythema Elevatum et Diutinum . . . . . . . . . . . . . 67
9.3 Polyarteritis Nodosa . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . 69
9.4 Cryoglobulinemia . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . 71
10 Dermis Granulomatous Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
10.1 Granuloma Annulare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
10.2 Necrobiosis Lipoidica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
10.3 Interstitial Granulomatous Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
10.4 Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
10.5 Foreign Body Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
10.6 Mycobacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
10.7 Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
10.8 Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
11 Dermis Interstitial Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
11.1 Borreliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
11.2 Morphea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
12 Dermis Diffuse Mixed Inflammatory Infiltrates . . . . . . . . . . . . . . . . . . . . . . . 97
12.1 Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
12.2 Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome) . . . . . . . . . . . 99
12.3 Eosinophilic Cellulitis (Wells Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . 101
12.4 Arthropod Assault Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

13 Dermis - Degenerative and Metabolic Disorders . . . . . . . . . . . . . . . . . . . . . . . 105

13.1 Chondrodermatitis Helicis Nodularis Chronica . . . . . . . . . . . . . . . . . . . . 105
13.2 Pseudoxanthoma Elasticum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
13.3 Xanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
14 Dermis Inflammation of Adnexal Structures . . . . . . . . . . . . . . . . . . . . . . . . . 111
14.1 Folliculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
14.2 Alopecia Areata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
14.3 Lupus Erythematosus of the Scalp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
14.4 Folliculitis Decalvans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
14.5 Lichen Ruber Planopilaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
15 Subcutaneous Fat - Panniculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
15.1 Erythema Nodosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
15.2 Erythema Induratum and Nodular Vasculitis . . . . . . . . . . . . . . . . . . . . . 123
15.3 Lupus Panniculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Contents xi

16 Drug Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

16.1 Specific Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
16.2 Unspecific Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
17 Artifactual Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Part III Cysts

18 Epithelial Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
18.1 Epidermoid Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
18.2 Trichilemmal Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
18.3 Steatocystoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
18.4 Apocrine Hidrocystoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
19 Pseudocysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
19.1 Digital Mucous Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

Part IV Hamartomas and Neoplasms

20 Epidermal Hamartomas and Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
20.1 Epidermal Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
20.2 Nevus Sebaceus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
20.3 Seborrheic Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
20.4 Clear Cell Acanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
20.5 Porokeratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
20.6 Actinic Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
20.7 Bowen Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
20.8 Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
20.9 Keratoacanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
21 Melanocytic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
21.1 Mucosal Melanotic Macule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
21.2 Lentigo Simplex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
21.3 Melanocytic Nevi–Junctional and Compound Types . . . . . . . . . . . . . . . . 169
21.4 Melanocytic Nevi–Dermal and Congenital Types . . . . . . . . . . . . . . . . . . 171
21.5 Halo Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
21.6 Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
21.7 Dysplastic Melanocytic Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
21.8 Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
21.9 Desmoplastic Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
21.10 Pigmented Spindle Cell Nevus (Reed) . . . . . . . . . . . . . . . . . . . . . . . . . . 183
21.11 Clonal Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
21.12 Lentigo Maligna and Lentigo Maligna Melanoma . . . . . . . . . . . . . . . . . . 186
21.13 Superficial Spreading Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
21.14 Nodular Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
21.15 Acrolentiginous Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
21.16 Desmoplastic Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
21.17 Cutaneous Clear Cell Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
22 Adnexal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
22.1 Sebaceous Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
22.2 Sebaceous Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
22.3 Pilomatricoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
22.4 Syringoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
22.5 Syringocystadenoma Papilliferum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
xii Contents

22.6 Poroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

22.7 Hidradenoma Synonyms: Nodular Hidradenoma, Clear Cell
Hidradenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
22.8 Spiradenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
22.9 Cylindroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
22.10 Paget Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
22.11 Digital Papillary Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
22.12 Trichoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
22.13 Desmoplastic Trichoepithelioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
22.14 Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
22.15 Fibroepithelioma of Pinkus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
22.16 Mixed Tumor of the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
23 Soft Tissue Proliferations and Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
23.1 Scar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
23.2 Hypertrophic Scar and Keloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
23.3 Skin Tag Synonym: Fibroma Molle . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
23.4 Dermatofibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
23.5 Dermatofibrosarcoma Protuberans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
23.6 Atypical Fibroxanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
23.7 Leiomyoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
23.8 Nevus Lipomatosus Superficialis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
23.9 Lipoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
23.10 Neurofibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
23.11 Schwannoma Synonym: Neurilemmoma . . . . . . . . . . . . . . . . . . . . . . . . 251
23.12 Merkel Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
24 Vascular Tumors . . . . . . . . . . . . . . . . . . . . . . . ................... . . . . 255
24.1 Hemangioma . . . . . . . . . . . . . . . . . . . . . ................... . . . . 255
24.2 Pyogenic Granuloma (Synonyme: Lobular Capillary Hemangioma) . . . . . 257
24.3 Angiokeratoma . . . . . . . . . . . . . . . . . . . . ................... . . . . 259
24.4 Kaposi Sarcoma . . . . . . . . . . . . . . . . . . . ................... . . . . 261
24.5 Angiosarcoma . . . . . . . . . . . . . . . . . . . . ................... . . . . 263
25 Lymphomas and Pseudolymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
25.1 Mycosis Fungoides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
25.2 Primary Cutaneous CD30-positive Lymphoproliferative Disorders . . . . . . 268
25.3 Primary Cutaneous Marginal Zone Lymphoma . . . . . . . . . . . . . . . . . . . . 270
25.4 Primary Cutaneous Follicle Center Lymphoma . . . . . . . . . . . . . . . . . . . . 272
25.5 Cutaneous Diffuse Large B-cell Lymphoma, Leg Type . . . . . . . . . . . . . . 274
25.6 Cutaneous B-cell Pseudolymphoma Syn.: Lymphocytoma Cutis,
Lymphadenosis Cutis Benigna When Caused by Borrelial Infections . . . . 276

26 Histiocytoses and Mastocytoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

26.1 Langerhans Cell Histiocytoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
26.2 Juvenile Xanthogranuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
26.3 Cutaneous Mastocytoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
27 Cutaneous Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

Direct Immunofluorescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
 Part I
Basic Principles
 Principles of Diagnosis
1

When starting, the simplest approach is to examine the final answer is based on the expression of a pattern of
epidermis, then the dermis and finally the subcutaneous fat. specific tumor antigens (immunohistochemical profile).
This approach reduces the likelihood of overlooking some- Clinicopathologic correlation: This is the crux and beauty
thing. For this reason, we have arranged this book, starting of dermatopathology; no other branch of medicine has so many
with epidermal changes and moving down through dermal different names for the appearance of an organ and in many
and subcutaneous lesions. cases, each of the peculiar names has a histological correlate.
Inflammatory dermatoses are best approached by identi- On the other hand, the skin can only react in so many ways, so
fying first the pattern of inflammation (superficial vs. that some patterns such as “superficial lymphocytic perivas-
superficial and deep vs. subcutaneous; with and without cular infiltrate with sparse admixture of eosinophils” can be
epidermal involvement) and studying the cellular composi- associated with many different diagnoses ranging from viral
tion (lymphocytes, macrophages, neutrophils, eosinophils, exanthem to drug reaction or bullous pemphigoid. The digital
and mast cells). Cutaneous tumors are approached just like age has made it convenient to provide the dermatopathologist
all other tumors considering the pattern (symmetry, cir- not only with a detailed clinical history but also with clinical
cumscription, level of invasion) and cytomorphology (nu- pictures (e.g., digital images), both of which increase the
clear pleomorphism and mitotic activity). Increasingly the chances of the clinician receiving a helpful diagnosis.

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W. Kempf et al., Dermatopathology,
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 Skin Biopsy
2

2.1 Biopsy Techniques 2.2 Fixation

There are several ways of obtaining a skin biopsy; each has Skin biopsies are routinely fixed in a buffered 10% formalin
advantages and disadvantages. solution (about 4% formaldehyde in water) for at least
Excision. An excision is preferred when removing skin 6–12 h, being sure that the ratio of fixative to biopsy volume
tumors as it allows an adequate evaluation of the margins to exceeds 20:1. Specimens for immunofluorescent examina-
determine completeness of excision. An excisional biopsy is tion should be flash-frozen or transported in Michel solution.
required for deep inflammatory processes, especially pan- Specimens for electron microscopic examination require
niculitis, and is ideal for studying a disease process at all fixation in paraformaldehyde and glutaraldehyde in a
levels of the skin. cacodylate buffer.
Punch biopsy. Punch biopsies usually 3–4 mm in diam-
eter produce a cylindrical plug. They can be done rapidly,
heal satisfactory without suturing and are thus efficient; their 2.3 Embedding and Sectioning
downside is the risk of sampling error, especially for larger
lesions. Excision specimens usually require special handling. The
Shave biopsy. The shave biopsy is the quickest way to traditional method of bread-loafing the specimen―that is,
sample or remove a lesion but never allows adequate study multiple slices perpendicular to the long axis of an ellipse – is
of the depths of the lesion and often results in an incomplete the most widely accepted method for determining the ade-
lateral excision as well. The shave biopsy is perfect for small quacy of the excision and in our opinion the best approach
protuberant or papillomatous lesions but otherwise causes for smaller tumors. A variety of other methods are available
more trouble than the time savings it provides. for micrographic control of the tumor margins. These tech-
Curettage biopsy. Superficial lesions like actinic ker- niques, whether it is the Mohs method or the Tübinger Torte
atoses and seborrheic keratoses are often curetted. The in Europe, result in an almost complete three-dimensional
resulting fragments can be diagnosed, but in the event the control of the excision margins, allowing possible maximum
actinic keratosis is a squamous cell carcinoma, it is impos- preservation of tissue while best insuring complete excision.
sible to comment on the extension of the tumor to the depth The operating physician generally decides if micro-
and the adequacy of excision. graphic control is necessary or not. Ideally consultation with
Special sites. Biopsies on the scalp should be done par- the dermatopathologist should occur prior to the specimen
allel to the direction of the hair follicles and deep enough to appearing in the laboratory if there are special issues. Some
sample the hairs in the subcutaneous fat. Many prefer to indications for this more time-consuming process include:
obtain two deep punch biopsies for alopecia; one is pro-
cessed transversely (horizontal sections) and the other in the • Tumors with unclear clinical borders, locally-destructive
traditional fashion (vertical sections). Biopsies from the behavior or potential to metastasize (sclerotic basal cell
lower aspects of the legs always feature thickened vessels carcinoma, Merkel cell carcinoma)
and stasis changes in adults, while those from the elbow • Recurrent tumors, especially in the head and neck region
have pressure and rubbing changes. • Tumors with perineural growth patterns.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 5

W. Kempf et al., Dermatopathology,
https://doi.org/10.1007/978-3-030-82820-2_2
 Histopathological Techniques
3

stains. Thus these two comment pigments which both appear

3.1 Staining
yellow–brown on H&E stain can be accurately separated
with special stains. Exogenous dyes such as tattoos often
The tissues are embedded in paraffin, cut into 3–6 micron sec-
retain their intrinsic color in histological sections.
tions, placed on glass microscopic slides and stained. The
Gram stain is the usual method for identifying bacteria,
standard stain in dermatopathology is hematoxylin and eosin (H
while mycobacteria are best seen with the Ziehl–Neelsen
& E stain) which stains the nuclei blue and the cytoplasm pink.
stain and Mycobacterium leprae with the Fite-Faraco stain.
A variety of special stains serve to better visualize a wide
A more sensitive alternative approach is to use the anti-M.
variety of cellular and extracellular structures. The most
bovis BCG antibody which stains a wide range of microbes
common additional stain is the periodic acid-Schiff (PAS
(fungi, bacteria). The Giemsa stain is preferred for leish-
stain) which colors sugars and polysaccharides violet. It is
mania. Fungi can also be better visualized with silver stains
used to identify fungal elements, better visualize the base-
such as the Grocott stain.
ment membrane, and identify deposits of glycogen as in
Some prefer the Giemsa stain for studying nuclear detail,
some sweat gland or epithelial proliferations.
especially in the diagnosis of lymphomas. Mast cells are
Acid glycosamines in mucin are best seen with the alcian
usually identified with toluidine blue or Giemsa stains, while
blue stain. Congo red is used to identify amyloid, which also
the chloroacetate esterase (Leder) stain marks both neu-
has a green color when the specimen is polarized; in addi-
trophils and mast cells. Early myeloid cells are best seen
tion, the Pagoda stain imparts an orange color. Elastic fibers
with the myeloperoxidase stain. Extravasates of erythrocytes
are stained black with a variety of stains, usually acid orcein
stain brilliant orange with the Goldner stain, while the col-
or van Gieson; the latter also stains collagen pink and
lagen fibers are marked green.
muscles yellow. Areas of calcification are stained by the von
Lipids can be stained in frozen sections with Sudan
Kossa stain which colors calcium salts black.
orange. Routine processing removes the lipids but may
Melanin appears black in the Masson-Fontana stain.
leave behind distinctive empty spaces.
Hemosiderin colors blue with the iron (or Prussian blue)

Stain Structures identified Color

Acid orcein Elastic fibers Black

Alcian blue Acid glycosaminoglycans Blue
Chloroacetate esterase (Leder) Neutrophils, mast cells (myeloid cells) Red
Congo red Amyloid Red; green in polarized light
Fite-Faraco Mycobacterium leprae Red
Giemsa Nuclei Blue
Eosinophil granules Red
Mast cell granules Purple
Leishmania Blue
(continued)

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W. Kempf et al., Dermatopathology,
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8 3 Histopathological Techniques

Stain Structures identified Color

Gram Gram-positive bacteria Blue

Gram-negative bacteria Red
Goldner trichrome Erythrocytes Orange
Collagen, mucus Green
Grocott silver Fungi Black
Iron (Prussian blue) Hemosiderin Blue
Masson-Fontana Melanin Black
Myeloperoxidase Immature myeloid cells Orange
Pagoda Amyloid Orange
Periodic acid-Schiff (PAS) Glycogen Red
Fungi Red
Fibrin Red
Sudan Lipids (on frozen section) Orange
Toluidine blue Mast cell granules Blue
Van Gieson Collagen Red
Elastic fibers Black
Muscle fibers Yellow
Von Kossa Calcium salts Black
Warthin-Starry Spirochetes Black
Fungi Black
Ziehl–Neelsen Acid-fast bacteria Red

3.2 Immunohistochemical Stains 3.3 Immunofluorescence Studies

Immunohistochemical stains are essential for modern and 3.3.1 Direct Immunofluorescence
accurate dermatopathologic diagnosis. They are most
important in diagnosing tumors and identifying specific Direct immunofluorescence examination (DIF) serves to
organisms. Most of the relevant antibodies today can be identify immunoglobulins, complement factors or fibrinogen
employed on formalin-fixed, paraffin-embedded tissue. in the patient’s tissues. A biopsy is taken, then either
Almost all antibodies stain more than a single cell type. Thus flash-frozen or transported in Michel medium, and then
a panel of antibodies should always be employed, also to analyzed.
provide some internal control, and the final diagnosis should Fluorescence-labeled antibodies are applied to sections
balance the clinical history, histological diagnosis and and allowed to incubate. Then using a special microscope,
immunohistochemical panel. the sites of attachment of the labeled antibodies in the skin
Immunohistochemical stains incorporate either mono- can be identified. Typically, antibodies against IgG, IgM,
clonal or polyclonal antibodies. Some antigens are relatively IgA, C3 and fibrin are used. The most important indications
inaccessible after routine processing, so that antigen retrieval are the autoimmune bullous dermatoses, which were first
with enzymatic digestion or heating may be required prior to classified in a reproducible manner after the introduction of
applying the antibodies to the tissue. The antigen–antibody DIF. In addition, collagen-vascular disorders (lupus erythe-
complex can then be identified with different detection matosus and dermatomyositis) and immune complex vas-
systems producing various colors. culitides also have characteristic findings.
A sampling of the important antibodies and their antigens The site of the biopsy is important; generally, perilesional
as used in most dermatopathology practices is given below. skin adjacent to a fresh blister is preferred for bullous dis-
The information is incomplete but many other paper and eases. Biopsies from a blister may have non-specific deposits
electronic references are available. or because of degradation of immunoglobulins can be
3.3 Immunofluorescence Studies 9

false-negative. In analyzing patients with lupus erythe- The response can be titrated and for several disorders the
matosus, biopsies can be taken from lesional skin as well as titers correlate with the clinical course and can sometimes
non-sun-exposed skin (usually buttocks); the lupus band test predict flares. Anti-nuclear antibodies (ANA) are detected in
is no longer widely used because of increased sensitivity and the same way using substrate such as HEp-2 cells. Circu-
specificity of serologic tests for diagnosing the disorder. For lating antibodies can also be identified by ELISA and
vasculitides, DIF may be essential to differentiate immune immunoblot techniques.
complex vasculitides (especially Henoch-Schönlein purpura
with IgA deposits) from pauci-immune (usually
ANCA-positive) disorders; the latter have a much more 3.3.3 Salt-Split Skin
severe course.
When skin is incubated in 1 M NaCl solution, separation
occurs in the lamina lucida. When indirect immunofluores-
3.3.2 Indirect Immunofluorescence cence is then performed using the patient’s serum, sera from
bullous pemphigoid patients preferentially stain the roof of
Indirect immunofluorescence (IIF) uses the patient’s serum blister while those from epidermolysis bullosa acquisita
which is applied to a substrate such as monkey esophagus, patients label the floor of the blister. Often the two diseases
rat bladder, human skin or HEp-2 cells. Antibodies in the are identical clinically, histologically and on routine
serum attach to tissue antigens. After rinsing, a second immunofluorescence studies. Sera from patients with
labeling anti-immunoglobulin antibody is applied, identify- mucous membrane pemphigoid sometimes show reactivity
ing the sites of attachment of antibodies from the patient. with the roof and floor (laminin332-positive pemphigoid).

Disease Pattern Antigens

Autoimmune bullous diseases

• Pemphigus foliaceus IgG, C3—intercellular deposits in epidermis Desmoglein 1
• Pemphigus vulgaris IgG, C3—intercellular deposits in epidermis, mucosa Desmogleins 3 and 1, less often desmoglein 4 or
non-desmosomal antigens
• Bullous pemphigoid C3, IgG—linear deposits at DEJ; in early stages, IgM BP 180, BP 230
• Mucous membrane IgG, C3—linear deposits at DEJ; occasionally IgA BP 180, laminin 332 (formerly laminin 5 or epiligrin),
pemphigoic a6ß4 integrin
• Pemphigoid C3, IgG—linear deposits at DEJ BP 180 (BP 230)
gestationis
• Epidermolysis bullosa IgG, C3—linear deposits at DEJ, occasionally IgA Collagen type VII
acquisita
• Dermatitis IgA—granular deposits in papillary tips; rarely C3 Epidermal transglutaminase
herpetiformis
• Linear IgA disease IgA and C3—linear at DEJ BP 180 (BP 230)
Vasculitis
• Leukocytoclastic IgM, IgG, C3, fibrinogen around venules primarily in Unclear
vasculitis superficial dermis
• Henoch-Schönlein IgA in same pattern Unclear
purpura
Lupus erythematosus
• Chronic discoid LE IgG, IgM, IgA, C3—linear or granular deposits at DEJ in lesional skin; no deposits in unaffected, non-sun-exposed
skin
• Subacute cutaneous IgG, IgM, IgA, C3—linear or granular deposits at DEJ in lesional skin; no deposits in unaffected, non-sun-exposed
LE skin
• Systemic LE IgG, IgM, IgA, C3—linear or granular deposits at DEJ in lesional skin and unaffected, non-sun-exposed skin (lupus
band test)
Keratinocyte nuclei fluoresce in normal, non-sun-exposed skin (in vivo ANA)
DEJ = dermal–epidermal junction.
10 3 Histopathological Techniques

3.4 Molecular Biological Procedures • Advantages: Labeling of target sequence in tissue,

allowing one to identify which cells are involved.
Molecular biological methods are used in dermatopathology • Disadvantages: Harder to interpret than ISH because
primarily in tumor diagnosis and for identifying microbes. fluorescent signals may not be visualized in all planes of
The most common investigations include in situ hybridiza- sectioning.
tion, fluorescence in situ hybridization and polymerase chain • Indications :
reaction. Most studies can be performed on formalin-fixed, – Identification of chromosomal aberrations in soft tis-
paraffin-embedded tissue. All three techniques depend on the sue tumors (for example, dermatofibrosarcoma
binding of specific oligonucleotides (probes) to comple- protuberans)
mentary DNA or RNA target sequences.

3.4.1 In Situ Hybridization (ISH) 3.4.3 Polymerase Chain Reaction (PCR)

• Principle: Specific oligonucleotide probes bind to com- • Principle: After extraction of DNA from the tissue,
plementary RNA or DNA sequences in tissue (hy- specific oligonucleotide primers are added and attached to
bridization). Then they are visualized using enzymatic target sequences. The hybrid product is sequentially
color reactions. multiplied using cyclic temperature-dependent enzymatic
• Advantages: Labeling of target sequence in tissue, amplification over a period of hours. The amplification
allowing one to identify which cells are involved. product is identified using gel electrophoresis.
• Disadvantages: Less sensitive than PCR because there is • Advantages: Very sensitive because target sequences are
no amplification of target sequences. amplified, so that trace amounts of DNA or RNA can be
• Indications: identified.
– Identification of microorganisms, especially viruses • Disadvantages: The DNA or RNA sequences cannot be
(for example, HPV using type-specific or common localized in tissue. Because of the extreme sensitivity,
sequences). false-positive results are a major concern.
– Demonstration of clonality in B-cell lymphomas by • Indications:
determining mRNA expression of immunoglobulin – Identification of microorganisms: Viruses (human
kappa and lambda light chains. papilloma virus, herpes viruses), bacteria (Borrelia
burgdorferi, atypical mycobacteria) and parasites
(leishmania).
– Identification of monoclonality of T-cell receptor gamma
3.4.2 Fluorescence in Situ Hybridization (FISH) genes in T-cell lymphomas and of immunoglobulin
heavy chain genes in B-cell lymphomas.
• Principle: Same as ISH, but the probes are – Identification of mutations in oncogenes or tumor
fluorescence-labeled allowing the hybrid sequences to be suppressor genes in tumors and in structural proteins
visualized with fluorescence microscopy. in ichthyoses.