Clinical Manual of Dermatology [1st Edition] 9783030239398

Table of contents :
Contents......Page 5
Acknowledgments......Page 7
1.1 Embryology......Page 8
1.2 Biology of Keratinocytes and Cells of the Epidermis......Page 10
1.3 Biology of the Basement Membrane......Page 14
1.4 Extracellular Matrix......Page 16
1.5 Biology of Adnexal Glands......Page 18
1.6 Biology of Hair and Nails......Page 20
1.7 Vascular Biology......Page 23
1.8 Tumor Biology and Major Pathways......Page 24
1.9 Wound Healing......Page 26
1.10 Photobiology......Page 27
2.1 Innate Immunology......Page 29
2.2 Adaptive Immunology......Page 33
3.1 Eczematous Dermatoses......Page 37
3.2 Papulosquamous Dermatoses......Page 48
3.3 Lichenoid Dermatoses......Page 56
3.4 Follicular and Apocrine Diseases......Page 60
3.5 Connective Tissue Disorders......Page 67
3.6 Blistering Disorders......Page 84
3.7 Diseases of Hair and Nails......Page 95
3.8 Disorders of Pigmentation......Page 101
3.9 Vascular Diseases......Page 103
3.10 Neutrophilic Dermatoses......Page 109
3.11 Eosinophilic Dermatoses......Page 111
3.12 Granulomatous and Histiocytic Disorders......Page 113
3.13 Oral and Anogenital (Non-venereal) Disease......Page 121
3.14 Disorders of Lipid......Page 125
3.15 Depositional and Metabolic Disorders......Page 134
3.16 Pruritus and Psychocutaneous Disorders......Page 151
3.17 Photodermatoses......Page 152
3.18 Drug Reactions......Page 156
4.1 Benign and Malignant Tumors of the Epidermis......Page 159
4.2 Melanocytic Neoplasms......Page 164
4.3 Adnexal Neoplasms......Page 169
4.4 Soft Tissue Tumors......Page 176
4.5 Vascular Neoplasms......Page 180
4.6 Cutaneous Hematolymphoid Neoplasms......Page 183
5.1 Bacterial Infections......Page 188
5.2 Fungal Infections......Page 204
5.3 Viral Infections......Page 208
5.4 Protozoan Infections, Infestations, and Others......Page 215
6.1 Conditions of Newborns......Page 218
6.2 Congenital Infections......Page 219
6.3 Inherited Disorders of Cornification......Page 223
6.4 Inherited Disorders of Pigmentation......Page 231
6.5 Inherited Disorders of Hair and Nails......Page 234
6.6 Vascular Disorders......Page 236
6.7 Neurocutaneous Syndromes......Page 240
6.8 Inherited Tumor Syndromes......Page 243
6.9 Disorders of DNA Repair......Page 246
7.1 Antihistamines......Page 247
7.2 Retinoids......Page 248
7.3 Corticosteroids......Page 249
7.4 Systemic Immunomodulators, Cytotoxic, and Oncolytic Agents......Page 251
7.5 Antimicrobials......Page 255
7.6 Other Miscellaneous......Page 264
8.1 Anesthetics......Page 266
8.2 Suture......Page 268
8.3 Preoperative Considerations......Page 270
8.4 Cryosurgery, Excision, Flaps, and Grafts......Page 272
9.1 Aging and the Skin......Page 277
9.2 Neurotoxins and Filler......Page 279
9.3 Chemical Peels......Page 281
9.4 Sclerotherapy......Page 282
9.5 Hair Transplantation......Page 283
Index......Page 284

Citation preview

Clinical Manual of Dermatology William W. Huang Christine S. Ahn

123

Clinical Manual of Dermatology

William W. Huang • Christine S. Ahn

Clinical Manual of Dermatology

William W. Huang Department of Dermatology Wake Forest University School of Medicine Winston Salem, NC USA

Christine S. Ahn Department of Dermatology Wake Forest University School of Medicine Winston Salem, NC USA

ISBN 978-3-030-23939-8    ISBN 978-3-030-23940-4 (eBook) https://doi.org/10.1007/978-3-030-23940-4 © 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, express 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

Contents

1 Basic Science��������������������������������������������������������������������������������������������    1 1.1 Embryology��������������������������������������������������������������������������������������    1 1.2 Biology of Keratinocytes and Cells of the Epidermis����������������������    3 1.3 Biology of the Basement Membrane������������������������������������������������    7 1.4 Extracellular Matrix��������������������������������������������������������������������������    9 1.5 Biology of Adnexal Glands��������������������������������������������������������������   11 1.6 Biology of Hair and Nails ����������������������������������������������������������������   13 1.7 Vascular Biology������������������������������������������������������������������������������   16 1.8 Tumor Biology and Major Pathways������������������������������������������������   17 1.9 Wound Healing ��������������������������������������������������������������������������������   19 1.10 Photobiology ������������������������������������������������������������������������������������   20 2 Immunology����������������������������������������������������������������������������������������������   23 2.1 Innate Immunology��������������������������������������������������������������������������   23 2.2 Adaptive Immunology����������������������������������������������������������������������   27 3 General Dermatology������������������������������������������������������������������������������   31 3.1 Eczematous Dermatoses ������������������������������������������������������������������   31 3.2 Papulosquamous Dermatoses������������������������������������������������������������   42 3.3 Lichenoid Dermatoses����������������������������������������������������������������������   50 3.4 Follicular and Apocrine Diseases������������������������������������������������������   54 3.5 Connective Tissue Disorders������������������������������������������������������������   61 3.6 Blistering Disorders��������������������������������������������������������������������������   78 3.7 Diseases of Hair and Nails����������������������������������������������������������������   89 3.8 Disorders of Pigmentation����������������������������������������������������������������   95 3.9 Vascular Diseases������������������������������������������������������������������������������   97 3.10 Neutrophilic Dermatoses������������������������������������������������������������������  103 3.11 Eosinophilic Dermatoses������������������������������������������������������������������  105 3.12 Granulomatous and Histiocytic Disorders����������������������������������������  107 3.13 Oral and Anogenital (Non-venereal) Disease ����������������������������������  115 3.14 Disorders of Lipid ����������������������������������������������������������������������������  119 3.15 Depositional and Metabolic Disorders����������������������������������������������  128 v

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Contents

3.16 Pruritus and Psychocutaneous Disorders������������������������������������������  145 3.17 Photodermatoses ������������������������������������������������������������������������������  146 3.18 Drug Reactions����������������������������������������������������������������������������������  150 4 Cutaneous Neoplasms������������������������������������������������������������������������������  153 4.1 Benign and Malignant Tumors of the Epidermis������������������������������  153 4.2 Melanocytic Neoplasms��������������������������������������������������������������������  158 4.3 Adnexal Neoplasms��������������������������������������������������������������������������  163 4.4 Soft Tissue Tumors ��������������������������������������������������������������������������  170 4.5 Vascular Neoplasms��������������������������������������������������������������������������  174 4.6 Cutaneous Hematolymphoid Neoplasms������������������������������������������  177 5 Infectious Diseases ����������������������������������������������������������������������������������  183 5.1 Bacterial Infections ��������������������������������������������������������������������������  183 5.2 Fungal Infections������������������������������������������������������������������������������  199 5.3 Viral Infections����������������������������������������������������������������������������������  203 5.4 Protozoan Infections, Infestations, and Others ��������������������������������  210 6 Pediatric Dermatology����������������������������������������������������������������������������  213 6.1 Conditions of Newborns ������������������������������������������������������������������  213 6.2 Congenital Infections������������������������������������������������������������������������  214 6.3 Inherited Disorders of Cornification ������������������������������������������������  218 6.4 Inherited Disorders of Pigmentation������������������������������������������������  226 6.5 Inherited Disorders of Hair and Nails����������������������������������������������  229 6.6 Vascular Disorders����������������������������������������������������������������������������  231 6.7 Neurocutaneous Syndromes��������������������������������������������������������������  235 6.8 Inherited Tumor Syndromes ������������������������������������������������������������  238 6.9 Disorders of DNA Repair ����������������������������������������������������������������  241 7 Dermatopharmacology����������������������������������������������������������������������������  243 7.1 Antihistamines����������������������������������������������������������������������������������  243 7.2 Retinoids ������������������������������������������������������������������������������������������  244 7.3 Corticosteroids����������������������������������������������������������������������������������  245 7.4 Systemic Immunomodulators, Cytotoxic, and Oncolytic Agents��������  247 7.5 Antimicrobials����������������������������������������������������������������������������������  251 7.6 Other Miscellaneous ������������������������������������������������������������������������  260 8 Dermatologic Surgery������������������������������������������������������������������������������  263 8.1 Anesthetics����������������������������������������������������������������������������������������  263 8.2 Suture������������������������������������������������������������������������������������������������  265 8.3 Preoperative Considerations ������������������������������������������������������������  267 8.4 Cryosurgery, Excision, Flaps, and Grafts ����������������������������������������  269 9 Cosmetic Dermatology����������������������������������������������������������������������������  275 9.1 Aging and the Skin����������������������������������������������������������������������������  275 9.2 Neurotoxins and Filler����������������������������������������������������������������������  276 9.3 Chemical Peels����������������������������������������������������������������������������������  279 9.4 Sclerotherapy������������������������������������������������������������������������������������  280 9.5 Hair Transplantation ������������������������������������������������������������������������  281 Index�������������������������������������������������������������������������������������������������������������������� 283

Acknowledgments

This text was developed as a study aid, adapted from key resources in dermatology including Dermatology (4th ed) by Bolognia JL, Schaffer JV, Cerroni L, Review of Dermatology by Alikhan A, Hocker TLH, and Dermatology: Illustrated Study Guide and Comprehensive Board Review by Jain S.

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Chapter 1

Basic Science

1.1  Embryology • Skin composed of cells from different lineage –– Ectodermal: keratinocytes, melanocytes, Merkel cells, neurons –– Mesodermal: fibroblasts, Langerhans cells, endothelial cells • Epidermis –– Timeline ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

5 weeks: outer periderm and inner basal epidermal layer exists 8 weeks: stratification of embryonic epidermis begins 12 weeks: terminal differentiation of keratinizing epidermal cells begins 12–16 weeks: epidermal melanin production begins 15 weeks: early cornification within hair canal observed 20 weeks: melanosome transfer to keratinocytes begins 22–24  weeks: cornification in interfollicular epidermis (head  →  palms, soles) ◦◦ 24–26 weeks: cornified cell layer starts to form ◦◦ 30–34 weeks: epidermis morphologically similar to adult skin ◦◦ Full skin barrier function at 3 weeks postpartum

–– Epidermal cells of interest ◦◦ 9–12 weeks: melanocytes, Langerhans cells, and Merkel cells migrate into epidermis (Box 1.1) • Dermis and subcutaneous tissue –– Timeline ◦◦ 6–8 weeks: dermal fibroblasts present under developing epidermis ◦◦ 9 weeks: demarcation between dermis and underlying tissue © Springer Nature Switzerland AG 2020 W. W. Huang, C. S. Ahn, Clinical Manual of Dermatology, https://doi.org/10.1007/978-3-030-23940-4_1

1

2

1  Basic Science

Box 1.1 Clinicopathologic Correlation: Newborn vs. Adult skin Skin thickness Papillary dermis Reticular dermis

Newborn 1.2 mm

Adult 2.1 mm

Small collagen fibers

Small collagen fibers

Small/intermediate collagen fibers, small/immature elastic fibers

Large collagen fibers, large elastic fibers in reticular dermis

◦◦ 12–15 weeks: distinction between extracellular matrix of papillary dermis and reticular dermis ◦◦ 13–25 weeks: accumulation of subcutaneous fat ◦◦ 22–24 weeks: elastic fibers developing ◦◦ 26 weeks: distinct lobules of subcutaneous fat separated by fibrous septae begin to form • Dermo-epidermal junction –– Derived from ectodermal (keratin proteins) and mesodermal (dermal fibroblasts) origin –– 8 weeks: DEJ components began to mature with onset of epidermal stratification –– 12 weeks: all structures of mature DEJ in place • Adnexal structures –– Hair Follicle ◦◦ ◦◦ ◦◦ ◦◦

12–14 weeks: hair peg formed 14–20 weeks: concentric layers of hair follicles undergo maturation 18–21 weeks: hair canal fully formed 24–28 weeks: hairs continue to grow

–– Nail ◦◦ ◦◦ ◦◦ ◦◦

8–10 weeks: fingernail development begins 11 weeks: nail bed keratinizes 13 weeks: proximal nail fold developed 20 weeks: development complete

–– Sebaceous glands—development parallels follicular development ◦◦ 13–16 weeks: develop as superficial bulge on developing hair follicle

1.2 Biology of Keratinocytes and Cells of the Epidermis

3

Box 1.2 Clinical Relevance of Embryology: Related Disorders Epidermis

Melanocyte migration Dermis DEJ Adnexae

Lamellar ichthyosis Congenital ichthyosiform erythroderma Harlequin ichthyosis Piebaldism Waardenburg syndrome Ehlers-Danlos syndrome Goltz syndrome Epidermolysis bullosa Ectodermal dysplasia

–– Eccrine glands—do not mature or function until postnatal period ◦◦ 6–9 weeks: mesenchymal bulges/pads form on palms/soles ◦◦ 12 weeks: palmoplantar eccrine glands developed ◦◦ 12–14 weeks: parallel ectodermal ridges induced in epidermis overlying pads ◦◦ 14–16 weeks: primordia bud along ectodermal ridges, elongate as cords of cells ◦◦ 16 weeks: glandular structures form at terminal end, secretory myoepithelial cells appear, canalization of intradermal duct complete ◦◦ 20 weeks: interfollicular glands begin to form ◦◦ 22 weeks: canalization of intraepidermal duct complete –– Apocrine glands—functional in third trimester then inactive ◦◦ 20 weeks: interfollicular glands begin to form (arise from upper portion of hair follicle) (Box 1.2)

1.2  Biology of Keratinocytes and Cells of the Epidermis I. Structure & Function • Barrier function to protect against harmful substance and water loss • Established during embryogenesis, maintained by self-renewal and terminal differentiation II. Differentiation • Begins with epidermal stem cells in basal layer of interfollicular epidermis— ends with creation of cornified envelope and desquamation

4

1  Basic Science

• 28 days total transit time (basal layer → stratum corneum (14 days) → desquamation (14 days) • Stratum basale –– K5, K14 produced –– Ornithine decarboxylase expression associated with proliferative states, inhibited by corticosteroids, retinoids, and vitamin D3 –– 10% stem cells • Stratum spinulosum –– K1, K10 produced –– K5, K15 present –– TG1, TG5 expressed –– Lamellar granules (Odland bodies) produced → contain ceramide, glycoproteins, glycolipids, phospholipids • Stratum granulosum –– TG1, TG5 expressed –– Keratohyalin granules produced → contain loricrin, profilaggrin, involucrin –– Cornified cell envelope produced (upper spinous and granular layer)— highly cross-linked, lipid-covered • Stratum lucidum –– Present on acral skin • Stratum corneum –– K1, K2, K10 expressed –– TG3 expressed (Box 1.3) (a) Regulatory Pathways • TP63: gene responsible for establishing and maintaining basal keratinocytes (see Box 1.4)

Box 1.3 Granules in the Epidermis Lamellar granules (Odland bodies)

Keratohyaline granules

Spinous layer Contain lipids (ceramide, glycolipids, phospholipids, glycoproteins) Made in golgi Granular layer Contain protein (profilaggrin, loricrin, keratin intermediate filaments, involucrin)

1.2 Biology of Keratinocytes and Cells of the Epidermis

5

Box 1.4 Ectodermal Dysplasias Due to p63 Mutations All feature wiry/sparse hair, dystrophic nails, hypohidrosis, decreased teeth and/or hypoplastic enamel Rapp-Hodgkin syndrome •  Cleft lip/palate/uvula •  Hypoplasia of maxilla •  Small narrow nails •  Small conical teeth •  Congenital ankyloblepharon Ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (Hay-Well’s syndrome) • Facial clefting, mid-facial hypoplasia •  Collodion-like peeling at birth • Chronic erosive dermatitis of scalp (S. aureus) Ectrodactyly ectodermal dysplasia-cleft lip/palate •  Ectrodactyly (lobster claw) syndrome •  Facial clefting •  Conductive hearing loss •  GU anomalies

–– P63 null mice born with single-layered epithelium not stratified epidermis –– P63 induces K5, K14 –– P63 inhibits K18 (keratin expressed in single-layer epithelia), cell cycle inhibitors (to maintain proliferative state of basal keratinocytes) • ΔNp63α: isoform of p63 responsible for terminal differentiation –– P63 + Notch pathway induce K1 • Ca2+: role in keratinocyte terminal differentiation –– Extracellular Ca2+ gradient ↑ from st. basale to st. corneum • Notch: required for formation of stratum spinulosum –– Ablation of Notch → thin spinous layer –– Constitutive activation of Notch → thick spinous layer III. Cells of the Epidermis (a) Keratinocytes: • Primary cells of epidermis • Produce proteins and lipids for barrier function • Keratin intermediate filaments make up the cytoskeleton of the epidermis → functional unit consists of heterodimer of type I and II keratin filaments (see Box 1.5) • Multiple cell junctions in keratinocytes: desmosomes, adherens junctions, tight junctions, gap junctions (see Box 1.6)

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1  Basic Science

Box 1.5 Keratin Intermediate filaments Type I keratins •  Low molecular weight • Acidic • K9–28 •  K31–40 (hair keratins) •  Chromosome 17

Type II keratins •  High molecular weight • Basic • K1–8 •  K81–86 (hair keratins) •  Chromosome 12

Box 1.6 Keratinocyte Cell Junctions Desmosomes

Primary keratinocyte intercellular junction, anchored to keratin filaments Adherens Mediate tight intercellular binding, junctions anchored to actin filaments Tight Form tight seal against water loss junctions in granular layer Gap junctions Mediate intercellular communication

Desmoplakin, plakophilin, plakoglobin, desmocollin 1/2/3, desmoglein 1/3 α-catenin, β-catenin, plakoglobin, E-cadherin, P-cadherin Claudin, occludin Connexons (tubular channel of 6 connexins)

(b) Melanocytes: • Derived from neural crest forming along dorsal neural tube and migrate via dorsolateral then ventral pathway and from Schwann cell/melanocyte precursor ells that migrate along nerves to skin via ventral pathway • KIT receptor activation required for melanocyte development/migration –– KIT ligand (aka steel factor or stem cell growth factor) –– KIT mutation responsible for piebaldism • Located in basal layer: interface via cadherins in 1:10 ratio with keratinocytes in basal layer (2D plane), 1:30–40 with keratinocytes (3D plane)—transfer melanosomes to surrounding keratinocytes, also known as epidermal melanin unit • Melanosomes (lysosomal organelles) produce melanin, transported to neighboring keratinocytes via dendritic processes –– –– –– ––

Tyrosine → DOPA → DOPAquinone → pheomelanin/eumelanin First two steps require tyrosinase (Cu-dependent enzyme) Pheomelanin: yellow/red, made by round melanosomes Eumelanin: black/brown, made by elliptical melanosomes

1.3 Biology of the Basement Membrane

7

Box 1.7 Determinants of Skin Pigmentation Melanosome size Number of melanosomes per cell Melanosome degradation Distribution of melanosomes

Darkly pigmented Large >200 Slow Single

Lightly pigmented Small  hematopoietic (leukemia, lymphoma), mesenchymal (sarcoma) –– Results of genomic instability (usually in germline cells) and spontaneous mutation (in somatic cells) –– Six traits due to spontaneous mutations that can lead to carcinogenesis: (1) activation of oncogenes, (2) loss of function of tumor suppressor genes, (3) evasion of apoptosis, (4) limitless replicative potential, (5) sustained angiogenesis, (6) tissue invasion/metastasis –– p53: “guardian of genome”, regulates cell cycle progression, DNA repair, apoptotic cell death

18

1  Basic Science

(a) Oncogenes • Mutation in 1 of 2 inherited alleles leads to gain of function → increased production of growth factors, growth factor receptors, or protein involved in signal production • Ras, Myc, Src, Fos (3 letter code) (b) Tumor suppressors • Mutation in 1 allele has no effect, second mutation in normal (wildtype) allele leads to loss of heterozygosity • Inhibit proteins that control cell cycle progression • Rb, p53, bcl-2 II. Pathogenesis of cutaneous neoplasms (a) SCC • Cumulative UV significant risk factor • Risk of metastasis: tumor thickness 2.1–6  mm–4% rate metastases; >6 mm–16%, immunosuppression, location on lips or ear • Most common gene alterations: p53, ras (10–50%), c-Myc (up to 50%), NOTCH1 or NOTCH2 (up to 75%) (b) BCC • Associated with intermittent sun exposure • Only develop in skin with pilosebaceous units • Most common gene alterations: PTCH, p53 (50%), SMO (up to 20%), CDKN2A, H-ras (up to 30%) • Unbound Patched (PTCH) silences smoothened (SMO) signaling, which prevents downstream transcription • Bound PTCH by hedgehog removes inhibition of SMO, leads to downstream transcription of target genes • Mutated PTCH leads to unopposed SMO or mutated SMO causes constitutively activated smoothened, causing signaling to Gli and transcription of target genes • Vismodegib inhibits smoothened (c) Melanoma • Risk factors: genetic predisposition, mutagenic environmental events, antitumor host response –– Genetic risk factors: family history (CDKN2A gene mutation), lightly pigmented skin, tendency to burn, red hair color, DNA repair defects (xeroderma pigmentosum) –– Environmental risk factors: intense intermittent sun exposure, chronic sun exposure, immunosuppression, tanning bed use, equatorial latitudes

1.9 Wound Healing

19

–– Other risk factors: >100 melanocytic nevi, >5 atypical melanocytic nevi, many solar lentigines, personal history of melanoma • Genetic aberrations affect signaling pathways: MAPK, P13K, WNT, MC1R-MITF • MAPK pathway: regulates cellular proliferation, growth, migration –– 30–40% acral/mucosal melanoma and chronic sun-exposed skin have KIT mutation –– 15–20% all melanoma have NRAS mutation –– 50–60% all melanoma have BRAF mutation –– CDKN2A associated with familial melanoma • PI3K pathway: phosphoinositide 3-kinases regulate cell growth, proliferation, differentiation, motility, survival –– Inactivation of PTEN (inhibitor of pathway) often seen • WNT pathway: involved in differentiation, migration, proliferation, stem cell maintenance –– WNT binds the frizzled/LRP receptor complex, which activates disheveled (DSH), inhibits β-catenin complex –– APC and β-catenin mutations rarely seen in melanoma • MC1R-MITF pathway –– MC1R is G-coupled protein receptor activated by ACTH and α-MSH –– MITF is transcription factor that regulates expression of melanocytespecific genes, such as those that encode tyrosinase –– MITF often amplified in melanoma

1.9  Wound Healing I. Timeline of wound healing (4 overlapping phases) (a) Hemostasis (immediate) • Occurs immediately after exposed collagen triggers coagulation cascade • Platelets activated, adhere, aggregate, form platelet plug and fibrin deposition • Platelets secrete PDGF and TGF-β → attract macrophages, neutrophils, fibroblasts, endothelial cells, smooth muscle cells (b) Inflammatory (starts within 6–8 h, lasts 3–4 days) • Begins when neutrophils adhere to endothelium • Macrophages arrive, dominate at days 3–5 (most important cell for wound healing)

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–– Phagocytose organisms, degrade wound debris, stimulate granulation tissue formation and angiogenesis –– Produce PDGF, TGF-β, FGF, IL-1, IL-6, TNF-α • TGF-β stimulates macrophages, influences fibroblast function, chemotaxis, and collagen deposition (c) Proliferation (starts within 5–7 days, lasts up to 1 month) • Includes fibroplasia, granulation, epithelialization, and angiogenesis • Keratinocytes “leap-frog” from wound edge and hair follicles to layer over keratinocytes in wound bed • Low oxygen causes upregulation of VEGF → angiogenesis, smooth muscle cell migration • Fibroblasts (arrive within 48–72 h) lead to dermal matrix proliferation –– Produce elastin, collagen, ECM proteins, MMPs • Collagen appears within 48–72  h, maximal at 5–7  days post-injury (mostly collagen III) • Remodeling (starts 3–4 weeks, lasts up to 1 year) • Scar matrix formation and regression of granulation tissue • MMP and tissue inhibitors of MMP reorganize collagen, cause change from collagen III → collagen I • Scar strength: 1 week–5%, 3 weeks–20%, 3 months–50%, 1 year–80%

1.10  Photobiology I. UV Light • 200–400 nm (shorter = higher frequency, higher energy, less penetration of skin) –– UVA: 320–400 nm ◦◦ UVA1: 340–400 nm ◦◦ UVA2: 320–340 nm ◦◦ 95% UV radiation at earth surface is UVA –– UVB: 290–320 nm –– UVC: 200–290 nm ◦◦ Most UVC absorbed by oxygen and ozone • Absorption spectrum: portion of UV light absorbed by biomolecules in skin –– Chromophores in epidermis: nucleic acid, protein, melanin, urocanic acid –– Chromophores in dermis: hemoglobin, porphyrins • Action spectrum: portion of electromagnetic spectrum that produces a biologic effect • Normal effects of sun exposures:

1.10 Photobiology

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–– Sunburn: ~300 nm most erythemogenic, starts 30 min to hours after exposure, peaks at 6–24 h –– Epidermal hyperplasia: after UVB/UVC exposure –– Pigment darkening: immediate with UVA from oxidation of pre-existing melanin, redistribution of melanosomes, delayed with UVB from increased melanocytes, melanin, melanosome transfer –– Pro-inflammatory effects: 5-HT, prostaglandins, IL-1, IL-6, IL-8, TNF-α –– Anti-inflammatory effects: IL-10, α-MSH, increased Treg cells, decreased or modified Langerhans cell function –– Vitamin D3 synthesis: UVB converts epidermal 7-dehydrocholesterol → previtamin D3 → isomerizes to vitamin D3 (cholecalciferol) → converted to 25-hydroxyvitamin D (liver) → converted to active 1,25-dihydroxyvitamin D (kidneys) –– Photoaging: increased proteases and decreased collagen synthesis II. Photocarcinogenesis and Repair • UVR causes DNA damage, immunosuppression • C → T is UVB signature mutation • Pyrimidine dimers are most important for carcinogenesis –– T-T > C-T > T-C and C-C • Nucleotide excision repair (NER) repairs bulky mutations such as pyrimidine dimers (defective in xeroderma pigmentosum) • Base excision repair repairs non-bulky mutations such as oxidative DNA base modifications • Other protections against photocarcinogenesis: hair, skin thickening in response to UV exposure, antioxidant enzymes, constitutive and inducible melanin, immune surveillance (Box 1.14)

Box 1.14 UVA and UVB Wavelength Sunburn Darkening Drug-induced photosensitivity Carcinogenesis Immunosuppression Glass penetration Photoaging Vitamin D3 synthesis

UVA 320–400 nm Minor role, causes immediate erythema Immediate pigment darkening Major role

UVB 290–320 nm Major role in sunburn (1000× more erythemogenic than UVA) Delayed melanogenesis

Minor role

Major role (leads to mutations in keratinocyte DNA) Major role No Minor role Yes

Minor role Yes Major role No

Minor role

Chapter 2

Immunology

2.1  Innate Immunology • • • •

Rapid, nonspecific No memory response Recognize foreign antigens only (not self-antigens) Pathogen-associated molecular patterns (PAMPs) bind to pattern recognition receptors (toll-like receptors)

I. Non-cellular components (a) Complement • Complement proteins made in liver, also act as acute phase reactants • Functions include: direct lysis of bacteria via opsonization of bacteria, clear immune complexes, activate immune response, opsonization of bacteria, anaphylaxis • 3 pathways—all lead to formation of membrane attack complex (MAC), C5b-C9 –– Classical pathway ◦◦ Activated by immune complexes (IgM, IgG3 > IgG1 > IgG2, ∗not IgG4) ◦◦ C1 (C1q,r,s) • Fc portion of Ag-bound Ab binds C1q → activated C1r,s • C1r,s → cleavage of C4 and C2 → forms C3 convertase (C4b/ C2a) ◦◦ C3 convertase • Cleaves C3 → C3a (anaphylotoxin) and C3b (opsonin) • Forms C5 convertase (C4b/C2a/C3a)

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◦◦ C5 convertase • Cleaves C5 → C5a (anaphylotoxin, neutrophil chemotactic) and C5b ◦◦ MAC formed (C5b, C6–C9) –– Alternative pathway ◦◦ Activated by microbial cell surface structures without antibodies → ↓ levels of C3 cleavage ◦◦ C3b • Binds factor B ◦◦ Factor D • Cleaves factor B → Ba and Bb • Forms C3 convertase (C3b/Bb)—stabilized by properidin ◦◦ ◦◦ ◦◦ ◦◦

C3 convertase (C3/Bb) C5 convertase (C3b/Bb/properidin) Similar steps as classical pathway Factor H—regulatory protein, inhibits formation of C3 convertase

–– Lectin pathway ◦◦ Activated by mannose-binding lectin protein (without antibodies) ◦◦ Binds to cell surface polysaccharides on bacteria, fungi, virus, protozoa ◦◦ Cleavage of C4 and C2 → then follows pathway similar to classical • See Box 2.1 on complement deficiencies (b) Cytokines (See Box 2.2) • Psoriasis cytokines: all Th1 cytokines, IL-6, IL-17, IL-22, IL-23 (c) Toll-like receptors (See Box 2.3) • Expressed on APCs → recognize PAMPs • Activation of TLR leads to phagocytosis of pathogen → activation of pro-­ inflammatory environment (secretion of cytokines, chemokines) • All use myd88 signaling pathway after activated except TLR3 (d) Antimicrobial peptides • Cathelicidins (LL-37): ↑ in psoriasis, rosacea, verruca vulgaris • Human β-defensins (↑ psoriasis, ↓ atopic dermatitis) II. Cells of significance (a) Natural killer (NK) cells • Cell markers: CD2, CD16, CD56 • Activated by: IL-12, IL-15 • Secrete: IFN-γ

2.1  Innate Immunology

25

Box 2.1 Complement Deficiency C2

C3

Most frequent complement deficiency seen ↑ risk SLE, SLE-like syndrome, infections, anaphylactoid purpura, lethal dermatomyositis, vasculitis, cold urticaria Seen in pyogenic infections, glomerulonephritis, partial lipodystrophy C3 levels are ↓ in cryoglobulinemia

Box 2.2 Important Cytokines IL-1

Promotes isotype switch from IgM to IgE Pyrogenic, responsible for fever in sunburn, causes B cell maturation and NK cell activation IL-2 KEY part of Th1 immunity → promotes growth, proliferation, and activation of T, B, and NK cells (autocrine factor for activated T cells) Denileukin diftitox—fusion of diphtheria toxin & IL-2 → binds to CD25 (IL-2 receptors) on T cells Tacrolimus binds calcineurin, NFAT cannot be dephosphorylated (stays inactive) → stop transcription of IL-2 IL-3 Elicit mast cells IL-4 B-cell growth factor, shifts immune response towards Th2 Promotes isotype switching from IgM to IgE and Th2 differentiation IL-5 Eosinophil growth factor IL-6 B-cell proliferation/differentiation (plasma cells), essential for development of IL-23-­elicited responses and epidermal hyperplasia in psoriasis IL-8 Most important in recruiting neutrophils (activating and chemoattractant) IL-­10 Downregulates Th1 immunity IL-­13 Isotype switching IL-­17 Implicated in psoriasis (especially nail) Target of secukinumab, ixekizumab, brodalumab IL-­22 Implicated in psoriasis—critical in causing epidermal acanthosis IL-­23 Implicated in psoriasis—involved in development of Th17 cells, also part of epidermal acanthosis TNF Th1 response, TNF-α responsible for Jarisch-Herxheimer response IFN-­α Major part of antiviral response IFN-­γ Main macrophage-activating cytokine, main cytokine secreted by Th1 cells

• Kill virally infected or tumor cells by either (1) antibody-dependent cellular toxicity, (2) perforin/granzyme system (b) Mononuclear phagocytes • Cell markers: CD11a,b,c, CD6 • Antigen-presenting cells with major role in tissue remodeling, wound healing, coagulation • Ingest pathogens into phagosomes → fuse with lysosomes → destroy by producing reactive oxygen species via phagocyte oxidase

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Box 2.3 Toll-Like Receptors (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) TLR1 Lipopeptides from gram-negative bacteria Mycobacteria TLR2 Lipopeptides from gram-positive bacteria

TLR3 Viral dsDNA TLR4 Lipopolysaccharide (LPS) from gram-negative bacteria TLR5 Flagellin (bacterial) TLR6 Mycobacterial lipopeptides TLR7 Viral ssRNA TLR8 Viral ssRNA TLR8 Unmethylated bacterial DNA

Activated by P. acnes Downregulated by some topical retinoids TLR2 and TLR9 polymorphisms a/w atopic dermatitis Triggered by Nickel in allergic contact dermatitis

Ligand for imiquimod Suppressed by hydroxychloroquine, implicated in interaction between smoking and hydroxychloroquine

(c) Eosinophils • Activated by: IL-5 • Defense against parasites, helminths, play role in allergic disease • Cytoplasmic granules contain major basic protein, eosinophilic cationic protein, eosinophilic peroxidase, eosinophil-derived neurotoxin (d) Mast cells • Cell markers: CD34, CD117 (c-kit receptor), CD13 • Secrete: IL-8 • Important in immediate-type hypersensitivity reactions (anaphylaxis, urticaria, angioedema) • Degranulation triggers: cross-linking of FceRI-bound IgE, substance P, NSAIDs, opiates, aspirin, vancomycin, polymyxin B, curare, radiocontrast media, IL-3, C3a, C4a, C5a, stem cell factor (e) Neutrophils • 1st cells to arrive to acute inflammatory cells via chemotactic factors (C5a, IL-8, kallikrein)

2.2  Adaptive Immunology

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2.2  Adaptive Immunology • Slower onset, more specific (antigen-specific T and B cells generated) –– Lag phase before activation/differentiation of lymphocytes in response to antigens • Capable of memory • Recognize both foreign and self-antigens (responsible for autoimmune disease processes) I. Non-cellular components • Immunoglobulins (See Box 2.4) II. Cells of significance (a) Langerhans cells • • • • • • •

Cell surface makers: CD1a, CD45, CD207 (langerin), S100, vimentin APCs, poorly phagocytic Require TGF-β1 and M-CSFR to develop Adhere to keratinocytes via E-cadherin Take up antigen, move to lymph node and present T cells After activation, express CD80, CD86 (B7 molecules) Antigen presentation to T cells:

Box 2.4 Immunoglobulins (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) IgA Found in mucous membrane secretions Agglutinate antigens, activate alternate not classical complement pathway Promoted by IL-5, TGF-β IgG Crosses placenta Most common in circulation Strongest complement binding IgG3 IgG4 does not bind complement Promoted by IL-2, 4, 6, IFN-ɣ IgD NOT in circulation (except in Hyper-IgD syndrome, mevalonate kinase gene—↑ serum IgD) Surface receptor on B cells IgE Anaphylactic antibody Seen in nearly all allergic and anaphylactic type reactions ↑ in atopic dermatitis Ab against IgE receptor a/w chronic idiopathic urticaria Promoted by IL-4 IgM Produced in early stages of antibody responses Pentamer, can agglutinate and activate classic complement pathway

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–– Antigen-derived peptides are bound to MHC molecules on APCs and presented to T cells (See Box 2.5) –– CD4+ T cells recognize antigens complexed to MHC II molecules ◦◦ MHC II: exogenous antigens taken up via macro or micropinocytosis –– CD8+ T cells recognize antigens complexed to MHC II molecules ◦◦ MHC I: intracellular processing of endogenous antigens (viral or tumor) ( b) T cells • C  ell surface markers: CD2, CD3, CD7, CD4/8, CD25, CD28, TCR, LFA1, CTLA-4 • Primary stimulation from TCR recognizing antigen complexed on MHC I or II • Co-stimulation occurs between T cell and APC in following pairs: –– CD28 ↔ B7-1/B7-2 –– CD2 ↔ LFA-3 –– LFA-1 ↔ ICAM-1 • Inhibitory co-stimulatory signals –– CTLA-4 ↔ B7-1/B7-2 ◦◦ CTLA-4 is target of ipilimumab → leads to greater T cell activation and anti-­tumor activity • Th1 vs Th2 cells and disease states (See Boxes 2.6 and 2.7) (c) B cells • C  ell surface markers: CD19, CD20, CD22, CD79a, Fc receptor, MHC Class I and II • Produce antibodies (Box 2.4) and differentiate into plasma cells • Isotype switch after interaction with T-helper cells • Initial exposure: primary immune response → lower antibody production, some B-cells become memory B cells or plasma cells • Subsequent exposure: secondary immune response → memory B cells rapidly develop into plasma cells, increased isotype switching, increased high-­affinity antibody production (IgA, E, G) • Activation of CD40 on B cells (by CD4-lignad or CD154) on T cell induces switch from IgM → IgG –– Defect in CD40-ligand results in hyperIgM syndrome

2.2  Adaptive Immunology

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Box 2.5 MHC T cell Expression

Genes Diseases of interest

MHC class I Present endogenous antigens to CD8+ T cells All nucleated cells

HLA-A, HLA-B, HLA-C HLA-B8: oral lichen planus HLA-B27: reactive arthritis, psoriatic arthritis HLA-B51: Behcet’s disease HLA-B13: guttate psoriasis HLA-Cw6: psoriasis

MHC class II Present exogenous antigens to CD4+ T cells APCs (monocyte, macrophage, dendritic cells, B cells, activated T cells) HLA-DP, HLA-DQ, HLA-DR HLA-DR3: lupus (SLE, SCLE) HLA-DR3, -DR4: herpes gestationis HLA-DR4, -DRw6: pemphigus vulgaris

Box 2.6 T Cell Subtypes T-helper—CD4+ Th1  – Activate macrophages via stimulation by IL-12 and IFN-γ  – Produce IFN-γ, IL-2, IL-12, TNF-α  – Important in cell mediated immunity, delayed-type hypersensitivity reactions Th2  – Activate eosinophils  – Produce IL-4, IL-5, IL-6, IL-10, IL-13  – IL-4 is key Th17  – Depend on STAT3, TGF-β  – Produce IL-6, IL-17, IL-21, IL-22, IL-23, IL-36, TNF-α  – Activate endothelium, infiltration by neutrophils, cell-­mediated inflammation Treg  – Downregulate immune response  – Express CD25, FOXP3  – Produce IL-10, IL-35, TGF-β

Cytotoxic—CD8+ –R  ecognize cytoplasmic antigens on MHC I – Lead to cell death by (1) perforin/ granzyme pathway; (2) Fas ligand (CD95L) binding to death receptor Fas (CD95) on target cells, (3) release of TNF-α and IFN-γ – Produce IFN-γ, TNF

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Box 2.7 Th Disease States to Know Th1  IL-1, 2, 12, 15, 18, 23 IFN-ɣ

Th2  IL-4, 5, 10, 13

Psoriasis Tuberculoid leprosy (high immune) Leishmaniasis (cutaneous—self resolving) CTCL (non-Sezary) Allergic contact dermatitis Sarcoidosis Atopic dermatitis Lepromatous leprosy (low immune) Leishmaniasis (chronic indolent) Sezary syndrome Scleroderma Systemic lupus Helminth infections

Chapter 3

General Dermatology

3.1  Eczematous Dermatoses I. Atopic dermatitis (AD) • 10–30% children, 2–10% adults • Significantly higher prevalence in urban, high-income countries • 3 subsets –– Early onset: within 2 years—most common, 50% develop allergen-specific IgE ab by 2 years of age –– Late onset: after puberty –– Senile onset: after 60 years (unusual) • Pathogenesis—3 major factors –– –– –– –– –– –– –– –– –– –– –– ––

Genetic factors Accounts for 90% of susceptibility to early-onset AD Epidermal barrier dysfunction Higher level of transepidermal water loss Loss of function filaggrin (FLG) mutations—strongest known genetic risk factor for AD FLG a/w early onset AD, greater disease severity, persistence into adulthood, ↑ risk asthma Abnormal loading and secretion of lamellar bodies ↑ endogenous serine proteases (KLK5/7) Imbalance of protease inhibitors such as LEKTI (encoded by SPINK5— Netherton syndrome) Increased skin surface pH, exogenous proteases from allergens Immune dysregulation Acute: Th2 cytokines → IL-4, 5, 13, activation of eosinophils and mast cells

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–– Chronic: Th1, Th22 cytokines –– Variable Th17 cytokines in both acute and chronic AD –– TSLP (thymic stromal lymphopoietin)—IL-7-like cytokine, known as “master-­switch of allergic inflammation” → evokes Th2 response via dendritic cell activation ◦◦ Can be triggered by exposure to allergens, viral infections, trauma, and other cytokines ◦◦ TSLP highly expressed in acute and chronic lesions of AD –– IL-4: key role in driving Th2 differentiation, IgE production, eosinophil recruitment –– IL-13 has independent role in AD pathogenesis ◦◦ Dupilumab is IL-4Rα monoclonal antibody → heterodimeric receptors for IL-4 and IL-13 BOTH contain the IL-4 receptor α subunit and activate STAT6, which promotes differentiation of naïve T cells into Th2 effector cells –– Th17 cells are important in innate immunity, especially in neutrophil recruitment ◦◦ Found in acute and chronic AD lesions ◦◦ Production of IL-17 and IL-19 characteristic of new-onset pediatric AD –– IL-31: Th2 cytokine highly expressed in AD, prurigo nodularis ◦◦ Studying nemolizumab—humanized monoclonal ab against IL-31 receptor A subunit –– IL-33: member of IL-1 cytokine family, protects against helminth infection by promoting Th2-type immune response • Cutaneous microbiome –– –– –– –– ––

>90% AD have S. aureus colonizing skin Disrupted acid mantle Decreased antimicrobial peptides (cathelicidins, defensins) Altered cytokine milieu of AD skin Bacterial diversity decreases during AD flares—S. aureus makes up 90% of microbiome (up from 35%) –– Superantigens can promote Th2 immune response –– Exotoxins with superantigenic properties produced by up to 65% of S. aureus strains that colonize AD patients –– FLG deficiency increases susceptibility of keratinocytes to S. aureus α-toxin-­induced cytotoxicity

• Clinical features based on age of presentation: –– Infantile (12 years)—subacute-chronic lichenified lesions –– Senile (>60 years)—marked xerosis • Regional variants: –– –– –– –– –– –– –– –– –– –– –– ––

Cheilitis sicca Lip-licker’s eczema Ear eczema Eyelid eczema Head & Neck dermatitis Juvenile plantar dermatosis Atopic hand eczema Dyshidrotic eczema Prurigo form Discoid/nummular form Frictional lichenoid eruption Nipple eczema

• Diagnostic criteria –– IgE-associated or allergic form of dermatitis—formerly known as extrinsic AD • Those with AD linked to presence of allergen-specific IgE antibodies in the serum—as documented by positive enzyme immunoassays (RAST) or skin prick tests –– Non-IgE-associated or non-allergic form of dermatitis—formerly known as intrinsic AD • Remaining 20–30% of patients with clinical phenotype of AD with no evidence of IgE-sensitization –– Essential features ◦◦ Pruritus ◦◦ Eczematous morphology ◦◦ Chronic or relapsing course –– Important features ◦◦ Onset infancy/childhood ◦◦ Personal and/or family history of atopy ◦◦ Xerosis –– Associated features ◦◦ Filaggrin deficiency-associated conditions: keratosis pilaris, hyperlinear palms, ichthyosis vulgaris ◦◦ Follicular prominence, lichenification, prurigo lesions

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◦◦ Recurrent conjunctivitis, anterior subcapsular cataract, periorbital pleats or darkening ◦◦ Perioral or periauricular dermatitis, pityriasis alba ◦◦ Midfacial pallor, white dermatographism, delayed blanch –– Triggers ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Temperature extremes, ↓ humidity Wool/rough fabrics, perspiration, detergents, solvents Infection Dust mites, pollen, contact allergens Small minority have food triggers: egg> milk, peanuts, tree nuts, soy, etc.

• Histopathology –– Acute: prominent spongiosis, intraepidermal vesiculation, perivascular lymphocytic inflammation ± eosinophils –– Subacute: spongiosis with acanthosis –– Chronic: irregular or psoriasiform acanthosis, minimal spongiosis, hyperkeratosis, intraepidermal lymphocytes • Treatment –– Topical anti-inflammatory ◦◦ Topical corticosteroids (TCS) ◦◦ Topical calcineurin inhibitors (TCI) • Suppress T-cell activation • Modulate secretion of cytokines and other proinflammatory mediators • Decrease mast cell and dendritic cell activity ◦◦ Crisaborole 2% • PDE4-inhibitor • PDE4 degrades CAMP, leading to ↑ production of IL-4, IL-10 ◦◦ Wet wrap therapy –– Phototherapy ◦◦ NB-UVB, UVA1, UVA+UVB can improve atopic dermatitis and associated pruritus ◦◦ Decrease expression of Th2 cytokines: IL-5, IL-13, IL-31 ◦◦ UVB decreases S. aureus colonization of skin –– Systemic anti-inflammatory therapy ◦◦ Dupilumab • Targets IL-4Rα • 600 mg SC followed by 300 mg every other week • AEs: Injection site reactions, conjunctivitis 10%

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◦◦ Cyclosporine • Potent inhibitor of T-cell-dependent immune responses and IL-2 production ◦◦ Azathioprine • Inhibitor of purine synthesis • Reduces leukocyte proliferation • Check TPMT before starting therapy ◦◦ MTX • Anti-inflammatory effects, reduces allergen-specific T-cell activity ◦◦ Mycophenolate mofetil • Inhibits de novo pathway of purine synthesis • Suppression of lymphocyte function –– Adjunctive therapy ◦◦ Omalizumab • Anti-IgE monoclonal antibody—approved for CIU in patients >12 years, asthma >6 years II. Seborrheic dermatitis • Common mild chronic eczema confined to skin with high sebum production • Infantile form—self-limited, seen in first 3 months of life • Adult form—chronic, peak 40–60, M > F • Extensive and treatment-resistant in HIV, more common in patients with Parkinson’s disease, cerebrovascular accidents, mood disorders • Pathogenesis: –– M. furfur plays role (lipophilic yeast, part of skin flora) –– Sebaceous gland activity: ↑ levels of triglycerides and cholesterol, ↓ squalene, free fatty acids • Sharply demarcated patches or plaques with flaky “greasy” scales on the scalp, face, ears, presternal regions > intertriginous areas –– Can be associated with vesiculation, crusting, itching • Pityriasis simplex capillitia (dandruff) → diffuse white or greasy scaling of scalp and terminal hair-bearing areas of face without erythema • Histopathology: spongiosis, perivascular/perifollicular lymphocytic infiltrate, acanthosis, focal parakeratosis (often around hair follicle) • Treatment –– Infantile: bathing, emollients, ketoconazole 2% cream, low-potency topical corticosteroids

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–– Adult: topical ketoconazole cream or shampoo, ciclopirox olamine (antifungal and anti-inflammatory), low-potency topical steroids, emollients ◦◦ 2nd line: zinc pyrithione, selenium sulfide, tar shampoos, topical calcineurin inhibitors III. Asteatotic eczema • Characterized by dry, rough, scaly skin with superficial cracking, due to barrier dysfunction of stratum corneum • Affects shins, extremities, trunk but spares face, neck, acral sites • Crisscross pattern of superficial fissures of horny layer—pink/red • Treatment: topical corticosteroids, regular use of emollients, ceramide- or lactic acid-containing preparations, elimination of aggravating factors IV. Nummular dermatitis • Uncommon disseminated eczema with coin-shaped lesions • Often associated with contact sensitization, xerosis, venous hypertension • Round eczematous patches on extremities (favor lower legs in men, forearms/dorsal hands in women) • Treatment –– Medium-to-high-potency topical corticosteroids, topical calcineurin inhibitors, emollients –– 2nd line: phototherapy V. Regional eczematous disorders (See Box 3.1)

Box 3.1 Regional Eczematous Disorders Stasis dermatitis Dyshidrotic eczema

Infectious eczematous dermatitis Juvenile plantar dermatosis Diaper dermatitis

Pitting edema of medial shin and around ankles Overlying dry skin Palmoplantar firm, deep-seated vesicles, typically late-stage manifestation of atopic dermatitis Can be seen following administration of IVIg Eczematous reaction to localized infection with purulent drainage, most often due to Staphylococcus or Streptococcus Pustules, vesicles spread from infectious nidus Symmetric, shiny, red plaques on the balls of feet and toe pads, often with cracks/fissures Confined to diaper area with erythema, erosions, scaling Due to cumulative dampness, exposure to urine/feces

3.1 Eczematous Dermatoses

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VI. Allergic contact dermatitis • Delayed-type hypersensitivity reaction –– Allergen-specific reaction, requires prior sensitization –– Initial sensitization at first contact → subsequent re-exposure leads to T-cell response → release of cytokines, chemotactic factors • Clinical patterns follow allergen involved –– Well-demarcated, pruritic eczematous eruption usually localized to area of skin in contact with allergen but can be diffuse depending on nature of allergen (such as body wash or shampoo) –– Acute: blistered, weeping, edema –– Chronic: lichenified, scaly plaques • Diagnosis with patch testing –– TRUE test—35 allergens (60+ in expanded series) –– No topical corticosteroids to site of testing for 1 week before testing –– No systemic corticosteroids for 1–2  weeks before testing (or do not exceed equivalent of prednisone 20 mg daily during testing) –– Antihistamines can be prescribed –– Patches applied to upper back, keep back dry for 48 h, remove patches, then return in 72 h to 1 week after initial application of patches for second reading VII. Irritant dermatitis • Localized, non-immunologically initiated cutaneous reaction from direct cytotoxic effect from single or repeated application of chemical substance/ physical insult • Most common form of occupational skin disease –– Rubber chemicals, soaps/cleansers, wet work, resins, acrylics, and nickel are most common sources for contact dermatitis –– Patients with AD have 13.5× greater risk of developing occupational dermatitis –– Excessive exposure to water, soaps and detergents plays a role • Mechanisms commonly a/w irritant contact dermatitis (ICD): denaturation of epidermal keratins, disruption of permeability barrier, damage to cell membranes, direct cytotoxic effects –– Acute phase of ICD: penetration through permeability barrier, mild damage to keratinocytes, release of mediators of inflammation –– Chronic phase of ICD—stratum corneum as barrier is disrupted • Clinical features of different subtypes (see Box 3.2)

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Box 3.2 Subtypes of Irritant Contact Dermatitis (ICD) Acute

• Commonly seen with occupational accident, irritant rxn reaches peak quickly then heals • Lesions restricted to area where irritant/toxicant damaged tissue with sharply demarcated borders and asymmetry pointing to an exogenous cause Acute delayed • Retarded inflammatory response characteristic of certain irritants: anthralin, benzalkonium chloride, and ethylene oxide • Rxn to these chemicals considered idiosyncratic • Visible inflammation not seen until 8–24 h after exposure, may mimic ACD Irritant reaction • Subclinical irritant dermatitis in those exposed to wet chemical environments such as hairdressers, caterers, metal workers • Examples are scaling, redness, vesicles, pustules, erosions that begin under occlusive jewelry such as rings • May stimulate dyshidrotic dermatitis, can result in cumulative ICD if exposure prolonged Cumulative • Result of multiple sub-threshold skin insults without sufficient time between them for complete restoration of s kin barrier function Asteatotic • Special variant seen primarily during dry winter months a/w severe pruritus, ichthyosiform scale Traumatic • Can develop after acute skin trauma such as burns, lacerations, or acute ICD • Characterized by eczematous lesions on hands, last for weeks-month with redness, infiltration, scale, and fissuring Pustular/ • Results from exposure to certain irritants such as metals, croton oil, acneiform mineral oils, tars, greases, cutting and metal working fluids, and naphthalenes Subjective or • Reports of stinging/burning in absence of visible cutaneous signs of sensory irritations • Irritants: propylene glycol, hydroxyl acids, ethanol, lactic acid, azelaic acid, benzoic acid, benzoyl peroxide, mequinol, tretinoin Airborne • Irritant-exposed sensitive skin of face, periorbital regions Frictional • Due to repeated low-grade frictional trauma, usually involves hyperkeratosis, acanthosis, lichenification and can progress to thickening, hardening, and increased toughness

• Treatment –– Avoidance of irritants –– Treatment with maintenance measures, at earliest sign of skin changes –– Topical corticosteroids, systemic steroids, PUVA or NB-UVB Plant Dermatoses • Plant reactions can be classified into: –– Urticaria: immunologic and non-immunologic/toxin-mediated –– Irritant dermatitis: mechanical and chemical

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39

–– Phototoxic dermatitis (phytophotodermatitis) –– Allergic contact dermatitis • Immunologic contact urticaria –– Risk factors: atopy, frequent contact with fresh fruits and vegetables –– Oral allergy syndrome = mucosal contact urticarial caused by antigens similar to allergenic pollen ◦◦ Cross-sensitized to pollen and similar allergens in fruits/vegetables ◦◦ After eating a cross-reacting food → sudden IgE-mediated oral cavity itching, stinging, pain, edema of lips/tongue/palate ◦◦ GI symptoms and anaphylaxis possible if enough ingested ◦◦ Birch pollen → cross-react with apples, pears, cherries, pears, plums, apricots, almonds, celery, carrots, potatoes, kiwis, hazelnuts, mangoes ◦◦ Usually edible when heated –– Protein contact dermatitis = eczematous eruption arising from repeated urticarial reactions ◦◦ Describes chronic dermatitis where patch tests NEG, prick tests to large protein allergens POS ◦◦ Patients develop a chronic dermatitis that acutely urticates within minutes of contact with offending allergen ◦◦ One of mechanisms by which plants can cause chronic hand/fingertip eczema –– Common urticants: vegetables (celery, onions, potatoes, lettuce), fruits (tomatoes, bananas, lemons), herbs (parsley, dill), nuts, shrubs, algae, lichens, trees, grasses ◦◦ IgE-mediated release of vasoactive mediators from mast cells → local urticarial ∗mostly histamine • Toxin-mediated (non-immunologic) contact urticaria –– Most common cause: stinging nettles (Urtica dioica) –– Plants have sharp hairs = trichomes –– Rubs off and releases irritant chemical cocktail of histamine, acetylcholine, serotonin –– Wheals, erythema, burning, pruritus –– Paresthesias can last 12+ h • Mechanical irritant dermatitis –– Plants that can inflict mechanical injury via small or large emergencies –– Glochids = tufts of hundreds of short barbed/hooked hairs that arise from pincushion-like structures called areoles –– Sabra dermatitis = form of glochid dermatitis from prickly pears (Opuntia), pruritic papular eruption, can erupt with rash resembling fiberglass dermatitis or scabies –– Treatment: detach, apply glue/gauze, after dried, peel off gauze

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• Chemical irritant dermatitis –– Calcium oxalate is one of most common chemical irritants ◦◦ Dumb cane—if chewed can cause salivation, burning, edema, blistering, hoarseness/aphonia requiring IV steroids ◦◦ Pineapple—enhances irritancy of other chemicals, creates microabrasions that let bromelin in to exert proteolytic effect in dermal blood vessels (wear nitrile gloves) ◦◦ Daffodils, hyacinths—bulb dermatitis, dryness, scaling, fissures, erythema –– Latex—seen in spurges, Manchineel tree in Caribbean during rainstorm can cause intense swelling by transfer of latex by rain, and poinsettia latex is only mildly irritating –– Buttercups contain ranunculin, which is converted to protoanemonin after plant injury → causes severe, linear vesiculation that can resemble early phytophotodermatitis –– “Chili burns” from those removing skins of chili peppers, capsaicin depolarizes nerves—erythema only –– Century plant—pruritus/stinging due to latex-derived calcium oxalate crystal and saponins • Phytophotodermatitis –– –– –– ––

Phototoxic reactions with erythema + delayed hyperpigmentation UVA + topical/oral contact with photosensitizer Apiaceae and Rutaceae family plants are common causes Apiaceae features floral umbel with small flowers held together ◦◦ Major causes of phytophoto are hogweeds

–– Rutaceae includes citruses –– Moraceae is the mulberry family, includes the fig tree which contains psoralens in sap of leaves/shoots –– Psoralens (furocoumarins) form reactive oxygen species in presence of UVA (320–340 nm peak effectiveness) –– Furocoumarins serve function to protect plants from fungal attack –– Erythema, edema, bullae within 24 h, peak at 72 h after contact with furocoumarins + UVA exposure –– Hyperpigmentation 1–2 weeks after (can last months-years) • Allergic contact dermatitis –– Anacardiaceae and Asteraceae families most common causes of ACD due to plants –– Most common allergenic plants and botanical screening trays in patch testing ◦◦ Asteraceae family • Compositae mix 6%, sesquiterpene lactones mix

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41

◦◦ Rutaceae family • Neroli oil 4% ◦◦ Myrtaceae family • Lavender 2% ◦◦ Lamiaceae family • Spearmint oil 5% ◦◦ Geraniaceae family • Geranium oil 2% ◦◦ Rosaceae family • Rose oil (Bulgarian) 2% ◦◦ Santalaceae family • Sandalwood oil 2% ◦◦ Asteraceae family • Dandelion 2.5% –– Main allergens in toxicodendron are catechols –– Anacardiaceae and related families—allergens are long-chain catechols and resorcinols found in the urushiol oleoresin –– Most common allergenic members of Anacardiaceae family and cross-reactants: ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Poison ivy, poison oak, poison sumac (Toxicodendron) Cashew nut tree (Anacardium occidentale) Mango tree (Mangifera indica) Indian marking nut tree (Semecarpus anacardium) Japanese lacquer tree (Toxicodendron verniciflua) Rengas tree (Gluta renghas) Brazilian pepper tree or Florida holly (Schinus terebinthifolius) Cross-reactors Ginkgo tree (Ginkgo biloba) → contain allergenic catechol ginkgolic acid ◦◦ Spider flower, silk oak, Hawaiian tree, kahili tree (Grevillea) → pentadecylresorcinol

–– Urushiol partly water-soluble allergen, should be washed off –– Develops up to 3 weeks after primary contact or within hours after secondary contact –– Predominant effector cells against poison ivy catechols are CD8+ (why AIDS patients still react) –– “Black spot” poison ivy dermatitis occurs when urushiol acts as both irritant and allergen, and oxidized resin creates black discoloration on the skin

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–– Erythema multiforme can be sequela of severe poison ivy rxns 2 weeks after ACD ∗∗Erythema multiforme can be seen in setting of severe ACD to poison ivy/oak/sumac (Anacardiaceae), tea tree oil (Myrtaceae), and wild feverfew (Asteraceae) –– Asteraceae and related families—allergens are sesquiterpene lactones (SQLs) –– Most common allergenic members of Asteraceae family: ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

American ragweed (Ambrosia) Dandelion (Taraxacum officinale) Pyrethrum (Tanacetum cinerariifolium) Scourge of India, congress grass, wild feverfew (Parthenium hysterophorus)—probably most common cause of Asteraceae dermatitis worldwide Chrysanthemum (Dendranthema cultivars)—common cause of SQL dermatitis—most common for home gardeners Sunflower (Helianthus annuus)—windblown trichomes can cause airborne contact dermatitis Endive (Cichorium endive) Artichoke (Cynara scolymus)

–– Remember patch testing for SQL—“Compositae mix” –– Resembles airborne contact dermatitis, with chronic pruritus and lichenified dermatitis –– Parthenium hysterophorus accounts for 40% of all ACD visits in India, most commonly an airborne pattern –– Alliaceae can also cause ACD (garlic most common), irritant and allergen is diallyl disulfide → remember that disposable gloves like vinyl, latex, polyethylene, and nitrile do NOT protect, can use rubber gloves –– Alstroemeriaceae and Liliaceae can cause “tulip fingers” which is a combined ACD/ICD, and tuliposide A is a glycoside that is converted via acidic hydrolysis into tulipalin A which is allergen –– Myrtaceae increasingly reported as cause of ACD, most sensitizers are degradation product after exposure to light, warmth, and moisture

3.2  Papulosquamous Dermatoses I. Psoriasis • Chronic, immune-mediated disorder • Major associated systemic manifestations: psoriatic arthritis (asymmetric oligoarthritis) > depression, metabolic syndrome, cardiovascular disease • Peaks: 20–30 and 50–60 –– 75% present at 50% have ↑ antistreptolysin O, anti-DNase B, streptozyme titer Erythrodermic Generalized erythema, scaling Triggered most often by discontinuation of steroids Impetigo Generalized pustular psoriasis in pregnancy herpetiformis Pregnancy-associated, begins in flexures and generalizes Von Zumbusch Painful skin, associated with ↑ WBC, ↓ albumin, ↓ Ca2+ Palmoplantar Sterile pustules of palmoplantar surface admixed with yellow/brown pustulosis macules Minority have chronic plaque psoriasis elsewhere Can be a/w SAPHO—synovitis, acne, pustulosis, hyperostosis, osteitis Acrodermatitis Pustules on distal digits, can be in nail bed (beneath nail plate) and associated with nail shedding continua of May be a/w annulus migrans of the tongue Hallopeau Scalp One of most common sites for psoriasis—often advances onto periphery of face, retroauricular, posterior upper neck #1 cause of pityriasis amiantacea, can coexist with seborrheic dermatitis Inverse Shiny, pink, thin plaques in skin folds and creases, often with central fissures Oral Annulus migrans—presents like geographic tongue, seen in pustular psoriasis, migratory annular erythematous lesions with hydrated white scale Nails Fingernails > toenails, ↑ incidence of psoriatic arthritis (10–80% have nail involvement) Proximal matrix → pits Distal matrix → leukonychia, subungual hyperkeratosis Entire matrix → crumble, poorly adherent nail Nail bed → oil spots, Salmon patches, splinter hemorrhage, onycholysis, subungual hyperkeratosis

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Box 3.5 Variants of Psoriatic Arthritis Type Mono- and asymmetric oligoarthritis (60–70%) Arthritis of distal interphalangeal joints (16%)

Rheumatoid arthritis-like presentation (15%) Arthritis mutilans (5%)

Spondylitis and sacroiliitis (5%)

Clinical findings • Most common • DIP & PIP of hands, feet • “Sausage” digit • MCP typically not involved • Exclusive DIP joints • Uncommon but classic • “Sausage” digit and nail changes • Joints can become fixed in flexed position • Symmetric polyarthritis of small and medium joints—PIP, MCP, wrist, ankle, elbow • Seronegative for RF • Least common • Severe, rapidly progressive joint inflammation • Digits shorter, wider, soft from osteolysis, telescoping • Often HLA-B27+ • May have associated IBD, uveitis • Resembles ankylosing spondylitis—axial arthritis, knees, sacroiliac joints

• Histopathology –– Papulosquamous lesions: –– Initial lesion—perivascular infiltrate of lymphocytes, macrophages, papillary edema, dilation of capillaries –– Active lesion—↑ capillaries, edema, perivascular lymphocytes, neutrophils, epidermal acanthosis, focal neuts ◦◦ Spongiform pustule of Kogoj—neutrophils within spongiotic pustule ◦◦ Microabscess of Munro—neutrophil remnants in st. corneum surrounded by parakeratosis –– Stable lesion—characteristic acanthosis, squared off appearance –– Pustular psoriasis –– Accumulation of neutrophils is predominant feature—accumulates between eosinophilic strands of keratinocytes • Treatment –– Topicals: retinoids (tazarotene), salicylic acid, coal tar, steroids, anthralin, vitamin D3 analogs –– Systemic: apremilast (PDE4 inhibitor), tofacitinib (JAK1/3 inhibitor), MTX, cyclosporine, acitretin, biologics –– See Box 3.6 for preferred treatments for psoriasis in the setting of comorbidities

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Box 3.6 Psoriasis Treatments in the setting of comorbidities Comorbidity Immunosuppression (HIV/ AIDS) H/o internal malignancy H/o numerous skin cancers Pregnancy

Topicals Phototherapy Systemics Yes Yes (UVB) Retinoids Yes Yes Yes

Yes No Yes (UVB)

Liver disease Hepatitis B/C

Yes Yes

Yes (UVB) Yes (UVB)

Metabolic syndrome

Yes

Yes

Retinoids Retinoids Biologics (pregnancy B), cyclosporine (pregnancy C) Biologics Biologics (etanercept > adalimumab, ustekinumab.> secukinumab) MTX, cyclosporine, biologics

Box 3.7 Summary of Biologic Treatments for Psoriasis Biologic Etanercept Adalimumab Infliximab Ustekinumab

Target TNF-α TNF-α TNF-α P40 subunit of IL-12/23 Guselkumab IL-23 Secukinumab IL-17A Ixekizumab IL-17A Brodalumab IL17 receptor

Notes Do not use if high titer ANA+, autoimmune connective tissue disorder, blood dyscrasia, congestive heart failure, or demyelination disorder Do not use if BCG vaccine received within 12 months

Do not use in active Crohn disease (can exacerbate)

–– See Box 3.7 for summary of biologic therapies –– Topical steroids and vitamin D3 analogues: 1st line for mild-moderate psoriasis –– Anthralin and topical retinoids: 2nd line therapy as monotherapy or in combination –– Methotrexate: 1st line for chronic plaque, pustule, erythrodermic, severe nail psoriasis –– Apremilast: main adverse effects are GI disturbance, depression –– Phototherapy: 1st line for moderate-severe psoriasis –– NB-UVB (311-313), BB-UVB (more effective for guttate psoriasis) –– Goeckermann: crude coal tar + BB-UVB –– Pustular psoriasis: acitretin > cyclosporine, MTX, biologics –– Impetigo herpetiformis: early delivery, prednisone –– Guttate: BB-UVB –– Erythrodermic: cyclosporine, infliximab, acitretin

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II. Pityriasis rubra pilaris • • • •

Most acquired, some familial (See Box 3.8) AD: CARD14 mutation (PSORS2 psoriasis susceptibility gene) Usually self-limited, resolving 3–5 years in almost all cases PRP-type eruption can be seen in patients with dermatomyositis (Wong type) and CTCL • Tx: isotretinoin, acitretin, MTX > TNF-α, secukinumab, ustekinumab –– Topical steroids, tar, calcipotriene, keratolytics, tretinoin can be used as adjuncts to therapy III. Pityriasis lichenoides • Both characterized by recurrent crops of spontaneously regressing erythematous papules • Unclear pathogenesis—possible response to foreign antigens such as infectious agents and drugs, infections (HIV, parvovirus B19), medications (estrogen-progesterone, TNF-α inhibitors, statins), and radiocontrast dye • Diffuse distribution associated with faster resolution • Lesional T-cell infiltrates –– CD8+ in pityriasis lichenoides et varioliformis acuita (PLEVA) –– CD4+ in pityriasis lichenoides chronica (PLC) • Occasionally a/w other lymphoproliferative disorders such as CTCL, Hodgkin disease, other lymphomas

Box 3.8 Clinical Subtypes of PRP Type I Classic adult

55%

Type II Atypical adult

5%

Type III Classic juvenile Type IV Circumscribed juvenile Type V Atypical juvenile Type VI HIV-associated

10% 25%

5% systemic steroids, IVIg, cyclosporine IV. Pityriasis rosea • • • • • •

Acute, self-limited Slight female predilection, lasts 6–8 weeks Possible HHV-6 and HHV-7 link Lesions follow Langer cleavage lines Atypical forms: inverse, urticarial, EM-like, vesicular, pustular, purpuric Some drug eruptions can mimic PR: ACEI, β-blockers, metronidazole, isotretinoin, arsenic, bismuth, gold, barbiturates, clonidine, HCTZ, imatinib, omeprazole, terbinafine, TNF-α inhibitors, NSAIDs –– Typically slower to resolve

• Tx: Topical steroids or antipruritic lotions • Severe cases may need UVB phototherapy or natural sunlight, oral antihistamines V. Pityriasis rotunda • • • • •

Asymptomatic dermatosis Seen in Far East and Mediterranean population Adults 25–45 years, F > M slightly May be a/w malnutrition Large circular polycyclic lesion, hyperpigmented with sharp margin, no inflammation, fine scale

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–– Type I: hyperpigmented lesions, blacks and Asians, possibly internal malignancy –– Type II: numerous lesions, Caucasians, no internal malignancy • Tx: topical lactic acid, urea, tars, emollients, corticosteroids, tretinoin VI. Granular parakeratosis • Seen in adult women > infants • Acquired keratotic dermatosis—possibly due to disorder of keratinization • Keratotic brown-red papules coalescing into plaques in intertriginous areas • Pruritus, irritation most common • Bx: thickened compact st. corneum with visible retention of basophilic keratohyalin granules within areas of parakeratosis • Tx: topical steroids, vitamin D, retinoids, ammonium lactate, antifungals

3.3  Lichenoid Dermatoses I. Lichen planus (LP) • • • • • • •

Prototype of lichenoid dermatoses Idiopathic inflammatory disease of skin, mucous membranes 0.2–1% adults (cutaneous); 1–4% (oral) Affects 50–60s (2/3rds develops between 30–60 years) Up to 75% of cutaneous LP have oral involvement Only 10–20% with oral LP eventually develop cutaneous LP Pathogenesis –– T-cell-mediated autoimmune damage to basal keratinocytes that express altered self-antigens –– Target antigens: T cells that normally do NOT respond to skin-­restricted antigens are primed by exogenous agent that have cross-reactive antigens that can activate autoreactive T cells via molecular mimicry –– Hepatitis C virus (HCV)—higher prevalence, strongest association in Japanese, Mediterranean populations ◦◦ Oral LP most commonly viewed as manifestation of HCV infxn ◦◦ ↑ frequency of HLA-DR6 allele in Italian patients with HCV-associated oral LP –– Other viruses ◦◦ ◦◦ ◦◦ ◦◦

HHV-6 HHV-7 Sporadic case reports of HSV, VZV Possible link with HPV

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51

–– Contact allergens ◦◦ Metals—exacerbate/induce oral LP ◦◦ Amalgam (mercury), Copper, Gold—up to 95% have improvement after removing sensitizing metal –– Drugs ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ –– –– –– –– ––

ACEI, propranolol Chloroquine, hydroxychloroquine, quinacrine TNF-α (etanercept, infliximab) HCTZ, chlorothiazide Gold salts NSAIDs Nivolumab, pembrolizumab Penicillamine Quinidine

Autoantigens (including tumor antigens) HLA-B27, HLA-B51, HLA-Bw57 → oral LP in English HLA-DR1 → cutaneous and oral LP HLA-DR9 → oral LP in Chinese, Japanese HLA-DR6 → HCV-associated oral LP

• Characterized by flat-topped, violaceous papules and plaques favoring wrists, forearms, genitalia, shins, and presacral area • Wide range of clinical presentation (See Box 3.9)

Box 3.9 Clinical Variants of Lichen Planus Actinic Acute (exanthematous) Annular Atrophic Bullous Lichen planus pemphigoides Hypertrophic Inverse Lichen planus pigmentosus

Young, spring/summer, sun-exposed skin of face > neck, dorsal hands/arms Rapid dissemination, trunk, inner wrists, dorsal feet Papules spread peripherally, central area resolves, annular in 10%, axillae > penis, extremities, groin, often asymptomatic Intertriginous zones, legs, more due to thinning of epidermis than degeneration of elastic fibers Vesicles, bullae within pre-existing LP lesions due to intense lichenoid inflammation and epidermal damage Circulating IgG ab against BPAG1, BP180—diagnosis of LP usually precedes LP verrucosus, symmetric/chronic on shins and dorsal feet, extremely pruritic, SCC can arise Inverse distribution in intertriginous zones (axillae > inguinal/ inframammary > popliteal and antecubital fossae) Brown-gray macules in sun-exposed areas of face, neck, favors skin types III, IV and can involve intertriginous sites

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Box 3.9  (cont.) Actinic Lichen planopilaris

Linear Discoid lupus erythematous/LP overlap Nail Oral

Ulcerative Vulvovaginal Drug-induced

Young, spring/summer, sun-exposed skin of face > neck, dorsal hands/arms Follicular LP or LP acuminatus—keratotic plugs with violaceous rim, can affect hair bearing sites Graham-Little-Piccardi-Lassueur syndrome: Non-cicatricial loss of pubic and axillary hair and disseminated spinous or acuminated follicular papules; typical cutaneous or mucosal LP; scarring alopecia of scalp Affects sites of scratching or trauma Typically affects acral sites

Nail affected in 10% of patients with LP, lateral thinning, longitudinal ridging, fissuring—due to matrix damage Many forms: atrophic, bullous, erosive, popular, pigmented, plaque-­like, reticular Considered “premalignant condition” due to risk of SCC Ulcers within palmoplantar lesions (esp soles), chronic ulcerative at risk for SCC Vulvovaginal-gingival when oral mucosal involvement, monitor for SCC More generalized, eczematous/psoriasiform or PR-like, mucous membranes spared

• Histopathology –– –– –– –– –– –– –– –– ––

Hyperkeratosis without parakeratosis Oral LP often show parakeratosis, atrophic epidermis Focal increases in granular layer Irregular acanthosis with sawtooth vacuolar degeneration of basal cell layer Colloid bodies—apoptotic or dyskeratotic keratinocytes—Civatte, hyaline, cytoid bodies Vacuolar changes in basal cell layer can become confluent, create small separations between epidermis and dermis = Max-Joseph spaces Pigment incontinence, dermal melanophages LPP—inflammation in upper ½ follicle (isthmus affected in 1/3 patients) DIF: colloid bodies stain for IgM, IgA, IgG, C3—non-specific sponge-like manner

• Treatment –– TCS, TCI, systemic steroids, sulfasalazine, acitretin –– 308 nm excimer laser for oral LP, NB-UVB, PUVA, UVA1 –– Intralesional steroids, oral metronidazole, griseofulvin, apremilast, lowdose MTX, mycophenolate mofetil, thalidomide

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53

–– Hydroxychloroquine for LPP, FFA –– Oral sulfasalazine for cutaneous LP –– Low-dose MTX for oral LP II. Lichen striatus • Linear lichenoid dermatosis → often with residual hypopigmentation • Blaschko linear acquired/inflammatory skin eruption = BLAISE • Band of discrete or clustered pink/tan papules that are flat-topped, smooth, or scaly • Often single unilateral streak on extremity along Blaschko lines—uncommon to involve trunk, head, neck • BX: lymphoid aggregates perivascular and in eccrine coil • DDx: linear porokeratosis, linear psoriasis, ILVEN, linear lichen sclerosus, linear GVHD • TX: not needed, self-limited III. Lichen nitidus • Tiny skin-colored pinhead-sized papules—flat, shiny surface • Flexor aspects of arms, chest, abdomen, genitalia, dorsal hands (oral lesions rare), nail involvement in 10% with pitting, rippling, longitudinal ridging, terminal splitting, increased longitudinal linear striations • Koebner phenomenon • BX: Ball and claw with overlying atrophic epidermis • Tx: TCS, oral antihistamines, TCI, for generalized—systemic CS, NB-­ UVB, PUVA IV. Erythema dyschromicum perstans • Ashy dermatosis • Seen in darkly pigmented Latin Americans, occasionally in Asians and Caucasians • Occurs in 1st to 3rd decades of life • Slow progression of gray/brown/blue macules and patches • Many oval, follow skin cleavage lines (similar to pityriasis rosea) • Neck, trunk, proximal arms—often symmetric • Typically spares palms, soles, scalp, mucous membranes; occasionally can be asymmetric and follow Blaschko’s lines • BX: Vacuolization of basal layer, colloid bodies, mild lichenoid lymphocytic infiltrate—seen in active border, pigment incontinence—seen in chronic inactive ashy-colored lesions—indistinguishable from postinflammatory hyperpigmentation (PIH) • DDx: PIH, PR, LP, generalized fixed drug eruption • TX: sun protection, TCS, retinoids, vitamin C, chemical peels, oral abx, vitamin A, antimalarials, griseofulvin, systemic CS V. Keratosis lichenoides chronica • Violaceous keratotic lichenoid papules in linear/reticulated pattern

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• Symmetric on limbs and trunk • Greasy, scaly eruption involving upper part of face—seb derm-like mid-facial eruption or psoriasiform scaling plaques • Keratotic papules may be present on palms and soles, nails/scalp can be affected • BX: Similar to LP • TX: topical or systemic CS, MTX, cyclosporine, vitamin A, PUVA

3.4  Follicular and Apocrine Diseases I. Acne vulgaris • Multifactorial disorder of pilosebaceous unit • Affects all age groups, peaks in adolescence • Risk factors –– ↑ risk in XYY karyotype, PCOS, hyperandrogenism, hypercortisolism, precocious puberty –– Genetic factors: number, size, activity of sebaceous glands, high concordance for prevalence/severity among identical twins –– Dietary factors: remains controversial, some studies show skim milk positively a/w acne prevalence/severity, exacerbation with use of whey protein supplements for body building, possible vitamin B12 trigger, and link with high glycemic-load diet • Pathogenesis –– Follicular hyperkeratinization: corneocytes accumulate due to increased follicular keratinocyte proliferation and corneocyte cohesiveness → hyperkeratotic plug → formation of microcomedo (precursor of all clinical acne lesions) –– Hormonal influence on sebum production/composition: sebaceous gland controlled by androgens (especially DHT—principal androgen mediating sebum production) –– Androgen receptors found in basal layer of sebaceous gland and ORS of hair follicle –– Sebaceous gland activity affected by androgens in neonatal period and at adrenarche –– Inflammation (mediated by P. acnes) –– P. acnes produces TLR2 → activates TLR2 pathway and stimulates release of proinflammatory mediators: IL-1α, IL-8 (causes neutrophil recruitment), IL-12 (promotes Th1 response), TNF-α, MMP –– P. acnes increases keratinocyte expression of TLR2 and TLR4 –– P. acnes activates NOD-like receptor protein 3 (NLRP3) of inflammasomes in cytoplasm of neutrophils and monocytes → release of proinflammatory IL-1β • Found in sites with well-developed sebaceous glands (face, upper trunk) • Acne variants (See Box 3.10)

3.4 Follicular and Apocrine Diseases

Box 3.10 Acne Variants Post-adolescent Inflammatory acne in women >25 years, associated with high level acne psychologic stress Usually affects mandibular area Acne fulminans Most severe form of acne, abrupt development nodular and suppurative lesions with systemic manifestations: fever, arthralgias, myalgias, hepatosplenomegaly, severe malaise Osteolytic bone lesions (clavicle, sternum most often) Boys 13–16 years, affect face, neck, trunk, arms, and can ulcerate and lead to significant scarring Erythema nodosum can be associated ToC: prednisone monotherapy for 2–4 weeks followed by low-dose isotretinoin for 4 weeks, then slowly increase isotretinoin to avoid paradoxical flare during acute inflammatory phase Others: topical/intralesional corticosteroids, oral antibiotics, TNF-α inhibitors, IL-1 antagonists, azathioprine, cyclosporine, dapsone Acne Severe nodulocystic form of acne with eruptive onset without systemic conglobata manifestations Part of follicular occlusion tetrad: dissecting cellulitis of scalp, hidradenitis suppurativa, pilonidal cyst, acne conglobata PAPA—sterile pyogenic arthritis, pyoderma gangrenosum, acne conglobata (PSTPIP1 mutation) PAPASH—pyogenic arthritis, pyoderma gangrenosum, acne, suppurative hidradenitis Solid facial Solid facial edema, woody induration, impaired lymphatic drainage edema and fibrosis ToC: tretinoin Others: prednisone Neonatal acne Neonatal cephalic pustulosis Seen in >20% healthy newborns around 2 weeks of age, resolves within 3 months, papules and pustules on cheeks, foreheads, eyelids, chin, upper trunk Infantile acne Presents at 2–12 months of life, prominent comedo formation, pitted scarring, occasional deep suppurative nodules Resolves within 6–18 months but associated with ↑ severe acne during adolescence Toc: topical retinoids, benzoyl peroxide Others: erythromycin, azithromycin, isotretinoin for severe cases Mid-childhood Seen in children between 1–7 years, possibility of underlying acne hyperandrogenic condition should be considered Preadolescent Seen in children 7–11 years of age, primarily comedonal, favors acne forehead and central face Acne excoriée Excoriation of typical comedones and inflammatory papules, residual crusted erosions and scars, seen most often in young women

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• Acneiform eruptions –– Drug-induced acne: anabolic steroids, bromides, corticosteroids, EGFR inhibitors, iodides, isoniazid, lithium, MEK inhibitors (trametinib), phenytoin, progestins –– Occupational acne: comedones with papules, pustules, cystic lesions due to exposure to insoluble, follicle-occluding substances such as cutting oils, petroleum-based products, chlorinated aromatic hydrocarbons, coal tar derivatives –– Acne cosmetica: comedonal acne (mostly closed comedones) due to chronic exposure to follicle-occluding cosmetics –– Pomade acne: comedonal facial acne at the forehead and temples due to follicle-­occlusion by hair products –– Chloracne: occurs several weeks after systemic exposure to halogenated aromatic hydrocarbons (percutaneous absorption, inhalation ingestion)—found in insecticides, insulators, fungicides, herbicides, wood preservatives –– Acne mechanica: comedo formation due to repeated mechanical and frictional obstruction of pilosebaceous unit –– Tropical acne: acneiform eruption after exposure to extreme heat –– Radiation acne: comedo-like papules at sites of previous exposure to therapeutic ionizing radiation –– Pseudoacne of the nasal crease: transverse nasal crease with milia, cysts, and comedones lining up along the fold –– Idiopathic facial aseptic granuloma: affects young children, usually single painless nodule on cheek, resolve spontaneous after 1 year –– Childhood flexural comedones: discrete, double-orifice comedones localized to axillae > groin, usually single lesion, and no association with hidradenitis suppurativa, acne vulgaris, or precocious puberty • Histopathology –– Early: microcomedones, mildly distended follicle, prominent granular layer –– Closed comedones: ↑ follicular distention, compact cystic structure containing keratinaceous debris, hair, bacteria, atrophic/absent sebaceous glands –– Late: rupture of cystic contents, marked inflammatory response, neutrophils, foreign body granulomatous inflammation • Treatment –– Mild comedonal: topical retinoid –– Others: azelaic acid, salicylic acid –– Mild popular/pustular: benzoyl peroxide ± topical antibiotic or topical retinoid + topical antimicrobial –– Others: azelaic acid, salicylic acid, topical dapsone –– Moderate popular/pustular: oral (or topical) antibiotic + topical tretinoin ± benzoyl peroxide –– Others: oral contraceptive/antiandrogen

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–– Moderate nodular: oral antibiotic + topical tretinoin ± benzoyl peroxide –– Others: oral isotretinoin, oral contraceptive/antiandrogen, azelaic acid, intralesional corticosteroid –– Severe: oral isotretinoin (may require oral corticosteroid) –– Others: oral antibiotic, topical tretinoin, benzoyl peroxide, oral dapsone, intralesional corticosteroid, oral contraceptive/antiandrogen II. Rosacea • Encompasses constellation of signs/symptoms: persistent facial erythema, telangiectasias, flushing, non-pitting facial edema, ocular inflammation, phymatous changes • Rosacea fulminans: explosive onset of inflammatory papules/pustules on background of facial erythema, ± fever • Rosacea conglobata: inflammatory facial cysts with associated scarring • Granulomatous rosacea: persistent red-brown to skin-colored facial papules with non-caseating granulomatous histology • Seen most in Caucasians, fair skin type, genetic predisposition • Pathogenesis –– May be related to UV exposure and photodamage → production of ROS, induces upregulation of matrix metalloproteinases → damage to blood vessels and dermal matrix –– Upregulation of cathelicidin and its processing serine protease (kallikrein 5) –– Elevated expression of VEGF, CD31, and lymphatic endothelial marker D2-40 –– Neurogenic inflammation can result in vasodilation, extravasation of plasma proteins, recruitment of inflammatory cells • Middle age onset • 4 major forms: –– Erythematotelangiectatic: tendency for flushing, background of persistent facial erythema –– Papulopustular rosacea: centrofacial eruption of multiple small erythematous papules –– Phymatous rosacea: hypertrophy of sebaceous glands (earliest sign are dilated pores—patulous follicles) –– Ocular rosacea: nonspecific complaints of itching, tearing, dryness, gritty sensations, crusting of eyelids, inability to wear contact lenses, meibomian glands (chalazion) • Other variants: granulomatous rosacea, rosacea fulminans (pyoderma faciale) • Histopathology –– Erythematotelangiectatic—can be subtle, vascular ectasia and mild edema –– Papulopustular—more prominent perivascular and perifollicular lymphohistiocytic infiltrate –– Granulomatous—non-caseating epithelioid granulomas within dermis

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• Treatment –– Erythematotelangiectatic: therapy focused on preventing flushing, facial skin care, avoidance of sun exposure –– Papulopustular: topical and systemic antibiotics –– Rhinophyma: isotretinoin, CO2 laser, electrosurgery, surgical excision • Rosacea-like disorders –– Morbihan’s disease: progressive then persistent asymptomatic non-pitting swelling of the central upper face, a/w fixed facial erythema –– Periorificial dermatitis: superficial resemblance to rosacea but there are superficial papulovesicles or papulopustules in the same stage of development usually perioral –– Rosaceiform dermatitis: drug eruption caused by application of topical calcineurin inhibitors to face –– Papulopustular eruptions due to EGFR inhibitors: increasingly seen –– Steroid-induced rosacea –– Pityriasis folliculorum: affects young/middle-aged women, rough white scaly skin surface on background of faint erythema and scattered fine papules and pustules –– Haber’s syndrome: rare familial genodermatosis characterized by earlyonset facial erythema, verrucous papules, truncal keratotic lesions, pitted atrophic scars—sometimes grouped with Dowling-Degos disease and reticulate acropigmentation of Kitamura III. Folliculitis and other follicular disorders • Superficial folliculitis –– Follicular pustules on erythematous base on areas with terminal hairs, trunk, buttocks, and legs –– Most common infectious etiology is S. aureus –– Histopathology: perifollicular infiltrate of lymphocytes, neutrophils, macrophages, with extension into follicular epithelium –– Other forms: • Gram-negative folliculitis: Klebsiella, E. coli, Enterobacter, Proteus, seen in patients with acne receiving long-term antibiotic therapy, present with pustules in facial T zone; topical gentamicin, benzoyl peroxide, oral quinolone, or isotretinoin • Hot tub folliculitis: Pseudomonas aeruginosa, seen in patients after use of hot tub/whirlpool 12–48  h before onset, present with edematous pink/red follicular papules and pustules on trunk; self-limited • Dermatophyte folliculitis: T. mentagrophytes or T. verrucosum, seen in male farm workers, present as inflammatory papules and pustules in beard area, treat with terbinafine, griseofulvin, itraconazole • Majocchi granuloma: T. rubrum, seen in women who shave legs, present with follicular papules or nodules with pustules at edge; oral antifungals recommended

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• Malassezia (Pityrosporum) folliculitis: seen in young adults, may a/w antibiotic therapy, immunosuppression, present with pruritic follicular papules on back, chest, shoulders; topical antifungals, selenium sulfide, oral fluconazole or itraconazole • Candida folliculitis: seen primarily in diabetics, pruritic satellite pustules around intertriginous candidiasis; topical antifungals or oral fluconazole • Herpes simplex folliculitis: seen most often in men with history of facial HSV infection who shave with blade razor, rapid development of follicular pustules/vesicles; acyclovir, famciclovir, valacyclovir • Demodex folliculitis: may be associated with immunosuppression, erythematous follicular papules and pustules on face, nose, neck; topical ivermectin or permethrin, single dose oral ivermectin • Eosinophilic folliculitis –– 3 major types: ◦◦ Eosinophilic pustular folliculitis (Ofuji disease) • Characterized by recurrent crops of intensely pruritic grouped, follicular pustules and papules in sebaceous areas: face, back, extensor arms • Lesions last 7–10 days, tend to relapse • Treatment –– 1st line: oral indomethacin –– 2nd line: UVB phototherapy, minocycline, dapsone, systemic corticosteroids, colchicine –– 3rd line/refractory disease: cyclosporine ◦◦ Immunosuppression or HIV-associated eosinophilic pustular folliculitis • Chronic pruritic follicular popular eruption on face, scalp, upper trunk • Treatment: underlying viral infection, topical corticosteroids, UVB phototherapy ◦◦ Eosinophilic pustular folliculitis of infancy • Sterile pustules on erythematous base, most often on scalp, face, neck, trunk, extremities • Self-limited, treatment typically not required • Disseminate and recurrent infundibulofolliculitis –– Pruritic, 1–2 mm skin-colored papules on trunk, neck, buttocks, arms –– Resembles papular eczema –– BX: perifollicular edema, infiltration of lymphocytes in the infundibular portion of hair follicle –– TX: TCS, lactic acid preparations, PUVA, vitamin A and isotretinoin • Keratosis pilaris atrophicans –– Group of disorders with abnormal follicular keratinization along with atrophy and scarring alopecia –– TX: keratolytics, topical retinoids, topical or intralesional corticosteroids

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• Lichen spinulosus –– Symmetric clusters of follicular papules with central keratotic spine –– Favors neck, shoulders, extensor surfaces of arms, abdomen, buttocks, popliteal –– Resembles keratosis pilaris on histology –– TX: topical lactic acid, urea, salicylic acid preparations • Phrynoderma –– Seen in association with vitamin A deficiency most commonly –– Follicular papules with conical keratotic plugs on extensor surfaces of extremities • Pseudofolliculitis barbae –– Chronic disorder of beard area of men who shave –– Seen more often in individuals with darkly pigmented skin, tightly curled hair –– Caused by intrafollicular and transfollicular penetration of tightly curled hairs within the bearded area –– Present with inflammatory papules and pustules or firm papules and keloidal scars –– Definitive treatment is to stop shaving or laser therapy (1064 nm Nd:YAG) for hair removal • Acne keloidalis –– Most often seen in darkly pigmented skin –– Begins as folliculitis of the posterior scalp and neck, development of firm follicular papules –– Progresses into keloid-like plaques in band-like distribution at posterior hairline –– Associated alopecia, may develop subcutaneous abscesses with draining sinuses –– TX: 1st line is prevention, topical or systemic antibiotics, topical retinoids, intralesional corticosteroids, punch excision with hair transplant for advanced lesions, CO2 laser excision, oral isotretinoin • Hidradenitis suppurativa –– Cutaneous disorder of apocrine gland-bearing skin—axillae, anogenital region –– Women affected 3× more, higher incidence in individuals of African descent –– Pathogenesis ◦◦ Inflammatory disorder originating from hair follicle ◦◦ Familial form—AD, mutations of components of γ-secretase complex (NCSTN, PSEN1, PSENEN) ◦◦ Overproduction of IL-1β and TNF-α

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◦◦ Exacerbated by lithium and smoking • Inflammatory nodules and sterile abscesses form with predilection of axillae, groin, perianal, inframammary areas • Sinus tracts or double-ended pseudocomedones and hypertrophic scars form, may have associated chronic drainage • Complications: anemia, secondary amyloidosis, lymphedema, fistulae formation, SCC, hypercalcemia ◦◦ Treatment: ◦◦ General measures: weight reduction, reduce friction and moisture, antiseptic soaps, smoking cessation • Treatment: Topical antibiotics, oral antibiotics, oral anti-androgen therapy, intralesional corticosteroids, acitretin, TNF-α inhibitors (adalimumab, infliximab), cyclosporine, anakinra, ustekinumab • Surgical treatments: local excision, Nd:YAG laser treatments, CO2 laser ablation

3.5  Connective Tissue Disorders I. Lupus erythematosus • Strongest factors: –– Female (6:1 in SLE, 3:1 in cutaneous) –– African American race (4× higher in African American women, develop earlier, higher mortality) • Pathogenesis –– Complex—involves genetic, environmental factors (UVR, medications, possible viral triggers) –– Complex inflammatory cascade of cytokine, chemokine, inflammatory responses → lichenoid tissue reaction → cytotoxic keratinocyte damage –– TYK2, IRF5, CTLA4 are genes associated with SLE, DLE, SCLE –– TREX1 associated with familial chilblain lupus –– Anti-Ro/SSA associated with SCLE, neonatal lupus ◦◦ Anti-Ro60 (cell survival after UV radiation) ◦◦ Anti-Ro52 (regulatory role in inflammation) –– UVA, UVB exacerbates lupus → ◦◦ induce proinflammatory cytokines TNF-α, IL-1, HMGB1, IL-18, resulting in production of chemokines ◦◦ Upregulate antimicrobial peptides ◦◦ Release extracellular traps by dying neutrophils ◦◦ Cause complex production of chemokines from keratinocytes ◦◦ This increase in chemokines is seen within lesions of cutaneous LE— CCL5, CCL20, CCL22, CXCL8

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◦◦ Increased secretion of IFNα ◦◦ Increased CD123+ plasmacytoid and myeloid dendritic cells • 3 major forms of cutaneous lupus –– Discoid lupus erythematosus (DLE) ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Most common type of chronic cutaneous LE More sensitive to UVB than UVA as trigger 5–20% progress to SLE (↑ childhood, widespread DLE) Face, scalp, ears, can be widespread (somewhat photodistributed) Rarely, SCC develops within longstanding lesion ∗LE tumidus, lupus panniculitis, and chilblain lupus are often grouped under CCLE even though they often lack interface dermatitis (especially LE tumidus) ◦◦ See Box 3.11 for chronic cutaneous lupus erythematosus variants

Box 3.11 Chronic Cutaneous Lupus Erythematosus Variants Discoid LE

Hypertrophic LE

Chilblain LE

Tumid LE

LE panniculitis/ profundus

LE/LP overlap Mucosal LE

Clinical features Plaques with scaly border, central atrophy/ hypopigmentation, peripheral hyperpigmentation Scalp, face, ears Thick, hyperkeratotic plaques Favors upper half of body

Histologic features Vacuolar interface, epidermal atrophy, BMZ thickening, Follicular plugging, sup/deep lymphohistiocytic infiltrate, mucin deposition

Orthohyperkeratosis Endophytic buds of hyperplastic follicular epithelium (can look like SCC) DLE and papillary edema, Red/dusky purple papules/ plaques Fingertips, rims of perivascular/dermal lymphohistiocytic infiltrate ears, calves, heels Minimal epidermal change, Edematous, indurated massive mucin deposition annular plaques without epidermal change Face, trunk Lymphocytic lobular Indurated non-tender SQ nodules or plaques that heal panniculitis, dermal mucin, may have overlying DLE with atrophy Upper arms, trunk, breast, buttocks, thighs, face Coexisting DLE/LP Features of both Palmoplantar Hyperkeratosis, atrophy of Plaque with central rete pegs, sup/deep erythema, surrounding lymphocytic infiltrate white keratotic border Hard palate, buccal mucosa, vermillion lip

Notes +LBT 75% lesional skin ANA+ 5–25% DIF: +LBT ↑ SCC risk Persists all year round +LBT 50%

+LBT 35–70% 15% a/w SLE

+LBT ↑ SCC risk ↑ risk SLE if ulcerated

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–– Subacute cutaneous lupus erythematosus (SCLE) ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Typically photosensitive, sun-exposed distribution 30–50% progress to SLE HLA-B8, HLA-DR3 Associated with early complement deficiencies 20–30% linked with medication Terbinafine, HCTZ, TNF-α, PPI, calcium channel blockers, anti-epileptics, taxanes, thrombocyte inhibitors ◦◦ >>ACEI, β-blockers, doxorubicin, Interferon α and β, leflunomide, ranitidine, statins ◦◦ Associated with anti-SSA/Ro autoantibodies (also w Sjögren’s syndrome so there is overlap) ◦◦ SCLE and SCLE-like syndromes (see Box 3.12)

–– Acute cutaneous lupus (ACLE) ◦◦ Malar butterfly rash, sparing of nasolabial folds, knuckles spared ◦◦ Oral ulcerations ◦◦ Poikiloderma, atrophy, dyspigmentation on V-neck, upper back, extremities, hands (spares knuckles) ◦◦ Strongest association with SLE ◦◦ + EM-like lesions → “Rowell’s syndrome”

Box 3.12 SCLE and SCLE-Like Syndromes SCLE

Drug-­ induced SCLE

Neonatal LE

Clinical features Photosensitivity—50% Papulosquamous SCLE (psoriasiform plaques) Annular SCLE Lateral face, neck, V-chest, upper back Arthralgias most common systemic sx (70%)

Labs Anti-Ro/SSA (75–90%) Anti-La/SSB (30–40%) ANA, speckled (60–80%) Leukopenia Complement deficiency Skin always involved, rare to Anti-Ro/SSA (80%) have systemic Anti-La/SSB Photosensitive papulosquamous eruption Upper body Anti-Ro/SSA Transplacental pass of (99%) maternal ab (Ro/SSA) ↑ LFTs Annular erythematous Thrombocytopenia plaques, periorbital edema, cardiac (70% abnormality, 30–40% heart block), hepatobiliary (50%), heme

Notes 30–50% meet SLE ToC: antimalarials, photoprotection

HCTZ #1, terbinafine, griseofulvin, CCBs, NSAIDs, antihistamines, PPIs, docetaxel, ACEI, TNF-α (etanercept) 25% risk in subsequent children Prenatal CS, antimalarials Heart block irreversible

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–– Other findings suggestive of SLE ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Diffuse non-scarring alopecia Periungual telangiectasias Mucosal ulcers LCV > urticarial vasculitis, PNGD/IGDA Antiphospholipid syndrome Livedo reticularis, atrophie blanche, Degos-like lesions, ulcerations Papulonodular mucinosis 2° Raynaud’s Multiple eruptive dermatofibromas Calcinosis cutis

–– See Box 3.13 for drug-induced SCLE and SLE –– Additional variants ◦◦ Lupus erythematosus tumidus: Indurated erythematous plaques without scale or follicular plugging, epidermis appears uninvolved but there is intense dermal perivascular and periadnexal inflammatory infiltrate and mucin deposition, relative lack of serologies, low prevalence of SLE, low prevalence of Ig deposition leads some to question if truly variant of lupus or independent entity ◦◦ Lupus panniculitis: Intense inflammation in fat, affects face, scalp, upper arms, upper trunk, breasts, buttocks, thigh; If there are overlying discoid lesions, referred to as lupus profundus Box 3.13 Drug-Induced SCLE vs Drug-Induced SLE Culprit meds

Serology

Drug-induced SCLE Hctz #1 Terbinafine, Griseofulvin, Nsaids, Ccb, Antihistamines, Ppis, Docetaxel, Acei, etanercept + Ro/SSA (80%)

Exceptions

Clinical features

Always have skin findings, rare systemic Photosensitive papulosquamous eruption

Drug-induced SLE High risk: procainamide, hydralazine Med/low risk: quinidine, methyldopa, isoniazid, D-penicillamine, TNF-α, minocycline + anti-histone (95%) − dsDNA D-penicillamine may unmask true SLE Minocycline often-anti-histone, +ANCA TNF-α-induced +dsDNA, -anti-histone, ↓ complement Generally do not meet criteria, lack skin findings, milder or no systemic… EXCEPT TNF-α inhibitors almost always have skin involvement (malar rash photosensitivity, SCLE, DLE lesions) Arthritis/arthralgia (90%), myalgia (50%), serositis, fever, weight loss

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◦◦ Chilblain lupus (aka lupus pernio): Red/dusky papules and plaques on the toes, fingers, nose, elbows, knees, lower leg; Familial form (childhood onset)—TREX1, SAMHD1 • TREX1, SAMHD1, ADAR1, IFIH1, RNASEH2A/B/C → Aicardi-­ Goutières syndrome: AR autoinflammatory disorder with recurrent sterile fevers, progressive developmental delay, chilblains ◦◦ Neonatal lupus erythematosus (NLE): Neonatal form of SCLE—identical to adult SCLE histologically, ~100% are +anti-SSA/Ro (and occasionally anti-U1RNP); Occurs in infants to mothers with anti-SSA/Ro autoantibodies, Face (periorbital, scalp), Non-scarring, +dyspigmentation; Congenital heart block (+/- cardiomyopathy), hepatobiliary disease, thrombocytopenia; Cardiac NLE mortality 20%, 2/3 require pacemaker • Others: Bullous lesions, EM major, TEN-like eruption in ACLE or SCLE, Lupus/lichen planus overlap syndrome • Treatment –– Topical/intralesional corticosteroids mainstay –– Topical immunomodulators –– Hydroxychloroquine (200 mg once or twice daily) ◦◦ Eye toxicity minimized by not exceeding 6.5 mg/kg ideal body weight/ day –– Chloroquine (125–250 mg/day) –– Quinacrine (100 mg daily)—alone or in combination with hydroxychloroquine or chloroquine –– Others: retinoids, thalidomide, lenalidomide, dapsone (for bullous SLE), methotrexate, azathioprine, mycophenolate mofetil, systemic corticosteroids, sulfasalazine II. Dermatomyositis • Autoantigens activate a humoral immune process in which complement deposits in capillaries • Bimodal age distribution—adult and juvenile forms (malignancy in 25% adults) • 20% have clinically amyopathic disease • Affects women 2–3× more • Adult classic DM: ~50 years (malignancy 30%) • Adult amyopathic DM: ~50 years (malignancy 14%) • Juvenile classic DM: ~7.7 years (malignancy 0%) • Juvenile amyopathic DM: ~10.5 years (malignancy 0%) • Pathogenesis –– Immune-mediated process triggered by other factors in genetically predisposed individuals

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–– Patients with +antisynthetase ab often have overlap syndromes ◦◦ Antisynthetase syndrome: +ab, fever, erosive polyarthritis, “mechanic’s hands”, Raynaud phenomenon, interstitial lung disease –– Genetics ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

HLA-DR3, HLA-B8 (juvenile DM) HLA-DR52 (+anti-Jo1 ab DM) HLA-DR7, HLA-DRw53 (+anti-Mi-2 ab) HLA-B14, HLA-B41 (adult with DM overlap) HLA-DRB1∗15021 (Japanese juvenile DM) See Box 3.14 for dermatomyositis-related antibodies

–– Cellular immunity ◦◦ CD8+ lymphocytes in skin and muscle –– Humoral immunity ◦◦ Associated with autoimmune diseases (primary biliary cirrhosis, Hashimoto, Graves, myasthenia gravis, DM I, DH, vitiligo, other CTD) ◦◦ Upregulation of IFN and complement activation –– Infectious precipitants ◦◦ E. coli ◦◦ Coxsackivirus-9 myositis ◦◦ Echovirus in patients with hypogammaglobulinemia Box 3.14 Dermatomyositis Antibodies Jo-1 Mi-2 SRP Ku PL7, PL12 MDA5 (CADM) p155 (TIFγ), p140 (NXP2)

Anti-synthetase U1-RNP

↑ risk pulmonary fibrosis, Raynaud’s, polyarthritis Favorable prognosis Shawl sign, cuticular dystrophy Poor prognosis Cardiac disease Sclerodermatomyositis i.e. polymyositis overlapping with SLE, Sjogren syndrome, or scleroderma Pulmonary disease Clinically amyopathic DM (CADM) a/w ILD Cancer-associated myositis (except in kids)—Ovarian, GI a/w classic DM or CADM Rapid onset, skin necrosis, periungual erythema NXP2 especially a/w calcinosis and contractures in juvenile variant Rapidly progressive ILD, mechanic’s hands Mixed CTD

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–– Drug/vaccine precipitants ◦◦ Hydroxyurea, statins, TNF-α inhibitors, NSAIDs, cyclophosphamide, ipilimumab ◦◦ BCG vaccine –– Malignancy association ◦◦ TIF-1ɣ ab ◦◦ NXP-2 ab ◦◦ Up to 80% of patients with cancer-associated DM had antibodies to either of above • Cutaneous disease –– Heliotrope, facial erythema (involves nasolabial folds) –– Gottron’s papules (knuckles), Gottron’s sign (elbow, knees) –– Palmar papules—painful, a/w anti-CADM140 –– Poikiloderma on upper chest (V neck), upper back (shawl sign), lateral thigh (holster sign) –– Intensely pruritic (helps differentiate from lupus) –– Cuticular dystrophy, nail-fold telangiectasias –– Vasculitis—a/w malignancy in adults and Banker variant in juvenile –– Mechanic’s hands—a/w antisynthetase syndrome –– Calcinosis cutis (more in juvenile, 25–70%), a/w anti-p140 (NXP2) –– Others: flagellate erythema, acquired lipodystrophy, hypertrichosis, Raynaud’s phenomenon, erythroderma, psoriasiform dermatitis of the scalp –– Wong-type DM—Asians, mimics PRP –– See Box 3.15 for dermatomyositis variants • Systemic disease –– Myopathy—proximal (extensor: triceps, quadriceps) ◦◦ True dysphagia—consider overlap with systemic sclerosis ◦◦ Cricopharyngeal muscle dysfunction ◦◦ Distal esophageal involvement (can present as GERD) –– Pulmonary (15–30%) ◦◦ Diffuse ILD—resistant to corticosteroids, clinical course independent from muscle disease ◦◦ Higher risk of rapidly progressive lung disease in Eastern Asians with anti-­MDA5 (CADM) ◦◦ Higher risk in antisynthetase syndrome –– Cardiac ◦◦ Usually asymptomatic but can present as arrhythmia or conduction defect

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Box 3.15 Dermatomyositis Variants Adult CAM (cancer-associated)

Adult CADM (clinically amyopathic) Antisynthetase syndrome DM overlap syndromes

Juvenile dermatomyositis

Classic juvenile dermatomyositis Vasculopathic/ulcerative juvenile dermatomyositis

a/w p155/140 ab NO antisynthetase sx Ovarian, GI #1 Nasopharyngeal in Asians a/w ILD, CADM140 (MDA5) Acute onset, constitutional sx, Raynaud’s, mechanics hands, ILD Mixed CTD = U1RNP Polymyositis + SLE/Sjogren/Scleroderma = Ku DM/PM + scleroderma = PM-1 Not a/w malignancy, ↑ ↑ calcinosis cutis CADM140 (MDA5) = ILD P155/140 = extensive skin but NOT malignancy P140 (NXP2) = calcinosis cutis, contractures Brunsting variant, 90% Banker variant, men (except linear morphea) • 10% have substantial disability • Prevalence increases with age • 20% are children/teenagers, mean age 7 years, girls > boys • Pathogenesis –– Increased prevalence of ssDNA, topoisomerase IIα, phospholipid, fibrillin-1, and anti-histone antibodies –– High titers of ANA in juvenile patients with linear morphea and patients with generalized morphea –– Presence of ssDNA, AHA seems a/w increased risk of functional impairment –– Vascular changes ◦◦ Reduced capillaries ◦◦ Primary event may be hypoxia resulting from microvascular injury ◦◦ All based on what has been observed with SSc –– Fibroblasts ◦◦ Fibroblasts from sclerotic tissue produce increased amounts of collagen I, II, III and ECM proteins ◦◦ Fibroblasts maintain this phenotype for weeks ◦◦ This abnormal collagen production is directed by surrounding cells— particularly T cells ◦◦ T-cell-derived cytokines induce enhanced production of collagen/ECM → IL-4, IL-13, TGF-β ◦◦ IL-4 produced by CD4+ Th2 cells, enhances TGF-β ◦◦ IL-4 is most potent driving force for Th2 differentiation so it enhances pathologic collagen production by fibroblasts and induces recruitment of eosinophils –– Triggering events for morphea thought to be local within skin—trauma, injections, vaccines, X-irradiation • Subtypes: Plaque, linear, generalized, deep, guttate, nodular, Parry-Romberg • Plaque –– Red/violaceous edematous plaque, centrifugal expansion, often asx –– Central part transforms to sclerotic tissue (white), and periphery violaceous—“lilac ring” –– May have itch and loss of hairs and sweat glands • Atrophoderma of Pasini and Pierini—considered superficial type or “burntout” morphea, located on posterior trunk, may follow lines of Blaschko • Linear –– En coup de sabre—forehead/scalp

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–– Parry-Romberg syndrome—hemifacial atrophy along trigeminal nerve • Generalized—starts as classic plaque but continues to spread (often sparing only nipple) –– Disabling pansclerotic morphea of children—similar to generalized of adult, starts 14, causes severe lifelong disability • High titers ANA or ssDNA, histones in 40–80% with linear and generalized morphea • ~40% children/adolescents +ANA • Histopathology –– Infiltrate around vessels (lymphocytes, plasma, eosinophils), collagen densely packed, eccrine glands atrophic and “trapped” within thickened dermis V. Lichen sclerosus • Sclerotic, ivory-white papules/plaques with epidermal atrophy and follicular plugging • Women > men • Anogenital area affected in 85% • Peak 8–13 years, 50–60s • HLA-DQ7 • Ab to ECM-1 in 80% • Extragenital causes dryness and itching, favors trunk and proximal extremities (neck, shoulders, flexor wrist, sites of trauma) • In advanced disease, telangiectasias or follicular plugging can be seen • Can develop areas of purpura, hemorrhage • In male, phimosis or recurrent balanitis are primary presentations, perianal involvement rare (particularly in uncircumcised males) • SCC in 5% of women • Treatment –– Phototherapy ◦◦ PUVA (most experience with morphea, less so for lichen sclerosus) –– Topicals ◦◦ Ultrapotent steroids (LSA > morphea) ◦◦ Calcineurin inhibitors (LSA > morphea) ◦◦ Imiquimod (morphea) –– Systemic ◦◦ ◦◦ ◦◦ ◦◦

MTX (morphea) Prednisone Acitretin (morphea, LSA, sclerodermoid GVHD) Calcitriol

–– Surgery –– Physical therapy

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VI. Other rheumatologic disorders and autoinflammatory diseases • Systemic-Onset juvenile idiopathic arthritis (still disease) –– Most common rheumatic disease of childhood –– Increased risk in children exposed to multiple courses of antibiotic therapy –– Classified as autoinflammatory disease ◦◦ Dysregulated IL-1 due to inflammasome activation ◦◦ Dysregulated alternative secretory pathway of caspase-1 responsible for production of proteins secreted during neutrophil and monocyte activation –– 7 major types: (1) systemic onset, (2) RF+ polyarticular, (3) RF- polyarticular, (4) oligo/pauciarticular, (5) enthesitis-related arthritis, (6) psoriatic arthritis, (7) other arthritis –– Type I: 1–8 year olds, uveitis in up to 50%, ANA+, RF− –– Type II: 9–16 year olds, HLA-B27 association, ANA−, RF− –– Daily high fevers, polyarthritis (knees, ankles, hips > small joints of hands) –– Exanthem 90%—transient, non-pruritic, erythematous favoring axillae and waist, can be linear due to Koebner phenomenon –– Less common: persistent plaques, periorbital edema, erythema –– Other features: leukocytosis, thrombocytosis, ↑ LFT, ESR, polyclonal gammopathy, ↑ ferritin –– 40–50% resolves completely, ~50% have chronic persistent arthritis and systemic complications –– Macrophage activation syndrome: 10%, potentially lethal complication with fever, cytopenias, liver dysfunction, coagulopathy, hypofibrinogenemia, hypertriglyceridemia, high serum ferritin, ↑ IL-18, ↓ NK cell function –– Treatment: NSAID, systemic corticosteroids, MTX, TNF-α, thalidomide, IL-1 receptor antagonist (anakinra, rilonacept, canakinumab), IL-6 receptor antagonist (tocilizumab) • Adult-Onset Still Disease –– Young adults ( men –– Linked to HLA-B14, B17, B18, B35, Bw35, Cw4, DR2, DR7, DR4 –– Infectious triggers: viruses (rubella, mumps, CMV, EBV, influenza, coxsackievirus, HHV-6, parvovirus B19, hepatitis B and C) and bacteria (M. pneumoniae, Yersinia) –– ↑ serum levels of Th1 cytokines: IL-2, IL-6, IL-18, TNF-α, IFN-γ –– Sore throat, arthralgias, myalgias, fever (spiking pattern) –– Asymptomatic and transient cutaneous eruption—salmon pink color favoring sites of pressure, + Koebner –– Persistent violaceous to red/brown scaly papules and plaques can occur –– Carpal ankylosis

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–– Treatment: high-dose aspirin, NSAIDs, oral corticosteroids, MTX, IL-1 receptor or IL-6 receptor antagonists • Relapsing polychondritis –– Onset 20–60 years, affects men and women equally –– Immunologic reaction against type II collagen (circulating antibodies to type II collagen present in PF except in Finland, Tunisia, Brazil ∗Fogo selvagem similar to PF but endemic to Brazil, affects children, live close to rivers with black flies—Simulium –– 17:1 PF:PV in Brazil

• Pathogenesis –– –– –– –– –– –– –– –– ––

Neonates have transient disease due to maternal IgG crossing placenta Pemphigus is disease of CADHERINS Cadherins: calcium-dependent cell-cell adhesion molecules Role in formation/maintenance of tissue integrity, produce cellular adhesion “Cadherin repeats” = conserved AA sequences with Ca-binding motifs in extracellular domains Well-conserved cytoplasmic domains associated with plaque proteins (α-catenin, β-catenin, plakoglobin) Classic = E-, P-, N-cadherin Desmosomal = Desmoglein, Desmocollin Adhering junctions of epithelial cells: Adherens Junctions ◦◦ ◦◦ ◦◦ ◦◦

Quick/weak cellular adhesion Bundles actin microfilaments Classic cadherins (transmembrane) α-catenin, β-catenin, plakoglobin (cytoplasmic)

–– Desmosomes ◦◦ ◦◦ ◦◦ ◦◦

Slow/strong cellular adhesion Bundles intermediate filaments Desmosomal cadherins (transmembrane) Plakoglobin, plakophilin, desmoplakin (cytoplasmic)

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–– Desmogleins ◦◦ ◦◦ ◦◦ ◦◦

4 isoforms of desmoglein (Dsg1-4) Dsg1, Dsg3 restricted to stratified squamous epithelia Dsg2 in simple epithelia, myocardium Dsg4 in hair follicles

–– Desmocollins ◦◦ 3 isoforms (Dsc1-3) –– Plakoglobin, plakophilin, β-catenin = armadillo family –– Desmoglein compensation theory ◦◦ Dsg1 expressed throughout epidermis (more superficial) ◦◦ Dsg3 expressed in lower epidermis (basal, parabasal) ◦◦ Dsg3 in neonates found throughout epidermis (explains why neonates do not get pemphigus foliaceus) ◦◦ Reminder: exfoliative toxins from S. aureus cleave Dsg1 –– Paraneoplastic pemphigus is different! ◦◦ Humoral/cellular autoimmunity play role ◦◦ IgG against multiple antigens: Dsg3, Dsg1, plakin family (plectin, epiplakin, desmoplakin I, II, BPAG1, envoplakin, periplakin). ◦◦ Cell-mediated cytotoxicity is involved—more severe, refractory oral erosions and stomatitis, more polymorphic skin eruptions ◦◦ T cells not only help B cells produce IgG against Dsg3 but directly infiltrate epidermis and induce an interface dermatitis –– Diagnostic tests: ◦◦ DIF: examine skin/mucous membrane for in vivo bound IgG; most reliable, sensitive test for all forms ◦◦ IIF: examine serum for circulating IgG antibodies; recommended substrates based on antibody to optimize sensitivity • Pemphigus vulgaris—monkey esophagus (anti-Dsg3) • Pemphigus foliaceus—guinea pig esophagus (anti-Dsg1) • Paraneoplastic pemphigus—monkey and guinea pig esophagus (anti-­Dsg1, Dsg3) or rat bladder (anti-plakin) ◦◦ ELISA: examine serum to help distinguish between pemphigus vulgaris and foliaceus by demonstrating target antibodies; scores parallel disease activity • Pemphigus Vulgaris –– –– –– ––

Almost all have painful erosions on oral mucosa Mucosal-dominant—mucosal erosions, minimal skin (Dsg 3) Mucocutaneous type—extensive skin blisters, erosions, mucosal (Dsg3+1) Histopathology: Suprabasilar acantholysis, “row of tombstones” are basal cells still attached via hemidesmosomes

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–– Blister cavity may contain few inflammatory cells (eosinophils) –– DDx: herpetic stomatitis, aphthous stomatitis, EM major, SJS, LP, SLE, cicatricial pemphigoid, Hailey-Hailey, Grover’s disease –– Treatment: Prednisone ± azathioprine, mycophenolate, cyclophosphamide, cyclosporine, MTX, IVIg, Rituximab –– Unusual presentations: ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Isolated crusted plaque on face/scalp Paronychia and/or onychomadesis Foot ulcers Dyshidrotic eczema or pompholyx Macroglossia

• Pemphigus Vegetans –– Rare, vegetative variant—reactive pattern of skin –– Flaccid blisters become erosions then fungoid vegetations or papillomatous proliferations –– Favor face, scalp, intertriginous areas –– Pustules more common than vesicles –– Tongue can have cerebriform appearance –– 2 subtypes: Neumann (severe), Hallopeau (mild) –– DDx: pemphigoid vegetans, blastomycosis-like pyoderma, pyodermatitis-­ pyostomatitis vegetans, infection, Paget’s, Hailey-Hailey • Pemphigus Foliaceus –– –– –– ––

Scaly, crusted cutaneous erosions Favor face, scalp, upper trunk (seborrheic distribution) Rare to have mucosal involvement Histopathology: Acantholysis in upper epidermis, within or adjacent to granular layer—may be just few acantholytic keratinocytes –– Blister cavity may contain neutrophils –– DDx: bullous impetigo, subcorneal pustular dermatosis, SCLE, seborrheic dermatitis –– Treatment: Same as PV, but dapsone can also be helpful

• Pemphigus erythematosus (Senear-Usher Syndrome) –– Localized variant of pemphigus foliaceus –– Scaly, crusted lesions on malar face and other seborrheic areas • Herpetiform pemphigus –– Usually a clinical variant of pemphigus foliaceus (although some may have variant of pemphigus vulgaris) –– Erythematous urticarial plaques and tense vesicles in a herpetiform arrangement –– Target is Dsg1 >> Dsg3

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• Drug-induced Pemphigus –– A/w penicillamine, captopril –– Penicillamine causes PF > PV 4:1 –– Sulfhydryl groups in these drugs may interact with those of Dsg1 and Dsg3 and modify antigenicity of the desmogleins, leading to ab production –– Most go away after drug discontinued (but not all!) • Paraneoplastic Pemphigus –– Non-Hodgkin lymphoma, CLL, Castleman disease, malignant/benign thymomas, sarcomas, Waldenström macroglobulinemia –– Intractable stomatitis—persists, resistant to therapy –– Erosions and ulcerations affecting all surfaces of oropharynx, extend onto vermilion lip –– Severe pseudomembranous conjunctivitis –– Cutaneous findings can be very polymorphic—resemble pemphigus vulgaris, bullous pemphigoid, EM –– DDx: HSV, EM major, contact cheilitis, SJS/TEN • IgA Pemphigus –– Intraepidermal blistering disease with vesiculopustular eruption, neutrophilic infiltration of skin –– IgA ab against cell surface keratinocytes (NO IgG ab) –– Middle-aged or elderly –– Present with pustules coalescing into annular or circinate pattern with crusts in center –– Histopathology: Intraepidermal pustule or vesicles, mostly containing neutrophils, usually not much acantholysis –– DDx: subcorneal pustular dermatosis, bullous impetigo, DH, linear IgA bullous dermatosis, pustular psoriasis –– TX: Dapsone (ToC), sulfapyridine, acitretin –– Subcorneal pustular dermatosis type ◦◦ Indistinguishable from Sneddon-Wilkinson disease → need immunologic evaluation to differentiate ◦◦ IgA tend to react against upper epidermal surfaces –– Intraepidermal neutrophilic type ◦◦ “Sunflower” configuration of pustules ◦◦ IgA positive throughout entire epidermis –– –– –– ––

Axilla, groin most often affected Mucosa rarely affected IgA on DIF Circulating IgA on IIF

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II. Pemphigoid • Bullous pemphigoid –– –– –– –– ––

Most common autoimmune subepidermal blistering disease Onset >60 years HLA-DQB1∗0301 in Caucasians HLA-DRB1∗04, DRB1∗1101, DQB1∗0302 in Japanese Pathogenesis ◦◦ 2 self-antigens: BP180 (BPAG2, type XVII collagen) & BP230 (BPAG1) ◦◦ BPAG2: transmembrane protein with large collagenous extracellular domain ◦◦ BPAG1: cytoplasmic protein belonging to plakin family ◦◦ Both are components of hemidesmosomes—promote epithelial-stromal adhesion in stratified and other complex epithelia ◦◦ Humoral & cellular responses • Almost all have circulating IgG to BP180—non-collagenous NC16A domain (located extracellular but close to transmembrane domain) • Also significant autoreactivity to BP230—C-terminal region of this autoantigen • Presence of several antigenic sites due to epitope spreading • Auto-reactive T-cell response to BP180, BP230 → stimulates B cells to produce autoantibodies • Th2 and Th17 cytokines seem to be important to pathophysiology of BP—predominate within lesional tissue and in sera • IgG4 subclass (secretion regulated by Th2 cytokines) is one of major isotypes of BP180 autoantibodies ◦◦ Ab to BP180 and BP230 bind to target antigens in DEJ and result in complement activation and release of chemoattractants and direct interference with function/reduction in expression of BP180/230 → leads to recruitment of eosinophils/neutrophils and release of proteolytic enzymes AND disturbance of assembly of hemidesmosome, defective adhesive function

–– Clinical features ◦◦ Non-bullous pemphigoid • Prodromal non-bullous phase—mild to intractable pruritus • At least 20% of patients have neither obvious blisters nor eruptions at time of diagnosis ◦◦ Bullous phase • Vesicles and bullae on normal or erythematous skin with urticarial and infiltrated papules and plaques—can be annular or figurate pattern

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• Oral cavity involved 10–30% • ~50% have peripheral eosinophilia ◦◦ Clinical variants (See Box 3.17) • • • • • • • • •

Dyshidrosiform pemphigoid Pemphigoid vegetans Pemphigoid nodularis Vesicular pemphigoid (DH-like presentation) Eczematous pemphigoid Erythrodermic pemphigoid Pemphigoid gestationis Infantile/childhood BP Vulvar childhood pemphigoid

–– Associated disease ◦◦ Marginal trend towards increased risk of malignancy ◦◦ Rare associations with IBD, Hashimoto thyroiditis, RA, dermatomyositis, LE ◦◦ May be triggered by trauma, burns, radiotherapy, PUVA ◦◦ May be seen with other dermatoses—psoriasis, lichen planus ◦◦ Significantly a/w neurological disorders: Parkinson disease, dementia, psychiatric disorder, stroke ◦◦ Drug-induced BP: • Diuretics—furosemide, spironolactone Box 3.17 Pemphigoid Variants Pemphigoid gestationis

Drug-induced pemphigoid Lichen planus pemphigoides Pemphigoid vegetans Childhood pemphigoid Pemphigoid nodularis Localized pemphigoid Anti-p200 pemphigoid Anti-p105 pemphigoid

• 2nd/3rd trimester, immediately postpartum • a/w trophoblastic tumors (choriocarcinoma, hydatidiform mole) • HLA-DR3, DR4 • ↑ risk premature delivery, SGA • Transient neonatal blistering • a/w Graves’ disease, anti-thyroid ab • Furosemide #1 > ACEI, cephalosporins, β-lactams, D-penicillamine • LP/BP overlap with ab to BP180 • Vegetative plaques in intertriginous areas ↑ facial, genital involvement, acral Resembles prurigo nodularis, lacks bullae Pretibial, peristomal, vulvar, umbilical, stump a/w psoriasis Targets laminin γ1 Resembles SJS/TEN

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• NSAIDs—ibuprofen, topical diclofenac • Abx—amoxicillin, ciprofloxacin • ACEI, TNF-α inhibitors, vaccines, dipeptidyl peptidase-4 inhibitors, and checkpoint inhibitors –– Histopathology: eosinophilic spongiosis ± dermal infiltrates of eosinophils, subepidermal blister with infiltrate of eosinophils and mononuclear cells ◦◦ DIF: linear IgG ± C3 (IgG4 and IgG1 predominant), n-serrated pattern, epidermal side of salt split skin ◦◦ IIF: salt split normal human skin is substrate of choice—IgG detectable in 60–80%, bind to epidermal side or sometimes both ◦◦ ELISA: target antigens: NC16A domain of BP180, C-terminus of BP230 –– Treatment ◦◦ Extensive disease: • ToC: Oral corticosteroids + topical corticosteroids • 2nd line/adjunct: MTX, mycophenolate mofetil, azathioprine ◦◦ Localized/mild disease: • 1st line: superpotent TCS • 2nd line: oral steroids, nicotinamide + minocycline, doxycycline, tetracycline • Mucous membrane pemphigoid –– Subepithelial blistering disorder w predominant involvement of external mucosal surfaces, tends to scar –– Tissue-bound (and less often circulating—20–30% IIF) autoantibodies against BO180, laminin 332, integrin β4 subunit –– Group of diseases with lesions that favor mucosal surfaces and less frequently the skin –– HLA-DQw7 association in both oral and ocular forms –– Anti-epiligrin cicatricial pemphigoid a/w ↑ risk cancer –– Pathogenesis ◦◦ Mucocutaneous lesions result from ab binding to BMZ of stratified epithelia of mucosae and skin ◦◦ 4 distinct subgroups: ◦◦ Anti-laminin-332 (laminin 5, epiligrin)—18–30% ◦◦ Ocular mucous membrane—β4 subunit of α6β4 integrin ◦◦ Anti BP antigen mucous membrane pemphigoid ◦◦ Heterogeneous—variable mucosae without involvement of skin –– Clinical Features ◦◦ Oral and conjunctiva are most often involved

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◦◦ 90% have oral involvement—gingiva, buccal mucosa, palate most often affected ◦◦ Desquamative gingivitis with erosions, paresthesia ◦◦ Lesions on tongue on lateral and ventral surfaces ◦◦ 40% have conjunctival involvement—can result in blindness ◦◦ 33% have nasopharyngeal involvement—typically chronic asymptomatic ◦◦ 25–40% have skin involvement—scalp, face, neck, upper trunk ◦◦ Brunsting-Perry variant: skin on head/neck, absent/minimal mucosal involvement –– Histopathology: subepithelial blister, mixed cellular infiltrate with predominance of neutrophils (not as many eos as BP), may see scarring in older lesions ◦◦ DIF: linear IgG ± C3 along BMZ (more likely positive on mucosae than skin)—mostly IgG4, IgG1 ◦◦ IIF: circulating IgG > IgA, IgE > IgM, positive in 20–30% with MMP ◦◦ ELISA: confirm targeted antigens based on subtype –– Treatment ◦◦ Chronic, most important complication if vision impairment ◦◦ Systemic: 1st line: dapsone (especially if IgA deposition), 1st line for severe ocular is cyclophosphamide 1–2  mg/kg/day alone or with steroids • Others: Azathioprine, mycophenolate 2 g/day • Adjunctive: IVIg, MTX, TNF-α, rituximab could be helpful III. Dermatitis herpetiformis • >90% have gluten-sensitive enteropathy • 20% have intestinal symptoms of celiac disease • 4 findings: –– Pruritic papulovesicles on extensor surfaces –– Neutrophils in dermal papillae with vesicles at DEJ –– Granular IgA within dermal papillae • Response to dapsone • Pathogenesis –– HLA-DQ2 (A1∗0501, B1∗02) = 90% of celiac disease and DH patients –– HLA-DQ8 = 10% of DH patients –– Previous descriptions of associations with HLA-B8, DR3, DR5/7 are class I/II molecules in linkage disequilibrium with DQ2 but > other autoimmune –– Symmetric on extensor surfaces, back, buttock –– Isolated scalp involvement can occur –– Less common: isolated facial, exclusive macular, and hemorrhagic acral macules • Histopathology: collections of neutrophils within the dermal papillae –– DIF: Granular IgA localized to dermal papillae in 85% (continuous granular deposition along BMZ in 5–10%) –– Labs: anti-endomysial ab (80% DH, >95% celiac disease)—TG2 • Treatment –– Dapsone & gluten-free diet –– Screen for G6PD deficiency first, start 25–50 mg in adults or 0.5 mg/kg in children ◦◦ Methemoglobin—does not require change in dapsone dose if no cardiopulmonary sx ◦◦ Agranulocytosis—2 to 12 weeks after starting ◦◦ Dapsone hypersensitivity syndrome—2 to 7 weeks after starting ◦◦ Peripheral neuropathy—can occur within first 4 months ◦◦ 2nd line—sulfapyridine IV. Linear IgA bullous dermatosis • Linear IgA or chronic bullous disease of childhood • Average onset: >60 years in adults, 4.5 years in children • Pathogenesis –– Deposition at lamina lucida but antigenic specificity different from BP

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–– In BP: IgG bind to MCW-1 region of NC16 domain of BPAG2 (transmembrane portion) –– In LABD: IgA to carboxy terminus—97  kDa referred to as LABD97 (collagenous portion) –– Reports of LAB associated with: GI, autoimmune disease, malignancies, infections –– Drugs: vancomycin > penicillins, cephalosporins, ACEI (esp. captopril), NSAIDs >> phenytoin, sulfonamide abx • Clinical features –– –– –– ––

Vesiculobullous lesions in herpetiform arrangement Expanding annular plaques Isomorphic response Can present as variant of mucous membrane pemphigoid—oral, nasal, pharyngeal, esophageal lesions –– Ocular LABD clinically indistinguishable from ocular MMP –– LABD 2° to drugs (esp. vancomycin) can have TEN-like or morbilliform presentation

• Histopathology: Subepidermal blister, neutrophil predominant –– Early lesions—neutrophils aligned along BMZ + vacuolar change, sometimes neutrophilic microabscesses in dermal papillae (can resemble DH) –– Eosinophils more numerous over time, closer mimic to BP –– DIF: Linear IgA along BMZ –– IIF: circulating anti-BMZ IgA ab demonstrated in 60–70% (in contrast to DH patients, who typically do NOT have circulating ab that bind to skin, and 60–70% of BP patients with circulating IgG ab) –– Adhere to roof OR dermal side of salt split skin • Treatment –– Dapsone > sulfapyridine V. Epidermolysis bullosa • Acquired subepidermal bullous disease • Antibodies to type VII collagen—part of anchoring fibrils at DEJ • Can present with mechanobullous disorder or manifestations resembling BP, Brunsting-Perry variant, or rarely MMP • Pathogenesis –– Tissue bound and circulating IgG against type VII collagen—major component of anchoring fibrils—located within lamina densa/sublamina densa region

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–– 3 identical α-chains flanked by NC1 (non-collagenous) N terminal domain and NC2 C terminal region –– Ab target epitopes in NC1 domain • Clinical Features –– Adults >> children –– Classic presentation is non-inflammatory mechanobullous disease— acral blisters heal with scarring, milia, dyspigmentation –– Blisters localized to trauma-prone surfaces –– Can eventually lead to mitten deformity, webbing, nail dystrophy, and nail loss –– Scalp involvement up to 20% –– Severe inflammatory EBA has been described—BP-like presentation is most common inflammatory form of EBA—usually heal without milia or scar –– MMP-like, Brunsting-Perry-like, linear IgA-like—less common variants –– Mucosal involvement can be seen in ~50% patients with mechanobullous and BP-like presentations • Histopathology: Subepidermal cleavage with minimal-absent cellular infiltrate in mechanobullous type, and neutrophils > eosinophils, lymphocytes in the inflammatory type –– DIF: IgG in broad, linear patter along BMZ, U-serrated pattern, floor of salt split skin –– IIF: IgG circulating ab seen in 50% –– Immunoelectron microscopy was gold standard for diagnosing EBA esp when circulating autoantibodies absent and cannot be characterized by IIF or ELISA –– ELISA: NC1 or NC2 domains of collagen VII • Treatment –– Systemic steroids and other immunosuppressive agents VI. Other vesiculobullous diseases • See Box 3.18

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Box 3.18 Other Causes of Blisters (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) Bullous diabeticorum

Coma bullae

Friction bullae

Develop in longstanding diabetics w neuropathy, retinopathy Prolonged immobilization (coma, drugsbarbiturates > benzos) Young, active individuals Edema, anasarca

Subepidermal (cell poor) Tense, non-inflammatory Feet >> legs, hands, forearms Tense bullae at sites Subepidermal (cell poor) ∗ of pressure Sweat gland necrosis

Painful bulla at sites of friction Edema bullae Tense bullae at dependent sites Distal extremities Bullous small Seen in setting of Hemorrhagic vessel vasculitis small vasculitis vesicles and bullae Distal legs Grouped pruritic Bullous Children or arthropod bite malignancy (CLL >> papules mantle cell lymphoma, NK/T cell lymphoma) Seen at site of prior Tense bullae, Delayed trauma appears weeks to post-graft months after wound blister

Intraepidermal (beneath granular layer) Subepidermal (cell poor)

Subepidermal with ongoing LCV Intraepidermal, eosinophilic spongiosis, with superficial and deep inflammation Subepidermal (cell poor)

3.7  Diseases of Hair and Nails I. Androgenetic alopecia (AGA) • • • •

Androgen-dependent hereditary physical trait Conversion of scalp terminal hairs into miniaturized vellus hairs By 70 years of age, 50% women and 80% men show evidence Pathogenesis –– ↑ DHT (testosterone → DHT by 5α reductase (3 isoenzymes—types I, II, III) –– Type I 5α-reductase: in sebaceous glands and liver –– Type II 5α-reductase: in scalp, beard, chest hair follicles, liver, prostate ◦◦ ∗Genetic absence of type II 5α-reductase prevents development of male AGA –– Type III 5α-reductase: throughout epidermis/dermis (unknown functional role)

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• Symmetric and progressive • Hamilton and Norwood → classifies patterns of male AGA based on frontoparietal and frontal recession and vertex thinning • Ludwig and Sinclair → grading scales for female pattern, frontal accentuation of hair loss creating “Christmas tree” pattern • Histopathology: normal total number of follicles without significant inflammation, ↑ number and percentage of vellus hairs with fibrous “streamers” • Treatment: –– MPHL: topical minoxidil (2%, 5%), oral finasteride 1  mg daily, hair transplantation –– FPHL: topical minoxidil (2%, 5%), oral contraceptives, spironolactone, finasteride 2.5–5 mg daily, dutasteride 0.5 mg daily II. Telogen effluvium • • • •

~10% hairs on normal scalp in telogen, lasts for 3 months Normally, 50–200 hairs undergo exogen and are shed TE is period of excessive shedding Most common causes: medications, systemic disease (HIV, infection, postsurgical, postfebrile, hypothyroidism, starvation/malnutrition or crash diets), altered physiologic states (newborn, postpartum) –– Oral contraceptives, retinoids, anticoagulants (heparin especially), antithyroid (propylthiouracil, methimazole), anticonvulsants, heavy metals, β-blockers, interferon-α-2b

• Histopathology: normal total number of hairs with increased telogen count to >20%, no inflammation or scarring • Thinning of hair involving entire scalp, can be seen in pubic and axillary hair • Hair pull test: positive for 2+ telogen hairs • Treatment: supportive care, check ferritin (desire levels at least 40 ng/dl) III. Alopecia areata • 0.1–0.2% population • Pathogenesis: involves environmental insult, viral infection, genetic susceptibility to T-cell mediated autoimmunity –– HLA-DQ7, -DQ3, DR11—susceptibility markers for all forms of alopecia –– HLA-DR4, HLA-DQ7—markers for severe longstanding alopecia totalis/universalis • Round or oval patches of non-scarring hair loss with short “exclamation point” hairs (broader distal end compared to proximal) at the periphery of alopecia patches • Ophiasis pattern: band-like at temporal and occipital scalp • Alopecia totalis: loss of all scalp hair • Alopecia universalis: loss of all scalp and body hair • Reticular alopecia: recurrent patchy disease

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• Diffuse alopecia: widespread thinning or affect the crown/vertex primarily • Histopathology: –– Early disease has normal total number of hairs with peribulbar infiltrate with lymphocytes and occasional eosinophils, degenerative changes in the hair matrix, occasional exocytosis of inflammatory cells into the bulbar epithelium –– Chronic disease shows most hairs in catagen or telogen phases, miniaturized hairs and mild peribulbar lymphocytic infiltrate • Treatment: –– Topical or intralesional corticosteroids, topical minoxidil 2% or 5%, topical anthralin (0.5–1% cream daily), combination therapy –– Systemic: pulsed dosing corticosteroids, JAK/STAT pathway inhibitors (tofacitinib, ruxolitinib), PUVA, excimer laser, cyclosporine –– Topical immunotherapy with diphencyprone or squaric acid dibutyl ester for extensive disease IV. Trichotillomania • Self-induced plucking or breakage of hair, listed in DSM-5 as one of obsessive-­compulsive and related disorders • Usually pluck scalp hair or can pluck from other regions (eyebrows, eyelashes, face, extremities, pubic region) • Patches have irregular borders, bizarre shapes, hairs of varying lengths • Histopathology: normal sized follicles with normal total number of hairs, minimal inflammation, trichomalacia and pigment casts present and incomplete, disrupted follicular anatomy • Treatment: behavioral modification therapy, 1st line pharmacological therapy is clomipramine V. Other non-scarring alopecias • Temporal triangular alopecia –– Present at birth of acquired within first decade of life –– Triangularly shaped areas that appear hairless but have fine vellus hairs • Lipedematous alopecia –– Thick boggy scalp vertex with hair loss—approximate doubling of scalp thickness due to expansion of subcutaneous fat layer • Psoriasiform alopecia –– Alopecia can occur in context of psoriasis (circumscribed in 75%, diffuse in 25%) –– Psoriasiform alopecia observed in patients on TNF-α inhibitors (especially infliximab, adalimumab) • Congenital atrichia with papules –– Inherited defect in Hairless gene

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–– Individuals fail to regrow hair after shedding after birth –– Associated with follicular cysts and milia-like lesions later in life VI. Scarring alopecia • Central centrifugal cicatricial alopecia –– Chronic progressive disease on crown or vertex of scalp –– Most common form of scarring alopecia –– Disease progression or aggravation may be related to harsh hair care products or hairstyles that cause traction –– Due to follicular damage due to premature desquamation of inner root sheath –– Presents as thinning on crown/vertex, expands in centrifugal fashion –– May have pustules or crusting in chronic disease or bacterial superinfection –– Histopathology: premature desquamation of IRS, epithelial atrophy with hair shafts close to dermis, concentric lamellar fibroplasia, variable amounts of lymphocytic perifollicular inflammation at upper isthmus and lower infundibulum –– Treatment: oral tetracycline, topical corticosteroid for early disease ◦◦ For highly inflammatory disease, oral rifampin, clindamycin • Lichen planopilaris –– Affects women more than men, 80% skin) Favors face, dorsal hands, nipples, axillae, umbilicus, sacral, inguinal, anogenital areas • Periorificial distribution on face and sites of trauma on extremities –– Koebner phenomenon or isomorphic response • • • •

Wood’s lamp accentuates in individuals with lighter skin Vitiligo ponctue: confetti-like amelanotic macules Inflammatory vitiligo: raised inflammatory borders Blue vitiligo: arise within areas of postinflammatory dermal pigmentation • Trichrome vitiligo: hypopigmented zone between normal and depigmented skin • Hypochromic vitiligo: persistent hypopigmented macules in seborrheic distribution • Associations and differential diagnoses: –– a/w thyroid (#1), DM1, Addison’s, pernicious anemia, halo nevi, alopecia areata, uveitis –– Patients with APECED syndrome often develop vitiligo (autosomal recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) –– Vogt-Koyanagi-Harada syndrome: b/l granulomatous uveitis, aseptic meningitis, deafness, poliosis, vitiligo –– Alezzandrini syndrome: unilateral facial vitiligo/poliosis, hearing/ visual impairment –– Kabuki syndrome: developmental delay, congenital heart defect

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• Histopathology: absent or decreased melanocytes –– Use Melan-A (MART-1), MITF, HMB-45 • Treatment: –– Topical: corticosteroids, calcineurin inhibitors –– Phototherapy: NB-UVB, PUVA, excimer –– Systemic: corticosteroids—high dose or mini pulses to arrest spread and induce repigmentation –– Micropigmentation and depigmentation (monobenzyl ether of hydroquinone) II. Other causes of hypopigmentation and depigmentation • See Box 3.21 III. Disorders of hyperpigmentation • See Box 3.22

Box 3.21 Other Causes of Hypopigmentation and Depigmentation Halo nevus

Chemical leukoderma Idiopathic guttate hypomelanosis Progressive macular hypomelanosis Nevus anemicus

Hypomelanosis of Ito

Nevus depigmentosus

Melanocytic nevus with surrounding hypo/depigmented skin Usually on back, may be melanoma marker Phenols, catechols, sulfhydryls Monobenzyl ether of hydroquinone → depigmentation Sun exposure, genetics, aging Possible role of P. acnes Ill-defined hypopigmented macules/patches on trunk/ upper extremities, seen in tropical regions Pale unilateral area of skin, present from birth Usually on trunk, caused by ↓ blood flow/ vasoconstriction Hypopigmentation along Blaschko’s lines, mosaicism Linear nevoid hypopigmentation Present at birth, 30% have CNS, MSK or ophthalmologic abnormalities Hypomelanotic patch with irregular border, pigmentary mosaicism

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Box 3.22 Disorders of Hyperpigmentation Melasma

Lichen planus pigmentosus

Linear and whorled nevoid hypermelanosis Prurigo pigmentosa

Familial progressive hyperpigmentation

Sun exposure, estrogen, genetic, thyroid, meds (phenytoin, phototoxic drugs) ↑ melanin in all layers of epidermis TX: photoprotection, hydroquinone, tretinoin, steroids Variant of LP in skin types III-IV Oval, brown, grayish macules, patches in sun-exposed or intertriginous Mosaic skin condition with hyperpigmented macular Blaschkoid whorls and streaks, occurs before 1 year ± neuro, MSK, cardiac findings Japanese, young adult, F > M Pruritic erythematous papules, vesicles on back, neck, chest TX: TCN, dapsone AD, mutation KIT ligand Starts in infancy, diffuse hyperpigmented patches develop

3.9  Vascular Diseases I. Cutaneous vasculitis • Vasculitis can be categorized by vessel size of involvement (Box 3.23) • Small vessel vasculitis • Caused by immune complex deposition in post-capillary venules → complement-­mediated chemotaxis of neutrophils • Symmetric palpable purpura on legs, dependent areas, appearing 7–10 days after exposure, resolves 3–4 weeks • Usually asymptomatic but can itch, burn, sting • Triggers: –– Idiopathic 50% –– Infection 15–20% → group A β-hemolytic streptococcus, HCV –– Inflammatory d/o 15–20% → AICTD (SLE, Sjögren’s, RA > DM, Scleroderma) –– Drug 10–15% → β-lactam, sulfonamides, NSAIDs, TNF-α, levamisole –– Neoplasm 24 h

Box 3.24 Cutaneous Small Vessel Vasculitis (CSVV)

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Box 3.25 Small and Medium Vessel Vasculitides Palpable purpura, oral Granulomatosis cANCA ulcers (gingival with polyangiitis (PR3)—Th1 immune response hyperplasia, strawberry gums), PG-like nodules Necrotizing granulomas of RT, cough/hemoptysis, rhinorrhea, sinusitis, arthralgias, conjunctivitis, peripheral neuropathy, CVA glomerulonephritis (death from renal >80% of untreated) Palpable purpura, Microscopic a/w infective petechiae > livedo polyangiitis endocarditis, reticularis, retiform medications, purpura, ulcers malignancy Pulmonary-renal syndrome (focal segmental necrotizing GN, pulmonary capillaritis/hemorrhage), mononeuritis multiplex, peripheral neuropathy Palpable purpura, nodules Churg-Strauss Mixed disease inflammatory and on extremities, scalp ANCA-mediated Adult onset asthma, nasal polyps, allergic rhinitis tissue damage (stage I), eosinophilia, Triggers: pneumonia, N/V, abdom leukotriene pain (stage II) inhibitor, anti-IgE ab, rapid Systemic necrotizing vasculitis, mononeuritis steroid taper, multiplex, pericarditis, vaccine endocardiomyopathy (cause of death) (stage III) Limited renal involvement

↑ ESR, WBC + cANCA UA, CXR Cyclophosphamide + steroids, MTX, azathioprine

UA, CXR/CT pANCA (MPO) > cANCA Cyclophosphamide + steroids, MTX, azathioprine

pANCA > cANCA Steroids (+cyclophosphamide if organ involvement)

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Box 3.26 Medium Vessel Vasculitides Polyarteritis 40–60 years, M > F nodosa Triggers: med, infxn, IBD, SLE, hairy cell leukemia, HBV, HCV, strep in children Necrotizing arteritis of med vessels, microaneurysms IgG ± C3 in walls

Kawasaki disease

80% F ↑ Japanese Inflammation, scarring, stenosis, aneurysm of arteries (including coronary artery)

Classic: palpable purpura, SQ nodules, livedo reticularis (rare digital/ penile infarction) a/w HTN, renal failure (cause of death), cardiomyopathy, MI, orchitis Cutaneous (C-PAN): pink/purple nodules on legs near malleoli, atrophie blanche, livedo reticularis Fever for 5 days + conjunctival injection, fissured lips, strawberry tongue, polymorphous eruption on skin, cervical LAD, peripheral edema, erythema of hands/feet, periungual desquamation a/w coronary artery aneurysm/ectasia, myocarditis, arthralgia, arthritis, pneumonitis, aseptic meningitis, facial nerve palsy, anterior uveitis

C-PAN: steroids, NSAIDs Systemic: cyclophosphamide + steroids, MTX, IVIg RARE pulmonary involvement

↑ CRP, ESR, ↓ Hgb, ↑ WBC ↓ albumin, Na, K, HDL ↑ LFTs, GGT Check echo at 0, 2, 6, 8 weeks ASA + IVIg a/w MI (#1 cause acquired ped heart disease in US)

Box 3.27 Large Vessel Vasculitides Temporal arteritis

>50 years Any med-large vessel—temporal artery Granulomatous vasculitis

Takayasu arteritis

M Granulomatous vasculitis → stenosis, occlusion, aneurysm Aorta and main branches

Tenderness, erythema along scalp/temples, cord-like nodule, unilateral temporal headache, loss of temporal pulse, jaw claudication, glossitis Polymyalgia rheumatica (40–60%) with limb and girdle muscle pain, vision loss (14%), stroke Purpura, PG-like lesions, EN-like lesions, Raynaud’s phenomenon, digital gangrene Loss of carotid/radial pulse, HTN

↑ ESR, CRP MRA Temporal bx ASA + steroids

↑ ESR MRA Prednisone, MTX, cyclophosphamide

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II. Vascular occlusion syndromes • Antiphospholipid syndrome (APLS) –– F>M –– 53% primary APLS, 36% associated with lupus, 5% associated with lupus-­like syndromes –– Antiphospholipid antibodies/lupus anticoagulants cause purpuric cutaneous lesions and microvascular occlusion –– Catastrophic APLS presents with multi-organ failure (usually renal and pulmonary involvement) –– Cutaneous findings in patients with APLS include vasculitis-like lesions, splinter hemorrhage, livedo reticularis, retiform purpura, Sneddon syndrome, livedoid vasculopathy or Degos-like lesions, Raynaud phenomenon, widespread cutaneous necrosis (in catastrophic APLS) –– Anticardiolipin (more sensitive), lupus anticoagulants (more specific) –– ToC: heparin followed by chronic anticoagulation with oral vitamin K antagonists ◦◦ For life-threatening catastrophic APLS: systemic corticosteroids, plasma exchange, IVIg • Livedoid vasculopathy –– Chronic cutaneous disease in young/middle-aged women –– Altered control of coagulation, formation of fibrin thrombi within superficial dermal blood vessels –– Present with painful, persistent, punched out ulcers on legs, favor malleoli –– Histopathology: mild perivascular lymphocytic infiltrates, extravasated erythrocytes, hyalinized walls and luminal fibrin deposition of superficial dermal vessels –– Treatment with antiplatelet, anticoagulant, fibrinolytic therapies • Malignant atrophic papulosis –– Also known as Degos disease –– Small vessel vasculopathy affecting skin, GI tract, CNS –– Crops of erythematous papules on trunk and extremities that develop central atrophic porcelain white scar with rim of telangiectasias –– Bowel perforation and CNS manifestations are leading causes of death –– Histopathology: wedge-shaped area of ischemic dermis with overlying atrophic epidermis –– Treatment: aspirin, dipyridamole, eculizumab, treprostinil • Sneddon syndrome –– Idiopathic livedo reticularis with cerebrovascular accidents –– Seen in young women –– Often considered a manifestation of APLS

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–– Consists of labile hypertension, CNS disease (TIA, ischemic strokes, dementia), and widespread and persistent livedo racemose –– Treatment: warfarin • Miscellaneous disorders of occlusion –– Hydroxyurea-associated vascular occlusion: seen in patients with myeloproliferative diseases treated with hydroxyurea ◦◦ Perimalleolar, can trigger pyoderma gangrenosum –– Interferon-associated cutaneous necrosis: at injection sites, can develop microvascular occlusion with evidence of cutaneous necrosis or necrotic panniculitis –– Hematoma-associated retiform purpura: compression of subcutaneous arterioles by hematoma can cause retiform purpura

3.10  Neutrophilic Dermatoses I. Sweet syndrome • Acute febrile neutrophilic dermatosis • Average onset 30–60 years, F>M • Up to 50% have associated disorder or trigger: –– 15–30% internal malignancy (hematologic more common than solid organ) –– 25% preceding infection (upper respiratory tract, CMB, hepatitis B and C, Yersinia, mycobacterial, fungal) –– 10% drug exposure (antibiotics, furosemide, antineoplastics, contraceptives, NSAIDs, retinoids –– Others: inflammatory bowel disease, autoimmune connective tissue disease • Pathogenesis unknown, likely hypersensitivity reaction • Present with tender erythematous papules, plaques with pronounced edema (pseudovesicular in appearance) • Favors head/neck, upper extremities • Associated with fever, leukocytosis, arthralgias, arthritis, ocular involvement • Histopathology: papillary edema and diffuse neutrophilic infiltrate without evidence of vasculitis –– Histiocytoid variant: dermal infiltrate of histiocyte-like myeloid cells • Treatment: oral prednisone (ToC), potassium iodide, dapsone, colchicine II. Pyoderma gangrenosum • Uncommon chronic recurrent ulcerative disease • Average onset 20–50 years

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• 50% have underlying systemic disease: inflammatory bowel disease, arthritis, hematologic disorder • Pathogenesis not fully understand; enhanced IL-1 pathway thought to play a role (↑ expression of IL-1, IL-1β, IL-8, IL-17, TNF-α reported) • Classic morphology is ulcer with irregular, undermined gunmetal grey border that expands • Variants: –– Pustular: multiple small pustules most commonly seen in patients with IBD –– Superficial granulomatous: localized superficial vegetative or ulcerative lesion, often after trauma, responsive to less aggressive therapy –– Pyoderma/pyostomatitis vegetans: chronic vegetative pyoderma of labial and buccal mucosa, seen in patients with IBD • Histopathology: early lesions show neutrophilic vascular reaction, and later lesions show more tissue necrosis and mononuclear cell infiltrates • Treatment: systemic corticosteroids, cyclosporine, thalidomide, TNF-α inhibitors, topical calcineurin inhibitors, colchicine, dapsone, IL-12/23 antagonists, methotrexate III. Behçet’s disease • Multisystemic disease characterized by recurrent oral ulceration, recurrent genital ulceration, ocular abnormalities, and cutaneous lesions • Seen along the Silk Route—greater incidence in Middle Eastern countries and Asia • Pathogenesis involves genetic and environmental factors • HLA-B51 • Aphthous stomatitis, genital aphthae (larger, tend to heal with scarring), acral and facial sterile vesiculopustules, erythema nodosum-like lesions • Retinal vasculitis (most often a/w blindness), posterior uveitis (most characteristic), anterior uveitis, conjunctivitis, scleritis, arthritics, abdominal pain, neurologic findings (a/w poor prognosis), aneurysmal or occlusive arterial disease, superficial or deep venous thrombosis, glomerulonephritis • MAGIC syndrome: Behcet’s disease and relapsing polychondritis • Treatment: colchicine, dapsone, thalidomide, interferon-α-2a, azathioprine, chlorambucil, cyclosporine IV. Bowel-associated dermatosis-arthritis syndrome • Characterized by diarrhea and malabsorption, arthritis, and skin lesions • Seen in patients after intestinal bypass surgery, blind loops of bowel following surgery, biliopancreatic diversion, or other gastrointestinal disorders such as IBD, diverticulitis, peptic ulcer disease • Due to bacterial overgrowth that leads to immune complex deposition in skin and synovium • Present with erythematous macules on proximal extremities and trunk, progress to purpuric vesiculopustules, recur at 4–6 week intervals

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• Treatment: surgical revision (resect blind loop or revise bowel bypass), systemic corticosteroids, oral antibiotics (tetracycline, doxycycline, minocycline, clindamycin, metronidazole) V. Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome • Spectrum of aseptic neutrophilic dermatoses • Affects children and young/middle-aged adults • Features aseptic osteoarticular lesions—inflammatory synovitis, arthrosteitis, hyperostosis or (most often sternum, clavicle, ribs or axial skeleton) • Associated cutaneous disorders: palmoplantar pustulosis, follicular occlusion tetrad (especially acne conglobata), acne fulminans • Treatment: NSAIDs, isotretinoin, corticosteroids, other immunosuppressants, TNF-α antagonists, IL-1 antagonists

3.11  Eosinophilic Dermatoses I. Granuloma faciale • Idiopathic cutaneous disorder characterized by red-brown plaques on the face • Seen predominantly in middle-aged white men • Pathogenesis unknown, but likely role of IFN-γ, elevated local IL-5 production • Solitary, asymptomatic, smooth red/brown to violaceous plaque on face, can have rare involvement of extrafacial sites (trunk, extremities, scalp), sinonasal mucosal variant (aka “eosinophilic angiocentric fibrosis”) • Histopathology: dense nodular dermal infiltrate of lymphocytes, neutrophils, plasma cells, and eosinophils, + neutrophilic dust and hemorrhage • Differential includes lymphoma, pseudolymphoma, sarcoid, tumid lupus, fixed drug, rhinophyma, EED (extrafacial) • Treatment: typically resistant, IL steroids, oral dapsone, clofazimine, excision, cryotherapy, CO2 laser II. Papuloerythroderma of Ofuji • Seen predominantly in elderly Japanese man (only about 100 cases reported to date) • Pathogenesis unknown • Widespread symmetric pruritic eruption of flat-topped red/brown papules, acute exacerbations are characterized by erythroderma sparing the skin folds creating “deck-chair” sign, may be a/w peripheral lymphopenia, eosinophilia, lymphadenopathy • Histopathology: nonspecific, superficial/deep infiltrate of lymphocytes, eosinophils ± plasma cells and histiocytes • Treatment: systemic steroids, PUVA, UVB, cyclosporine, etretinate, azathioprine

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III. Wells syndrome • Disease of unknown etiology characterized by indurated plaques resembling cellulitis • Pathogenesis unknown, thought to be local hypersensitivity, possible triggers like myeloproliferative disorders, infections/infestations, insect bites/stings. • Present with recurrent episodes of prodromal itching/burning followed by edematous nodules and plaques with annular/arcuate configuration • Histopathology: Characterized by interstitial inflammation of eosinophils with lymphocytes and histiocytes, characteristic eosinophilic staining flame figures consisting of collagen fibers coated with eosinophil granule proteins • Treatment: Oral steroids, can consider others such as minocycline, colchicine, antimalarials, dapsone, griseofulvin IV. Hypereosinophilic syndromes • This term encompasses multiple entities: –– Lymphocytic form: clonal proliferations of T cells with increased production of Th2 cytokines (particularly IL-5) –– Myeloproliferative form: HES with FIPL1-PDGFRA fusion gene (includes eosinophilic leukemia) • Lymphocytic HES → abnormal clonal lymphocyte populations, often CD3+4-8- or CD3-4+, these T cells become activated and secrete Th2 cytokines (IL-4, -5, -13) –– Relatively benign but can undergo progressive transformation into lymphoma • Myeloproliferative HES → eosinophilic leukemia and individuals with FIP1L1-PDGFRA fusion gene (deletion on chromosome 4q12) –– Can have elevated serum tryptase, develop splenomegaly, endomyocardial fibrosis, cardiomyopathy, elevated serum vitamin B12 levels • Clinical Features: –– Diagnostic criteria: (1) peripheral blood eosinophilia for at least 6 months or if legs Face, neck, forearms (sun-­exposed skin)

Interstitial (70%), palisaded (25%), sarcoidal (5%)

Phagocytosed elastic fibers in histiocytes, giant cells Annular plaques or linear Small rosettes of ANA+ 50% palisading histiocytes, cords “rope sign” Immune complex “bottom heavy”, no deposition → low-level Trunk, buttocks, folds vasculitis vasculitis SV-LCV, basophilic Umbilicated papules ± collagen degeneration perforation/ulceration Extensor digits, elbows Square bx, layered Plaques w ↑ borders Subacute dermal palisaded granulomatous Anterior/lateral shin, ischemia → dermal inflammation ulceration collagen degeneration 5% w eye manifestations Yellow ulcerative Palisading plaques, periorbital xanthogranulomas Exaggerated Th1, Th17 Labial, scrotal edema, Tuberculoid granulomas, response sinus tract, fissures Langerhans GCs CD4+ Th1 cells Many different forms Naked epithelioid granulomas

Th1 delayed hypersensitivity rxn HLA-Bw35 (generalized GA) 50–70 years; F > M

Box 3.28 Non-infectious Granulomas

Topical/IL CS

Kveim-­Siltzbach test

Prednisone

RA, SLE, ANCA vasculitides, autoimmune disease, malignancy Topical/IL CS 22% with NLD have DM, only 0.03% of DM have NL IgG κ monoclonal gammopathy Oral metronidazole

RA, seroneg arthritis, thyroiditis, SLE, (arthralgias 50%)

High potency TCS, Generalized a/w HLD, type I DM, HIV, thyroid, TNF-α Phototherapy, triple malignancy abx Seen w actinic damage Poor tx response

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Box 3.29 Sarcoidosis Variants (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) Lupus pernio

Darier-Roussy Lofgren syndrome

Poor prognosis Strong a/w chronic lung (75%), URT disease (50%), cystic degeneration of bones of distal phalanges, ocular involvement Subcutaneous sarcoid—painless Good prognosis deep nodules, “pseudorheumatoid” Hilar adenopathy (90%) Good prognosis Acute form: fever, hilar Scandinavian whites adenopathy, erythema nodosum, migrating polyarthritis, acute iritis Uveitis, parotid gland enlargement, fever, CN palsy Violaceous papules coalescing into infiltrative plaques, “beaded appearance”, scarring Nose, earlobes, cheeks

Heerfordt syndrome “Uveoparotid fever” Blau syndrome Sarcoid-like disease with skin, eye, joint disease Drug-induced sarcoid

Onset trunk extremities ◦◦ Spontaneous resolution over months-years ◦◦ Rare systemic involvement ◦◦ +Factor XIIIa, CD68, HAM56 –– Juvenile xanthogranuloma ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Most common histiocytosis Affects infants and young children >15% present at birth, 75% present during 1st year of life Clinical variants: small nodular, large nodular Pink to red-brown dome-shaped papules, can appear yellow Most common on head/neck > upper trunk, upper extremities > lower extremities

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Box 3.30 Langerhans Cell Histiocytoses (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease)

Letterer-Siwe

Age Birth/ days

Presentation Widespread, localized, or single Red/brown/purple papulonodules → crust and resolve

7 years Cranium >> ribs, vertebrae, pelvis Asymptomatic granulomatous lesion of bone (cutaneous lesions rare)

Systemic/Other Rare systemic involvement Can resemble blueberry muffin Can have later onset DI Hematopoietic, lung, liver, bone Cranium Poor prognosis a/w hematologic involvement 80% bone lesions 30% DI Vasopressin sensitive

Spontaneous fracture or otitis media

◦◦ Oral JXB rare, lateral tongue or hard palate ◦◦ Ocular JXG unilateral, most common extracutaneous site, upper trunk, extremities > lateral tongue/midline hard palate Pink to red/yellow papules NXG 50s Periorbital > face, trunk, extremities Yellow xanthomatous plaques Reticulohistiocytosis 30–40s Head (solitary) Acral sites—head, hands, elbows (multicentric) Solitary red/yellow nodule Red/brown or yellow nodules, coral bead Rosai-Dorfman Skin-limited: Eyelids, malar cheek Bilateral cervical LAD, adults fever Systemic: adults, children Xanthoma Any age Symmetric flexural or disseminatum intertriginous Cutaneous xanthomas, mucosal xanthomas, DI

Systemic/other No systemic symptoms usually (rare diabetes insipidus) Self-limited course Self-limited course Rare a/w leukemia

Rare visceral, bone lesions Must be distinguished based on immunostains 0.5% unilateral eye (iris) Triple association: JXG, NF-1, JMML

50% eye HSM, leukopenia IgG κ monoclonal (70%) gammopathy 45% arthritis mutilans 50% oral/nasopharyngeal 30% solid organ malignancy Can develop Leonine facies

Any internal organ 15% immune d/o 40% 1+ extranodal site Polyclonal gammopathy SLC29A3 mutation 40% DI 40–60% mucous membrane involvement Monoclonal gammopathy Plasma cell dyscrasia

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–– Necrobiotic xanthogranuloma ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Rare, onset in adulthood Asymptomatic indurated yellow papule, nodule, or plaque Periorbital > trunk, face, proximal extremities 50% ophthalmic manifestations: orbital mass, ectropion, ptosis, keratitis, scleritis, anterior uveitis a/w paraproteinemia—IgG monoclonal gammopathy in 70% cases Other associations: plasma cell dyscrasia, cryoglobulinemia, lymphoproliferative disorder Histopathology: palisading xanthogranuloma with histiocytes, foamy cells, lymphoid follicles, plasma cells, giant cells with zones of necrobiosis Treatment limited, reports of corticosteroids plus chlorambucil, melphalan, or cyclophosphamide, radiation therapy, CO2 laser, plasmapheresis

–– Giant cell reticulohistiocytoma ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Also known as solitary reticulohistiocytoma Observed in young adults Single, asymptomatic, yellow to red nodule Head and neck Spontaneous resolution in most cases Excision is curative

–– Multicentric reticulohistiocytosis ◦◦ 40s, F>M ◦◦ Cutaneous and mucous membrane reticulohistiocytomas, severe arthropathy ◦◦ a/w hyperlipidemia, + tuberculin skin test, vasculitis, autoimmune disease, malignancy (25–30%) ◦◦ small pink, red-brown or yellow papules ◦◦ Favor head, hands, fingers, ears, extremities, oral, pharyngeal, nasal mucosae ◦◦ Uncommon presentation: severe facial involvement leading to leonine facies ◦◦ “Coral bead” appearance of small papules lined along nail folds ◦◦ Symmetric, erosive arthritis → progress to arthritis mutilans ◦◦ Rare involvement of other organs (heart, lungs, eyes, thyroid) ◦◦ Histopathology: dense infiltrate of lymphocytes, histiocytes, few plasma cells and eosinophils; histiocytes with ground-glass eosinophilic cytoplasm –– Rosai-Dorfman disease ◦◦ Sinus histiocytosis with massive lymphadenopathy

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◦◦ Affects children and young adults ◦◦ Massive, painless bilateral cervical lymphadenopathy, fever, anemia, polyclonal hypergammaglobulinemia, immune disorders ◦◦ Cutaneous lesions seen in minority of cases (10%), skin-limited form increasingly recognized ◦◦ Indolent, self-limited disease ◦◦ 40% have at least one extranodal site involved: skin, soft tissue, eye, respiratory tract, major salivary glands, CNS, bone most common ◦◦ Present in skin as red-brown or xanthomatous macules, papules, nodules, or plaques, favor eyelids and malar region ◦◦ Skin-limited form may present as single lesions ◦◦ Histopathology: dense dermal infiltrate of histiocytes with lymphocytes, plasma cells, and neutrophils; emperipolesis ◦◦ +S100, CD68, CD163, CD11c, CD14 –– Xanthoma disseminatum ◦◦ Normolipemic histiocytic proliferative disorder ◦◦ Seen in young adults more commonly, M > F ◦◦ Triad of cutaneous xanthomas, mucous membrane xanthomas, diabetes insipidus ◦◦ Presents as eruption of numerous symmetric papules on the face and flexural areas ◦◦ Mucous membrane lesions (upper airway and oral mucosa) 40–60% ◦◦ Hypothalamus and pituitary stalk 40% → lead to diabetes insipidus ◦◦ Histopathology: dermal infiltrate of histiocytes, foamy cells, lymphocytes, plasma cells, Touton cells –– Papular xanthoma ◦◦ Generalized yellow papules, relative sparing of flexures ◦◦ Can involve mucous membranes –– Progressive nodular histiocytoma ◦◦ Generalized yellow papules and nodules, may have prominent facial involvement ◦◦ Thought to be on spectrum with papular xanthoma –– Hereditary progressive mucinous histiocytosis ◦◦ Onset during childhood and adolescent ◦◦ Present with generalized skin-colored to erythematous papules and nodules ◦◦ Histopathology: histiocytes and prominent dermal mucin –– Erdheim-Chester disease ◦◦ Primarily systemic histiocytosis with skin involvement in up to 25% of patients

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◦◦ Present with red-brown to yellow nodules and plaques on head and neck, trunk, and axillae ◦◦ Associated with fever, bone pain, exophthalmos, diabetes insipidus ◦◦ Up to 50% have involvement of lungs, kidneys, adrenal glands, or heart ◦◦ Up to 55% have BRAF V600E mutation ◦◦ Histopathology: foamy histiocytes with Touton giant cells ◦◦ +CD68, CD163 ◦◦ −CD1a –– Sea-blue histiocyte syndrome ◦◦ Inherited or acquired, presents in adolescence and young adulthood ◦◦ Skin involvement observed in inherited form, presents as macular hyperpigmentation on the face ◦◦ Histopathology: histiocytes containing cytoplasmic granules (MayGrunwald stain blue) • Indeterminate –– Positive for S100, CD1a, CD68, CD163, HAM56 –– Negative for Langerin –– Rare, displays both LCH and non-LCH immunophenotypic features but lack Birbeck granules ◦◦ +S100, CD1a ◦◦ +CD68, CD163 ◦◦ −CD207 (Langerin) –– –– –– –– ––

Solitary and generalized variants Trunk and extremities > genitalia, head/neck Generalized present as firm red-brown papules Solitary presents as single erythematous lesion ± ulceration Clinical course variable—can experience partial/complete regression or progressive course

3.13  Oral and Anogenital (Non-venereal) Disease I. Benign conditions of the tongue • Geographic tongue –– “Psoriasiform mucositis” –– Well-demarcated erythema on the dorsal tongue with surrounding white serpiginous borders, atrophy of filiform papillae within the erythematous areas

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–– Associated with psoriasis, atopic dermatitis, fissured tongue –– Histopathology: similar to psoriasis, loss of papilla at edge of lesion • Fissured tongue –– “Scrotal tongue” –– Multiple asymptomatic grooves 2–3 mm in depth on the dorsal tongue –– Associated with Melkersson-Rosenthal, Down syndrome, Cowden syndrome, pachyonychia congenita, acromegaly, or can be a polygenic trait or AD trait with incomplete penetrance • Hairy tongue –– “Black hairy tongue” –– Confluent hair-like projections on the dorsal tongue with brown-black elongated papillae –– Associated with halitosis, dysgeusia –– Due to retained keratin at tips of papillae, which can occur due to decreased food intake or a soft/liquid diet, poor oral hygiene, oxidizing mouthwashes, or hot beverages –– Treatment: tongue scraping or brushing for symptomatic relief • Median rhomboid glossitis –– Well demarcated oval or diamond area of erythema and atrophy in the midline posterior dorsal tongue –– Associated with chronic candidiasis, HIV/immunosuppression –– Histopathology: loss of filiform papillae, parakeratosis with C. albicans –– Treatment: anticandidal therapy II. Periodontal disease • Necrotizing ulcerative gingivitis –– Presents as painful, hemorrhagic, necrotic gingivae with punched out interdental papillae –– Due to presence of mixed bacteria, increased risk in smokers, immunosuppressed, individuals with malnutrition or poor oral hygiene. –– Associated with fever, malaise, malodor –– Treatment: broad spectrum antibiotics, chlorhexidine oral rinse, debridement • Desquamative gingivitis –– Also known as erosive gingivostomatitis –– Presents as gingival erythema with varying degrees of mucosal sloughing or erosions –– Most commonly associated with lichen planus and mucous membrane pemphigoid –– Other associations: pemphigus vulgaris, lichenoid mucositis, linear IgA bullous dermatosis, lupus, epidermolysis bullosa acquisita, and chronic ulcerative stomatitis

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III. Physical and chemical injuries • Fibroma –– Presents as sessile, soft, smooth pink nodule on buccal mucosa along bite line –– Represents reactive hyperplasia of fibrous connective tissue due to trauma • Chemical burn –– Most common causes: aspirin, vitamin C tablets, hydrogen peroxide, rubbing alcohol, silver nitrate, phenol, eugenol, battery acid, gasoline, OTC toothache medications –– Presents as erythema that progresses to appear as a wrinkled white membrane due to superficial necrosis • Morsicatio buccarum –– Presents as bilateral white, shaggy lesions on anterior buccal mucosa along line where upper and lower teeth meet –– Histopathology: hyperparakeratosis of surface epithelium with ragged morphology • Traumatic ulcer –– Present as ulcer covered by fibrinopurulent membrane, surrounding erythema, and moderately painful –– Typically self-limited, resolves within 1 week • Drug-related gingival hyperplasia –– Most commonly associated with phenytoin (50%), nifedipine (25%), cyclosporine (25%) –– Correlation with poor oral hygiene –– Present during first year of drug administration, gingival enlargement starts in interdental papillae of anterior teeth, may extend over all involved teeth –– Involved gingiva can be normal in color, firm, and nodular or red and friable –– Edentulous areas spared –– Treatment: stop agent, strict oral hygiene, chlorhexidine rinse, extirpation of excess tissue IV. Aphthous stomatitis • Simplex—minor, major, and herpetiform) –– Minor: most common, sharply demarcated superficial painful ulcers, measure buccal, labial, alveolar, palatal mucosa • Histopathology: dense infiltrate of eosinophils, pleomorphic mononuclear cells extending to submucosal tissue and muscle • Large atypical cells may be CD30+ VI. Salivary gland diseases • Mucocele –– Due to disruption of minor salivary gland, leading to mucous in adjacent submucosal tissue –– Present as abrupt onset, painless, soft submucosal swelling –– Lower labial mucosa > ventral tongue, buccal mucosa, hard palate –– Histopathology: collection of mucous surrounding by chronic inflammatory cells and granulation tissue • Cheilitis glandularis –– Rare inflammatory hyperplasia of lower labial salivary glands, may be due to chronic inflammation –– Presents as slightly hypertrophic lower lip or nodular enlargement leading to eversion of lower lip –– Inflammation of secretory ducts an appear as pinpoint red mucosal macules –– Treatment: vermilionectomy of lower lip, cosmetic debulking • Necrotizing sialometaplasia –– Caused by ischemia of salivary gland of posterior hard palate or anterior soft palate –– Present as abrupt onset swelling of palate with associated pain and anesthesia, leading to well-demarcated ulcer –– Histopathology: metaplasia and ischemic changes confined to salivary gland lobule –– No treatment necessary • Sjögren syndrome –– Xerostomia, can affect minor and major salivary glands –– Presents as non-tender, bilateral enlargement of glands, oral pain, dysphagia, oral candidiasis –– Treatment: pilocarpine or cevimeline for glandular function

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3.14  Disorders of Lipid I. Lipodystrophies • Acquired or inherited disorders characterized by decreased or absent fat in a characteristic body distribution • Generalized, partial, or local • Localized may be due to injection of medications or vaccines, pressure, surgery, trauma, or panniculitis • Adipose tissue secretes hormones and adipocytokines (leptin, TNF-α, IL-6, adiponectin) → play role in development of metabolic changes and insulin resistance seen in lipodystrophies, similar to those seen in metabolic syndrome and obesity • Defective adipocyte triglyceride storage—due to (1) enzyme deficiency (1-acylglycerol-3-phosphate O-acyltransferase 2), (2) defective adipocyte development due to mutation BSCL2/seipin, PPARG, LMNA, (3) adipocyte apoptosis, (4) autoimmune or drug-mediated adipocyte destruction • Adiponectin expressed/secreted by adipocytes –– Regulates insulin sensitivity, glucose/lipid homeostasis –– ↓ in lipodystrophies • Histopathology: near-complete loss of subcutaneous fat, dermis and fascia almost in direct apposition –– In acquired generalized lipodystrophy, lobular panniculitis may be present • Treatment directed at cosmesis, correcting any metabolic imbalances, and management of systemic associations • Congenital or familial lipodystrophies –– Congenital generalized lipodystrophy ◦◦ “Berardinelli-Sep Syndrome” ◦◦ Type 1: mutation in AGPAT2 → ↓ triglyceride and phospholipid synthesis, abnormal adipocyte function ◦◦ Type 2: mutation in BSCL2/seipin → affects seipin (protein in endoplasmic reticulum), critical for lipid droplet morphology ◦◦ Type 3: mutation in CAV1 → encodes caveolin 1, which binds fatty acids and translocates to lipid droplets ◦◦ Type 4: mutation in CAVIN1/PTRF → involved in biogenesis of caveolae and expression of caveolin 1, 3 ◦◦ All types have loss or absence of metabolically active subcutaneous fat from birth → muscular habitus, lack of buccal fat on face, preservation of fat deposits in mechanical sites such as palms, soles, tongue, breasts, orbit (in types 1, 3, 4) ◦◦ Types 1, 2 show deficiency of bone marrow fat

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◦◦ Types 1, 3, 4 show deficiency of visceral fat ◦◦ Anabolic features apparent at early childhood: muscular hypertrophy with prominent veins, increased appetite and high basal metabolic rate, heat intolerance, facial acromegaly, advanced bone and dental age, accelerated growth ◦◦ Metabolic disturbances including insulin resistance, hyperlipidemia, hypertriglyceridemia, low HDL-cholesterol, ↓ plasma leptin ◦◦ In females, oligomenorrhea, polycystic ovaries, infertility, rare cliteromegaly ◦◦ Coarse skin, acanthosis nigricans, hypertrichosis, hyperhidrosis, xanthomas ◦◦ Systemic features include hypertrophic cardiomyopathy, hepatomegaly, organomegaly, hypothalamic-pituitary dysfunction, proteinuric nephropathy –– Familial partial lipodystrophy ◦◦ AD >> AR ◦◦ Type 1: unknown genetic basis ◦◦ Type 2 (most common): mutation in LMNA → encodes lamins A, C, leads to disruption of nuclear function and apoptosis/premature death of adipocytes • Progressive symmetric loss of subcutaneous fat in early adolescence of extremities/trunk • Compensatory accumulation of fat in head and neck leading to round face, increased supraclavicular fat, acromegalic features ◦◦ Type 3: mutation of PPARG → encodes PPAR-γ protein, important in adipogenesis • Milder phenotype than FPLD2 (later age of onset) • More severe metabolic disturbances: glucose intolerance, acute pancreatitis, hepatic steatosis/cirrhosis, hypertrophic cardiomyopathy • Tuberous xanthomas, acanthosis nigricans, hirsutism ◦◦ Type 4: mutation PLIN1 → responsible for formation, maturation, function of lipid droplets within adipocytes ◦◦ Types 5 and 6: based on few reports • Acquired lipodystrophies –– Acquired generalized lipodystrophy ◦◦ “Lawrence syndrome” ◦◦ No known genetic defect ◦◦ Antecedent autoimmune disease, viral/bacterial infection in up to 33%

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◦◦ Selective loss of large areas of face, trunk, extremities, may involve palms/soles ◦◦ Bone marrow fat preserved ◦◦ Acanthosis nigricans, hepatosplenomegaly ◦◦ Can be associated with diabetes or insulin resistance, elevated triglyceride and/or decreased HDL-cholesterol, reduced serum leptin and adiponectin –– Acquired partial lipodystrophy syndrome ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

“Barraquer-Simons syndrome” AD or sporadic (mutation in LMNB2) Loss of subcutaneous fat after viral illness Possible link to adipson, protein produced by adipocytes, leading to dysregulated activation of alternative pathway Second most common type of non-localized lipodystrophy (after HIV/ART-­related lipodystrophy) Fat loss in upper half of body with or without hypertrophy of lower half of body, or hemilipodystrophy where one half of face/body affected Begins in childhood as symmetric progressive loss of subcutaneous fat Starts on face, progresses cephalocaudal Loss of retro-orbital and periorbital tissue

–– Localized lipoatrophy ◦◦ Can occur after abscess, lobular panniculitis, localized autoimmune connective tissue disease, subcutaneous panniculitis-like T cell lymphoma, injected medications (insulin, corticosteroids, antibiotics, MTX, vaccines) ◦◦ One or multiple depressed areas ◦◦ Involutional lipoatrophy—idiopathic, non-inflammatory focal loss of fat, often corresponds to sites of frequent injections ◦◦ Atrophic connective tissue panniculitis—associated with lupus panniculitis > dermatomyositis, vitiligo, juvenile idiopathic arthritis ◦◦ Lipoatrophia semicircularis—symmetric curvilinear depression, may represent repetitive trauma or pressure-induced changes from constant or intermittent pressure ◦◦ Annular lipoatrophy—pseudosclerotic band encircling arm or ankle, may represent end-stage presentation of atrophic connective tissue disease panniculitis ◦◦ Lipodystrophia centrifugalis abdominalis infantilis—idiopathic, well-­demarcated area of lipoatrophy with erythema and scale on the trunk with associated lymphadenopathy, occurs in association with mechanical trauma or focal infection

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• HIV/ART-Associated lipodystrophy –– Most common form of non-localized lipodystrophy (up to 40% patients within 1–2 years of initiation of ART) –– Linked to protease inhibitors (PIs) and nucleoside analogue reverse transcriptase inhibitors (NRTIs)—particularly stavudine, zidovudine, didanosine –– Lipoatrophy of peripheral sites, central lipohypertrophy, and metabolic abnormalities –– NRTI and PI both can cause impaired adipocyte differentiation, increased adipocyte apoptosis via ↑ TNF-α signaling, increased lipolysis due to less expression of perilipin, decreased lipogenesis –– NRTI cause inhibition of DNA polymerase-γ within mitochondria → mitochondrial toxicity particularly in adipose tissue –– PIs cause toxicity on sterol regulatory element-binding proteins (SREBP), preventing its active form in adipocytes and halting adipocyte differentiation –– PIs also decrease expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) which can reduce differentiation of adipocytes –– Clinical features: ◦◦ Peripheral lipoatrophy of face, limbs, buttocks, heel pads causing characteristic cachectic facies –– Risk factors: age >40 years, disease severity at onset of therapy, duration of therapy with PI and/or NRTI –– Must screen for dyslipidemia, diabetes mellitus, hypertension II. Xanthomas • Lipoproteins transport plasma lipids to peripheral cells –– Inner core = triglycerides + cholesterol esters –– Outer shell = phospholipids, free cholesterol, apoproteins –– See Box 3.32 • Hyperlipoproteinemias –– Type I ◦◦ ◦◦ ◦◦ ◦◦

Familial LPL deficiency—ApoCII deficiency Familial hyperchylomicronemia—Deficient or abnormal LPL ↓ LDL, HDL, ↑ TG Develop eruptive xanthomas

–– Type II ◦◦ Familial hypercholesterolemia ◦◦ Familial defective apoB-100 ◦◦ ↑ LDL and cholesterol

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Box 3.32 Lipoproteins Chylomicron VLDL IDL LDL HDL Apo A-I Apo B-48 Apo B-100 Apo C-II E

Exogenous production Core of TG, Outer shell of Apo B-48, E, A-I, A-II, C-II Endogenous production in liver Core of TG, Outer shell of Apo B-100, E, C-II Remnant of VLDL after hydrolysis of TG (by lipoprotein lipase) Remnant after hydrolysis of TG of IDL Core cholesterol ester, outer B-100 Removes cholesterol from tissues Requires apo A-I Major protein of HDL; activates LCAT Seen on chylomicrons, HDL Unique marker for chylomicrons Seen on chylomicrons/remnants Major protein of LDL Seen on VLDL, IDL, LDL Activates lipoprotein lipase Seen on all but LDL Binds to LDL receptor Seen on all but LDL

◦◦ Develop tendinous, tuberoeruptive, tuberous, planar (folds, xanthelasma, intertriginous sites) ◦◦ Risk factor for atherosclerosis –– Type III ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Familial dysbetalipoproteinemia Impairment of hepatic remnants ↑ IDL, chylomicron remnants ↑ cholesterol, TG Develop tuberoeruptive, tuberous, and plane (particularly palmar)

–– Type IV ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Endogenous familial hypertriglyceridemia ↑ production of VLDL a/w glucose intolerance, hyperinsulinemia ↑ VLDL, TG Develop eruptive xanthomas Risk factor for type II diabetes mellitus, obesity, alcohol

–– Type V ◦◦ ◦◦ ◦◦ ◦◦

Due to elevated chylomicrons and VLDL ↓ LDL, HDL, ↑ TG Develop eruptive xanthomas Risk factor for diabetes mellitus

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III. Panniculitis • Many forms of panniculitis with diverse etiologies • Classified as predominately septal or lobular • Erythema nodosum –– Most common in women, 20–40s –– Considered delayed hypersensitivity response with Th1 cytokine pattern (IL2, IFN-γ) to antigenic stimuli –– Present as bilateral, tender, erythematous nodules, most common on shins –– May be sign of systemic disease → evaluate for synovitis, diarrhea, abnormal chest X-ray, preceding upper respiratory infection, elevated anti-streptolysin O, PPD –– Histopathology: septal panniculitis with collections of macrophages within septa with surrounding neutrophils –– Treatment: NSAIDs, potassium iodide, colchicine, dapsone, prednisone, bed rest • Subacute nodular migratory panniculitis –– Unilateral nodules that migrate or expand in a centrifugal manner –– Idiopathic or associated with streptococcal infections and thyroid disease –– Histopathology: chronic septal panniculitis with greater septal thickening and more granulomatous inflammation –– Treatment: potassium iodide • Morphea/scleroderma panniculitis –– Both affect subcutaneous fat –– Indurated plaques on the extremities and trunk –– Histopathology: septal panniculitis, mucin deposition, lymphoplasmacytic inflammation at the dermal-subcutaneous junction • α1-antitrypsin deficiency panniculitis –– Unclear etiology, possible trauma as inciting factor –– Deficiency of α1-antitrypsin leads to activation of lymphocytes, unopposed complement cascade, accumulation of neutrophils, leading to tissue damage –– Large tender nodules on lower trunk and proximal extremities, ulcerate with oily discharge –– Prolonged course, heal with scarring –– Histopathology: liquefactive necrosis of dermis and subcutaneous septae, may be lobular or mixed lobular and septal panniculitis with neutrophils –– Treatment: doxycycline 200 mg BID for 3 months for mild cases, liver transplant in severe

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• Erythema induratum –– More common in women, 30–40 years, more frequently in areas of high prevalence of tuberculosis –– Strong association with tuberculosis, type IV cell-mediated response to antigenic stimuli –– Tender, erythematous nodules on calves, may present with ulceration –– Histopathology: lobular or mixed panniculitis with vasculitis –– Treatment: directed at underlying cause, supportive care, NSAIDs, potassium iodide, steroids • Pancreatic panniculitis –– Seen in up to 2% of patients with pancreatic disease (ranges from acute and chronic pancreatitis to pancreatic carcinoma) –– Pathogenesis linked to enzymes lipase, amylase, and trypsin –– Trypsin and amylase may increase permeability of vessels, allowing lipase to hydrolyze fat and form glycerol and free fatty acids, leading to fat necrosis and inflammation –– Subcutaneous nodules on the legs, arise in crops and migrate, may ulcerate and drain oily material –– Subcutaneous nodules, polyarthritis, and eosinophilia → known as Schmid’s triad (a/w poor prognosis) –– Panniculitis can precede pancreatic disease by up to 7 months –– Histopathology: mixed septal and lobular panniculitis with “ghost cells”—represent lipocytes with no nucleus and thick walls; deposition of basophilic material due to saponification of fat by calcium salts • Sclerema neonatorum –– Seen in premature infants during 1st week of life –– M > F –– Occurs in setting of increased saturated:unsaturated fatty acid ratio defect in ability to mobilize fatty acids –– Present with diffuse hardening of skin with mottled discoloration of the skin –– Associated with cardiopulmonary failure, intestinal obstruction –– Mortality in up to 75% –– Histopathology: needle-shaped clefts in lipocytes with septal thickening and minimal inflammation –– Treatment: supportive therapy • Subcutaneous fat necrosis of the newborn –– Seen in full-term neonates during 2nd to 3rd weeks of life –– Occurs due to stress imposed on fetal fat resulting in increased ratio of saturated:unsaturated fatty acids, leading to crystallization, adipocyte injury, and granulomatous inflammation

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–– Can be precipitated by hypothermia or birth-related trauma –– Present with erythematous, indurated subcutaneous nodules on cheeks, shoulders, trunk, buttocks, and thighs –– Associated with hypercalcemia (can be delayed up to several months), thrombocytopenia, hypertriglyceridemia –– Histopathology: lobular panniculitis with neutrophils, lymphocytes, macrophages, needle-shaped clefts with lipocytes and giant cells –– Treatment: supportive, monitor calcium for 4 months • Post-steroid panniculitis –– Children and adolescents –– Occurs after rapid withdrawal of systemic steroids, by unknown mechanism –– Firm, red plaques on cheeks, arms, trunk –– Occurs 1–40 days after cessation –– Histopathology: lobular panniculitis with lymphocytes, macrophages, multinucleated histiocytes, needle-shaped clefts in lipocytes, and giant cells –– Treatment: none, self-resolving • Lupus panniculitis –– –– –– –– –– –– –– –– –– ––

2–3% of patients with cutaneous LE 10–15% have SLE Widespread lupus panniculitis associated with partial C4 deficiency Tender, subcutaneous nodules and plaques on face, upper arms, hips, trunk May have history of associated trauma Overlying skin may have discoid lesion or appear erythematous Heals with subcutaneous atrophy Chronic and relapsing course Histopathology: lobular panniculitis with mucin deposition, hyaline lobular necrosis, lymphocytes forming follicles, and plasma cells Treatment: antimalarials

• Panniculitis of dermatomyositis –– Uncommon feature of dermatomyositis –– Often with microscopic involvement of subcutaneous fat without apparent clinical features –– Present with persistent, indurated, painful nodules on buttocks, abdomen, thighs, arms –– May ulcerate and lead to lipoatrophy –– Histopathology: lobular or mixed with fat necrosis, lipomembranous changes, calcification may be present –– Treatment: prednisone, methotrexate, azathioprine, cyclosporine, IVIg

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• Traumatic panniculitis –– Occurs after various injuries (cold exposure, injectables, blunt trauma) –– Cold panniculitis: seen in infants, small children, thighs of equestrians ◦◦ Histopathology: septal and lobular inflammation in the dermis and subcutaneous tissue and around adnexae –– Sclerosing lipogranuloma: injection of oils or other impurities, present as nodules on the scrotum due to self-injection of oily materials. ◦◦ Histopathology: granulomatous lobular panniculitis with marked fibrosis, round vacuoles in dermis and subcutaneous tissue –– Panniculitis secondary to injectables: due to therapeutic agents (vitamin K, IL-2, bovine collagen) ◦◦ Texier’s disease—panniculitis due to vitamin K injections, presenting as sclerotic lesions with a lilac border on the buttocks and thighs ◦◦ Histopathology: central nidus of subcutaneous inflammation, sometimes with fibrosis or polarizing foreign material –– Traumatic panniculitis: due to blunt trauma, granulomas form containing material derived from breakdown of erythrocyte membranes ◦◦ Histopathology: organizing hematoma, focal granulomas • Lipodermatosclerosis –– Most often in women >40 years –– Due to venous insufficiency causing increased capillary permeability → leakage of fibrinogen and polymerization to form fibrin cuffs around vessels –– Decreased oxygen exchange over time, leading to tissue anoxia –– Acute phase presents with warmth, pain, induration on medial lower leg over malleolus –– Chronic phase presents with marked sclerosis of dermis and subcutaneous tissue, creating “inverted wine bottle” appearance –– Histopathology: septal and lobular panniculitis with lipomembranous changes, cystic formation, and papillary configurations –– Treatment: aimed towards fixing venous insufficiency, leg elevation, compression • Infection-induced panniculitis –– Seen in immunosuppressed individuals or diabetes –– Caused by direct inoculation from bacteremia or transfascial spread → local swelling, erythema, fluctuant nodules that ulcerate and drain –– Histopathology: mixed septal and lobular panniculitis, neutrophilic infiltrate, vascular proliferation, hemorrhage, necrosis of lipocytes –– Special stains and cultures help identify infectious source –– Treatment: antibiotics, surgery for isolated lesions due to mycetomas

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• Cytophagic histiocytic panniculitis –– Seen in patients with primary cutaneous γ δ T-cell lymphoma, EBV-­ associated extranodal NK/T-cell lymphoma, nasal type –– Histopathology: infiltrates of macrophages containing erythrocytes, lymphocytes, karyorrhectic debris in the subcutaneous fat

3.15  Depositional and Metabolic Disorders I. Mucinoses • Mucin = component of dermal ECM –– Produced in small amount by fibroblasts –– Jelly-like, amorphous mix of (mucopolysaccharides) –– Can absorb 1000× weight in water

acid

glycosaminoglycans

• Stains: Alcian blue, colloidal iron, toluidine blue –– PAS –– Hyaluronidase-sensitive (if composed of HA) • Improved detection when fixed in alcohol over formalin • Scleromyxedema –– Dermal mucin + ↑ dermal collagen –– Nearly 100% associated with paraproteinemia → monoclonal gammopathy—IgGλ ◦◦ Can be a/w dysphagia, myositis, coma, peripheral neuropathy, arthropathy, carpal tunnel symptoms, restrictive or obstructive lung disease, scleroderma-­like renal disease ◦◦ Dermato-neuro syndrome: life-threatening encephalopathy, worsening skin lesions, flu-like prodrome, fever, seizures, coma • Adults, M = F • Waxy, firm papules in linear array • Head/neck, upper trunk, hands, forearms, thighs (spares mucous membranes and scalp) • Leonine facies, deep furrowing (can happen on trunk/extremities = “SharPei sign”) • Can develop skin stiffening, sclerodactyly, decreased motility, central depression surrounded by elevated rim—“doughnut sign” • Histopathology: (1) diffuse mucin in upper and mid-reticular dermis; (2) ↑ collagen deposition; (3) proliferation of irregularly arranged fibroblasts • Differential diagnosis: scleroderma, scleredema, lichen myxedematosus

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• Treatment: IVIg (ToC), thalidomide, steroids (2nd line, adjunct), autologous HSCT (3rd line), PUVA, UVA1, retinoids, cyclosporine, plasmapheresis, extracorporeal photochemotherapy • Lichen myxedematosus • Cutaneous only, no associated sclerosis, systemic involvement, paraproteinemia • Can be a/w HIV, HCV, or historical exposure to toxic oil or L-tryptophan • Discrete papular lichen myxedematosus –– Papules symmetrically on limbs/trunk –– Not indurated, spares face –– Progress slowly without systemic involvement • Acral persistent papular mucinosis –– Ivory to skin-colored papules on dorsal hands, extensor distal forearms • Cutaneous mucinosis of infancy –– Firm opalescent papules on neck, elbows, trunk –– No systemic sx, no spontaneous resolution • Nodular lichen myxedematosus –– Multiple nodules on limbs/trunk • Localized lichen myxedematosus in HIV-infected patients –– Many have hypergammaglobulinemia, up to 10% have MGUS but connection unclear –– No patients have systemic involvement due to mucin deposition • Localized lichen myxedematosus in “toxic” syndromes –– Toxic oil syndrome—adulterated rapeseed oil in Spain in 1980s –– L-tryptophan-associated eosinophilia-myalgia –– Peripheral eosinophilia, hyperpigmentation, sclerodermoid appearance, mucinous papular eruption • Histopathology: mucin in upper/mid reticular dermis, variable fibroblast proliferation • Differential diagnosis: papular GA, amyloidosis, colloid milium, molluscum, papular elastorrhexis, eruptive collagenomas • Treatment: none needed but can try topical corticosteroids, pimecrolimus, tacrolimus • Self-healing cutaneous mucinosis –– Children –– Acute eruption of multiple papules (coalesce into linear infiltrated plaques) –– Face, neck, scalp, abdomen, thighs

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–– Mucinous subcutaneous nodules in periarticular areas, periorbital swelling –– NO paraproteinemia, thyroid dysfunction • Scleredema –– Diffuse induration of upper body due to thickened dermis and deposition of mucin • Type 1: children, middle-aged women, preceded by fever, malaise, URI –– Can be after strep infection • Type 2: similar as 1, subtle onset, no preceding illness –– Often a/w monoclonal gammopathy • Type 3: obese middle-aged men, IDDM –– ↑ amt of glycosylated collagen • Histopathology: thickening of reticular dermis, reduced elastic fibers, no increase in fibroblasts • Differential diagnosis: Scleroderma (but no Raynaud, telangiectasias), cellulitis • Treatment: Phototherapy (UVA1, PUVA) (ToC), corticosteroids, intralesional hyaluronidase, abx, MTX, cyclosporine • Mucinoses associated with altered thyroid function –– Pretibial Myxedema ◦◦ Induration of shins, a/w hyperthyroidism (Grave’s disease)—1 to 5% (up to 25% with exophthalmos) ◦◦ Erythematous waxy indurated nodules/plaques—“peau d’orange” appearance ◦◦ Shins >> face, shoulders, arms, lower abdomen, scars, donor graft sites ◦◦ Histopathology: Mucin in reticular dermis causing collagen bundles to separate, large stellate fibroblasts, subepidermal grenz of normal collagen, reduced elastic fibers, often a/w papillomatosis/hyperplasia of epidermis ◦◦ Differential diagnosis: LSC, hypertrophic LP, lymphedema, lipedema, obesity-­associated lymphedematous mucinosis ◦◦ Treatment: Corticosteroids topical or IL (ToC), can consider for severe elephantiasis form: IVIg, rituximab, plasmapheresis, octreotide, compression ∗control of hyperthyroidism makes no difference –– Generalized Myxedema ◦◦ Manifestation of severe hypothyroidism (congenital or cretinism, juvenile, or adult)

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◦◦ Cool, waxy, dry skin, absence of sweating, diffuse non-scarring alopecia, purpura, delayed wound healing ◦◦ Histopathology: Perivascular/perifollicular mucin, reduced elastic fibers ◦◦ Treatment: correct thyroid levels • Reticular erythematous mucinosis –– Middle aged women > men, children –– Papules or plaques on midline back/chest with reticular or net-like configuration –– Reports of lupus, hypothyroidism, internal malignancy –– Histopathology: Interstitial mucin in upper dermis, vascular dilation, DIF usually negative –– DDx: LE tumidus –– Treatment: hydroxychloroquine or chloroquine (+/- quinacrine) > corticosteroids, calcineurin inhibitors, antihistamines, antibiotics, UVB, pulsed dye laser • Papulonodular mucinosis associated with autoimmune connective tissue disease –– Papules, nodules, plaques secondary to mucin deposition seen with AICTD (lupus > DM, scleroderma) –– Histopathology: mucin in upper/mid dermis, with perivascular lymphocytic infiltrate –– Treatment: similar to treatment of LE or dermatomyositis • Follicular mucinosis –– –– –– –– –– ––

Idiopathic benign form of disease Acute/subacute in children, young adults Plaque with grouped follicular papules, may have associated scale, alopecia Histopathology: Mucin within follicular epithelium and sebaceous glands Differential diagnosis: mycosis fungoides (folliculotropic) Treatment: none > topical/IL steroids, antimalarials, PUVA, minocycline, isotretinoin

• Urticaria-like follicular mucinosis –– Very rare –– Pruritic urticarial papules/plaques on head/neck in erythematous seborrheic background II. Amyloidosis • Amyloidosis is a term used to refer to several diseases that share feature of abnormal extracellular deposition of amyloid (fibrillar proteinaceous material)

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• Classified clinically into systemic/generalized forms and organ-limited/ localized forms –– In systemic form, precursor secreted into circulation and amyloid deposited at distant site • In localized form, amyloid deposition at/near site of synthesis • Pathogenesis: –– Major component of amyloid = fibril protein Minor components = amyloid P component, apoE, glycosaminoglycans –– ~18 distinct forms of amyloid fibril proteins identified: ◦◦ ◦◦ ◦◦ ◦◦

AL (amyloid light chains) AA (amyloid-associated) Aβ—found in cerebral lesions of Alzheimer’s ATTR—found in some familial amyloidosis

–– These precursor proteins are initially insoluble then aggregate, polymerize, form fibrils, and deposit in tissue as insoluble amyloid –– Primary systemic amyloidosis: amino acids in specific positions in variable region of Ig light chain are replaced, which potentially destabilizes the light chains and increases likelihood of converting to amyloid fibrils –– Primary cutaneous amyloidosis: precise pathogenesis not fully understood but multiple hypotheses: (1) prolonged friction, (2) genetic disposition, (3) EBV, (4) environmental factors ◦◦ Amyloid of macular and lichenoid variants of primary cutaneous amyloid are keratinocyte-derived ◦◦ Fibrillar theory: tonofilaments of keratinocytes undergo filamentous degeneration, pass into dermis where they are modified by histiocytes/ fibroblasts into amyloid ◦◦ Alternative theory: material produced at DEJ ◦◦ Nodular amyloid thought to have different origin (plasma cell) • • • • • • •

Histopathology: amorphous, eosinophilic fissured masses Congo red: orange/red color by light microscopy Polarized light: green birefringence Other special stains: crystal violet, methyl violet, PAS, Sirius red, pagoda red, Dylon stain, Thioflavin T EM: non-branching, non-anastomosing fibrils Primary cutaneous amyloidosis –– Deposition of amyloid in apparently normal skin without associated deposits in internal organs –– Macular amyloidosis ◦◦ Hyperpigmented (confluent or rippled), often on the upper back –– Lichen amyloidosis

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◦◦ Most common form of primary cutaneous amyloidosis ◦◦ Persistent, pruritic plaque on shin/extensor surface of extremities ◦◦ Initially discrete, firm, scaly papules later coalescing into plaques in rippled/ridged pattern ◦◦ Both have been described in association with autoimmune connective tissue disorders –– Nodular amyloidosis ◦◦ Rare, single or multiple waxy nodules/plaques on trunk or extremities ◦◦ May be associated with Sjögren syndrome –– Can progress to systemic involvement so long-term f/u is necessary (risk ~7%) –– Histopathology: ◦◦ In macular/lichen forms, deposits of amyloid restricted to upper dermis, ± melanophages, sparse perivascular lymphohistiocytic infiltrate ◦◦ In nodular form, dermis, subcutis, and blood vessel walls diffusely infiltrated with amyloid –– Differential diagnosis: ◦◦ Macular amyloid: nostalgia paresthetica ◦◦ Lichen amyloid: LSC, hypertrophic LP, papular mucinosis, pretibial myxedema, prurigo nodularis, pemphigoid nodularis, lichen ruber moniliformis, colloid milium, epidermolysis bullosa pruriginosa ◦◦ Nodular amyloid: lymphoma cutis, pseudolymphoma, pretibial myxedema, sarcoidosis, GA, reticulohistiocytosis, granuloma faciale –– Treatment: Directed at breaking itch-scratch cycle, topical steroids +/mild keratolytic, UVB, PUVA, systemic retinoids (etretinate, acitretin), surgical excision, cryotherapy, electrodesiccation, CO2 laser • Secondary amyloidosis –– Refers to clinically inapparent amyloid deposits seen histopathologically within skin tumors such as dermatofibromas, intradermal melanocytic nevi, SKs, pilomatricomas, trichoepitheliomas, sweat gland tumors, BCCs, Bowen’s disease, and porokeratosis • Systemic amyloidosis –– Primary Systemic Amyloidosis ◦◦ Manifestation of underlying plasma cell dyscrasia ◦◦ Fibrils composed of AL protein, consists of Ig light chains (75–80% λ) ◦◦ Rubbery swellings/infiltration of mucosa, macroglossia, ± hemorrhagic papules, plaques, blisters

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◦◦ Petechiae, purpura, ecchymoses, especially on eyelids, neck, axillae, anogenital region ◦◦ Waxy translucent or purpuric papules, nodules, plaques ◦◦ Less often, diffuse cutaneous infiltration resulting in infiltrated sclerodermoid appearance ◦◦ Nail dystrophy, acquired acral cutis laxa, hemorrhagic blisters resembling PCT or EBA ◦◦ Dx can be made in 80–90% from rectal mucosa bx or abdominal SQ fat aspirates (gingival/tongue, BM bx) ◦◦ Histopathology: Amyloid deposits in dermis + subcutis ◦◦ Differential diagnosis: Papular mucinosis, lipoid proteinosis, adnexal tumors (face) ◦◦ Treatment: Melphalan, steroids, stem cell transplant • For older patients or with cardiac involvement, can use newer targeted agents (lenalidomide, bortezomib) • Poor prognosis if untreated (13 mo median survival) –– Secondary Systemic Amyloidosis ◦◦ Occurs as complication of severe chronic inflammatory disease such as tuberculosis, lepromatous leprosy, RA, ankylosing spondylitis ◦◦ Less often a/w hidradenitis suppurativa, dystrophic EB, psoriasis, scleroderma, dermatomyositis, SLE ◦◦ Deposition of non-immunoglobulin protein AA (amyloid A protein) ◦◦ Usually affects kidneys, liver, spleen, adrenals, heart (cutaneous lesions rarely seen in this type) ◦◦ Treatment directed at treatment of underlying infectious/inflammatory disease –– Hemodialysis-Associated Amyloidosis ◦◦ Results from decreased excretion of β2-microglobulin, seen in patients on long-term HD for ESRD ◦◦ The β2-microglobulin fails to be filtered through dialysis membranes, tends to deposit in synovial membranes → carpal tunnel syndrome, bone cysts, destructive spondyloarthropathy –– Inherited Amyloidosis ◦◦ Muckle-Wells syndrome: can have associated AA amyloid nephropathy ◦◦ Familial Mediterranean fever: AR, NLRP3 cryopyrin inflammasome, can have AA amyloid deposition ◦◦ Sipple syndrome (MEN2A): AD, associated with nostalgia paresthetica, macular & lichen amyloidosis ◦◦ Hypotrichosis simplex of the scalp: uncommon AD disorder, mutation in gene encoding corneodesmosin, develop deposits of truncated

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protein accumulating as amorphous amyloid deposits around hair follicles –– X-Linked Reticulate Pigmentary Disorder (Partington Amyloidosis) ◦◦ Report of a family with an X-linked disease where women had linear streaks of hyperpigmentation, men had reticulated mottled brown pigmentation which demonstrated dermal deposits of amyloid ◦◦ Amyloid deposits are keratin-positive, limited to skin in women, but men would also have recurrent respiratory infections, corneal dystrophy, and photophobia. III. Porphyria • Porphyrias result from dysfunction in one of 8 enzymes involved in porphyrin-heme biosynthetic pathway (See Box 3.33) • Mutations in any of genes encoding enzymes in the heme biosynthetic pathway can lead to a pathologic accumulation and measurable excretion of porphyrins and/or porphyrin precursors

Box 3.33 Heme Biosynthetic Pathway Step Products (enzyme) 1 Glycine + succinyl CoA → δ-ALA (aminolevulinic acid synthase 2) 2 δ-ALA → Porphobilinogen (ALA dehydratase) 3 Porphobilinogen → hydroxymethylbilane (porphobilinogen deaminase) 4 Hydroxymethylbilane → uroporphyrinogen, uroporphyrin I and III (uroporphyrinogen III synthase) 5 Uroporphyrinogen → coproporphyrinogen, coproporphyrin I and III (uroporphyrinogen decarboxylase) 6 Coproporphyrinogen → protoporphyrinogen IX (coproporphyrinogen oxidase) 7 Protoporphyrinogen IX → protoporphyrin IX (protoporphyrinogen oxidase) 8 Protoporphyrin IX → heme + globin + apoprotein (ferrochelatase + Fe2+)

Location Disease Mitochondrion X-linked dominant protoporphyria Cytosol ALA dehydratase deficiency porphyria Acute intermittent porphyria (AIP) Congenital erythropoietic porphyria (CEP)

Porphyria cutanea tarda (PCT) Hepatoerythropoietic porphyria (HEP) Mitochondrion Hereditary coproporphyria

Variegate porphyria

Erythropoietic protoporphyria

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• No single factor can explain the photosensitization evoked by porphyrins plus UV radiation, number of mediators thought to be involved (ROS, complement, eicosanoids, MMPs) • Porphyrins absorb light energy in the Soret band (400–410 nm) → excited state, transfer energy to oxygen → ROS → cellular and tissue damage • Accumulation of water-soluble uro- and coproporphyrins → blistering (most cutaneous porphyrias) • Accumulation of lipophilic protoporphyrins → immediate cutaneous burning sensation after exposure to the appropriate wavelengths of light, accompanied by erythema and edema • Acute porphyric attacks: –– ALA and PBG are non-phototoxic precursors –– ALA and PBG, which are excreted in massive amounts from the liver during an acute attack, are extremely neurotoxic • Non-acute porphyrias • All present primarily with cutaneous findings • Porphyria cutanea tarda (PCT) –– Most common porphyria worldwide –– Caused by decreased catalytic decarboxylase –– Two Types:

activity

of

uroporphyrinogen

◦◦ Type 1: sporadic (acquired), dysfunctional enzyme exclusively expressed in the LIVER ◦◦ Type 2: AD (hereditary), dysfunctional enzyme is expressed in all tissue –– Photosensitivity and skin fragility + blistering, erosions, crusts, milia and scars in sun-exposed sites + PIH, hypertrichosis, scarring alopecia, and morpheaform/sclerodermoid changes –– Histopathology: cell-poor subepidermal blister with festooning; DIF w/ IgG (>IgM), complement and fibrinogen at DEJ and around papillary dermal blood vessels –– Biochemical testing: ◦◦ ↑ URINARY excretion of uroporphyrin, hepta-carboxylate porphyrin, and coproporphyrin • urine turns red/brown after several hours of exposure to natural light • pink/red fluorescence when exposed to UVA light ◦◦ ↑ FECAL excretion of isocoproporphyrin (exclusive to CPT and HEP) –– Possible triggers: alcohol, estrogens, polychlorinated hydrocarbons, dialysis in patients with renal failure, iron, inheritance of specific mutations in the HFE gene which underlie classic hemochromatosis, and viral infections such as hepatitis C and HIV –– PCT patients have ↑ risk of hepatocellular carcinoma

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• Erythropoietic protoporphyria (EPP) –– Due to a deficiency in ferrochelatase –– Presents with photosensitivity in early childhood, occurs within minutes of sun exposure, particularly nose, cheeks and dorsal hands, usually no blistering, rarely associated with palmar keratoderma –– Biochemical testing: ↑ free protoporphyrin levels in erythrocytes, plasma, feces, and other tissues such as the liver –– Complications: rapid accumulation of protoporphyrin in liver and biliary system → cholestasis → hepatic damage → liver failure • X-linked dominant protoporphyria –– deficiency of the erythroid tissue-specific isoform of δ-aminolevulinic acid synthase 2 (ALAS2 gene on the X chromosome) –– Clinically indistinguishable from EPP –– Biochemical: higher total protoporphyrin levels in erythrocytes (than EPP) • Congenital erythropoietic porphyria (CEP) –– Gunther disease –– AR, due to decreased activity of uroporphyrinogen III synthase –– Manifests shortly after birth with severe cutaneous photosensitivity, blistering, erosions, crusts and ulcerations, followed by extensive scarring and deformation, primarily of the hands –– Erythrodontia, acro-osteolysis and skeletal abnormalities (e.g. demineralization) are common clinical features –– Variable degrees of hematologic involvement, (mild hemolytic anemia to intrauterine hydrops fetalis and hepatosplenomegaly) –– Early clue: pink, red or violet staining of diapers –– Biochemical: ↑ URINARY excretion of uroporphyrin I and coproporphyrin I plus ↑ levels of coproporphyrin I in the STOOL • Hepatoerythropoietic porphyria (HEP) –– Homozygous variant of hereditary PCT due to a pronounced decrease in uroporphyrinogen decarboxylase activity –– Presents during early childhood, dark urine in the diapers followed by severe cutaneous photosensitivity (blistering, pruritus, hypertrichosis, hyperpigmentation and scleroderma-like scarring) –– Not usually a/w hematologic abnormalities –– Biochemical: ↑ URINARY levels of uroporphyrin and hepta-carboxylated porphyrins + ↑ FECAL levels of coproporphyrin and isocoproporphyrin • Treatment of all non-acute porphyrias: –– Avoidance of triggers, UV exposure, use of sun-protective clothing and sunscreen (only physical blockers work within the 400–410 nm range)

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–– For Iron overload → phlebotomy (500 ml q2wks) –– Low dose hydroxychloroquine or chloroquine (may accelerate excretion of porphyrins and/or inhibit porphyrin synthesis) ◦◦ Dosing 200 (HCh)/125(Ch) twice weekly –– In EPP, β-carotene may be beneficial in reducing photosensitivity ◦◦ Afamelanotide has been designated an orphan drug for the treatment of EPP • Pseudoporphyria –– Condition that closely resembles PCT –– Presents with skin fragility, erosions, blisters, and scarring have a predilection for the dorsal aspect of the hands the face, and the extensor surfaces of the legs –– No biochemical abnormalities in porphyrin metabolism are detected –– Commonly seen in patients with CKD or in those undergoing renal dialysis (HD>PD) –– Also seen with the ingestion of specific drugs → NSAIDs (e.g. naproxen, nabumetone, ketoprofen), furosemide, abx (e.g. nalidixic acid, tetracycline) and retinoids • Acute porphyrias • Broad range of clinical findings, including persistent colicky abdominal pain, nausea and vomiting, obstipation, tachycardia, hypertension, seizures, paresthesias, para- and tetraplegia, and acute psychosis • Acute Intermittent Porphyria: –– Worldwide, the most common acute porphyria –– AD deficiency of porphobilinogen deaminase –– No skin manifestations • Variegate Porphyria –– AD deficiency in protoporphyrinogen oxidase –– Skin findings indistinguishable from PCT, but w/ acute attacks similar to those in AIP –– Biochemical analyses of fecal porphyrins are mandatory in order to establish the diagnosis of VP ◦◦ Plasma fluorescence emission peak of 624–626  nm is seen only in symptomatic patients, including those with cutaneous involvement • Hereditary Coproporphyria –– AD deficiency in coproporphyrinogen oxidase –– Clinically similar to VP –– Coproporphyrins in the stool are higher than those of protoporphyrin (compared to VP)

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• ALA-D deficiency porphyria –– AR—less than 10 cases reported, no important clinical presentation • Treatment: –– Cutaneous: similar to non-acute porphyrias (phlebotomy of no benefit) –– Acute attacks: prompt administration of IV heme preparations (heme arginate or hemin), glucose infusion is an option in heme preparation is not available IV. Calcifying and ossifying disorders of the skin • 4 broad categories of disease: (1) Dystrophic—localized tissue damage → damages cell membranes → Ca influx → intracellular crystallization (2) Metastatic—normal tissue with dysfunction of the calcium regulatory systems (3) Idiopathic—no known local or systemic factors can be identified (4) Iatrogenic • Dystrophic Calcification • Autoimmune Connective Tissue disease –– Childhood dermatomyositis, CREST >> lupus erythematosus, generalized morphea –– Childhood dermatomyositis ◦◦ 50–70% of children develop calcification, only ~20% of adults ◦◦ Small deposits may occur in the skin or larger firm masses may begin in the muscle groups ◦◦ Elbows, knees, buttocks and shoulders ◦◦ Extrusion of calcium through the skin causes significant morbidity with pain and secondary infection ◦◦ Calcinosis universalis—most severe form with diffuse sheet-like masses of calcium along fascial planes, causes severe functional impairment. –– CREST ◦◦ Less severe calcification than in DM ◦◦ Restricted to hands and upper extremities over bony prominences and tendons ◦◦ Extrusion of white chalky material is sometimes followed by localized ulceration, often at sites of trauma such as the digits –– Treatment: ◦◦ Low calcium and phosphate diet, aluminum hydroxide and bisphosphonates, colchicine, probenecid, sodium thiosulfate, diltiazem ◦◦ Surgical excision if painful or interfere with function.

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• Lobular panniculitis –– Pancreatitis or pancreatic cancer release pancreatic enzymes that cause lipolysis of subcutaneous fat → Fatty acids released combine with calcium → calcium soaps ◦◦ Crops of nodules appear on the lower extremities and, less often, on the trunk, which may ulcerate and drain. –– Subcutaneous fat necrosis of the newborn ◦◦ Cheeks, back, buttocks and extremities; clear spontaneously –– Lupus profundus • Genetic disorders –– PXE—calcification of the elastic fibers of the skin, progressive calcification of elastic tissue in Bruch’s membrane of the retina and in the cardiovascular system may occur in these patients; mutation in ABCC6 gene (membrane transporter system); low serum levels of fetuin-A, a major anti-mineralization protein, → allow unchecked calcification of elastic fibers in affected tissues –– Ehlers Danlos—hard subcutaneous nodules known as spheroids (herniated calcified fat lobules) –– PCT—head and neck region or on the dorsal surface of the hands –– Werner syndrome, Rothmund–Thompson syndrome • Infections –– Calcified cysts around larvae or worms; Intrauterine herpes simplex → newborn calcinosis cutis • Neoplasms –– Pilomatricomas (Activating mutations in the β-catenin gene), BCC, pilar cysts, EIC, chondroid syringomas> melanocytic nevi, AFX, pyogenic granulomas, trichoep, seb keratoses • Trauma: heel sticks in neonates, subcutaneous/ IM injections sites, surgical and burn scars, keloids • Metastatic Calcification –– Renal Disease ◦◦ Benign nodular calcification • CRF with prolonged secondary hyperparathyroidism. Impaired ability to clear phosphate + Impaired synthesis of 1,25-dihydroxyvitamin D3 → decreased absorption of calcium from the intestine and hypocalcemia → increased levels of parathyroid hormone → increased mobilization of calcium and phosphate → calcium concentration is normalized, but significant hyperphosphatemia

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may develop, and, if the solubility product of calcium and phosphate is exceeded, metastatic calcification can result in one of two forms: benign nodular calcification or calciphylaxis. • Large, often asymptomatic deposits of calcium often in periarticular sites. Normalization of Ca and PO4 levels may result in resorption of the lesions; surgical removal if needed ◦◦ Calciphylaxis • progressive vascular calcification → ischemic necrosis; cause of calciphylaxis remains unclear—no differences in the serum levels of calcium, phosphate, PTH compared to control dialysis patients; Protein C dysfunction ? • early lesions are violaceous reticulated patches → Bullae → ulcer formation; extremely painful even at the earliest stages of development. Death is often due to gangrene and sepsis; predominantly female diabetics; • 85% overall mortality; proximal involvement = worse prognosis. • Treatment: low calcium dialysis + phosphate binders, parathyroidectomy, aggressive wound care, sodium thiosulfate, pamidronate, cinacalcet, hyperbaric oxygen and low-dose tissue plasminogen activator ◦◦ Milk-Alkali syndrome • Excessive Ca containing foods or antacids → nephrocalcinosis, irreversible renal failure and diffuse subcutaneous calcification. ◦◦ Hypervitaminosis D • Excessive vitamin D →hypercalcemia and hypercalciuria → Nephrolithiasis and calcinosis cutis • Idiopathic –– Idiopathic calcified nodules of the scrotum—firm, whitish nodules; calcified EIC? Vulva lesions also described –– Subepidermal calcified nodule—solitary firm nodule on head/neck, often ears; often in children. –– Tumoral calcinosis—large, often painful, deposits around large joints. sporadic or familial (AR, primary hyperphosphatemia) –– Milia-like lesions—dorsal surface of the hands, face; often in Down syndrome; calcification of syringomas • Iatrogenic –– Due to rapid precipitation of calcium salts within the skin –– Often due to extravasation of calcium gluconate, calcium chloride or phosphate-­containing intravenous solutions, calcium alginate dressings for STSG, lung transplants patients—citrates used during surgery

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• Ossifying Disorders (osteoma cutis) –– Genetic Disorders ◦◦ Fibrodysplasia ossificans progressiva—AD, dysregulation of bone morphogenic protein (BMP), die early age; endochondral bone formation that extends to skin (others are intramembranous bone formation in the dermis) ◦◦ Progressive osseous heteroplasia—asymptomatic papules and nodules; ‘rice-­grain” texture” ◦◦ Plate-like osteoma cutis—limited form of progressive osseous heteroplasia ◦◦ Albright hereditary osteodystrophy—associated with pseudohypoparathyroidism + brachydactyly, obesity, short stature, round facies –– Miliary osteomas– multiple, scattered foci of cutaneous ossification on the face of adults; often hx of chronic acne –– Secondary cutaneous ossification—melanocytic nevi, pilomatricomas, pilar, EIC, BCC –– Treatment—excision of neoformed bone, recurrence is common in the genetic disorders V. Nutritional diseases • 2 groups of malnutrition: –– Protein-energy deficient nutrition ◦◦ Exogenous or primary form: • Low-income countries • Restrictive diets, psychiatric illness, mental impairment (EtOH) ◦◦ Endogenous or secondary form: • Inadequate absorption, metabolism, or increased nutritional requirements (GI disease, late-stage malignancy or other chronic systemic diseases, AIDS) –– Protein-energy excessive nutrition ◦◦ Obesity • Industrialized countries, excessive consumption of foods high in calories, low in nutrients • 2 classic protein-energy malnutrition syndromes: –– Marasmus ◦◦ Develops months-years ◦◦ 1° causes: Poverty, EtOH, drug abuse, psychiatric d/o, restrictive diets, child/elderly neglect/abuse

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◦◦ 2° causes: Intestinal malabsorption, chronic diarrhea, malignancies, chronic systemic diseases, AIDS, metabolic disorders ◦◦ Follicular hyperkeratosis, folliculitis, fine scaling, hyperpigmentation, lanugo hair, purpura ◦◦ Starved appearance ◦◦ Recurrent infections ◦◦ Slowly replace proteins/calories, supplement with linoleic acid and Zn ◦◦ 10% mortality –– Kwashiorkor’s ◦◦ Can develop as early as few weeks (Acute) ◦◦ Rice-based diet, protein-losing enteropathies, GI sx, HIV ◦◦ Can also develop after weaning from breast milk and diet with carbs but no proteins ◦◦ Occurs in setting of acute illness over chronic state of milder malnutrition ◦◦ Dyschromia, pallor, “enamel paint spots” or “flaky paint”, “flag sign” hair, cheilitis ◦◦ Relatively well-nourished appearance ◦◦ Peripheral edema/anasarca + hypoalbuminemia ◦◦ Aggressive nutritional support ◦◦ Poor prognosis in adults even with aggressive nutritional support • Essential Fatty Acid Deficiency –– –– –– ––

EFA are unsaturated, need from exogenous source Linoleic (= omega 6 FA), linolenic, arachidonic acids Constitute 13–30% skin’s fatty acids Occurs after parenteral nutrition without lipid supplementation, often a/w other nutritional deficiencies

• Dx: ↑ eicosatrienoic acid + ↓ linoleic, linolenic acids • Clinical Features (Know the mucocutaneous clues to suggest a possibly nutritional disorder!) –– –– –– –– –– –– –– –– –– –– –– ––

Alopecia, sparse hair, brittle easily broken hair, “flag” sign Conjunctivitis, blepharitis Seborrheic and perioral dermatitis-like eruption Bleeding gums, mucosal erosions, gingival hypertrophy Angular cheilitis Glossitis Photodistributed dermatitis with a shellac-like scale Ecchymoses, petechiae, purpura Erythema, erosions, scale-crust Koilonychia, soft thin nails, pustular paronychia Follicular hyperkeratosis, corkscrew hairs, perifollicular hemorrhage Poor wound healing

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• Vitamin and Trace Elements –– –– –– ––

Vitamins essential for development, maintenance of bodily functions Fat-soluble = ADEK (symptomatic excess more likely) Water-soluble = all others, most serve as cofactors for enzymes Function of Vitamin D ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Role in absorption of Ca, P Antiproliferation, pro-differentiation hormone No cutaneous signs of vitamin D deficiency Best measure is total serum 25-hydroxyvitamin D (T1/2 2 weeks—better reflects body stores) Deficiency ≤20 Insufficiency = 20–29 Endogenous source = 7-dehydrocholesterol → previtamin D3 with UVB exposure Vitamin D3 → 25-hydroxyvitamin D3 (liver—Vitamin D 25-hydroxylase) → 1,25-dihydroxyvitamin D3 25-hydroxyvitamin D3 (kidney—25(OH)D-1α-hydroxylase)

–– Function of Select Trace Elements Trace elements & minerals = 3% body weight at birth, 4% in adults Important as cofactors for enzymes and prosthetic groups in metalloproteins –– Zn ◦◦ Critical role in metalloenzymes ◦◦ Human breast milk, animal-based foods, shellfish, legumes, leafy greens ◦◦ Enhances wound healing, immune function, antioxidant (? protect against UV-induced damage?) ◦◦ Deficiency: • • • • • •

Perioral, acral, anogenital erythema, scale, crust, erosions Alopecia, paronychia, onychodystrophy Blepharitis, conjunctivitis, stomatitis, angular cheilitis Triad (20%)—diarrhea, depression, erosive dermatitis 2º Candida, Staph infxns Children with chronic—growth retardation, hypogonadism

◦◦ Inherited deficiency = Acrodermatitis enteropathica • AR, SLC9A4 • Presents 1–2 weeks after weaning breast milk, 4–10 weeks if bottle fed ◦◦ Risk factors: Children with cystic fibrosis, EtOH, anorexia, vegan diet, phytate high diet ◦◦ ↓ Zn, ↓ Alk P (Zn-dependent enzyme)

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–– Cu ◦◦ In blood, 90% Cu a/w ceruloplasmin, remainder bound to albumin ◦◦ Seen in infants receiving milk ↓ in Cu, protein-energy malnutrition, excessive Zn intake ◦◦ FTT, anemia, neutropenia ◦◦ Menkes disease • XLR, ATP7A- defective Cu absorption, ↓ Cu levels in blood, liver, hair • Pudgy cheeks, cupid’s bow of upper lip, horizontal eyebrows • Alopecia with abnormal hair shafts: pili torti, monilethrix, trichorrhexis nodosa ◦◦ Cu toxicity • Excessive ingestion → GI sx, childhood cirrhosis • Inherited → Wilson disease (ATP7B)—role in Cu secretion into plasma and excretion into bile • Dx: ↓ serum ceruloplasmin, ↑ urinary Cu excretion, ↑ hepatic Cu content • Hepatomegaly, cirrhosis, Kayser-Fleischer corneal rings, neuro sx • Tx: penicillamine, trientine (facilitate excretion of Cu) –– Se ◦◦ Selenocysteine essential in thyroid hormone metabolism, protecting against oxidative damage ◦◦ Deficiency leads to cardiomyopathy, muscle pain, weakness ◦◦ Hypopigmentation of skin and hair, leukonychia, xerosis ◦◦ ↑ CK, LFTs ◦◦ Seen in those receiving TPN or poor soil content ◦◦ Se toxicity “Selenosis”- peripheral neuropathy, dermatitis, alopecia, abnormal nails, n/v, garlic breath odor

3.16  Pruritus and Psychocutaneous Disorders I. Primary psychocutaneous disorders • Delusions of parasitosis –– Somatic type of delusional disorder –– Isolated, fixed belief that skin infested by parasites in absence of infestation –– Findings range from none to self-induced excoriations, lichenification, prurigo nodularis, ulcerations –– Often present with pieces of skin, lint, samples of “parasites” known as “matchbox sign”

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–– Associated with sensations of crawling, biting, stinging –– Treatment: establish rapport, communication, pimozide (ToC), risperidone, olanzapine, aripiprazole • Body dysmorphic disorder –– Preoccupation with perceived faults in skin, hair, or body structures causing distress to patient –– Spans a spectrum of obsession with perceived inadequacies to delusions about appearance –– Treatment: SSRI (ToC) for obsessive variant of disease, antipsychotics for delusional patients • Trichotillomania –– Body-focused repetitive behavior disorder manifesting as hair pulling –– Scalp, eyebrows, eyelashes, and pubic region –– May be associated with anxiety, boredom, or tingling sensation resulting in gratification or relief once hair is pulled –– Trichophagy can be associated, can lead to intestinal obstruction from trichobezoar –– Classic findings are irregularly shaped areas of alopecia, hairs of varying lengths –– Trichoscopy reveals irregularly broken hairs, coiled hairs, follicular hemorrhage –– Histopathology: deformed hair shafts (trichomalacia), empty follicles, pigmented hair casts –– Treatment: preschool children tend to outgrow, pre-adolescent/young adults tend to follow chronic relapsing course, behavioral modification therapy (ToC), SSRI, olanzapine, N-acetylcysteine • Others –– Excoriation disorder: recurrent picking, scratching, or rubbing that results in skin lesions –– Acne excoriee: subset of excoriation disorder where patients with underlying acne pick at lesions, may lead to scarring –– Dermatitis artefacta: factitious disorder in which patients inflict cutaneous lesions upon themselves

3.17  Photodermatoses • All skin can react to light due to chromophores ability to absorb UVR • Photodermatoses can result from abnormal tissue responses after absorption or expected responses to absorption by porphyrins or photosensitizing drugs or chemicals

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I. Immunologically-Mediated Photodermatoses • PMLE –– –– –– –– –– –– –– –– –– –– –– ––

Minutes/hours → fades over days/weeks Non-scarring pruritic papules, vesicles, plaques Highest prevalence in Scandinavia, UK, northern US Lower prevalence in Australia, equatorial Singapore (likely due to “hardening”) Action spectrum UVB-UVA (rarely visible light) Delayed-type hypersensitivity (DTH) response to endogenous photoinduced antigens Neck, outer arms, dorsal hands, face (areas continuously exposed are often spared) Juvenile spring eruption—variant on ears of boys, vesicles, ± fever, malaise, headache, nausea Can be lifelong, but usually improves/resolves in >50% over 16 years, 75% by 32 years Histopathology: epidermal spongiosis, sup/deep perivascular/periappendageal lymphohistiocytic infiltrate, + eos & neuts, significant papillary edema Differential: LE, atopic derm, seb derm, solar urticaria, EPP Treatment: Photoprotection, hardening (NB-UVB 2–3×/week), prednisone, hydroxychloroquine, topical CS

• Actinic prurigo –– Aka Familial/hereditary PMLE –– Seen in Native Americans (Mestizos) at high altitudes, much less commonly in Europe and Asia –– Flares in spring/summer –– May represent persistent variant of PMLE –– Strong a/w HLA-DR4 (DRB1∗0401) –– Appears in childhood, girl > boys –– Erythematous papules, nodules, hemorrhagic crusts on sun-exposed sites (face/nose, distal limbs), can also involve covered sites (buttocks) –– Cheilitis, conjunctivitis common (cheilitis can be the only manifestation) –– Histopathology: epidermal spongiosis, acanthosis, dermal perivascular mononuclear cell infiltrate, ± eos –– Treatment: Photoprotection, topical CS, tacrolimus, NB-UVB, thalidomide, TNF-α • Hydroa vacciniforme –– Scarring childhood-onset photodermatosis –– Possible link to EBV

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–– Hours → clustered, pruritic/burning macules that turn to papules, plaques surrounded by vesicles or bullae, then umbilicating ± malaise, fever, headache –– Heals over weeks, leaving varioliform scars –– Patients with severe HV-like eruptions in systemic EBV, more widespread, sun-protected sites, facial swelling, ulcerated nodules, exaggerated rxn to mosquito bites, high-grade fever, HSM –– Histopathology: reticular keratinocyte degeneration, intraepidermal vesicles, confluent epidermal necrosis –– Treatment: Photoprotection (tinted windows), BB-UVB, NB-UVB, PUVA, antimalarials, azathioprine, thalidomide, cyclosporine • Chronic actinic dermatitis –– Men 50–60 –– Action spectra: UVB+UVA > UVB, UVA+UVB+visible light > UVA alone –– May be rxn to endogenous, photoinduced cutaneous antigen –– Affects older outdoor workers, esp those with pre-existing sensitization to Compositae or sunscreen –– Eczematous lesions with lichenification, pseudolymphomatous papules/ plaques –– Sharp cut-off at lines of clothing, spare skin furrows –– Resolution 10% over 5 years, 20% over 10 years, 50% over 15 years –– Histopathology: epidermal spongiosis, acanthosis, lymphocytic exocytosis, sup/deep perivascular lymphohistiocytic dermal cellular infiltrate, + eos & plasma cells –– Differential diagnosis: CTCL (CAD infiltrates predominantly CD8+, TCR rearrangement neg), erythroderma –– Treatment: Photoprotection, avoid contact allergens, block UVR, oral/ topical CS, cyclosporine, azathioprine, mycophenolate • Solar urticaria –– –– –– –– –– –– –– –– –– –– ––

Physical urticaria induced by sun exposure 5–10 min → resolves within 1–2 h Action spectra: UVA+visible light > UVB Can coexist with PMLE, CAD, EPP (rarely) IgE-mediated response against photoinduced endogenous cutaneous antigen, mast cells play role Wheals in sun-exposed (upper chest, extensor arms) within 5–10  min, resolve over 1–2 h Severe attacks can have malaise, light-headedness, nausea, bronchospasm, syncope Resolution 15% over 5 years, 25% over 10 years Fixed solar urticaria limited to specific areas, mast cell alteration just at those sites Drug-induced solar urticaria a/w chlorpromazine, tetracycline, tar Histology: similar to other urticarias

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–– Treatment: oral antihistamines (high doses), photoprotection, omalizumab, plasmapheresis, IVIg II. Normal cutaneous effects of UVR exposure • Acute and subacute –– Result of UVR absorption by DNA, RNA (except vitamin D synthesis) –– Acute inflammatory erythema ◦◦ 300 nm most erythemogenic ◦◦ Sunburn pain through TRPV4 ion channels ◦◦ Brief immediate erythema (sec-min) → delayed bright red (30 min to 8 h, peak 12–24 h) –– Pigment darkening and delayed tanning ◦◦ Immediate darkening lasts 10–20 min ◦◦ Photo-oxidative darkening, cellular redistribution of melanin within epidermal melanocytes ◦◦ Persistent pigment darkening (lasts >2 h) ◦◦ Delayed pigmentation/tanning (develops over hrs-days, lasts weeks-mo) –– Epidermal hyperplasia ◦◦ Occurs after UVB ◦◦ Due to increased cellular mitotic rate and DNA, RNA, protein synthesis –– Immunologic changes ◦◦ Alters Langerhans cell function, generates T lymphocytes, changes cutaneous cytokine profile –– Vitamin D3 synthesis ◦◦ UVB converts epidermal 7-dehydrocholesterol into previtamin D3 → isomerizes to vitamin D3 (cholecalciferol), converted in liver to 25-­hydroxyvitamin D, then in kidneys to 1,25-dihydroxyvitamin D • Chronic –– Photoaging in fair-skinned patients ◦◦ Solar (actinic) elastosis—thickened skin, yellow hue, increased altered dermal elastic fibers seen ◦◦ Cutis rhomboidalis nuchae—variant ◦◦ Solar lentigo—reticulated macule/patch, elongation of rete ridges and mild ↑ melanocytes ◦◦ Ephelide—red-brown/brown macule more apparent after sun exposure, hyperpigmentation of basal layer only ◦◦ Idiopathic guttate hypomelanosis ◦◦ Poikiloderma of Civatte—reticulated red/brown patches of telangiectasias sparing perifollicular skin

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◦◦ ◦◦ ◦◦ ◦◦

Favre-Racouchot syndrome—open comedones periorbital Solar purpura Colloid milium—translucent yellow papules Erosive pustular dermatosis—pustules, keratotic crusts, erosions, inflammation within atrophic photodamaged bald scalp ◦◦ Acquired elastotic hemangiomas—erythematous plaques within actinically damaged skin

–– Photoaging in darker skin types ◦◦ Small SK, melasma, mottled hyperpigmentation ◦◦ Fine wrinkles, appear later in life –– Photocarcinogenesis ◦◦ SCC—chronic sun-exposed in fair skin ◦◦ BCC—intermittent sun exposure ◦◦ Tanning beds—↑ risk for melanoma, SCC, BCC

3.18  Drug Reactions I. Erythema multiforme • EM minor & major, determined by presence or absence of mucosal involvement and systemic symptoms • Most commonly a/w HSV, M. pneumoniae, H. capsulatum, orf –– HSV 1 in 50% • Histoplasmosis-associated EM may occur more often in patients w concomitant erythema nodosum • Typical target lesion with 3 distinct zones • Can have ↑ atypical popular target lesions—round, edematous, palpable but only 2 zones and/or poorly defined border • Prefers face, upper extremities (dorsal hands, forearms, palms), neck, trunk • Koebner phenomenon • Vesiculobullous mucosal lesions → progress into painful erosions on buccal mucosa and lips > ocular/genital mucosae • Systemic sx almost always present in EM major → precede/accompany skin lesions: fever, asthenia, arthralgias + joint swelling, atypical pneumonia sx • Rapid development of lesions within 24 h, fixed for 7+ days, heals without sequelae (except rare ocular damage) • Histopathology: apoptosis of keratinocytes, mild spongiosis, focal vacuolar degeneration of basal keratinocytes, superficial dermal edema, perivascular lymphocytes • DIF nonspecific—granular IgM, C3 around blood vessels and at DEJ • Differential diagnosis: urticaria multiforme—variant of urticaria, new lesions appear daily, possible swelling of face, hands, feet, individuals

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lesions transient, central zone is normal skin or transiently dusky (not damaged like in EM, not dusky, bullous, crusted) • Treatment: Oral antihistamines, systemic corticosteroids or pulse methylprednisolone –– Prophylaxis ×6 months with acyclovir 100 mg/kg/day, valacyclovir 500– 100 mg/day, famciclovir 250 mg BID • If resistant to prophylaxis: azathioprine 100 mg/day, prednisone 0.5 mg/day, thalidomide, dapsone, cyclosporine, mycophenolate mofetil, PUVA II. Stevens-Johnson syndrome/toxic epidermal necrolysis • Prodrome of upper respiratory tract symptoms, fever, painful skin • Mortality 1–5% SJS, 25–35% TEN • Almost always drug-related—due to extensive keratinocyte cell death resulting in separation of skin at DEJ • F > M • Drugs: allopurinol, antibiotics, NSAIDs, aromatic anticonvulsants –– Sulfonamides most strongly associated > aminopenicillins, quinolones, cephalosporins, tetracyclines, antiretrovirals • Usually 7–21 days after initiation of causative drug if 1st exposure • Pathogenesis thought to involve exposure to drug, leads to immune reaction to drug or metabolite, resulting in expression of cytolytic molecule FasL on keratinocytes and secretion of granulysin from CTLs, NK cells and NKT cells and annexin A1 from monocytes –– FasL- and granulysin-mediated apoptosis and/or annexin-dependent necroptosis of keratinocytes, epidermal necrosis and detachment • Mucosal erosions in >90% patients • Photophobia, painful micturition • SCORTEN: poor outcomes: age >40  years, HR > 120, malignancy, BSA >10% on day 1, urea ↑, bicarb ↓, glucose ↑ • Death usually due to infection (S. aureus, Pseudomonas aeruginosa) • Re-epithelialization starts within days, complete within 3 weeks –– Proliferation/migration of keratinocytes from “reservoir” sites (explains why skin grafting not required) • Sequelae: symblepharon, synechiae, entropion, ingrowth of eyelashes, scarring, irregular pigmentation, eruptive melanocytic nevi, persistent erosions of mucous membranes, urethral stenosis, phimosis, vaginal synechiae, nail dystrophy, diffuse hair loss, sicca syndrome • Histopathology: Full thickness epidermal necrosis • Differential diagnosis: EM major, generalized FDE, autoimmune bullous disease, Kawasaki disease, SSS, drug-induced linear IgA, DRESS, acute GVHD, lupus erythematosus (Rowell syndrome—usually resembles EM but can have TEN-like presentation)

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• Treatment: Supportive care, antibiotic ointment around orifices, silicone dressings, cyclophosphamide, plasmapheresis, TNF-α inhibitors, corticosteroids, cyclosporine, IVIg –– IVIg contains ab that can block binding of FasL to Fas—high doses correlated with increased survival rate and lower mortality rate • Relative contraindications: hypercoagulable state, IgA deficiency, renal disease (less so) III. Acute generalized exanthematous pustulosis • Characterized by small pustules that appear on face, intertriginous sites → generalizes within hours • Associated with high fever, small sterile pustules on background of edema • Can present with purpuric or EM-like lesions, mucosal involvement, and edema of hands/face • Other features: ↑ WBC, peripheral neutrophilic, hypocalcemia, eosinophilia, renal insufficiency • Patch test + in 50–60% • Drugs: β-lactam antibiotics, macrolides, calcium channel blockers, antimalarials • Histopathology: subcorneal and intraepidermal pustules, dermal edema, eosinophils • Treatment: systemic corticosteroids IV. DRESS • Multi-organ drug reaction • Pathogenesis not fully understood—can be a/w HHV-6, HHV-7, EBV –– HLA-A∗3101 (Northern Europeans—carbamazepine), HLA-B5801 (Han Chinese—allopurinol) • Develops 2–6 weeks after drug initiation • Fever, morbilliform eruption → edematous with follicular accentuation • Face, upper trunk extremities (facial edema is frequent and hallmark finding—up to 25% cases) • Mucosal involvement mild, if present • Drugs: aromatic anticonvulsants, lamotrigine, sulfonamides, minocycline, dapsone, allopurinol, abacavir, nevirapine • Systemic features: lymphadenopathy, hepatic involvement, interstitial nephritis, myocarditis, pneumonitis, thyroiditis • Drugs: aromatic anticonvulsants (phenytoin, carbamazepine, phenobarbital), sulfonamides • Treatment: systemic corticosteroids, IVIg, cyclosporine, mycophenolate mofetil, rituximab

Chapter 4

Cutaneous Neoplasms

4.1  Benign and Malignant Tumors of the Epidermis I. Cysts (a) Epidermoid inclusion cyst • • • • •

Most common cutaneous cyst, derived from follicular infundibulum Occur anywhere, most common on face and upper trunk Skin-colored to yellowish dermal nodules, often with visible punctum Lining composed of follicular infundibular epithelium Intact granular layer, no adnexae

(b) Dermoid cyst • • • •

Occurs along embryonic fusion lines—often lateral eyebrow Discrete subcutaneous nodule Lined by stratified squamous epithelial with intact granular layer Contain other structures such as hair, sebaceous glands, eccrine glands, or apocrine glands

(c) Trichilemmal cyst • • • • •

Also known as pilar cyst Clinically indistinguishable from epidermoid cysts 90% occur on scalp Solitary or multiple, may be inherited as AD trait Wall shows keratinization analogous to outer root sheath of hair follicle at isthmus • Lined by stratified squamous epithelial cells and abrupt keratinization with no interventing granular layer • Cyst contains homogenous eosinophilic compact material

© Springer Nature Switzerland AG 2020 W. W. Huang, C. S. Ahn, Clinical Manual of Dermatology, https://doi.org/10.1007/978-3-030-23940-4_4

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(d) Proliferating trichilemmal • Also known as proliferating pilar tumor • 90% occur on scalp, most often in adult women • Generally have benign course but can have local recurrence and metastases • Broad anastomosing bands and nodules of squamous epithelium • Proliferates from center of lesion • Complete excision recommended (e) Vellus hair cyst • Numerous small, dome-shaped papules • Most common on trunk • Can be seen with steatocystoma multiplex or with pachyonychia congenita (eruptive) • Similar in appearance to epidermoid inclusion cyst but contains multiple vellus hairs in cavity (f) Steatocystoma • Located on chest, axillae, groin • Occur as single (steatocystoma simplex) or multiple (steatocystoma multiplex) • Small papules that drain oily fluid if punctured • Steatocystoma multiplex can be AD, mutation in KRT17 • Wavy eosinophilic “shark tooth” lining, sebaceous glands within wall • Associated with pachyonychia congenita type 2 (mutation in keratin 17) (g) Hidrocystoma • • • • •

Located on face, particularly on eyelids Blue, translucent cyst on face Solitary (Smith type) or multiple (Robinson type) Associated with Schöpf-Schulz-Passarge syndrome Apocrine hidrocystomas are unilocular or multilocular cysts lined by epithelial cells showing decapitation secretion • Eccrine hidrocystomas are unilocular cyst with clear fluid, 1–2 layers of cuboidal or flattened epithelium (h) Bronchogenic cyst • • • • •

Present at birth, solitary lesions Located at suprasternal notch or anterior neck Pseudostratified, ciliated, columnar epithelium Goblet cells within cyst lining Cartilage rarely present

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(i) Omphalomesenteric duct cyst • Developmental defect in closure of omphalomesenteric duct (fetal connection between midgut and yolk sac) • Can present as umbilical polyp • Ectopic gastrointestinal mucosa (j) Median raphe cyst • Solitary, seen in young men • Located on ventral penis, most often on or near glans • Stratified columnar epithelium without connection to overlying epithelium (k) Branchial cleft cyst • Located on preauricular area, mandibular region, or anterior border of sternocleidomastoid muscle • Stratified squamous epithelium or pseudostratified ciliated columnar epithlium • Dense lymphoid tissue often associated with cyst wall (l) Pseudocyst of the auricle • • • • •

Located on the scaphoid fossa of ear Presents as painless swelling Linked to chronic trauma from cell phones or wrestling Cavity within auricular cartilage containing clear fluid Treatment with aspiration, intralesional corticosteroids, incision/drainage

(m) Thyroglossal duct cyst • Located on midline anterior neck in children or young adults • Moves with swallowing • Thyroid carcinoma can originate from thyroglossal duct cyst in rare cases • Cuboidal, columnar, or stratified squamous epithlium • Hallmark is presence of thyroid follicles within cyst wall II. Benign keratinocytic neoplasms (a) Seborrheic keratosis • Activating mutations in FGFR3, PIK3CA • Leser-Trelat sign: eruption of seborrheic keratoses, associated with GI adenocarcinoma • Histologic subtypes: acanthotic, hyperkeratotic, reticulated, irritated, clonal, and melanoacanthoma • Horn pseudocysts highly characteristic, due to cross-sectioning of epidermal invagination

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(b) Porokeratosis • Keratotic papule or plaque, often with annular appearance • Characterized by column of parakeratosis (cornoid lamellae) • Porokeratosis of Mibelli –– Plaque on distal extremity –– Seen in infancy and childhood • Disseminated superficial actinic porokeratosis –– Pink and brown papules and plaques with peripheral scale –– Affect sun-exposed areas, most often extensor forearms and shins • Linear porokeratosis –– Streaks along lines of Blaschko –– Develop in infancy or childhood –– highest risk of progression to SCC • Punctate porokeratosis –– Palmoplantar papules –– Develop during adolescence or adulthood –– No associated risk of progression to SCC • Porokeratosis palmaris, plantaris, et disseminate (PPPD) –– Papules on palms and soles, trunk, extremities, mucous membranes –– Develop during childhood or adolescence • Porokeratosis ptychotropica –– Red-brown papules or plaques in intergluteal cleft and buttocks • Eruptive disseminated porokeratosis –– Abrupt onset of widespread, inflamed keratoses –– Associated with internal malignancy in up to 30% (c) Epidermal nevus • Mutations in FGFR3, PIK3CA • Epidermolytic hyperkeratosis may be present—a/w increased risk of bullous CIE in offspring (d) Nevus comedonicus • Mutation in FGFR2 –– FGFR2 also seen in Alagille syndrome, Apert syndrome, cardiocranial syndrome, Crouzon syndrome

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(e) Flegel disease • Rare disorder, seen in adults • Present as asymptomatic red-brown keratotic papules symmetrically on the extremities, including palms and soles • Associated with endocrine disorders (diabetes mellitus, hyperthyroidism) • Absent/altered lamellar granules (Odland bodies) (f) Warty dyskeratoma • Most commonly on head/neck • Seen in adults • Solitary papule with comedo-like plug and acantholysis III. Premalignant/malignant keratinocytic neoplasms (a) Actinic keratosis • UVB → thymidine dimer • P53 mutations • 0.075–0.096% risk of progression to SCC (b) Bowen’s disease • SCC in situ • Risk factors: exposure to arsenic, ionizing radiation, HPV, chronic irritation • Bowenoid papulosis—penile papules (does not tend to progress) • Erythroplasia of Queyrat—located on glans penis, ↑ risk of progression to invasive SCC (c) Verrucous carcinoma • • • • •

Low-grade, locally destructive HPV 6, 11 Epithelioma cuniculatum—plantar foot Buschke-Lowenstein—anogenital, giant condyloma Oral florid papillomatosis—oral lesions

(d) SCC • Risk factors: hypertrophic lupus erythematosus or lichen planus, chronic lichen sclerosis et atrophicus, HPV infection, Marjolin’s ulcer • Increased metastatic risk: location on lip or ear, diameter >2 cm, Breslow >2 mm, arising in a burn or scar (Marjolin’s ulcer), poorly differentiated • Increased risk of SCC in: CLL patients, smokers, transplant recipients (65-­fold increase), long-term therapy with voriconazole, vemurafenib, methotrexate and etanercept

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(e) KA • Well-differentiated squamous cell carcinoma that tend to follow benign course and involute spontaneously • Subungual KA—do not involute • Ferguson Smith: eruptive type seen in middle-aged (30–40  years old), sun-­exposed sites, self-resolving • Gryzbowski: eruptive type in older, present with thousands of milia-like KA, can affect airway and cause scarring, ectropion, mask-like facies • Increased risk in: Muirre-Torre syndrome, immunosuppressed, HPV (f) BCC • PTCH > P53 mutation • Fibroepithelioma of Pinkus: variant, most often on lower back

4.2  Melanocytic Neoplasms I. Nevi • Proliferation of melanocytes • Easy to confuse with other types of hyperpigmented macules (See Box 4.1) • Different benign nevi associated with specific mutations (See Box 4.2) (a) Congenital dermal melanocytosis • Present at birth • Most common in Asians and black • Lumbosacral (b) Congenital nevus • Large >20 cm → 2–3% risk melanoma (c) Becker’s melanosis • Androgen-mediated • Associated with ipsilateral breast hypoplasia (Poland syndrome) (d) Nevus of Ota • Located in V1/V2 distribution on face • Scleral—60% → glaucoma (10%) • Rare association with melanoma (e) Nevus of Ito • • • •

Located on shoulder, supraclavicular, scapular region No melanoma risk Hori’s nevus—acquired bilateral zygomatic region Sun’s nevus—acquired unilateral zygoma

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(f) Nevus spilus • Associated with phakomatosis pigmentovascularis and pigmentokeratotica (g) Common acquired nevi • Can be eruptive in epidermolysis bullosa and lichen sclerosus et atrophicus (h) Halo nevus • Most often on back • May be associated with vitiligo, melanoma, and infliximab use (i) Balloon cell nevus • Defined by >50% balloon cell changes (represents degeneration of melanosomes) II. Melanoma (a) Mutations • BRAF (V600E): most common mutation, a/w superficial spreading type, affects non sun-damaged skin • NRAS: chronic sun-damaged skin, a/w nodular type • C-KIT: chronic sun-damaged skin, a/w acral and mucosal • CCND1/CDK4: chronic sun-damaged skin, a/w acral, mucosa • GNAQ/GNA11: a/w uveal melanoma (and blue nevi, nevus of Ota) • BAP-1: a/w uveal melanoma, malignant cellular blue nevi, epithelioid spitzoid nevi, mesothelioma, and renal cell carcinoma (b) Pathogenesis • Initiating oncogenic events affect genes involved in MAPK and PI3K pathways: BRAF, NRAS, KIT • Secondary genetic alterations result in progression to malignant tumor: –– Amplification of CCND1 (encodes cyclin D1) –– Deletion/mutation of CDKN2A (encodes p16, p14) –– Mutation of TP53 (encodes p53) • RAS-RAF-MEK-ERK (MAPK) Pathway –– Mitogen-activated protein kinase (MAPK) is activated by growth factor binding to receptor tyrosine kinases (e.g. KIT) • Imatinib, dasatinib block receptor kinases –– Stimulus relayed to nucleus via GTPase activity of NRAS and kinase activity of BRAF, MEK, and ERK • Dabrafenib, encorafenib, vemurafenib block BRAF • Binimetinib, cobimetinib, trametinib block MEK

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–– P-ERK activates cyclin D1  in the nucleus, which complexes with CDK4/6 and phosphorylates Rb, leading to release of E2F from the Rb-E2F complex, which allowed E2F to allow cell cycle progression • Palbociclib blocks cyclin D1 • PI3K-AKT Pathway –– Another regular of cell survival, growth, and apoptosis –– PTEN key inhibitor—when inactivated, increased activity of pathway allowing for cell growth and proliferation (c) Melanoma staging • Most important components: Breslow thickness, presence of ulceration, and mitotic rate • Poor prognosis associated with Breslow >1  mm, ulceration, increased mitotic rate, increased age, male, palpable lymph node metastases, head, neck, and trunk location, and presence of visceral metastases • See Box 4.3 (d) Management • Primary melanoma (stage I, II) –– In situ: excision with 0.5 cm margins –– Lentigo maligna may be excised with 1 m margns, especially when lesions are large (>1.5–2  cm in diameter) or treated with Mohs or radiotherapy; topical imiquimod can be considered –– 2 mm Breslow: excision with 2.0 cm margins • Regional metastases (stage III) –– –– –– ––

Treatment of choice of cutaneous metastases is surgical Metastatic spread is regional in 70% 20% of melanoma >1 mm in depth have micrometastases Adjuvant therapy to treat clinically unapparent micrometastases include ipilimumab and IFN-α

• Distant metastases (stage IV) –– Resection of metastases, radiotherapy for palliation –– Systemic therapy (See Box 4.4) • Molecular targeted therapy: 45% melanoma have activating mutations in BRAF (V600E accounts for 90% of BRAF mutations), and MEK inhibitors can be used to reduce side effects and prolong time to resistance to BRAF inhibitors • Immunotherapy: antagonize inhibitor receptors on T cells, 1st line in patients with no BRAF mutation • Chemotherapy: ↓ but reproducible activity, dacarbazine (DTIC) most widely used single agent

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Box 4.1 Hyperpigmented Macules Ephelides

Café au lait macules

Solar lentigo

Lentigo simplex

Mucosal melanotic macule Dermal melanocytosis

1–3 mm Darken with UV exposure Sun-exposed skin Seen in 10–20% of population Associated with genodermatoses Sun-exposed skin

Occurs at any age or site Associated with genodermatoses Seen in adults Occur on vermillion border Congenital, nevus of Ota, nevus of Ito, Hori’s nevus, Sun’s nevus

↑ melanogenesis ↑ melanin transfer to keratinocytes ↑ melanin deposition in basilar keratinocytes

Normal melanocyte density ±enlarged melanocytes Normal melanocyte density

Elongated bulbous rete ridges with hyperpigmentation ↑ melanin deposition in basilar keratinocytes

Normal or mildly elevated melanocyte density Mildly elevated melanocyte density

Normal or mildly Acanthosis Mild ↑ melanin deposition elevated melanocyte density in basilar keratinocytes Elongated dendritic melanocytes

Box 4.2 Nevi with Associated Mutations Blue nevus

Spitz nevus

Deep penetrating Congenital nevus Common acquired nevi

Atypical nevi

Childhood, adolescence Located on scalp, sacrum, distal extremities HRAS/11p gains Childhood, BAP-1 loss adolescence Head/neck > extremities Lacks GNAQ/ 20–30 years GNA11 mutations Face, upper trunk, extremities NRAS >> BRAF

Associated with Carney complex Same mutations as uveal melanoma

BRAF (80%) > NRAS

Can be eruptive in epidermolysis bullosa and lichen sclerosis et atrophicus AD—familial atypical multiple mole melanoma syndrome (FAMMM)

GNAQ, GNA11 (83%)

CDKN2A (FAMMM)

Any age Trunk, scalp

+S100A6, S100, MelanA, p16

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Box 4.3 Melanoma Staging (Adapted from Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472–492) T Tis T1 T1a: 4.0 mm, + ulceration

N N0: 0 nodes N1: 1 node N1a: micrometastasis N1b: macrometastasis N1c: in-transit met/sat or microsatellite met N2: 2–3 nodes N2a: micrometastasis N2b: macrometastasis N2c: in-transit met/sat without metastatic node N3: 4+ nodes, matted nodes, or in-transit mets/ satellites with metastatic nodes

M M0: no distant metastasis M1a: distant skin, SQ, nodal metastasis M1a(0): Normal LDH M1a(1) ↑ LDH M1b: Lung metastasis M1b(0): Normal LDH M1b(1) ↑ LDH

M1c: non-CNS visceral metastasis M1c(0): normal LDH M1c(1) ↑ LDH M1d: CNS metastasis M1d(0): normal LDH M1d(1) ↑ LDH

Box 4.4 Melanoma Systemic Therapies Patients treated selective BRAF inhibitors alone develop tumor resistance after 6mo therapy ↑ SCC, KA in 25% Addition of MEK inhibitors prolong resistance MEK Trametinib to 10 months, reduce side effects inhibitors Cobimetinib Can use in patients with NRAS mutations Binimetinib (~25% response rate) KIT Imatinib Can consider in ALM or mucosal melanoma inhibitor Nilotinib with amplifications or mutations in KIT Ipilimumab Blocks CTLA4-B7 interaction, prevents AntiImmune Tremelimumab downregulation of T-cell activation (i.e. checkpoint CTLA-4 releases the “brake” on T cell activation) inhibitors antibody Response rate ~15% as monotherapy, 21% with dacarbazine Anti-PD-1 Nivolimumab More effective that ipilimumab antibody Pembrolizumab Blockade of PD1 or PD-L1 can restore immune fxn of dysfunctional T cells, Pidilizumab enhancing cytokine production and cytolysis Anti-PD-L1 Atezolizumab PD1 and PD-L1 interact and inhibit T cell proliferation, induces apoptosis of tumor antibodies Avelumab specific T cells Durvalumab

Molecular targeted therapy

BRAF inhibitors

Dabrafenib Vemurafenib Encorafenib

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4.3  Adnexal Neoplasms I. Sweat gland neoplasms (a) Syringoma • • • • •

Common benign sweat gland tumors Found on lower eyelids, cheeks of women Also can occur on genitalia, groin, buttocks, scalp, axillae, acral skin Multiple skin-colored papules Rare disseminated variant with hundreds erupting on face, trunk, genitalia, groin, extremities • Associated with diabetes mellitus, Ehlers-Danlos syndrome, Marfan syndrome, hyperthyroidism, Nicolau-Balus syndrome • Histopathology: –– Proliferation of small ductal structures in dermis –– May have comma-like tail –– Surrounding dense and fibrous stroma (b) Microcystic adnexal carcinoma • Rare infiltrative malignant tumor • Typically on head and neck • Presents as slow-growing nodule or plaque on upper lip, medial cheek, or chin • Risk factors: UV radiation and immunosuppression • Tend to be locally aggressive with perineural invasion common • Histopathology: –– Biphasic pattern of sweat ducts and basaloid nests –– Infiltrative growth pattern with deep invasion and perineural extension –– Red and sclerotic stroma and large horn cysts often present (c) Cylindroma • Nodules often on head and neck of adult women • Multiple seen in familial cylindromatosis (CYLD) and Brooke-Spiegler syndrome (d) Spiradenoma • • • •

Small solitary nodules, often painful Head and neck, less often on extremities Seen mostly in adults Histopathology: –– One or few large basophilic tumor islands in dermis –– Cells arranged in sheets, cords, or trabecular pattern with duct-like structures and eosinophilic hyalinized basement membrane outlining tumor island

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(e) Spiradenocarcinoma • Rare, malignant sweat gland tumor • Arise de novo or arise from spiradenoma • Rapidly growing mass from chronic lesion, may be tender, ulcerated, and bleed • Clinically aggressive with high metastatic potential • Treatment involves wide local excision • Histopathology: –– Tumor islands with large cells with pale nuclei and small cells with hyperchromatic nuclei –– Increased atypical mitotic figures (f) Poroma • Benign sweat gland tumor differentiating toward acrosyringium • Presents as solitary firm, dome-shaped papule, nodule or plaque in adults • Favor acral sites, may be associated with itching or pain • Increased risk for development in patients with history of electron bean therapy, chronic radiation dermatitis, and other conditions including Bowen’s disease, sarcoidosis, extramammary Paget’s disease • Histopathology: –– Well-circumscribed, extends down from basal epidermis into dermis –– Cuboidal or poroid cells with eosinophilic cytoplasm (g) Hidroacanthoma simplex • Verrucous or keratotic plaque • Often asymptomatic • Histopathology: –– Ovoid intraepidermal nests of acrosyringial keratinocytes, scattered cuticle-­lined ducts (h) Dermal duct tumor • Small dermal papules or nodules on the head and neck regions • Histopathology: –– Small dermal nests of acrosyringial cells, cuticle-lined ducts within tumor islands (i) Hidradenoma • Present as non-specific cutaneous or subcutaneous nodules that are solitary • Predominantly seen in women, can occur anywhere on the body • Histopathology:

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–– Well-circumscribed multilobulate derma tumors, occasional connection to epidermis –– Round, fusiform, or polygonal cells with glycogen –– Common ductal structures within tumor islands (j) Porocarcinoma • • • • • •

Rare malignant tumor Arise de novo or within long-standing poromas Most often on head, neck, legs Present as nodule or mass High local recurrence and metastatic rate Treatment includes wide local excision, Mohs micrographic surgery, and radiotherapy and chemotherapy for metastatic disease • Histopathology: –– Glycogen-rich anaplastic cells with large, irregular hyperchromatic nuclei –– Increased mitotic figures and necrosis common (k) Syringofibroadenoma • • • •

Eccrine syringofibroadenoma, syringofibroadenoma of Mascaro Benign tumor of acrosyringium of eccrine glands Most arise as solitary lesions Histopathology: –– Thin, parallel, or anastomosing strands of epithelial cells connected to epidermis at multiple points with ductal structures present

(l) Syringocystadenoma papilliferum (SPAP) • Rare adnexal tumor seen in adults • Present as solitary warty nodule or plaque, most often on scalp and face > chest, extremities, eyelids, scrotum • Up to 1/3 associated with nevus sebaceous • Histopathology: –– Duct-like structures extending down from epithelium –– Cells resemble secretory portion of sweat gland, –– Papillary fronds extend into cystic spaces with mesenchymal core containing plasma cells and lymphocytes (m) Hidradenoma papilliferum (HPAP) • Dermal nodule, almost always on vulvar or perianal areas of adult women (less often on scalp, face, eyelid, abdomen) • Histopathology: –– Large, well-circumscribed dermal maze-like nodule –– Arborizing fronds with decapitation secretion

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(n) Papillary digital carcinoma • Seen in younger patients • Solitary painless nodule or mass, usually on fingers, toes, or adjacent parts of hands and feet • High recurrence rate and metastatic potential • Treatment of choice is wide local surgical excision, often involves amputation • Histopathology: –– Poorly circumscribed, multinodular dermal tumors with cystic and glandular spaces with papillary projections –– Variable cytologic atypia, mitotic figures, poor glandular differentiation, necrosis, invasion (o) Tubular apocrine adenoma/papillary eccrine adenoma • Both benign sweat gland tumors, differentiate toward secretory segment and duct • Papillary eccrine adenoma most often on hand or foot • Tubular apocrine adenoma most often on scalp • Histopathology: –– Well-circumscribed mass in dermis –– Tubular structures lined with 2 rows of cells (p) Adenoid cystic carcinoma • • • •

Rare, seen on scalp and chest most often Non-tender nodules or tumors, slow-growing Local recurrence common, distant metastases rare Histopathology: –– Cords and strands of atypical basaloid cells with cribriform growth, tubular growth patterns –– Atypia, mitoses –– Loose, myxoid stroma

II. Follicular neoplasms (a) Hair follicle nevus • Benign congenital hamartomas with follicular differentiation • Small nodule or area of hypertrichosis composed of closely arranged vellus follicles • Usually on preauricular area of infants • Histopathology: –– Small mature hair follicles filling dermis –– Some consider on spectrum with trichofolliculoma

accessory

tragus

and

4.3 Adnexal Neoplasms

167

(b) Trichofolliculoma • Benign follicular tumor • Present as solitary papules or nodules of head and neck, most often on nose, cheek, ear • Often with central crater and multiple hairs arising from central opening • Histopathology: –– Central dilated cavity with small hair follicles radiating from walls of cavity –– Sebaceous trichofolliculoma is variant with prominent sebaceous glands and ducts within lobules (c) Trichoepithelioma • Benign tumors • Present as skin-colored papules on the face, most often nose, upper lip, cheeks • Histopathology: –– Basaloid islands in dermis with finger-like projections and cribriform nodules (d) Desmoplastic trichoepithelioma • Distinct variant of trichoepithelioma • Benign, asymptomatic, located on face of young adults • Histopathology: –– Basaloid cells in cords and small nests with dense, hypocellular stroma –– Often with calcification and horn cysts –– Must be distinguished from syringoma, morpheaform basal cell carcinoma, and microcystic adnexal carcinoma (e) Trichoblastoma • • • •

Rare, benign tumors of hair germ Solitary slow-growing dermal nodules on head and neck (favor the scalp) Can arise in association with nevus sebaceous Histopathology: –– Circumscribed basaloid tumors in mid/lower dermis –– No retraction artifact or mucin in stroma

(f) Pilomatricoma • Benign pilar tumor with differentiation toward hair matrix, cortex, and inner root sheath of hair follicle • Most often on head and neck, upper extremities

168

4  Cutaneous Neoplasms

• Firm, solitary nodules • Multiple lesions associated with myotonic dystrophy, Turner syndrome • Histopathology: –– Basophilic cells resembling hair matrix and eosinophilic shadow cells are two cell types –– Calcification and ossification can be seen in mature lesions (g) Fibrofolliculoma • • • •

Considered on same spectrum as trichodiscoma Asymptomatic skin-colored papules, often on face Associated with Birt-Hogg-Dubé syndrome Histopathology: –– Thin anastomosing strands and cords of epithelial cells radiating from follicle –– Stroma composed of loose connective tissue

(h) Trichodiscoma • Similar clinical presentation as fibrofolliculoma • Histopathology: –– Proliferation of loose connective tissue, stellate fibroblasts –– Areas on periphery may resemble fibrofolliculoma (i) Trichoadenoma • Benign tumor with non-germinative hair follicle-like differentiation • Seen in adults, most often on face and buttocks • Histopathology: –– Well-circumscribed dermal tumor –– Numerous cystic epithelial islands in the dermis (j) Trichilemmoma • • • •

Benign tumors arising from follicular infundibulum, Solitary papules, favor the face Associated with Cowden syndrome Histopathology: –– Well-circumscribed tumors connected to the epidermis –– Polygonal, clear cells due to glycogen vacuolization with underlying thickened hyaline eosinophilic basement membrane

(k) Tumor of the follicular infundibulum • Solitary scaly papules most often on head, neck, and upper chest of adults • Can also be seen in association with Cowden syndrome and SchöpfSchulz-­Passarge syndrome • Histopathology:

4.3 Adnexal Neoplasms

–– Well-circumscribed, subepidermal plate-like proliferation glycogen-­containing cells –– Connects to epidermis through many thin anastomosing strands

169

of

(l) Proliferating pilar tumor • Large exophytic nodules most often on scalp • Histopathology: –– Dermal proliferations of well-circumscribed solid and cystic tumors –– Lining of cystic structures show trichilemmal keratinization –– Cholesterol clefts and focal calcification seen often (m) Pilomatrical carcinoma • • • •

Rare malignant form of pilomatricoma Solitary lesion on scalp or face Usually arise de novo, associated with mutation in β-catenin Histopathology: –– Poorly circumscribed tumors, tend to be locally infiltrative –– Rare spread to regional lymph nodes –– Share features with pilomatricoma but with pleomorphic tumor cells and increased atypical mitotic figures

III. Sebaceous neoplasms (a) Sebaceous hyperplasia • • • •

Hyperplasia rather than true neoplasm Common finding on face of adults Yellow cerebriform papules on face, often with central dell Histopathology: –– Large sebaceous glands made of mature sebaceous lobules emptying into single dilated sebaceous duct

(b) Nevus sebaceous • Complex hamartoma, differentiates towards more than one adnexal structure • Usually presents at birth of early childhood • Most often on scalp and face, rare on external genitalia • Early lesions are tan or yellowish smooth hairless plaques, become pebbly and verrucous after puberty • Histopathology: –– Early lesions show mild acanthosis and papillomatosis –– Postpubertal lesions show prominent acanthosis, papillomatosis –– Sebaceous glands enlarged and situated high in dermis

170

4  Cutaneous Neoplasms

(c) Sebaceous adenoma • • • •

Benign neoplasm of sebaceous glands Slow growing papules or nodules on head and neck of adults Can be associated with Muire-Torre syndrome Histopathology: –– Well-circumscribed multilobular tumors in the dermis –– Increased germinative basal cell layer comprising 50%) rather than mature sebocytes (e) Sebaceous carcinoma • Most often arises from ocular adnexae—Meibomian gland and glands of Zeiss • Aggressive with high rate of metastases • Treatment of choice is wide local excision or Mohs micrographic surgery • Histopathology: –– Infiltrative growth pattern –– Lobules or sheets of atypical cells with sebaceous differentiation –– Can be difficult to differentate from basal cell carcinoma with sebaceous differentiation or squamous cell carcinoma with clear cell change—immunohistochemistry can help differentiate

4.4  Soft Tissue Tumors I. Neural tumors • Derived from peripheral nerves • Transverse section of peripheral nerve will show 90% of nuclei correspond to Schwann cells, 5% to fibroblasts, and 5% to mast cells or endothelial cells lining capillaries • Stains: –– –– –– –– ––

Perineurial cells: +EMA, claudin-1, Glut-1 Schwann cells: +S100, CD57 Myelin sheaths: +myelin basic protein Axons: +neurofilament Endoneurial spindle cells: +CD34

• See Box 4.5

4.4 Soft Tissue Tumors

171

Box 4.5 Neural Neoplasms Traumatic neuroma

Palisaded encapsulated neuroma (solitary circumscribed neuroma)

Schwannoma (neurilemmoma)

Sites of trauma (fingers, traumatic scars, limb amputation stumps) Face

Lower limbs > head/ neck

Neurofibroma

Nerve sheath myxoma (neurothekeoma)

Hands/fingers, forearms, knee

Cellular neurothekeoma

Face

Granular ell tumor

Tongue

Malignant peripheral nerve sheath tumor (MPNST)

Merkel cell carcinoma

Head/neck

Painful nodule Reactive proliferation of disorganized nerve fibers secondary to peripheral nerve damage Small firm papule Well-defined nodule with clefting at periphery located in superficial to mid dermis, rarely or partially encapsulated Multiple mucosal neuromas—a/w MEN2B Solitary, located in deeper dermis/fat Proliferation almost entirely of Schwann cells (S100+) with perineurial capsule (EMA+) Antoni A and Antoni B areas of cellular and less cellular areas, Verocay bodies Exophytic pedunculated lesion Multiple lesions—a/w NF1; plexiform neurofibroma—pathognomonic for NF1, ↑ risk for MPNST Non-encapsulated lesion of haphazardly arranged spindle cells filling dermis Plexiform proliferation of myxoid lobules, S100+ Well-demarcated multilobular with spindled or stellate cells in pattern within stroma F > M, nests/fascicles of epithelioid cells, S100-, S100A6+, NKI/C3+, PGP9.5+ Neural crest derived, non-encapsulated sheet of round or polyhedral cells with distinct granular cytoplasm in dermis Pustule-ovoid bodies of Milian, often with pseudoepitheliomatous hyperplasia Rapidly growing nodule within plexiform neurofibroma (lifetime risk 2–13%) Large fusiform hyperchromatic cells with pleomorphic nucleus Seen in elderly, immunosuppressed Merkel cell polyomavirus implicated

172

4  Cutaneous Neoplasms

II. Tumors of Smooth Muscle • See Box 4.6 Box 4.6 Smooth Muscle Neoplasms Leiomyoma

Trunk, extremities

Genital leiomyoma

Vulva, scrotum, areola Angioleiomyoma Leg

Leiomyosarcoma Extremities

Proliferation of smooth muscle of arrector pili, desmin+, SMA+ Painful, pseudo-Darier’s sign (stroking makes red, elevated due to contraction of smooth muscle) a/w Reed syndrome (AD, fumarate hydratase)— leiomyomas, RCC Asymptomatic

Proliferation of muscle in vessel well (not endothelial cells)—so central vascular lumens are compressed by muscular wall Middle-aged women, painful Red-brown nodules or plaques Deep variant (subfascial)—deep soft tissue sarcoma, fatal Superficial variant (suprafascial)—dermal (indolent, 10% metastatic), SQ (vascular smooth muscle-derived, more aggressive, ↑ risk metastases)

III. Fibrohistocytic tumors • Connective tissue composed of fibroblasts and ECM (made of collagen fibers, elastic fibers, ground substance) • Fibroblasts characterized by spindled cells with oval vesicular nuclei with 1–2 nucleoli • Synthesize ECM, produce procollagen and proelastin fibers and mucopolysaccharides of ground substance • Often with star-like (stellate) morphology (a) Dermatofibroma • Also known as fibrous histiocytoma • Benign neoplasm, arises secondary to acute trauma (folliculitis, insect bite, repetitive trauma)

4.4 Soft Tissue Tumors

173

• Firm dermal papule, overlying pigmentation, dimple sign • Histopathology: –– Spindled proliferation in dermis –– Can be highly cellular, contain lipid or hemosiderin deposits –– Variable epidermal hyperplasia and overlying follicular/adnexal induction –– Ill defined lesion with peripheral entrapment of thick collagen fibers –– +Factor XIIa, -CD34 (b) Dermatofibrosarcoma protuberans • • • • • • •

Onset 20–50s Solitary tumor with multilobulated surface, firm to palpation Slow-growing, often on trunk (especially back/shoulder) Fibrosarcomatous degeneration seen in 9–20% T(17;22)—COL1A1-PDGFB fusion Treatment options: Mohs micrographic surgery, imatinib Histopathology: –– Ill-defined cellular tumor composed of monomorphic spindled cells with elongated nuclei in storiform or swirling growth patterh –– Extends to SQ tissue, dissects isolated adipocytes in a “honeycomb” pattern –– +CD34, -Factor XIIIa, CD117, CD68, S100

(c) Atypical fibroxanthoma • Seen in elderly on sun-exposed sites • Presents as solitary tumor, often ulcerated • Superficial variant of pleomorphic undifferentiated sarcoma but with better prognosis • Histopathology: –– Diffuse infiltrate of spindled neoplasm in upper dermis –– Mix of spindle cells, histiocyte-like cells, xanthomatous cells with variable proportion of bizarre cells with large hyperchromatic pleomorphic nuclei –– -S100, PanMel, cytokeratin, SOX-10 –– No specific stains but often +CD10, CD68, CD99, SMA (d) Other fibroblastic proliferations • See Box 4.7

174

4  Cutaneous Neoplasms

Box 4.7 Other Fibroblastic Proliferations Angiofibroma

Sclerotic fibroma Pleomorphic fibroma Multinucleate cell angiohistiocytoma Epithelioid cell histiocytoma Acral fibrokeratoma Dermatomyofibroma

Infantile digital fibroma Fibromatosis Nodular fasciitis Fibrous hamartoma of infancy Myofibroma

Giant cell of tendon sheath Connective tissue nevus

Fibrous papule, pearly penile Dermal proliferation of stellate fibroblasts papule, facial/periungual Multiple facial: TS, MEN1, angiofibroma Birt-Hogg-Dube Firm/pearly papule/nodule Sclerotic collagen bundles; a/w Cowden Resemble skin tags Looks like acrochordon but scattered stellate cells Dorsal hands/legs of women Characteristic multinucleated in 40s giant cells, dilated dermal vessels, stains like DF Thigh #1, looks like pyogenic Dermal epithelioid cells, granuloma epidermal collarette Exophytic keratotic papule Hyperkeratosis, acanthosis, NO nerves Upper trunk/neck, plaque Long fascicles of spindled myofibroblasts, respects adnexae; SMA+, CD34-, S100-, Factor XIIIaInfants, fingers/toes Fascicles of spindle cells, pink-red inclusion bodies Dupuytren’s, Ledderhose, Long fascicles of wavy Peyronie’s fibroblasts Arms #1, head/neck #1 in Deep SQ nodule, tissue children culture appearance Infants, M/F Plump spindle cells, mesenchymal cells, mature fat Head/neck, worse in infantile Hypocellular and form hypercellular areas (staghorn vessels) Fingers, adults Osteoclastic giant cells Collagenoma, elastoma (subtle)

4.5  Vascular Neoplasms I. Benign vascular lesions • See Box 4.8

a/w TS, MEN-1, Buschke-­ Ollendorf, Proteus

4.5 Vascular Neoplasms

175

II. Intermediate vascular lesions (a) Kaposi sarcoma • Low-grade vascular neoplasm • HHV-8 infection and local and systemic inflammation key factors • 4 epidemiologic forms: (1) classic, (2) endemic, (3) iatrogenic, (4) AIDS-associated • Classic seen in elderly men of Mediterranean or Jewish descent, most often on lower legs and feet • Endemic seen in southern equatorial Africa, accounts for 10% of all malignancies in this region • Iatrogenic seen in setting of solid organ transplant or other immunosuppression • AIDS-associated is currently the second-most common tumor in HIV-­ infected individuals, tends to affect oral cavity and head/neck more than other variants, aggressive behavior • Treatment with surgical excision, radiotherapy, cryotherapy, laser, topical alitretinoin gel, and intralesional chemotherapy • Systemic agents used for disseminated disease including etoposide, vinblastine, bleomycin, docetaxel • Histopathology: –– Increased number of jagged, irregular vascular spaces dissecting through collagen –– Inflammatory infiltrate with lymphocytes, plasma cells, siderophages –– Sheets of spindle cells lining vascular spaces with hyaline globules –– +LANA (latency-associated nuclear antigen of HHV-8), CD31, CD34, D2-40. (b) Kaposiform hemangioendothelioma • • • •

Low-grade vascular neoplasm seen in infants and children Almost all present within 2 years, 60% in neonatal period Strong association with Kasabach-Merritt syndrome Cutaneous manifestations vary, range from purpura and ecchymoses to tumors • Histopathology: –– Coalescing lobules of spindled endothelial fascicles –– Ill-defined with dilated lymphatic vessels at periphery of nodules –– Shares histopathologic features with tufted angioma but differentiated by deeper infiltration and presence of spindled cells

176

4  Cutaneous Neoplasms

III. High-grade vascular lesions (a) Angiosarcoma • Rare malignant neoplasm derived from vascular endothelial cells • Can occur in various settings: (1) sporadic, (2) in setting of chronic lymphedema, and (3) following radiation therapy • Sporadic most common—head and neck most common site in elderly individuals on sun-damaged sites • In chronic lymphedema, originally seen in patients after radical mastectomy and axillary lymph node dissection for breast cancer • Radiation-associated angiosarcoma develops within area of irradiation or in immediate vicinity • Wide range of clinical presentations including papules, nodules, exophytic tumors, ecchymotic lesions or facial edema • Treatment is surgical excision and radiotherapy • Associated with high local recurrence rate and distant metastases • Histopathology: –– Irregular dilated vascular channels dissecting through dermis with large, pleomorphic, hyperchromatic endothelial cells –– Cells express endothelial markers: CD31, CD34, FLI-1, ERG and lymphatic markers: D2-40, VEGF, Prox1 –– C-MYC amplification reliably distinguishes between atypical vascular lesions and radiation-induced angiosarcoma

Box 4.8 Benign Vascular Lesions Vascular malformation PWS, present at birth— capillary, venous, lymphatic, or arteriovenous, GLUT-1IPEH Reactive, usually within vein, head/neck Slow-growing dusky nodule Angiokeratoma Angiokeratoma of Mibelli— fingers/toes Angiokeratoma of Fordyce—genitals Angiokeratoma corporis diffusum—Fabry Angiokeratoma circumscriptum—plaque Solitary and multiple angiokeratomas Infantile hemangioma Rapid growth (4–6 months) → involution Pyogenic granuloma Rapidly growing hemorrhagic papule

a/w Maffucci, Klippel-­ Trenaunay, Sturge-Weber, Blue Rubber Bleb Intraluminal proliferation of endothelial cells Dilated superficial dermal vessels, epidermal hyperplasia

Capillary proliferation, GLUT-1+ a/w trauma, pregnancy, meds

4.6 Cutaneous Hematolymphoid Neoplasms

Angiolymphoid hyperplasia with eosinophils (ALHE) Hobnail hemangioma

Tufted angioma Glomeruloid hemangioma Glomus tumor/ glomangioma

Ear > head/neck

177

Lobular dermal proliferation of capillaries, lymphs/eos

Legs, young adults

Upper dermis with dilated vessels and hobnail Lower dermis with slit-like vessels Neck/trunk—pink/red a/w Kasabach Merritt macules, 1st year life syndrome Trunk/extremities—↑ VEGF a/w POEMS > multicentric Castleman Subungual or multiple, painful Derived from Sucquet-Hoyer canal

4.6  Cutaneous Hematolymphoid Neoplasms I. Cutaneous T cell lymphomas (a) Mycosis fungoides • • • • • • • •

Epidermotropic primary cutaneous T-cell lymphoma 50% of all primary cutaneous lymphomas Adults/elderly >> children/adolescents Indolent Skin → lymph nodes, liver, spleen, lungs, blood (BM rare) Patch–Plaque–Tumor stages in skin Erythrodermic stage Histology –– Patch: ◦◦ Epidermotropism, superficial lichenoid infiltrate of lymphocytes and histiocytes ◦◦ Atypical cells (small-medium), cerebriform nuclei ◦◦ Lining up along epidermal basal layer as haloed cells –– Plaque: ◦◦ More epidermotropism, dermal band-like infiltrate ◦◦ Intraepidermal collections of atypical cells—“Pautrier microabscesses” –– Tumor: ◦◦ Less epidermotropism, dense dermal infiltrates ◦◦ Atypical cells increased number and size—small, medium, large cells ◦◦ Large cell transformation can occur- defined by >25% large lymphoid cells ±CD30

178

4  Cutaneous Neoplasms

• Immunophenotype: –– CD3+/CD4+/CD8− –– Usually loss of CD7, or CD5 or CD2 –– CD3+/CD4−/CD8+ → hypopigmented MF, cytotoxic phenotype, more interface changes • TCR gene rearrangement can be useful (but can be detected in some non-­ neoplastic inflammatory dermatoses like AD) • Clinical variants –– Folliculotropic ◦◦ ◦◦ ◦◦ ◦◦

10% of patients, head/neck with alopecia Infiltrates involving follicular epithelium, follicular mucinosis Severe pruritus, worse prognosis (similar to tumor stage MF) IHC similar to classic MF

–– Pagetoid reticulosis ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Psoriasiform or verrucous plaque on distal extremity or acral skin Prominent epidermotropism in pagetoid pattern Marked hyperkeratosis, acanthosis, parakeratosis Good prognosis IHC differs as often CD4−, CD8+

–– Granulomatous slack skin ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Very rare, slack skin in golds Granulomatous inflammation with multinucleated histiocytes Elastophagocytosis 30% develop Hodgkin lymphoma IHC CD3+, CD4+, CD8−

(b) Sezary syndrome • Triad: erythroderma, generalized lymphadenopathy, Sézary cells in skin, lymph nodes, peripheral blood • Requires: absolute Sézary cell count ≥1000 uL OR expanded CD4:CD8 > 10:1 OR loss of one or more T-cell antigen • Rare (60 years, M > F • Histopathology: –– Can be similar to MF ◦◦ Cellular infiltrates more monotonous ◦◦ Epidermotropism can be absent –– IHC: CD3+ CD4+ CD8− CD7− CD26− ◦◦ Almost all cases are PD1+ (CD279) ◦◦ CLA+ CCR4+

4.6 Cutaneous Hematolymphoid Neoplasms

179

–– Flow cytometry: CD4+/CD7− (>30%) or CD3+/CD26− (>40%) T cell population • Poor prognosis (c) Other cutaneous T cell lymphomas • See Box 4.9 Box 4.9 Other Cutaneous T Cell Lymphomas a/w HTLV-1 virus → Japan, Carribean, central Africa Leukemia, LAD, organomegaly, hypercalcemia Lymphomatoid papulosis Adults 40s (vs PLEVA (LyP) favors children), recurrent ulcerative papulonodules on trunk/extremities, heals with varioliform scars TCGR in 50%, excellent prognosis Tx: MTX—dramatic response in 90% Solitary, ulcerated, Anaplastic large cell lymphoma (ALCL) LARGE, do not come/go Excellent prognosis

Adult T-cell (ATLL)

Subcutaneous panniculitis-like T-cell lymphoma

Primary cutaneous γ/δ T-cell lymphoma

Extranodular NK/T-cell lymphoma, nasal type

Up to 20% a/w autoimmune disease— most common SLE Multiple subcutaneous nodules on extremities/ trunk Good prognosis (80–90%) Eroded nodules, plaques, visceral involvement Rapidly fatal

EBV+ lymphoma w NK phenotype, fatal Abrupt onset ulcerated tumor, present with nasal obstruction, epistaxis, extensive mid-facial lesions

Floret or clover-leaf T cells CD4+/CD8−/CD25+

A (75%): Reed-Sternberg-like CD30+ cells B (10–15%): resembles patch/ plaque MF C (10%): cannot distinguish from ALCL, large cell transformation of tumor MF D ( 50% Surgical debridement + clindamycin + PCN ± IVIg

II. Corynebacterial infections (a) Erythrasma • C. minutissimum—filamentous Gram (+) rod • Groin, toe webs • Wood lamp—coral red (coproporphyrin III) (b) Pitted keratolysis • Kytococcus sedentarius • Crateriform pits, foul odor, ↑ risk with hyperhidrosis, occlusion • TX: erythromycin, clindamycin, mupirocin, azole antifungals (c) Trichomycosis axillaris • C. tenuis • Concretions on axillary hair shafts • Wood lamp fluoresces • TX: shave axillary hair

186

5  Infectious Diseases

III. Polymicrobial and other gram-positive infections (a) Cellulitis • • • • • • •

Group A β-hemolytic Strep > S. aureus (#1 in kids) Head/neck (kids), legs (adults), arms (IVDU) Infection of deep dermis/SQ TX: PO dicloxacillin, cephalexin, clindamycin × 10 days Diabetic/decubitus: IV zosyn, cipro + metronidazole Severe: IV abx MRSA: Bactrim, minocycline/doxycycline, clindamycin

(b) Necrotizing fasciitis • Group A β-hemolytic Strep (M types 1, 3) (#1 in kids) > polymicrobial (#1 in adults) • Life-threatening, rapidly progressive • Fournier’s—genitalia, perineum, lower abdominal wall • Meleney’s—postop complication (polymicrobial) • ↑ mortality: age, ↑ time to debridement, extent of infection, ↑ lactic acid, Cr, FEMALE • TX: fasciotomy + IV abx (c) Anthrax • B. anthracis—spore-forming rod  →  Poly-D-glutamic acid capsule, Lethal toxin (↑ TNF-α, IL-1β), Edema toxin (↑ cAMP) • Cutaneous anthrax (>95%) >> pulmonary, GI • Woolsorter’s disease • TX: quinolone, doxycycline—MUST TREAT EARLY (d) Erysipeloid • Erysipelothrix rhusiopathiae (rod) • Fisherman, poultry/fish handlers—finger spaces • TX: PCN (e) Listeria • L. monocytogenes (motile rod) • Pregnant women, elderly immunosuppressed—skin lesions rare, more GI illness • TX: ampicillin >> Bactrim (f) Clostridium • • • •

C. perfringens—spore-forming rod → α toxin, perfringolysin Traumatic inoculation, causes gas gangrene (foul brown exudate) XR: gas in tissue TX: aggressive surgical debridement, clindamycin, CSN, HBO2

5.1  Bacterial Infections

187

IV. Filamentous bacteria (a) Actinomycosis Actinomyces israelii Gram+, not acid fast, filamentous Found in oral, GI/GU flora—infection after procedures Subacute-chronic granulomatous lesions with abscesses + sinus tracts Cervicofacial (70%) lumpy jaw disease—yellow sulfur granules, a/w poor dental hygiene • BX: granules with basophilic center/eosinophilic rim  =  SplendoreHoepplie phenomenon • TX: PCN, ampicillin • • • • •

(b) Nocardiosis Nocardia brasiliensis (#1 cause actinomycotic mycetoma) Nocardia asteroids (#1 cause pulm/systemic nocadiosis) Gram+, weakly acid fast, filamentous Found in soil—most often traumatic inoculation to foot BX: sulfur granules with branching filaments (gram+, AFB+, Fite+, GMS+) • TX: sulfonamides ± drainage

• • • • •

V. Pseudomonas infections • See Box 5.3

Box 5.3 Pseudomonas Infections Green nail syndrome

Green/blue-black nail (pyocyanin) a/w water, trauma TX: top quinolone, aminoglycoside, vinegar soaks Pseudomonal Affects covered areas folliculitis a/w poorly chlorinated hot tubs/whirlpools No treatment necessary, self-resolving Pseudomonal Painful red-violaceous nodules/plaques on weight-bearing areas of hot-foot syndrome plantar surface a/w wading pools No treatment necessary, self-resolving Pseudomonal Superficial erosive blue-green purulent exudate pyoderma a/w burn sites, toe, web infections, chronic wounds Otitis externa Affects external auditory canal—severe pain when pinna touched Malignant variant seen in diabetics and immunosuppressed Ecthyma Indicative of septicemia due to P. aeruginosa gangrenosum Seen in patients with severe neutropenia Most commonly affects anogenital area and extremities Tx: IV aminoglycoside + antipseudomonal PCN

188

5  Infectious Diseases

VI. Bartonella infections • Infection with Bartonella species: B. henselae, B.  Quintana, B. bacilliformis • Dx: Warthin-Starry stain, PCR, serology, culture on chocolate agar (40 days) • See Box 5.4 VII. Rickettsia infections • Infection with Rickettsia species and Orientia: R. ricketsii, R. conorii, R. akari, R. typhi, R. felis, R. prowazekii, and Orientia tsutsugamushi • Obligate intracellular gram-negative bacteria • Targets endothelial cells • See Box 5.5 VIII. Other gram-negative infections (a) Neisseria meningitidis • Affects children/young adults in close quarters (M  >  F), asplenic or C5–9 deficiency • 10–15% asx carrier in nasopharynx—respiratory droplet spread • Acute meningoccemia (Types B, C, Y in US): petechial, retiform purpura, hemorrhagic bullae → DIC Box 5.4 Bartonella Infections (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) Cat scratch disease

B. henselae

Bacillary peliosis Bacillary angiomatosis Endocarditis, chronic afebrile bacteremia Trench fever

B. henselae

Cat flea (Ctenoce­ phalides felis)

B. henselae B. quintana B. henselae B. quintana

B. quintana

Human body louse (Pediculosis humanus) Phlebotomine Bartonellosis: B. bacilliformis sand fly – Carrion’s (Lutzomyia – Oroya fever verrucarum) – Verruga peruana

Young, immuno­ competent >  immuno­compromised Hepatitis Immuno­compromised Immuno­compromised (HIV) Immuno­competent OR immuno­compromised

Supportive, Doxy + rifampin Erythromycin Erythromycin Erythromycin Doxy+rifampin

a/w homelessness and Doxycyline + aminoglycoside poor hygiene (urban trench fever) Oroya = acute Verruga peruana = chronic

Chloramphenicol + β lactam Rifampin + streptomycin

Scrub typhus group – Rash 50% Rickettsia-like bacteria

Typhus group – Axillae rash (only 50–80%) – NO ESCHAR

Spotted fever group – High fever – Petechiae (85–100%) – Systemic sx

R. ricketsii

Orientia tsutsugamushi

Scrub typhus (Asia—scrub vegetation) Human Monocytic Ehrlichiosis

Q fever

Humang granulocytic anaplasmosis

R. prowazekii

Epidemic typhus

Ehrlichia chaffeensis – Obligate intracellular, kills monocytes/ macrophages Anaplasma phagocytophilum – Obligate intracellular, kills neutrophils Coxiella burnetii

R. felis

R. typhi

Endemic/murine typhus Cat flea typhus

R. conorii Mediterranean spotted fever “Boutonneuse fever” Rickettsialpox R. akari

RMSF

Southern US—white-tailed deer Fever, myalgia, ↓plt, ↓WBC, petechial rash Same geography as Lyme Similar presentation as HME ↑ peripheral neuropathy Co-infxn Lyme, Babesiosis often Rare skin findings

I. scapularis I. Pacificus

Sheep, cattle

Doxycycline

Doxycycline

Doxycycline

Doxycycline

Doxycycline

Eschar at bite → fever, LAD, rash Doxycycline (pregnant: in axillae → spread azithromycin)

Crowded living conditions

Fever, systemic sx, rash in axillae

Self-resolving ∗Weil-Felix test (−)∗

Papulovesicle at bite → eschar → widespread eruption Fever, systemic sx, rash in axillae

Doxycycline

Mortality 25% DOXYCYCLINE (pregnant: chloramphenicol) Doxycycline >> azithromycin, clarithromycin (kids)

Fever, HA, myalgias, 90% rash (wrists/ankles) NO ESCHAR “Tache noir”—necrotic papule at bite (legs)

Amblyomma americanum (lone star tick)

Rhipicephalus sanguineus (brown dog tick) Liponyssoides sanguineus (house mouse mite) Xenopsylla cheopis (oriental rat flea) Ctenocephalides felis (cat flea) Pediculosis humanus (human body louse) Larval trombiculid mites (“chiggers”)

D. Variabilis—#1 D. andersoni—#2

Box 5.5 Infections with Rickettsia and Rickettsia-Like Bacteria (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017)

5.1  Bacterial Infections 189

190

5  Infectious Diseases

• Chronic meningococcemia: recurrent fever, arthralgia, rash • TX: IV penicillin (ToC), quinolones, chloramphenicol, CSN • PPX all close contacts: ciprofloxacin, rifampin, azithromycin (b) Rhinoscleroma • K. rhinoscleromatis—adults in tropical locations • Chronic granulomatous infection of nose, upper respiratory • Catarrhal (rhinitis) → granulomatous/infiltrative (dysphonia, anesthesia soft palate) → sclerotic phases (scarring) • Mikulicz cells (Warthin-Starry stain), Russell bodies • TX: tetracycline (ToC) (c) H. influenza cellulitis • Infants • Deep red-violaceous cellulitis on face (perorbital, buccal) • TX: third gen CSN (d) Malakoplakia • • • •

E. coli Immunosupressed (BMT > AIDS) Chronic granulomatous infection Ulcerated abscesses in perianal/genital region, most often affects GU tract • BX: von Hansemann cells containing Michaelis-Gutmann bodies (von Kossa, PAS, Perls, Giemsa stains) • TX: surgical excision > Bactrim, ciprofloxacin, clofazimine (e) Salmonellosis • • • •

Typhoid fever Salmonella typhi Nausea, vomiting, diarrhea, HA, “rose spots” on trunk TX: quinolones (ToC), third gen CSN in kids

(f) Gram-negative infections related to animals • See Box 5.6 • Most common bacteria in bites –– Dog: Pasteurella multocida, P. canis, Capnocytophaga canimorsus –– Cat: Pasteurella multocida >> Streptococcus –– Human: Eikenella corrodens, S. aureus, Peptostreptococcus, Enterococcus, Bacteroides –– Treatment: Augmentin

5.1  Bacterial Infections

191

Box 5.6 Animal-Related Gram-Negative Infections Brucellosis Malta fever, “Undulant fever”

Glanders/ Meliodosis

Tularemia

Rat-bite fever “Haverhill fever”

Plague

Vibrio vulnificus

Farmers, butchers, veterinarians—direct contact or inhalation (goats, sheep) Undulating fevers, arthralgia, LAD, skin findings  40 years, liver disease, diabetes, ESRD Shellfish Cutaneous exposure or consumption of raw/ undercooked shellfish Brucella

TX: doxycycline + streptomycin/rifampin/bactrim

TX: augmentin, Bactrim, doxycycline (localized); IV carbapenem + ciprofloxacin or doxycycline (septicemic)

TX: streptomycin (ToC)

TX: PCN (ToC)

TX: aminoglycosides (ToC)

TX: doxycycline + third gen CSN

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5  Infectious Diseases

IX. Syphilis • Infection with Treponema pallidum • Three stages: –– Primary (10–90 days incubation) ◦◦ Chancre—painless, indurated –– Secondary (3–10 weeks post-chancre) ◦◦ ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Papulosquamous rash—“copper colored” Moth-eaten alopecia Split papules—“syphilic perlèche” Hypopigmented macules on neck—“necklace of Venus” Condyloma lata Mucous patches in oropharynx

–– Tertiary (months-years after secondary) ◦◦ Gummas ◦◦ Cardiovascular (aortitis) ◦◦ Neurosyphilis • • • • • • •

↑ coinfection w HIV HIV a/w ↑ risk neurosyphilis Treponemal—FTA-ABS, MHA-TP (more sensitive, specific) Positive always Non-treponemal—RPR, VDRL (+within −2 weeks) Negative after successful treatment Tx: penicillin

X. Non-syphilis treponemes • Also known as endemic treponematoses (see Box 5.7) Box 5.7 Endemic Treponematoses (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) Yaws – Children  B. garinii Acrodermatitis chronica atrophicans B. afzelii (#1 Europe) >> B. garinii Louse-born relapsing fever B. recurrentis Tick-borne relapsing fever B. duttonii B. hermsii

Early localized Lyme— I. scapularis erythema migrans (90%) (dammini)—#1 US I. pacificus—Western disseminated (25–50%) US I. ricinus—Europe

Doxycycline Amoxicillin (preg,  BB, BT –– TX: prednisone • Lucio phenomenon –– –– –– ––

Severe necrotizing vasculitis w/thrombosis West Mexico, in LL Purpuric macules, ulcerative bullous lesions TX: prednisone

• See Box 5.10

Box 5.10 Summary of Leprosy LL Lepromatous leprosy

BL Borderline lepromatous

BB Borderline

BT Borderline tuberculoid

Small hypopigmented macules and diffuse infiltration (leonine), madarosis, saddle nose Numerous, symmetrical Bacilli smear (globi) 4+ Fite (AFB) +++ Lepromin 0 Th2 >> Th1

Grenz, diffuse parasitized foamy histiocytes (Virchow cells)—xanthoma-like, +globi ↑ risk type 2 rxn

Rifampin + dapsone + clofazimine (12 months)

Many 3+ +++ +

Few or many 2+ ++ +

Few 1+ + 2+

↑ risk type 2 rxn

↑ risk type 2 rxn Highest risk for type 1 rxn Rifampin + dapsone (6 months)

Rifampin + dapsone + clofazimine (12 months)

TT Tuberculoid Dry, scaly, hypopigmented, anesthetic plaques with raised periphery 1–3 0 0 3+ Strong cellmediated immunity Th1 >> Th2 Well-formed sarcoidal granulomas w/ linear arrangement along nerves ↑ risk type 2 rxn Highest risk for type 1 rxn

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5  Infectious Diseases

XVI. Other atypical mycobacteria • Slow-growers (2–3 weeks) –– Photochromogens: M. marinum, M. kansaii, M. simiae –– Scotochromogens: M. scrofulaceum, M. szulgai, M. gordonae, M. xenopi –– Nonchromogens (incapable of pigment production): M. tuberculosis, M. avium, M. ulcerans, M. intracellulare, M. bovis, M. haemiphilum, M. genavense, M. terrae • Rapid growers (3–5 days) –– M. fortuitum, M. chelonae, M. abscessus • Non growers –– M. leprae • See Box 5.11

Box 5.11 Other Atypical Mycobacteria • AIDS • Found in environment • Pulmonary infection → skin (pustules, nodules, ulcers on legs) • ↑ alk p M. marinum • Found in fish tanks, swimming pool • Cutaneous contact (ulcerating nodules in sporotrichoid pattern M. ulcerans • Africa “Buruli ulcer” • Nodule → ulcer (can extend to bone) M. fortuitum, • Fast growing mycobacteria • Responsible for infection of chelonae, posttrauma, surgery, implants, abscessus liposuction, botulinum toxin, tattoo, nail salon, footbath • Contaminated sx instruments • Most commonly present as inflamed SQ nodules in sporotrichoid pattern M. avium complex

TX: clarithromycin/ azithromycin + ethambutol ± rifampin

TX: clarithromycin ± rifampin, minocycline, bactrim

TX: excision (ToC), rifampin + streptomycin, amputation TX: clarithromycin

5.2  Fungal Infections

199

5.2  Fungal Infections I. Dermatophytoses • Infection due to fungi that only invade fully keratinized structures (stratum corneum, hair, nails) • Fungal infections caused by 3 genera of fungi that have unique ability to invade/multiple within keratinized tissue: Microsporum, Trichophyton, Epidermophyton • Transmission via 3 sources: anthropophilic, zoophilic, geophilic • First stage of inxn: contact with and adherence of infectious elements of fungus (arthroconidia) to skin • Dermatophytes produce keratinases that allow invasion of fungi into st. corneum • Mannans in cell walls of dermatophytes have immune-inhibitory effects—e.g. T. rubrum has mannans that decrease epidermal proliferation which decreases likelihood of fungus being sloughed off prior to invasion • Severity of clinical disease affected by host factors: sebum activity, breaks in skin barrier, immune status • First line treatment for uncomplicated localized cutaneous dermatophyte infections: topical antifungals • Systemic antifungal treatment for tinea manuum, capitis, and unguium • Tinea corporis—trunk/extremities, restricted to st. corneum, commonly affects exposed skin –– Most common pathogen worldwide: T. rubrum > T. mentagrophytes –– Incubation 1–3 weeks, spreads centrifugally with central clearing, can be less scaly (tinea incognito) –– Variants: tinea profunda (inflammatory response to dermatophyte such as kerion on scalp, can appear granulomatous or verrucous), Majocchi’s granuloma (caused by T. rubrum has perifollicular papulopustules or granulomatous nodules, usually in women with tinea pedis or onychomycosis and shave legs, represents deep dermatophyte folliculitis), tinea imbricate • Tinea cruris—inguinal region, crural folds –– Most common pathogens: E. floccosum, T. rubrum, T. mentagrophytes –– Predisposing factors: obesity, excessive sweating, men > women –– Begins as erythema/pruritus in fold between scrotum and inner leg, can be unilateral –– Scrotum itself spared in tinea cruris—if scrotum involved or there are erosions or satellite pustules, must consider cutaneous candidiasis

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5  Infectious Diseases

• Tinea manuum –– Palm and interdigital spaces –– Typical pathogens: E. floccosum, T. rubrum, T. mentagrophytes –– Often non-inflammatory, unilateral, diffuse hyperkeratosis of palms/digits that does not respond to emollients • Tinea barbae –– –– –– –– ––

Affects bearded areas of face/neck in men Causative organisms: T. mentag, T. verrucosum Dropped in incidence due to use of disposable razors and disinfectants Patients can have constitutional sx like malaise, LAD, scarring alopecia Another variant is superficial, less inflammatory, can be a/w alopecia, usually due to T. rubrum

• Tinea faciei –– Can be difficult to diagnose, must keep high index of suspicion • Tinea capitis –– Common in scalp of children –– Usually from Trichophyton and Microsporum –– T. tonsurans currently most common cause of tinea capitis in US, predilection for black patients (second most common is M. canis) –– Also increase in T. violaceum (endemic in Africa) • Tinea pedis –– Infection of soles and interdigital webs –– Causative organisms: T. rubrum, T. interdigitale, T. mentagrophytes, E. floccosum, and T. tonsurans (in children) –– Oral antifungals should be considered in diabetic patients, immunocompromised, and moccasin-type tinea pedis • Tinea unguium –– Onychomycosis refers to all fungal infections, including those due to dermatophytes and non-dermatophytes –– Tinea unguium refers to dermatophyte infection of nail unit –– Most common: T. rubrum, T. interdigitale, T. tonsurans (in children), E. floccosum –– Treatment: oral antifungal: 250 mg/day terbinafine × 6 weeks (fingernail only) or × 12 weeks (toenail ± fingernail involvement) ◦◦ Other agents: itraconazole, griseofulvin, fluconazole –– 3 patterns based on point of fungal entry into nail unit: ◦◦ Distal/lateral subungual ◦◦ Most common

5.2  Fungal Infections

201

◦◦ Invasion via hyponychium ◦◦ T. rubrum, T. interdigitale, E. floccosum –– Superficial white ◦◦ Direct penetration into dorsal surface ◦◦ T. interdigitale most common in classic form ◦◦ T. rubrum responsible for cases with transverse striate bands and deeper invasion (seen in children and in HIV) –– Proximal subungual ◦◦ Invasion into proximal nail fold ◦◦ Seen in immunocompromised hosts ◦◦ T. rubrum –– Non-dermatophyte molds can cause onychomycosis ◦◦ Superficial white → Fusarium, Aspergillus, Acremonium ◦◦ Lateral yellow-brown discoloration → Scopulariopsis brevicaulis ◦◦ Distal/lateral → Neoscytalidium hyalinum, N. dimidiatum II. Other superficial mycoses • Piedra –– Superficial infection of hair shaft –– 2 major forms: white and black –– Black: asymptomatic, brown/black nodules along hair shaft, usually infxn is from under cuticle of hair shaft, extends outward and can causes shaft rupture and/or envelope hair shaft –– White: infection from beneath cuticle and grows through hair shaft, causing weakness/breakage of hair, nodules are soft and less adherent –– Tx: clip hairs, shampoo with 2% ketoconazole, ± oral terbinafine • Tinea nigra –– Usually presents as single sharply marginated brown macule/patch with overlying scale, often asx –– Most often on palms but also on soles, neck, trunk –– Tx: keratolytics (Whitfield’s ointment), topical azole or allylamine antifungals • Pityriasis versicolor –– Multiple round/oval patches or thin plaques with mild, fine scale –– Favored sites of involvement are seborrheic regions, less often seen on face, scalp, AC fossae, submammary region and groin –– Most common colors are hyperpigmentation, but can see decreased pigmentation due to inhibitory effects of dicarboxylic acids (resulting from metabolism of surface lipids by yeast) on melanocytes

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5  Infectious Diseases

–– Tx: topical antimycotic treatment such as ketoconazole, selenium sulfide shampoo, oral fluconazole or itraconazole • Pityrosporum folliculitis –– Pruritic, monomorphic follicular papules/pustules on upper trunk, arms, neck, and on occasion the face –– Due to overgrowth of M. furfur and M. globosa within hair follicle • Pathology/Fungal culture –– Cut hair shafts and place in KOH with “crush preparation” –– Black piedra nodule will demonstrate demitaceous hyphae in cluster –– White piedra nodule demonstrates non-demitaceous hyphae, blastoconidia, and arthroconidia –– KOHS of M. furfur shows ziti and meatballs, of tinea nigra shows septate pigmented hyphae III. Subcutaneous mycoses • See Box 5.12 Box 5.12 Subcutaneous Mycoses Traumatic inoculation (wood splinter, sphagnum moss) Ascending ulcerated nodules or abscesses Keloid-like Lobomycosis Lacazia (Loboa loboi) Freshwater verrucous dolphin, ∗cannot be cultured fibrotic nodules S. America in vivo∗ Traumatic Madurella Southern Mycetoma tropics (Latin inoculation (Eumycetoma (young men, America, = fungus) India, Africa) poverty) (Actinomycetom Sinus tracts = bacteria) draining grains Feet/legs Chronic → bone/visceral Traumatic Chromo­ Fonsecaea pedrosoi > Tropical/ inoculation subtropical blastomycosis Rhinocladiella, Pruritic papules/ climates Phialophora nodules that verrucosa, become Cladophilalophora verrucous carrionii Chronic → SCC

Sporotrichosis

Sporothrix schenkii

Saprophyte Central/S. American, Africa

Itraconazole (ToC), SSKI, amphotericin B

Surgical excision

Itraconazole, 5-flucytosine Surgical excision

5.3  Viral Infections

203

IV. Systemic (dimorphic) mycoses • See Box 5.13 V. Opportunistic systemic mycoses • See Box 5.14

5.3  Viral Infections I. HPV • Double-stranded DNA virus • E1-E7 (Early proteins) → DNA replication –– E1, E2: first to be expressed in st. basale and spinulosum

Box 5.13 Systemic (Dimorphic) Mycoses Histoplasmosis

H. Capsulatum

Blastomycosis

Blastomyces dermatitides

Coccidioidomycosis

Coccioi­ domycosis

Paracoccidioidomycosis Paracoccid­ ioides brasiliensis

↑ risk in HIV 1° chancre with lymphangitis 2° cutaneous molluscoid nodules, cellulitis, ulcers, panniculitis, oral lesions INTRACELLULAR YEAST Eastern US, 2° cutaneous verrucous nodules, Great abscesses, ulcers (can Lakes, Mississippi be intraoral) BROAD-BASED River BUDS valley 2° cutaneous Central Valley/ San verrucous nodules, papules, pustules, Joaquin abscesses, ulcers Valley, ENDOSPORES Mexico, Central/S. America Granulomatous Southern ulcerative US, oropharyngeal and Mexico, perioral involvement Central/ S.America M >> F MARINER’S WHEEL

Ohio, Mississippi River valley Bird/bat feces

Itraconazole

Itraconazole, Amphotericin B

Itraconazole Amphotericin B

Bactrim Itracronazole Fluconazole or voriconazole Amphotericin B

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Box 5.14 Opportunistic Systemic Mycoses C. albicans, C. tropicalis C. parapsilosis (chronic paronychia) C. glabrata, C. krusei (fluconazole resistance) C. dubliniensis (oropharyngeal in HIV) C. neoformans C. gatti

Oral thrush, median rhomboid glossitis, chronic paronychia, candida intertrigo, erosion interdigitalis blastomycetica

↑ DM, steroid, HIV Nystatin, clotrimazole, fluconazole

Molluscum-like umbilicated papules, nodules Meningoencephalitis

Aspergillosis

Aspergillus fumigatus A. flavus A. niger (otomycosis)

↑ HIV, sarcoid, preg Fluconazole Amphotericine B & fluocytosine (CNS) Azoles, echinocandins, amphotericin B

Fusarium

Fusarium solani

Penicilliosis

Penicillium narneffei

Zygomycosis Aka mucormycosis

Rhizopus, Rhizomucor, Mucor

Phaeohy­ phomycosis

Dematiaceous fungi: Exophiala jeanselmei, Wangiella dermatitidis, Alternaria, Curvularis, Phialophora

1° by direct inoculation 2° heme spread, vascular invasion Erythematous, edematous plaques, nodules with necrotic centers, hemorrhagic bullae, necrotic ulcers Erythematous, edematous ↑ burn pt plaques, panniculitis No established med Debridement if possible Molluscum-like lesions (face, ↑ bamboo rat Terbinafine, arms, trunk)—similar to amphotericin B histoplasmosis Aggressive Immunosuppressed surgical resection, Rhinocerebral (DM with DKA), necrotic black plaques amphotericin B or eschars Excision Immunosuppressed Itraconazole Subcutaneous draining, inflammatory abscesses or cysts

Candidiasis

Cryptococcosis

5.3  Viral Infections

205

–– E4: Disrupts cytokeratin network –– E5, 6, 7: Amplification –– E6, E7: oncoproteins in high-risk mucosal subtypes, decrease host immune response (TLR9) –– E7: binds RB • L1-L2 (Late proteins) → Structural proteins required for virion –– Make up the capsid –– L1 = major structural protein –– L2 = minor structural protein • • • • • • •

Genus α: mucosal/cutaneous HPV types Genus β: epidermodysplasia verruciformis-associated types Common warts—1, 2, 4, 27, 57 57 can cause 10-nail dystrophy Ridged warts—retain normal dermatoglyphics, pigmented seen in Japan 60 Epidermodysplasia verruciformis—AR (TMC6, TMC8—EVER1, EVER2) –– Acquired seen in HIV –– HPV 5, 8 → Aks, SCC (>30%, in >30 years in sun-exposed)

• WHIM—AD, CXCR4 –– Warts, hypogammaglobulinemia, (myelokathexis)

infxn

(bacterial),

neutropenia

• WILD –– Warts, immunodeficiency, lymphedema, dysplasia (anogenital) • Genital warts (condyloma acuminata) –– Most common STD –– Can lead to cervical cancer if persistent with high-risk HPV (16, 18, 31, 33, 45) –– Vaccines—FDA for M/F 9–26 –– Quadrivalent: 6, 11, 16, 18 –– Bivalent: 16, 18 –– 9-valent: 6, 11, 16, 18, 31, 33, 45, 52, 58 • Bowenoid papulosis—a/w high-risk HPV, rare progression to SCC • Erythroplasia of Queyrat—HSIL or SCCIS, a/w high risk HPV, ↑ risk progression to SCC • Verrucous carcinomas (slow-growing, locally destructive):

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5  Infectious Diseases

–– Buschke-Lowenstein (penis)—6, 11 –– Oral florid papillomatosis (mouth)—6, 11 –– Epithelioma cuniculatum (sole of foot)—2, 11, 16 –– Papillomatis cutis carcinoides • Oral warts –– 6, 11 (more common in HIV) • Focal epithelial hyperplasia (Heck’s disease) –– 13, 32 –– Gingival, buccal, labial mucosa—seen in children in S. America • Recurrent respiratory papillomatosis –– 6, 11 –– #1 benign tumor of larynx –– ↑ risk SCC esp. in smokers II. HSV • • • • •

Double-stranded DNA virus Icosahedral capsid with linear dsDNA Glycoprotein-containing envelope Replicates in host nucleus See Box 5.15

III. Poxviruses • See Box 5.16 IV.  HIV/AIDS Dermatology • Mucocutaneous disorders are clues to HIV and markers of progression • HIV-1 >> HIV-2 (restricted to West Africa, less transmissible and virulent) • Enveloped ss RNA lentivirus (Retroviridae family) Box 5.15 HSV Types HHV-­1, HSV-1, Orolabial

Triggers: UV(B > A), chemical peels/laser Favors anterior mouth (buccal, gingivae—unlike herpangina) Eczema herpeticum—AD, Hailey-Hailey, Darier’s (Th2 shift) Herpetic whitlow (children), herpes gladiatorum, ocular HSV, HSV encephalitis (temporal lobe #1) #1 cause EM minor

Western blot = gold standard PCR = most sens/spec Penciclovir/valacyclovir (PO) Acyclovir (IV) Foscarnet, cidofovir (for resistant)

5.3  Viral Infections

HHV-­2 HSV-2, genital HHV-­3 VZV, varicella, herpes zoster

HHV-­4 EBV, infectious mononucleosis, oral hairy leukoplakia, Giannoti-Crosti, Burkitt’s lymphoma, nasopharyngeal carcinoma HHV-­5 CMV, TORCH or transplant/ immunosuppressed HHV-­6, Roseola infantum 7 HHV-­8 Kaposi

207

Herpetic whitlow (adults), ocular HSV (newborns) Immunosuppressed, elderly Congenital varicella—w/in 20 weeks gestation → CNS, ocular, limb Neonatal varicella—5 days pre ~ 2 days postdelivery → 30% mortality Ramsay-hunt—CN VII (geniculate ganglion of facial nerve) Aseptic meningitis and/or encephalitis—CN V Herpes zoster ophthalmicus— CN II, III, V (Hutchinson’s sign—V1 nasociliary), uveitis > keratitis Bell’s palsy—CN VII Infects B cells, continue to replicate in patients with low cell-mediated immunity → lymphoproliferative disorder Pharyngitis, fever, cervical LAD, splenomegaly

Recalcitrant perineal/leg ulcers in HIV

Acyclovir, famciclovir, valacyclovir (PO) Live attenuated vaccine Give vaccine within 72–120 h post-exposure if non-immune VZIG within 96 h to neonate, F, immunocompromised Acyclovir (IV in immunosupp) Famciclovir, valacyclovir (preferred)

Augmentin— hypersensitivity Monospot—IgM Heterophilic ab Supportive care

Ganciclovir (IV) Valganciclovir (PO)

a/w pityriasis rosea, DRESS a/w multicentric Castleman disease, primary effusion lymphoma, paraneoplastic pemphigus

• HIV-1 has 4 lineages: –– Group M = 99% of pandemic –– Group N, O, P = restricted to West Africa • HIV-1 viral envelope proteins gp120, gp41 interact with CD4 plus CCR5 or CXCR4 –– CCR5 and CXCR4 are found on activated CD4+ T cells, monocytes, macrophages, dendritic cells –– CXCR5—predominant fusion cofactor

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5  Infectious Diseases

Box 5.16 Poxviruses Smallpox (Orthopox—Variola virus) Vaccinia (Orthopox—Vaccinia virus) Monkeypox (Orthopox, Monkeypox virus) Cowpox (Orthopox, Cowpox virus) Orf (Parapox, Orf virus) Milker’s nodules “Pseudocowpox” (Parapox, Paravaccinia virus) Molluscum contagiosum (Molluscipox, Molluscum contagiosum virus)

• Palms/soles → spread, scars • Encephalitis, blindness, toxemia, hypotension • Used for live smallpox vaccine • Eczema vaccinatum, EM, lymphadenopathy, progressive vaccinia (can kill immunocompromised!) • African, US (prairie dogs) • Palms/soles → spread, scars (smallpox-like, but milder) • Papule at site of contact → eschar, ±LAD, fever • Contact w/ sheep, goats, reindeer • Papule at site goes through 6 stages then self-resolves • Contact with calves, cows • Papule at site of contact (looks like orf) • MCV-1: kids; MCV-2: HIV/AIDS (CD4  aethiopica, infantum, donovani • New World: Lutzomyia sand flies –– L. Mexicana, braziliensis, amazonensis • See Box 5.17 • Tx: pentavalent antimony for cutaneous and mucocutaneous, amphotericin B for visceral

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Box 5.17 Leishmaniasis Mucocutaneous New world

Cutaneous Old world > New world

Diffuse cutaneous Old world & New world

Skin only, more common in Old World (Middle East, Brazil, Peru) Old World: L. major, L. tropica – Solitary small nodule – Sporotrichoid spread – Heals with scarring New World: L. Mexicana – Chiclero (ear lesion), ulcerations

Skin and mucous Widespread membranes cutaneous lesions Almost all New World Usually immunosuppressed Old World: L. aethiopica

New World: L. amazonensis

New World: L. braziliensis > amazonensis, panamensis, guyanensis – Lip, nose, oropharyngeal infiltration and ulceration – Progressive destruction → mutilation of mouth, perforation nasal septum “tapir face” or espundia

Visceral Old world > New World (Kala-azar, “black fever”) Bone marrow, liver, spleen More common in Old World Old World: L. donovani (India, Sudan, Bangladesh), L. infantum (Europe, HIV), L. chagasi – Fever, weight loss, diarrhea, LAD, HSM, hemorrhage – Death w/in 2 years untreated – Papules, ulcers, purpura, hyperpigmentation, kwashiorkor changes – Post-kala-azar dermal leishmaniasis = new onset decades later

Chapter 6

Pediatric Dermatology

6.1  Conditions of Newborns I. Newborn Injuries • See Box 6.1 for comparison II. Newborn rashes (a) Subcutaneous fat necrosis • • • •

Seen in healthy full-term/post-term babies Nodules on back, cheeks, buttocks, thighs Needle-shaped clefts + inflammation Hypercalcemia (screen for 6 months)

(b) Sclerema neonatorum • • • •

Debilitated preterm and sick term Diffuse hardening of skin Needle-shaped clefts (NO granulomatous inflammation) ICU, most die from sepsis/shock

(c) Erythema toxicum neonatorum • • • •

Full term, >2500 g Presents from birth to 2 weeks → self resolves Spares palms/soles Wright stain: Eosinophils

(d) Transient neonatal pustular melanosis • • • •

Term, blacks Presents at birth Pustules, collarettes of scale, hyperpigmented macules Wright stain: Neutrophils

© Springer Nature Switzerland AG 2020 W. W. Huang, C. S. Ahn, Clinical Manual of Dermatology, https://doi.org/10.1007/978-3-030-23940-4_6

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Box 6.1 Newborn Injuries Capput succedaneum

Above periosteum

Cephalohematoma

Subperiosteum

Subgaleal hematoma

Subgaleal

Prolonged labor Diffuse swelling Crosses suture lines Prolonged labor Unilateral swelling Does not cross suture lines Traumatic or instrument delivery Dependent edema Crosses suture lines

(e) Neonatal cephalic pustulosis (Neonatal acne) • • • •

Healthy newborns (20%) Presents within weeks → resolves by 3 months Cheeks/nasal bridge, can be anywhere Tx: topical retinoid, abx, BPO, oral abx, isotretinoin

(f) Infantile acne • Presents 3–6 months → resolves by 2–3 years • Limited to face • Can produce scarring—tx necessary (same as above) (g) Aplasia cutis congenita • • • •

Localized absence of epidermis, dermis, subcutis, calvarium Hair collar sign → cranial dysraphism Teratogens—methimazole Adams-Oliver Syndrome –– ACC w/cranial defect + congenital heart defect + CMTC + limb abnormalities

• Bart Syndrome –– ACC + DDEB

6.2  Congenital Infections I. Infections associated with extramedullary hematopoiesis (a) Toxoplasmosis • Intracranial calcifications • Chorioretinitis, hydrocephalus • Tx: Pyrimethamine, sulfadiazine, folinic acid

6.2 Congenital Infections

215

(b) Rubella • Maternal infxn ( congenital heart disease, chorioretinitis, retinopathy, intracranial calcification • Tx: None • See Box 6.2 for sound-alike viral exanthems (c) CMV • Most common congenital infection/cause of EMH, most common infectious cause of congenital deafness and MR • Reactivation of latent disease, primary maternal infection, or postnatal exposure • Petechiae, IUGR • Deafness, MR • Tx: IV ganciclovir II. Other Viral Exanthems • See Box 6.3 III. Congenital syphilis • Presents at birth or first few days of life • Usually due to lack of prenatal care • T. pallidum invades placenta, bloodstream, organs, adheres to endothelium and can cause vasculitis • Tx: penicillin • Early findings (2 years) –– –– –– –– –– –– –– ––

Interstitial keratitis Saber shins Gummas Frontal bossing Higoumenakis sign—enlargement of medial clavicle Mulberry molars Hutchinson teeth Saddle nose

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6  Pediatric Dermatology

–– Perioral rhagades/Parrot lines –– Clutton joints—painless swelling of knees –– Tabes dorsalis IV. Congenital varicella • Fetal:  A6, Enterovirus 71 Gianotti-Crosti EBV (#1 US) Hepatitis B (#1 Aka Papular acrodermatitis worldwide) of childhood Unilateral laterothoracic exanthem Aka asymmetric periflexural exanthema of childhood Erythema infectiosum Aka Slapped cheek, fifth disease

Slapped cheeks (NOT VIREMIC) Lacy, reticulated rash favoring extremities Complications: Arthritis (small joints) Aplastic crisis, pancytopenia Hydrops fetalis Fetal loss rate highest in second trimester Symmetric edema and erythema of palms/soles (VIREMIC) Petechiae, purpura Vesicular eruption on palms, soles, buttocks, oral cavity ∗more severe with A6∗ Symmetric monomorphic skin-colored or erythematous popular eruption favoring face, extremities, buttocks Unilateral erythematous macules/papules favoring flexures “State of liberty sign”

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6.3  Inherited Disorders of Cornification I. Ichthyoses • Disorders of cornification • Abnormal differentiation and desquamation of the epidermis • Congenital or acquired (malnutrition, lymphoma, inflammatory disorders, leprosy) • Results in widespread scaling of the skin • Evident at birth or manifest in infancy • Specific clinical features, patterns of inheritance, and structural, biochemical, molecular abnormalities • Treatment: symptomatic, reduce hyperkeratosis (emollients, keratolytics, retinoids) • Erythrokeratoderma: Characterized by localized areas of erythema and hyperkeratosis without obvious scaling –– Mostly evident at birth or manifest in infancy (a) Non-syndromic ichthyoses (see Box 6.4) • Corneal envelope defects –– Ichthyosis vulgaris ◦◦ Filagrin defect –– X-linked recessive ichthyosis ◦◦ Steroid sulfatase defect –– Lamellar ichthyosis ◦◦ TGM1 or ABCA12 –– Congenital ichthyosiform erythroderma (CIE) ◦◦ TGM1, ALOXE3, ALOX12B –– Harlequin ichthyosis ◦◦ ABCA12 mutation • Keratin defects –– Epidermolytic ichthyosis (bullous CIE) ◦◦ KRT1 and KRT10 –– Superficial epidermolytic ichthyosis (ichthyosis bullosa of Siemens) ◦◦ KRT2

6.3 Inherited Disorders of Cornification

219

Box 6.4 Non-syndromic Ichthyoses Ichthyosis vulgaris

FLG Fine adherent (Semidominant) scale, hyperlinear (spares flexures), improves with age TGM1 (AR) > Collodion ABCA12 Thick plate-like scales in flexures

KP, atopic diathesis

Heat intolerance, scarring alopecia, dystrophic nails, ectropion, eclabium Corneal Dark/brown STS (XL) Steroid adherent scales opacities, Boys/men sulfatase cryptorchidism, spares palms, Female deficiency prolonged labor asymptomatic soles, face— in mother with “dirty neck carriers affected fetus disease” ↑ risk testicular ca Heat Collodion ALOXE3 Congenital Fine white scales intolerance, ichthyosiform ALOX12B hypohidrosis, in flexures, erythroderma TGM1 ±scarring erythroderma (non-bullous alopecia, CIE) ectropion, ↑ risk SCC in adults Extreme Harlequin ABCA12 (AR) Thick plates of ichthyosis scale with deep ectropion, eclabium, ear fissures deformities Neonatal death or develop severe CIE-like phenotype Neonatal death due to sepsis or respiratory insufficiency Erythroderma, Frequent Epidermolytic KRT1 infections, KRT10 blistering, ichthyosis malodor, skin erosions → (bullous CIE) fragility, failure hyperkeratosis to thrive with ridging in flexures

Lamellar ichthyosis

Absent/thin granular layer, orthohyperkeratosis

Massive orthokeratotic hyperkeratosis, acanthosis, thin or absent cornified cell envelope Hyperkeratosis or parakeratosis, larger and more keratohyaline granules

Parakeratosis, acanthosis, hypergranulosis

Orthokeratotic stratum corneum, plugging of hair follicles and sweat ducts, abnormal or missing lamellar bodies

Epidermolytic hyperkeratosis, acanthosis with hypergranulosis, Clumped keratin in suprabasal cells, retinoids exacerbate skin fragility

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KRT2 Superficial epidermolytic ichthyosis (Ichthyosis bullosa of Siemens)

Erythroderma, superficial blistering, “molting of skin” later

Normal at birth or mild blistering, later develop trauma-induced small blisters, “molting” of skin

KRT1 Ichthyosis hystrix Curth-Macklin

Mutilating PPK, hyperkeratosis with verrucous pattern on extremities/trunk Erythroderma, scaling at birth → confetti-like areas of scaling

Pseudoainhum, digital contractures

Ichthyosis en confetti

KRT10

Joint contractures

–– Ichthyosis hystrix Curth-Macklin ◦◦ KRT1 –– Ichthyosis en confetti ◦◦ AKRT10 (b) Syndromic ichthyoses (see Box 6.5) • Sjögren-Larsson syndrome –– Autosomal recessive; ALDH3A2 • Refsum disease –– Autosomal recessive; PHYH, PEX7 • Comèl-Netherton syndrome –– Autosomal recessive; SPINK5 • Trichothiodystrophy (Tay syndrome, (P)IBIDS) –– Autosomal recessive; ERCC2, ERCC3 • CHILD syndrome –– X-linked dominant; NSDHL • Conradi-Hünermann-Happle syndrome • X-linked dominant; EBP

Orthokeratotic hyperkeratosis, acanthosis, vacuolization of granular layer Clumping of tonofilaments limited to upper spinous and granular cell layers

6.3 Inherited Disorders of Cornification

221

Box 6.5 Syndromic Ichthyoses Netherton syndrome

Sjögren-­ Larsson

SPINK5 Erythroderma, ichthyosis linearis circumflexa vs CIE-like FALDH Erythema, hyperkeratosis, PPK

Neutral lipid storage disease

ABHD5 Generalized fine white scales, ±erythema

Refsum disease

PHYH, PEX7

CHILD syndrome

Fine white scales (resembles ichthyosis vulgaris) NSDHL Unilateral (R > L) (XLD) erythema, waxy yellow scale

EBL Conradi-­ Hünermann-­ (XLD) Happle

Ichthyosiform generalized erythroderma → replaced with follicular Blaschkoid atrophoderma

Trichorrhexis invaginata >>trichorrhexis nodosa, pili torti Progressive spastic di- or tetraplegia, perifoveal glistening dots, photophobia Developmental delay, hepatomegaly

• Erythrokeratoderma variabilis –– Autosomal dominant –– GJB3, GJB4 • Progressive symmetric erythrokeratoderma –– Autosomal dominant or recessive –– GJB4 • Keratitis-ichthyosis-deafness (KID) syndrome –– GJB2

Lipid vacuoles in granulocytes, eosinophils, monocytes in peripheral smear ↑ phytanic acid

Salt and pepper pigment, cerebellar ataxia ±stippled Ipsilateral skeletal hemidysplasia, organ epiphyses (in hypoplasia, alopecia early infancy, resolves during childhood) Unilateral cataracts, XR—stippling stippled epiphyses (chondrodysplasia punctata), asymmetric skeletal deformities (frontal bossing, flat nasal root), patchy scarring alopecia

(c) Erythrokeratodermas (see Box 6.6)

–– Autosomal dominant

No tacrolimus or keratolytics

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Box 6.6 Erythrokeratodermas KID syndrome

GJB2 (connexin 26)

Erythroderma → symmetric hyperkeratotic plaques on face, extremities, follicular keratosis, PPK, radial furrows around mouth

Erythrokeratoderma variabilis Aka Mendes da Costa syndrome

GJB3, GJB4 (connexin 31, 30.4)

Transient, variable erythematous patches; stable geographic hyperkeratotic plaques, PPK (50%) Fixed, slowly progressive plaques, PPK common, can involve face

GJB4 Progressive symmetric erythrokeratoderma

Sensorineural hearing impairment, keratitis, blindness, recurrent infections, alopecia, follicular occlusion triad Worsens until puberty, then stable chronic course

↑ SCC

Orthoperkatosis, acanthosis, prominent granular layer, papillomatosis

II. Keratoderma • Keratodermas—hyperkeratosis of the palms and soles • Inherited or acquired • Three broad types based on pattern –– Diffuse PPK—entire palmoplantar surface –– Focal PPK—localized, mostly over pressure points (nummular or striate/ linear) ◦◦ Can evolve to diffuse over time –– Punctate PPK—1 mm–1 cm keratotic papules • Other distinguishing features: –– Erythematous border (most have) –– Transgradient (thickening extends to the lateral or dorsal surfaces, especially over the knuckles. –– Hyperhidrosis

6.3 Inherited Disorders of Cornification

223

(a) Focal PPKs • Jadassohn-Lewandowsky (Pachyonychia congenita, type1) –– KRT 6a/16, –– Focal PPK –– Associated: nail dystrophy, follicular keratoses, oral leukokeratosis • Jackson-Lawler (Pachonychia congenita, type 2) –– KRT 6b/17 –– Focal PPK –– Associated: nail dystrophy, follicular keratoses, steatocystoma multiplex, epidermoid cysts, natal teeth • Carvajal syndrome –– –– –– ––

Autosomal recessive Desmoplakin Focal/striate PPK Associated: Woolly hair, Left Dilated cardiomyopathy

• Howel-Evans syndrome –– Autosomal dominant –– TOC • Richner-Hanhart syndrome –– Autosomal recessive –– TAT • See Box 6.7 (b) Diffuse PPKs • Unna-Thost type –– KRT1 –– Diffuse nonepidermolytic PPK • Vörner type –– KRT1, KRT9 –– Diffuse epidermolytic PPK • Vohwinkel syndrome –– GJB2 → connexin 26. (variant = loricrin) –– Diffuse honey-combed PPK, transgradient –– Associated: hearing loss, knuckle placks (Starfish-shaped), linear keratoses of elbows and knees; Pseudoainhum = digital constriction bands with autoamputation; Scarring alopecia.

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• Bart-Pumphrey syndrome –– GJB2 → connexin 26 –– Diffuse PPK, May have honeycomb appearance, transgradient –– Associated: hearing loss, knuckle pads, variable leukonychia • Clouston syndrome = Hidrotic ectodermal dysplasia –– GJB6 → connexin 30 –– PPK is initially over pressure points, diffuse with age; Transgradienst –– Associated: Pebbled skin on dorsal fingers, knees and elbows, Hypotrichosis, Nail dystrophy, Tufting of terminal phalanges and thickened skull bones • Mal de Meleda –– SLURP1 –– Diffuse, transgradient, Severe hyperhidrosis and malodor, –– Associated: Periorificial lesions, Thickened nails with koilonychia and subungual hyperkeratosis, Reports of melanoma arising in affected acral sites • Papillon-Lefevre syndrome –– CTSC → cathepsin C –– Diffuse, transgradient; Hyperhidrosis, fetid odor –– Associated: Destructive periodontitis, Premature loss of teeth, Cutaneous and systemic pyogenic infections, Including hepatic abscesses, Dural calcifications • Naxos disease –– Autosomal recessive –– Plakoglobin –– Diffuse mild nonepidermolytic PPK, Erythematous border, Non-transgradient –– Associated: Woolly hair, Right ventricular cardiomyopathy • See Box 6.8

6.3 Inherited Disorders of Cornification

225

Box 6.7 Focal PPKs (Adapted from Bolognia JL, Schaffer JV, Cerroni L. Dermatology, 4th Ed. Elsevier. 2018) Richner-­ Hanhart “Tyrosinemia II” Pachyonychia congenita

TAT (AR)

Focal painful PPK on weight-bearing areas

Dendritic keratitis, corneal ulcers, blindness

KRT6α, KRT6b, KRT16, KRT17

Large misformed keratohyaline granules on EM

Carvajal

Desmoplakin

PC1: more severe NEPPK PC2: mild NEPPK Both: focal PPK, hypertrophic nail dystrophy (wedgeshaped thickening), follicular keratoses Striate PPK

Howel-Evans

RHBDF2, IRHOM2

Thick yellow PPK on weight-bearing areas

Woolly hair, dilated LEFT ventricular cardiomyopathy, nail dystrophy, hypodontia ↑ risk esophageal ca (30–50 s)

Box 6.8 Diffuse PPKs (Adapted from Bolognia JL, Schaffer JV, Cerroni L. Dermatology, 4th Ed. Elsevier. 2018) Vörner

KRT1, KRT9

Epidermolytic PPK (EPPK)

Unna-Thost

KRT1, KRT6c

Non-epidermolytic PPK (NEPPK)

Mal de Meleda

SLURP-1

Transgradiens PPK Atopic dermatitis

Vohwinkel

LOR (+ichthyosis), GJB2 (+deafness) Cathepsin C

Honeycombed PPK Transgradients PPK

Plakoglobin

Diffuse NEPPK

Papillon Lefèvre Naxos

Diffuse, welldemarcated PPK w yellow hue BX: epidermolytic hyperkeratosis Diffuse, welldemarcated PPK Bx: orthokeratosis PPK with erythematous fissures, hyperhidrosis Pseudoainhum, starfish keratosis Soles > palms, pyogenic infections Woolly hair, RV cardiomyopathy

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6.4  Inherited Disorders of Pigmentation I. Oculocutaneous albinism (OCA) • • • • • • • •

AR Abnormal melanin and melanosome biosynthesis/transport OCA2 most common > OCA1 Photophobia, nystagmus, reduced visual acuity Bx: decreased melanoma content, normal # melanocytes ↑ risk SCC (most common), BCC, melanoma (worse in OCA1) OCA2-like hypopigmentation seen in Prader-Willi, Angelman See Box 6.9

II. Silvery hair syndromes • All AR • Impaired synthesis, storage, and/or transport of melanosomes • All have pigmentary dilution and variable immunologic/neurologic features • See Box 6.10 III. White forelock syndromes • Encompasses piebaldism and Waardenburg syndrome (four types) • See Box 6.11 IV. Hyperpigmentation (a) McCune-Albright Syndrome • GNAS1 • F > M Box 6.9 Oculocutaneous Albinism (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) OCA1a TYR (absent)

Near-complete lack of pigment, photosensitivity Amelanotic/pink nevi, gray irides ↓ visual acuity ↑↑↑ risk SCC OCA1b TYR (↓) No pigmentation of skin/hair at birth but develop over time Milder ocular complications OCA2 OCA2 (previously P gene) Variable pigment dilution Seen in Africans Gray/tan irides, light brown hair OCA3 TYRP1 Rare Red/bronze skin, red hair OCA4 Very rare, seen in Japan Resembles OCA2

6.4 Inherited Disorders of Pigmentation

227

Box 6.10 Silvery Hair Syndromes LYST/ CHS1

Griscelli syndrome

1—Severe neuro GS1: MYO5A impairment 2—T & B cell GS2: RAB27A immunodeficiency 3—Least severe (skin GS3: only) MLPH Griscelli syndrome + severe neurologic dysfunction

Elejalde syndrome Hermansky Pudlak

HPS1–9

Oculocutaneous albinism Immunodeficiency Bleeding diathesis Neurologic degeneration

Death by age 10 → lymphoproliferative accelerated phase/ hemophagocytic syndrome → pancytopenia, infiltration of liver/spleen/lymph nodes Giant melanosomes and neutrophilic granules Normal melanosomes and neutrophilic granules

Chediak Higashi syndrome

Oculocutaneous albinism Bleeding diathesis (nosebleeds, ecchymoses, menorrhagia) Lysosomal accumulation of ceroid lipofuscin Granulomatous colitis Pulmonary fibrosis Cardiomyopathy Renal failure

Seen in Puerto Ricans Absence of dense bodies in platelets on EM Death by 30–50s due to pulmonary fibrosis ↑ skin cancer

Box 6.11 White Forelock Syndromes Piebaldism

Waardenburg syndrome

AD, c-KIT Defective migration of melanoblasts from neural crest Type 1-AD, PAX3 Type 2-AD, MITF Type 3-AD, PAX3 Type 4-AD, SOX10

White forelock (90%) Congenital patterned areas of leukoderma No internal sequelae White forelock (20–60%) Synophrys (monobrow) Dystopia canthorum Heterochromia irides Deafness (20–40%) Similar to WS1 but no dystopia canthorum Deafness more common Similar to WS1 Upper limb abnormalities (hypoplasia, contractures, syndactyly) Similar to WS1 Hirschsprung’s disease

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6  Pediatric Dermatology

• Triad: –– CALM—“Coast of Maine” –– Polyostotic fibrous dysplasia—usually under CALM, gait abnormality, skeletal deformity, fractures –– Endocrine dysfunction—precocious puberty, hypophosphatemic rickets, Cushing sx (b) Reticulate acropigmentation of Kitamura • ADAM10 • Japanese • Depressed reticulated hyperpigmented macules on dorsal hands, feet ± palmoplantar pits, abnormal dermatogrphyics (c) Dowling-Degos disease • • • •

Keratin 5 Onset adulthood, reticulated hyperpigmentation of axillae, groin Comedo-like lesions, pitted scars, epidermoid cysts, HS Galli-Galli Disease is variant with suprabasilar acantholysis

V. Lentigines syndromes • See Box 6.12 for hyperpigmentation

summary

of

syndromes

with

associated

Box 6.12 Lentigines Syndromes (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) LEOPARD

AD PTPN11

Lentigines on face, neck, trunk (86%) CALMS Carney AD Periorificial lentigines PRKAR1A (77%) Blue nevi (43%) Epithelioid blue nevi (specific) Cutaneous myxomas CALM Pigmented macules on Peutz-Jeghers AD lips, buccal mucosa, STK11/ digits LBK1 Cronkhite-­ Lentigines on hands, Canada feet, buccal mucosa Nail dystrophy Alopecia PTEN Penile lentigines BannayanLipomas Riley Ruvalcaba

Hypertrophic cardiomyopathy Cryptorchidism, delayed puberty Facial dysmorphism Cardiac myxomas (50–80%) Primary pigmented adrenocortical disease Sertoli cell tumor (33%) Psammomatous melanotic schwannoma GI polyps (jejunum, ileum) → intussusception Malignancy (93%)—GI > others Intestinal polyposis

Macrocephaly Developmental delay ↑ risk malignancy Intestinal polyposis

6.5 Inherited Disorders of Hair and Nails

229

VI. Hereditary dyschromatoses (a) Dyschromatosis symmetrica hereditarian • ADAR (SRAD) (AD) • Japanese, Chinese • Dyschromia on sun-exposed skin by age 6 (b) Dyschromatosis universalis hereditaria • • • •

ABCB6 (AD) Japanese Generalized or torso-predominant dyschromia Nail dystrophy, pterygium

(c) Dyskeratosis congenita • • • • • • •

TERT, TERC (AD), DKC1 (XLR) Reticulated, poikilodermatous patches on face, neck, upper torso Onychodystrophy Bone marrow failure (up to 90%) Premalignant oral leukoplakia ↑ risk heme malignancy and SCC Death (teens) from bone marrow failure, pulmonary fibrosis, malignancy (30–40s)

(d) Naegeli-Franceschetti-Jadassohn syndrome/Dermatopathia pigmentosa reticularis • Keratin 14 (AD) • NFJS: reticulate dyschromia on abdomen ± dental anomalities, onychodystrophy, PPK, adermatoglyphia • DPR: persistent reticulate dyschromia on torso, diffuse non-scarring alopecia

6.5  Inherited Disorders of Hair and Nails I. Pachynonychia congenita • 3 findings: onychodystrophy, plantar keratoderma, plantar pain • Cheilitis, pilosebaceous cysts, corneal dystrophy, hoarseness (a) Type I—Jadassohn-Lewandowski • • • • •

KRT 6a, 16 Onset late childhood/adulthood Recurrent paronychia Benign oral leukoplakia Follicular hyperkeratosis (knees, elbows, back, buttocks)

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(b) Type II—Jackson-Lawler • KRT 6b, 17 • Natal teeth • Steatocystomas • Milder keratoderma and minimal oral leukokeratosis I I. Ectodermal dysplasia (a) Hypohidrotic/anhidrotic ectodermal dysplasia • Christ-Siemens-Touraine syndrome • XLR, ED1 (ectodysplasin) • ↓ sweating, hypotrichosis, abnormal dentition (peg, conical, missing)—See Box 6.13 for other causes of peg/conical teeth • Frontal bossing • Hypohidrotic ectodermal dysplasia with immunodeficiency: XLR, IKBKG/NEMO → recurrent pyogenic, atypical mycobacterial infxn (b) Hidrotic ectodermal dyplasia • • • • •

Clouston syndrome AD, GJB6 (connexin 30) Onychodystrophy, PPK, abnormal hair Normal sweating, facial features, teeth ±cataracts, tufted distal phalanges

(c) Ectodermal dysplasias due to p63 mutations • All feature wiry/sparse hair, dystrophic nails, hypohidrosis, decreased teeth/hypoplastic enamel • Rapp-Hodgkin syndrome –– –– –– ––

Cleft lip/palate/uvula Hypoplasia of maxilla Small narrow nails Small conical teeth

• Hay-Well’s syndrome –– –– –– –– ––

Ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome Congenital ankyloblepharon Facial clefting, mid-facial hypoplasia Collodion-like peeling at birth Chronic erosive dermatitis of scalp (S. aureus)

• Ectrodactyly ectodermal dysplasia-cleft lip/palate syndrome –– –– –– ––

Ectrodactylyl (lobster claw) Facial clefting Conductive hearing loss GU anomalies

6.6 Vascular Disorders

231

Box 6.13 Causes of Peg/Conical teeth • Hypohidrotic ectodermal dysplasia • Incontinentia pigmenti • Rapp-Hodgkin syndrome (ectodermal dysplasia due to p63 mutation)

6.6  Vascular Disorders I. Vascular tumors (a) PHACE • • • •

F > M Segmental hemangioma on face/neck (V1-V3) Cerebrovascular anomalies (most common) Posterior fossa malformation, Hemangioma, Arterial anomalies, Cardiac anomalies (coarctation), Eye anomalies (cataracts), Sternal cleft or Supraumbilical raphe • MRI/MRA needed • Tx: PO propranolol (b) LUMBAR/SACRAL • Segmental hemangioma on lower back, buttocks, genitalia • Lower body hemangioma, Urogenital anomalies, Myelopathy (myelomeningocele), Bony deformities, Anorectal malformation, Renal anomalies • Spinal dysraphism, Anogenital anomalies, Cutaneous anomalies, Renal/ anal anomalies, Angioma with Lumbosacral location • MRI spine > US • Tx: consider PO propranolol (c) Neonatal hemangiomatosis • Benign: 5+ hemangiomas • Diffuse: 5+ hemangiomas with organ involvement (liver  >  GI tract, brain, eyes, spleen, kidney, lungs) • Liver failure and/or high output cardiac failure • Tx: PO propranolo (d) Kasabach-Merritt phenomenon • Tufted angioma or kaposiform hemangioendothelioma • Platelet adhesion and trapping → consumptive coagulopathy • Thrombocytopenia, consumptive coag, hypofibrinogenemia, ↑ D-dimer, DIC, hemolytic anemia • 10–30% mortality • Tx: corticosteroids, vincristine

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II. Capillary malformations (a) Port wine stain • Sporadic, GNAQ • Present at birth, do not fade • Tx: PDL • See Box 6.14 for disorders with port wine stains (b) Sturge-Weber syndrome • Aka encephalotrigeminal angiomatosis • GNAQ • Capillary malformation in V1, V2 > V3 • Ipsilateral leptomeningeal capillary malformation of brain, eye • Seizures, developmental delay, neurologic defects (tram track on head CT) • Glaucoma (see Box 6.15 for disorders associated with glaucoma) (c) Phakomatosis pigmentovascularis • Widespread capillary malformation • I: PWS + epidermal nevus • II (85%): PWS + dermal melanocytosis ± nevus anemicus • III: PWS + nevus spilus • IV: PWS + nevus spilus + dermal melanocytosis • V: CMTC + dermal melanocytosis

Box 6.14 Disorders with Port Wine Stains (Capillary Malformation) • Sturge-Weber syndrome • Klippel-Trenaunay syndrome • Parkes-Weber syndrome • Proteus • PTEN hamartoma syndromes • Cobb syndrome • Beckwith-Wiedemann syndrome • Phakomatosis pigmentovascularis • Capillary malformation-arteriovenous malformation

Box 6.15 Disorders Associated with Glaucoma • Sturge-Weber syndrome • Cutis marmorata telangiectatica congenital • Neurofibromatosis type I • Homocystinuria • Gorlin syndrome • Marfan syndrome

6.6 Vascular Disorders

233

(d) Phakomatosis pigmentokeratotica • HRAS • Nevus spilus + nevus sebaceous (trichoblastoma > SPAP > BCC) • Hypophosphatemic vitamin D-resistant rickets (e) Klippel-Trenaunay syndrome • PIK3CA • C/V/L malformation and/or bone hypertrophy over 1 limb (lower extremities—95%) • DVT, thrombophlebitis, PE, GI bleeding, high-output cardiac failure (f) Proteus syndrome • • • • • • •

AKT1 Cerebriform connective tissue nevi, epidermal nevi, CALM, lipoma C/V/L malformation Overgrowth of extremities, digits, cranium Bilateral ovarian cystadenoma Organomegaly PE, DVT

(g) Beckwith-Wiedmann syndrome • p57 (KIP2)—85% sporadic • Macrosomia/gigantism • Facial capillary malformation, macroglossia, omphalocele, linear earlobe creases • Visceromegaly • Neonatal hypoglycemia • Wilm’s tumor, rhabdomyosarcoma (h) Macrocephaly capillary malformation syndrome • • • • •

AKT3, PIK3CA, PIK3R2 Mid-face reticulated capillary malformation Contralateral hemihypertrophy, progressive neuro dysfunction Syndactyly Wilm’s tumor

III. Venous malformations • 50% with mutation in TIE2 (TEK) • MRI > ultrasound (slow-flow lesion) (a) Maffuci syndrome • • • • •

IDH1, IDH2 (isocitrate dehydrogenase) Deep venous malformations on hands/feet Enchondromas → short stature, fractures, limb length discrepancies Hemangioendotheliomas, spindle cell hemangiomas 50% risk chondrosarcoma

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6  Pediatric Dermatology

(b) Blue-rubber bleb nevus • Papules/nodules with overlying hyperhidrosis • Involve trunk/extremities, mucosa, GI tract (hemorrhage) (c) Glomulovenous malformations • GLMN (globulin) • Modified smooth muscle cells of Sucquet-Hoyer canal • Multiple, legs, asymptomatic IV. Lymphatic malformations (a) Microcystic lymphatic malformations • • • •

Lymphangioma circumscriptum One anatomic region—abdomen, axillae, mouth (tongue), genital Clusters of papulovesicles—“frog spawn” +D2–40 (podoplanin), LYVE-1

(b) Macrocystic lymphatic malformations • • • • •

“Cystic hygroma” A/w Turner, Down, Noonan syndrome Transilluminates with light +D2–40 (podoplanin), LYVE-1 Mortality from airway obstruction or pneumonia

(c) Congenital lymphedema • • • •

“Nonne-Milroy syndrome” F > M FLT4 Painless pitting edema of bilateral legs, hydrocele

V. Arteriovenous malformations • • • •

Rarest but most dangerous Abnormal communication between fast-flow shunting Palpable thrill, pulsation Cephalic (70%)

(a) Parkes-Weber syndrome • • • • • •

RASA1 Multiple fast-flow AVM/shunts Legs with soft tissue and bony hypertrophy Duplex US, MRI/MRA High output cardiac failure (see Box 6.16) Lytic bone lesions

6.7 Neurocutaneous Syndromes

235

Box 6.16 Conditions that Predispose to High Output Congestive Heart Failure • Diffuse neonatal hemangiomatosis (Cap mal) • Klippel-Trenaunay syndrome (Cap mal) • Parkes-Weber syndrome (AVM) • Kasabach-Merritt lesions

(b) Cobb syndrome • Cutaneomeningospinal angiomatosis • Spinal AVM > hemangioma + cutaneous capillary malformation on torso • Neurologic abnormalities—back pain, headache, bowel/bladder dysfunction • MRI VI. Other vascular disorders (a) CMTC • • • • •

Present at birth Legs, unilateral—atrophy/ulceration → scar ±ipsilateral hypertrophy/atrophy ±glaucoma, MR, macrocephaly, seizures Adams-Oliver syndrome: CMTC, scalp ACC, transverse limb defects

(b) Angiokeratoma corporis diffusum • Fabry, fucosidosis, GM1 gangliosidosis, sialidosis • Fabry: XLR, GLA, worl-like corneal opacities, maltese crosses, CVA

6.7  Neurocutaneous Syndromes I. Neurofibromatosis • See Box 6.17 • Almost every organ system found to be involved in NF1 • Diagnostic criteria: 2+ –– –– –– –– –– –– ––

6 cALM (>0.5 or >1.5 cm) Intertriginous freckling Plexiform NF or >2 dermal NF >2 Lisch nodules Optic glioma Skeletal dysaplasia First degree relative

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6  Pediatric Dermatology

• Cutaneous: Neurofibromas (60–90%), café-au-lait macules (>90%), axillary/inguinal freckling (80%), plexiform neurofibroma (25%) • Ocular: lisch nodules (>90%), hypertelorism (25%), glaucoma • Neurologic: learning difficulties, seizures, mental retardation • Skeletal: macrocephaly (20–50%), sphenoid wing dysplasia (80%), cortical tubers (>90%), infantile spasms (70%), mental retardation, intracranial calcification on XR or CT, giant cell astrocytoma • Ocular: Retinal hamartomas (40%), achromatic retinal patches (40%), retinal astrocytoma • Renal: Multiple bilateral angiomyolipomas (75–90%), cysts, carcinoma • Endocrine: Precocious puberty, hypothyroidism • Cardiovascular: Myocardial rhabdomyoma (80%), WPW syndrome • Dental: Pitted enamel (>90%), gingival fibromas (up to 70%) • Pulmonary: Lymphangioleiomyomatosis • TS Timeline –– Infant/child ◦◦ ◦◦ ◦◦ ◦◦

Hypomelanotic macules Cardiac rhabdomyomas Subependymal nodules Seizures

–– Prepubertal ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Angiofibromas Shagreen patch Fibrous cephalic plaque Dental pits Renal hamartomas

–– Adolescence ◦◦ Ungual fibromas –– Adulthood ◦◦ Intraoral fibromas ◦◦ Renal cysts ◦◦ Pulmonary lymphangio-leiomyomatosis (F only)

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III. Incontinentia pigmenti • XLD, NEMO—prevents activation of NF-kB • Blaschkoid pattern—streaks and whorls • Cicatricial alopecia, subungual tumors • Pegged/conical teeth (50%) • Seizures • 4 stages: • Vesicular –– Birth—1 month • Verrucous –– < 2 years • Hyperpigmented –– Up to adolescence –– May not involve previously vesicular or verrucous location • Hypopigmented –– Persists

6.8  Inherited Tumor Syndromes I. Tumor syndromes (a) Gorlin syndrome • • • • • • • • • • • • • •

AD, PTCH (↑ transcription of GLI genes) BCC (>2 or 1 before 20yo) Palmoplantar pits Odontogenic keratocysts Calcification of falx cerebri Medulloblastoma (within 3 years) Bifid/fused ribs Cleft lip/palate Macrocephaly—frontal bossing Ovarian/cardiac fibroma ↑ risk fibrosarcoma, rhabdomyosarcoma Cryptorchidism, agenesis of corpus callosum Tx: vismodegib See Box 6.18 for syndromes with multiple BCCs

6.8 Inherited Tumor Syndromes

239

Box 6.18 Syndromes with Multiple BCCs Gorlin syndrome Bazex-Dupre-Christol syndrome Rombo syndrome Brooke-Spiegler syndrome Xeroderma pigmentosum Schöpf-Schulz-Passarge

BCC, odontogenic keratocysts, bifid ribs, medulloblastoma, ovarian fibromas & fibrosarcomas BCC, follicular atrophoderma BCC, vermicular atrophoderma, trichoepitheliomas BCC, trichoepitheliomas, cylindromas BCC, SCC, melanoma BCC, hidrocystoma, eccrine syringofibroadenomas

Box 6.19 Syndromes with Renal Cell Carcinoma Familial multiple cutaneous leiomyomatosis

Birt-Hogg-Dubé

• AD, fumarate hydratase • Cutaneous & uterine leiomyomas • Leiomyosarcomas • RCC • Fibrofolliculomas, trichodiscomas, acrochordons • Lipomas • Oral fibromas • RCC • Colon cancer • Medullary thyroid carcinoma

(b) Birt-Hogg-Dubé • AD, BHD (folliculin) • Fibrobolliculomas, trichodiscomas, acrochordons → manifest 30 s and older • Renal cell carcinoma, spontaneous pneumothorax, thyroid carcinoma • See Box 6.19 for syndromes with renal cell carcinoma (c) Brooke-Spiegler Syndrome • AD, CYLD • Cylindromas, trichoepithliomas, BCC, spiradenomas • Salivary/parotic gland tumors (d) Cowden Syndrome • AD, PTEN • Sclerotic fibromas, facial tricholemmomas, punctate PPK, keratotic papules, lipomas, inverted follicular keratoses • Cobblestone of lip, oral mucosa • Follicular carcinoma of thyroid (see Box 6.20 for syndromes with thyroid carcinoma)

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Box 6.20 Syndromes with Thyroid Carcinoma MEN IIA (Sipple) MEN IIB (multiple mucosal neuroma syndrome) Birt-Hogg-Dubé Cowden syndrome Gardner syndrome

• • • • •

Medullary thyroid carcinoma Medullary thyroid carcinoma Medullary thyroid carcinoma Follicular carcinoma (most common) Papillary thyroid carcinoma

Breast adenocarcinoma, fibrocystic disease, fibroadenoma Hamartomatous polyps in GI tract Endometrial carcinoma, ovarian cysts, uterine leiomyomas Craniomegaly Lhermitte-Duclos disease—pathognomonic (dysplastic gangliocytoma of cerebellum)

(e) Gardner AD, APC Epidemoid cysts (pilomatrical), fibromas, lipomas GI polyposis—risk of adenocarcinoma (colon/rectum) Desmoid tumors Congenital hypertrophy of retinal pigment epithelium Osteomas, odontomas, supernumerary teeth, papillary thyroid carcinoma • Turcot syndrome—subset with glioblastomas, medulloblastomas • Tx: ppx colectomy • • • • • •

II. MEN Tumor syndromes (a) MEN I • • • • • • •

Wermer AD, MEN1 3 P’s Pituitary (prolatinoma) Parathyroid Pancreas Facial angiofibromas, gingival papules, hypopigmented macules, CALM (similar to TSC)

(b) MEN IIA • Sipple • AD, RET • Parathyroid hyperplasia + (~100%) + pheochromocytoma • Lichen/macular amyloidosis

medullary

thyroid

carcinoma

6.9 Disorders of DNA Repair

241

(c) MEN IIB • • • • • • •

Multiple mucosal neuroma syndrome AD, RET Mucosal neuromas on tongue, lips Marfanoid habitus Medullary thyroid carcinoma (~100%) + pheochromocytoma Conjunctival neuromas Ganglioneuromatosis in GI tract

6.9  Disorders of DNA Repair • See Box 6.21 Box 6.21 Disorders of DNA Repair Hutchinson-­ Gilford Progeria

AD, LMNA

Sclerodermatous changes Mottled pigmentation Wrinkling, hair loss, atrophy

Werner

AR, RECQL2, WRN

Sclerodermatous, atrophic change Mottled pigmentation

Xeroderma Pigmentosum

AR, XPA-XPG A, C—US A—Japan B, D, G—a/w XP-Cockayne overlap Bloom syndrome AR, BLM/ RECQL3

Rothmund-­ Thomson

AR, RECQL4

Cockayne

AR, NER

Tay/PIBIDS

AR, ERCC2 ERCC 3

↑ sun sensitivity Trichiothiodystrophy (XPB,D) 1000× ↑ risk BCC, SCC, mel Photosensitivity, malar telangiectatic erythema

Enlarged head, beaked nose High voice Atherosclerosis, CVA CV disease—death CVA/MI ↑ malignancy: fibrosarcoma, osteogenic sarcoma Neurodevelopment (20–30%)

Hypogonaism ↑ IgA, ↓IgM ↑ lymphoma, leukemia, SCC, Juvenile cataracts, skeletal dysplasia Osteosarcoma

Erythema, edema, blisters cheeks Poikiloderma Acral verrucous warts → SCC Telgangietatic erythema Cachectic dwarfism Salt/pepper retinophaty NO ↑ risk skin cancer NO pigmentary change NO ↑ skin cancer Trichoschisis, trichorrhexic nososa

Chapter 7

Dermatopharmacology

7.1  Antihistamines I. First generation antihistamines • Diphenhydramine, chlorpheniramine, cyproheptadine, hydroxyzine, doxepin • Cyproheptadine interferes with hypothalamic function—increased appetite, growth retardation in children –– Preferred antihistamine for cold and physical urticaria • Associated with anticholinergic adverse effects: dry mouth, erectile dysfunction, blurry vision, constipation, dysuria, tachycardia • Lipophilic—crosses blood brain barrier, causing sedation and impaired cognition • Metabolized via P450 II. Second generation antihistamines • • • • • • •

Fexofenadine, loratadine, desloratadine, cetirizine, levocetirizine Loratidine and cetirizine dosing must be decreased in liver and real disease Desloratadine is active metabolite of loratadine, 5× more potent Cetirizine is most sedating, long-acting High therapeutic index (minimum toxic dose/minimum therapeutic dose) Poorly lipophilic, leads to less sedation Highly selective, fewer anticholinergic side effects

© Springer Nature Switzerland AG 2020 W. W. Huang, C. S. Ahn, Clinical Manual of Dermatology, https://doi.org/10.1007/978-3-030-23940-4_7

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7.2  Retinoids • • • •

See Box 7.1 Binds cytosolic retinoid binding protein Transported to neclus Binds intracellular nuclear receptors –– RAR (α, β, ɣ) –– RXR (α, β, ɣ)

• RAR-ɣ, RXR-α = major receptors in keratinocytes –– RAR-ɣ most abundant in skin • Photoaging: ↓RXR-α, RAR-ɣ • Topical retinoids: –– ↑ s. corneum thickness, dermal collagen I, VII, hyaluronic acid, papillary dermal elastic fibers –– ↓ angiogenesis, matrix metalloproteinases –– Inhibits TLR2 –– Downregulates K6, K16 –– Inhibits ornithine decarboxylase –– Inhibits AP1, NF-IL6 –– ↑ Th1 cytokines, ↓Th2 cytokines • Adverse effects (AEs): –– Systemic retinoids ◦◦ ◦◦ ◦◦ ◦◦

Photosensitivity, exacerbation of eczema Sticky sensation of palms/soles Pseudotumor cerebri Pancreatitis 2° ↑ TG

Box 7.1 Retinoids (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) First generation

2nd generation 3rd generation

Tretinoin Alitretinoin Isotretinoin Etretinate Acitretin Adapalene Tazarotene Bexarotene

RAR RAR, RXR – – – RAR-β/ɣ > α RAR-β/ɣ > α RXR

20 h 120 days 2 days

Acne, photoaging Kaposi sarcoma Acne, gram(−) folliculitis – Psoriasis (±PUVA) Acne, photoaging Acne, plaque psoriasis CTCL

7.3 Corticosteroids

245

◦◦ Teratogen—spontaneous abortion 20%, retinoid embryopathy 18–28% • Craniofacial, CNS, CV, thymic –– Isotretinoin ◦◦ ◦◦ ◦◦ ◦◦ ◦◦

Hyperostosis Pyogenic granulomas Excessive granulation Telogen effluvium ↑ S. aureus infections

–– Bexarotene ◦◦ Central hypothyroidism—80% (↓ TSH, T4)—reversible • Start low dose levothyroxine in all patients ◦◦ ↑ TGs (avoid gemfibrozil) ◦◦ Leukopenia • Retinoid interactions –– –– –– –– ––

Fatty meal = ↑ bioavailability MTX = ↑ liver toxicity EtOH + acitretin = conversion to etretinate Tetracyclines + isotretinoin = pseudotumor cerebri Gemfibrozil + bexarotene = severe ↑ TG • ↑ LDL—Tx statin • ↑ TG—fenofibrate

7.3  Corticosteroids • See Box 7.2 for list of corticosteroids • CS binds glucocorticoid receptor in cytoplasm

Box 7.2 Corticosteroids Short-acting Medium-acting

Long acting

Cortisone Prednisone Prednisolone Methylprednisolone Triamcinolone Betamethasone Dexamethasone

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7 Dermatopharmacology

• Transports to nucleus • Binds nuclear DNA, acts as transcription factor • Cortisol-binding globulin is main carrier protein –– Bound to CBG = inactive –– Unbound = active –– Estrogen therapy, pregnancy, hyperthyroidism associated with increased CBG (less free corticosteroid) –– Hypothyroidism, liver disease, renal disease, obesity associated with decreased CBG (more free corticosteroid) • Liver converts steroids to active form –– 11β—hydroxysteroid dehydrogenase –– Liver impairment—give active form like prednisolone • ↑ IL-10 (down-regulates cell-mediated immunity) • Decreases AP1, phospholipase A1, NFkB, activity of all types of WBCs, fibroblasts, and prostaglandin production • HPA axis –– –– –– –– ––

CRH → ACTH → cortisol Suppressed by exogenous CS Seen ≥3–4 weeks ↑ risk if abrupt cessation, major stressor, divided dosing ↓ risk if QOD dosing • ∗except cataracts, osteoporosis

• Mineralocorticoid axis –– Renin-angiotensin-aldosterone –– Not suppressed • See Box 7.3 for summary of AEs of corticosteroids Box 7.3 Corticosteroid AEs Mineralocorticoid effects Lipid Pediatric Bone

GI Ocular Psychiatric Neurologic Opportunistic Muscular Skin

HTN, CHF, weight gain, hypokalemia ↑ TG, lipodystrophy (moon face, buffalo hump, central obesity) Growth impairment (↓growth hormone, IGF-1 production) Osteoporosis—greatest reduction in bone mass 1st 6 mo Postmenopausal women ↑ fracture Young men most absolute bone mass loss Osteonecrosis ≥2–3 mo, proximal femur Bowel perforation, PUD Cataracts Psychosis, hypomania, depression Pseudotumor cerebri, seizures TB, deep fungus, HSV, PCP Myopathy, muscular atrophy ↓wound healing, striae, atrophy, telangiectasias, purpura, perioral dermatitis

7.4 Systemic Immunomodulators, Cytotoxic, and Oncolytic Agents

247

7.4  S  ystemic Immunomodulators, Cytotoxic, and Oncolytic Agents I. Immunomodulators • See Box 7.4

Box 7.4 Immunomodulators

Apremilast Azathioprine

Cyclosporine

MTX

Mycophenolate mofetil

Mechanism of Action PDE4 inhibitor Purine analog

Complex with cyclophilin, inhibit calcineurin reduces NFAT-1 ↓IL-2 Prevent conversion of DHF → THF Inhibit cell division

Inhibit inosine monophosphate dehydrogenase

Indication Psoriasis, PsA AD, chronic actinic dermatitis, Behcet’s, BP, CP, DM, oral LP, PV

AEs Main AE: diarrhea, nausea Xanthine oxidase and TPMT convert into inactive metabolites ↓TPMT or XO → ↑ risk life-threatening myelosuppression Do not use with ACEI, sulfasalazine, folate antagonists Can decrease efficacy of warfarin ↑ SCC, lymphoma (NHL) ↑ risk hepatosplenic T-cell lymphoma if given with TNF-α Psoriasis, AD, HTN (tx w CCV), nephrotoxic PG ↑ NMSC HLD, hypertrichosis, gingival hyperplasia, ↑ uric acid, K, ↓ Mag Bypass inhibition of Psoriasis, dihydrofolate with leucovorin Sezary or thymidine syndrome, Pancytopenia (idiosyncratic) PLEVA, LyP, BP/PV, AICTD, No data for ↑ malignancy Phototoxicity (UV, radiation sarcoid, MF recall) ↑ risk myelosuppression with trimethoprim, sulfonamides, dapsone ↑ levels MTX with tetracycline, phenytoin, phenothiazine, sulfonamides, NSAIDs, salicylates Requires gastric acidity (do Psoriasis, AD, BP, PV, AICTD, not use with antacids, PPIs) ↑ lymphoma, vasculitis, LP, lymphoproliferative sarcoid malignancies, NMSC?

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II. Biologics • See Box 7.5 Box 7.5 Summary of Biologics TNF

Biologic Agent Etanercept Fully human dimeric fusion protein (TNF-receptor linked to Fc portion of IgG Infliximab Chimeric monoclonal IgG to TNF-α

Adalimumab

IL-­ 12/23

Ustekinumab

Guselkumab

IL-17

Secukinumab

Ixekizumab

Brodalumab

IL-1

Anakinra, Rilonacept, Canakinumab, Gavokizumab

Fully human mab IgG to TNF-R Fully human mab IgG1 to p40 (IL-12, IL-23) Fully human mab IgG1λ to p19 subunit of IL-23 Human mab IgG1 to IL-17A Human mab IgG4 to IL-17A Humanized mab IgG2 to IL-17AR IL-1 or IL-1R antagonist

MoA AEs Binds soluble Injection site and membrane-­ rxn bound TNF-α, TNF-β

Infusion rxn, Soluble and transmembrane Infliximab-­ associated TNF-R anti-drug antibodies (ADA)—may be less if used with MTX ↑ CHF risk

All a/w psoriasis, vasculitis ↑ TB, opportunistic, fungal infxns Hepatosplenic T-cell lymphoma (with azathioprine) ↑ ANA, dsDNA

Reversible posterior leukoencephalopathy sx

Prevents interaction w IL-23R

Tinea, HSV, ↑ LFTs

Prevents interaction w IL-17R

IBD exacerbation, new onset

Neutropenia, candida, IBD

Prevents interaction w IL-17 Prevents IL-1 signaling

Neutropenia, IBD, REMS for suicidal ideation Used for pyoderma gangrenosum, PAPA syndrome, HS, lamellar ichthyosis, Sweet’s syndrome, panniculitis, Muckle-Wells syndrome, SAPHO Injection site reaction Must monitor absolute neutrophil count

7.4 Systemic Immunomodulators, Cytotoxic, and Oncolytic Agents

Others Omalizumab

Rituximab

Mab to IgE

Chimeric IgG mab to CD20

↓ IgE levels ↓ IgE receptors on mast cells, basophils Depletes B cells within 2–3 weeks

249

Used for CIU Major risk is anaphylaxis

Relative contraindication in bronchospasm, hypotension, angioedema

Box 7.6 Cytotoxic Agents Mechanism of Action Hydroxyurea Impairs DNA synthesis through inhibition of ribonucleotide diphosphate reductase Cylophosphamide Alkylating agent, nitrogen mustard derivative

Chlorambucil

Alkylating agent

Indication Sickle cell anemia, CML, SCC, some melanoma Also used for Sweet’s, HES, erythromelalgia MF

CLL, NXG, PG, Behcet’s, DM

AEs Megaloblastic anemia DM-like eruption Lichenoid drug Leg ulcers Hyperpigmentation Hemorrhagic cystitis ↑ risk transitional cell carcinoma, NHL, leukemia, SCC ↑ risk infertility Pigmented band on teeth, anagen effluvium, pigmentation of skin, nails Epileptogenic

III.  Cytotoxic Agents • See Box 7.6 IV.   Oncolytic Agents • See Box 7.7 for systemic oncolytic agents • Topical treatments for actinic keratoses and non-melanoma skin cancer –– 5-fluorouracil ◦◦ Pyrimidine analog, binds to thymidylate synthase ◦◦ Treatment for AK, SCCIS, superficial BCC ◦◦ AEs: erythema, blistering, necrosis, burning –– Imiquimod ◦◦ Activates TLR7 and TLR8 to activate NF-kB transcription factor → leads to release of TNF-α and IFN-γ stimulating immune pathway

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Box 7.7 Oncolytic Agents Notes Muscle spasms #1 Alopecia, dysgeusia, fatigue, nausea, anorexia, diarrhea Metastatic Rash, lifeIpilimumab Mab to ↑ T-cell (immunomodulator) CTLA-4 activation against melanoma threatening colitis, hypothyroidism, tumor cells transaminitis, hepatitis Serine/threonine Late stage ↑ SCC, KA, BRAF Vemurafenib melanoma verrucous inhibitors → signal Dabrafenib (↑ survival) keratosis target V600E transduction Encorafenib Exanthematous kinase (MAPK mutation rash, pathway) photosensitivity, retinal vein thrombosis, QT prolongation MEK 1/2 MAPK pathway Late stage May ↓ SCC risk Trametinib melanoma with dabrafenib inhibitors (used as Binimetinib Cardiomyopathy, monotherapy or Cobimetinib retinal vein combo with occlusion, ILD dabrafenib) Late stage Fewer side effects, PD-1 Checkpoint Pembrolizumab melanoma durable responses inhibitors inhibitor Nivolumab (↑ survival) Prevent T cell Avelumab Merkel cell deactivation (avelumab) causing ↑ immune-­ mediated tumoricidal activity Melanoma, Periorbital Imatinib mesylate Tyroskine edema #1, rash, DFSP, kinase hypopigmentation mHES inhibitor MF Contact Mechlorethamine Nitrogen dermatitis #1, hydrochloride mustard SCC, alkylating anaphylaxis agent

Vismodegib (signal transduction inhibitor)

Target Smoothened receptor inhibitor

MoA Targets sonic hedgehog pathway

Indications BCC

◦◦ Also has antiangiogenic, proapoptotic factors ◦◦ Treatment for AKs, superficial BCC, perianal/genital warts ◦◦ AEs: flu-like symptoms, GI symptoms if large areas treated, exacerbation of psoriasis, erythema, blistering, discomfort

7.5 Antimicrobials

251

–– Diclofenac ◦◦ ◦◦ ◦◦ ◦◦

Decreases cyclooxygenase enzymes causing apoptosis Treatment for AKs AEs: Mild irritation, contact dermatitis Contraindicated in patients with bleeding diathesis or NSAID hypersensitivity

–– Ingenol mebutate ◦◦ Derived from sap of Euphorbia peplus (milkweed) ◦◦ Induces cell death via mitochondrial swelling and plasma membrane disruption ◦◦ Induces delayed (days later) inflammatory response via protein kinase C activation ◦◦ Treatment for AKs ◦◦ AEs: erythema, scaling, crusting

7.5  Antimicrobials I. Antibiotics • Bacteriostatic vs bactericidal (See Box 7.8) (a) Penicillins • β-lactam • MoA: inhibits peptidoglycan cross-link in cell wall → cell wall breakdown

Box 7.8 Antimicrobials Bacteriostatic Inhibits growth and replication of bacteria, allowing immune system to kill pathogen Chloramphenicol Clindamycin Erythromycin Oxazolidinones Sulfonamides Tetracyclines Trimethoprim

Bactericidal Directly kills pathogen Aminoglycosides Bacitracin Cabapenems Monobactams Penicillins Polymyxin B Quinolones Vancomycin Lipoglycoproteins

Clindamycin∗—can be either bacteriostatic or bactericidal depending on susceptibility or organism and concentration at site of infection

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• first generation –– Dicloxacillin, oxacillin • second generation –– Ampicillin, amoxicillin –– Rash with mononucleosis, allopurinol, lymphocytic leukemia • 3rd/fourth generation –– Carbenicillin, piperacillin—anti-pseudomonal • Combo β-lactam + β-lactamase inhibitor –– Good for polymicrobial—bites, diabetic foot ulcers, burn wounds • Uses: Strep, MSSA, SSSS, syphilis, erysipeloid, anthrax, Lyme, leptospirosis • Note: –– 2% cross-reaction with cephalosporin allergy –– Probenecid prolongs renal excretion, ↑ penicillin or cephalosporin levels (b) Cephalosporins • Dβ-lactam +6-membered dihydrothiazine ring • MoA—similar to penicillin • First generation –– Cefadroxil, cephalexin • Second generation –– Cefaclor, cefuroxime • Third generation –– Cefixime, cefdinir, ceftazidime, ceftriaxone –– Can use Ceftazidime for Pseudomonas • Fourth generation –– Cefepime –– Broad coverage • Fifth generation –– Ceftaroline • Note: –– 5–10% cross-reactive with penicillin allergy –– ↑ risk nephrotoxicity with aminoglycosides –– AGEP

7.5 Antimicrobials

253

–– Serum sickness-like reaction (cefaclor) –– Jarisch-Herxheimer reaction (Lyme receiving cefuroxime) –– Disulfiram-like reaction (cefotetan) (c) Vancomycin • MoA: tricyclic glycopeptide → inhibits bacterial cell wall synthesis • Note: –– –– –– ––

Red man syndrome LABD Hearing loss in renal failure ↑ nephrotoxicity with aminoglycosides

(d) Macrolides • MoA: bind 50s subunit of bacterial ribosome → ↓ protein synthesis • Erythromycin –– Uses: Lyme, erythrasma/pitted keratolysis, anthrax, erysipeloid, chancroid, LGV –– QT prolongation, GI sx, hepatotoxicity to pregnant woman –– Potent CYP3A4 → monitor warfarin, mexiletine, theophylline, statins • Azithromycin –– Uses: second line ppx in derm surgery • Clarithromycin –– Uses: atypical mycobacteria –– FDE, LCV, bitter/metallic taste (e) Fluoroquinolones • MoA: inhibit DNA gyrase (bacterial topoisomerase II ± topoisomerase IV) → DNA fragmentation • First and second generation –– Ciprofloxacin, ofloxacin, nalidixic acid –– Target only topoisomerase II • Third and fourth generation –– Levofloxacin, moxifloxacin –– Target both topoisomerase forms (II, IV) –– Uses: GN (P. aeruginosa), cutaneous anthrax (ToC) • Notes: –– GI sx #1 –– Tendinitis, tendon rupture

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7 Dermatopharmacology

–– Photo-onycholysis (lomefloxacin, enoxacin, sparlfoxacin > > Cipro)—UVA spectrum (NOT a/w levofloxacin) –– ↓ absorption with divalent cations—Ca, Mg, Al, Zn –– CYP1A2 inhibitors → caution with warfarin, theophylline, caffeine, antiarrhythmics, zileuton, β-blockers, and cyclosporine (can ↑ Cr levels) (f) Tetracyclines • MoA: bind 30s subunit of bacterial ribosome → ↓ protein synthesis, anti-­ inflammatory properties (inhibit multiple MMPs, neutrophil migrations, ↓ innate cytokines) • Uses: perioral dermatitis, rosacea, BP, CARP, sarcoid, PLEVA, acneiform eruptions 2° EGFR inhibitors, MRSA, Rickettsia, Chlamydia, Lyme • Notes: –– Excreted renally except doxy (can use in renal failure) –– ↓absorption via chelation—metallic cations Ca, Fe, Zn, Mg,Al, Bismuth –– Lipophilic (minocycline > doxycycline > tetracycline) –– Food decreases absorption –– Pseudotumor cerebri (minocycline w isotretinoin) –– Photosensitivity/photo-onycholysis (demeclocycline > doxy > tetra > mino) –– GN acne/folliculitis –– Minocycline esp. a/w: serum sickness-like reaction, Sweet’s, autoimmune hepatitis, DRESS, lupus-like syndrome (ANA+, anti-histone+), vasculitis (pANCA+) (g) Rifampin • MoA: Binds β-subunit of bacterial DNA-dependent RNA polymerase → ↓ RNA/protein synthesis • Uses: mycobacteria, leishmaniasis, Bartonella, rhinoscleroma, some GN/GP • Notes: –– Major CYP450 inducer → ↑ drug clearance/ ↓ efficacy of OCPs, warfarin, azoles, CCBs, statins, cyclosporine –– Not to be used as monotherapy—rapid resistance –– Stains body fluids orange –– Worsens porphyria (induces δ-ALA synthetase) (h) Bactrim • MoA: trimethroprim (dihydrofolate reductase inhibitor)  +  sulfamethoxazole (dihydropteroate synthetase inhibitor) → ↓ tetrahydrofolic acid → ↓ bacterial nucleic acid/protein synthesis

7.5 Antimicrobials

255

• Uses: acne, HS, granuloma inguinale, actinomycetoma, cat-scratch, chronic meliodosis • Notes: –– –– –– –– ––

Caution in renal insufficiency 30% SJS/TEN Agranulocytosis, thrombocytopenia, folate deficiency ↑ dapsone levels Worse hematologic AEs in patients on MTX

(i) Clindamycin • Lincosamide • MoA: binds 50s subunit of bacterial ribosomal RNA • Uses: GP cocci, anaerobes, deep soft tissue infections (C. perfringens, streptococcal myositis, diabetic foot ulcers) • Notes: –– D zone test—inducible resistance in erythromycin-resistant organism (erm gene) –– Abx-associated colitis (j) Others • Linezolid –– MoA: binds 23S portion of 50S ribosomal subunit of bacteria –– Used for resistant cases (skin infections including MRSA) –– Notes: myelosuppression, serotonin syndrome if given with SSRIs, MAOIs, tricyclics • Quinupristin & dalfopristin –– MoA: diffuses through bacterial wall and binds 50S ribosomal subunit –– Used in complicated skin/soft tissue infections by GP –– Potent CYP3A4 inhibitor • Daptomycin –– MoA: depolarizes bacterial cell membrane –– Complicated skin/soft tissue infections by GP • Topical antibiotics –– Used for superficial infections –– Mupirocin (Pregnancy category: B) ◦◦ Bacteriostatic (bactericidal at high concentrations) against staphylococci, streptococci (A, B, C, G), and some G– aerobic bacteria

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7 Dermatopharmacology

◦◦ MOA: derived form Pseudomonas fluorescens; inhibits protein synthesis by binding to RNA synthase –– Retapamulin (Pregnancy category: B) ◦◦ Active against S. pyogenes and MRSA ◦◦ MOA: inhibits protein synthesis by interacting with 50S ribosomal subunit –– Neomycin (Pregnancy category: C) ◦◦ Active against G+ and G– bacteria (not effective against P. aeruginosa) ◦◦ MOA: aminoglycoside that inhibits protein synthesis by binding to 30S ribosomal subunit (may also inhibit DNA polymerase) –– Gentamicin (Pregnancy category: C) ◦◦ Active against streptococci, S. aureus, and G– bacteria (including P. aeruginosa) ◦◦ MOA: aminoglycoside that inhibits protein synthesis by binding to 30S ribosomal subunit (may also inhibit DNA polymerase) –– Bacitracin (Pregnancy category: C) ◦◦ Active against G+ (staphylococci, Corynebacterium, and clostridia) ◦◦ MOA: inhibits bacterial cell wall synthesis

streptococci,

–– Polymyxin B (Pregnancy category: C) ◦◦ Bactericidal against Gram– organisms (not against G+ organisms) ◦◦ MOA: interacts with phospholipids of bacterial cell membranes increasing cellular permeability –– Silver sulfadiazine ◦◦ Indications: thermal burns ◦◦ MOA: interacts with bacterial cell wall and membranes ◦◦ AE: sensitivity in patients with hypersensitivity to sulfonamides, risk of hemolysis in patients with G6PD deficiency, localized argyria II. Antivirals • See Box 7.9 • Contraindications/Considerations: hypersensitivity, dose consideration for patients with decreased renal function • Important interactions:

7.5 Antimicrobials

257

–– Amphotericin + acyclovir → increased levels of acyclovir –– Cimetidine + valacyclovir → impaired conversion to acyclovir (increased levels of both acyclovir and valacyclovir) –– Probenecid + valacyclovir  =  impaired conversion to acyclovir (increased levels of both acyclovir and valacyclovir) –– Zidovudine + acyclovir/valacyclovir  =  increased serum levels of ­acyclovir/valacyclovir Box 7.9 Antiviral Therapy Acyclovir

Probenecid ↑ Guanosine analog (requires thymidine kinase bioavailability, ↓ renal clearance → acyclovir monophosphate) Additional human cellular GMP kinase → acyclovir triphosphate

Valacyclovir

Prodrug

HSV, varicella, herpes zoster

Penciclovir

Same as acyclovir

Famciclovir

Prodrug of penciclovir

Use for herpes labialis only Herpes zoster, recurrent genital/ orolabial herpes, recurrent HSV in HIV patients

Cidofovir

Nucleoside phosphate analog of deoxycytidine monophosphate Does not need viral thymidine kinase

Foscarnet

Bleomycin

Podophyllin and podofilox Cantharidin Sinecatechins

HPV, HSV, CMV, orf, MC, condyloma acuminate, viral-­associated trichodysplasia spinulosa Pyrophosphate analog that ToC acyclovirresistant HSV binds to viral DNA CMV retinitis polymerase Warts Binds DNA → ss breaks → ↓ protein synthesis, ↑ k’cyte apoptosis/necrosis Antimitotic, binds tubulin Genital warts → arrest in metaphase Lytta vesicatoria— Warts, MC disrupts desmosomes Camellia sinensis-derived Genital, perianal warts polyphenol epigallocatechin gallate → apoptosis, inhibition of telomerase, antioxidant

IV infusions a/w crystalline nephropathy Morbilliform eruption, SJS, urticaria, angioedema Switch to foscarnet or cidofovir in case of resistance Better bioavailability Better ↓VZV pain TTP/ HUS in HIV patients (rare) Longer 1/2 life Even better bioavailability Better ↓VZV pain Pruritus, paresthesias, headache, fatigue, vomiting, diarrhea, flatulence Nephrotoxicity #1 Neutropenia, alopecia, cardiomyopathy, iritis, metabolic acidosis, GI disturbance

Penile erosions, thrombophlebitis, nephrotoxicity, seizures Injection pain, Raynaud’s, nail dystrophy, flagellate Local, teratogen Pain, ring wart

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III.  Antifungals • See Box 7.10 for mechanisms of action • Itraconazole –– Metabolized in liver (CYP3A4) –– Indications: onychomycosis, candidiasis, blastomycosis, histoplasmosis, aspergillosis –– Contraindicated in: CHF, acute liver disase –– Do not use w/ other CYP3A4 drugs: pimozide, quinidine, cisapride –– Do not use w/: levomethadyl, dofetilide, statins, midazolam, triazolam, nisoldipine, ergot alkaloids • Fluconazole –– CYP2C9 inhibitor –– Indications: Candidiasis, cryptococcal meningitis, coccidoidal meningitis, onychomycosis –– Do not use w/: pimozide, quinidine, cisapride, erythromycin, statins, voriconazole

Box 7.10 Antifungal Mechanisms of Action Azoles • Itraconazole • Fluconazole • Ketoconazole • Voriconazole • Miconazole • Clotrimazole • Econazole • Efinaconazole • Luliconazole Allylamines • Terbinafine • Naftifine • Butenafine Griseofulvin Ciclopirox Polyenes • Nystatin • Amphotericin B Echinocandins • Caspofungin • Micafungin • Anidulafungin

Inhibit 14α demethylase (catalyzes lanosterol → ergosterol) ↓ ergosterol → ↓cell membrane synthesis → cell death

Inhibit squalene epoxidase (catalyzes squalene → lanosterol) ↓ lanosterol → ↓ cell membrane synthesis Interferes with tubulin → inhibit mitosis Disrupts fungal cell membrane transport of molecules Binds irreversibly to cell membrane sterols (ergosterol) → ↑ permeability → ↑ cell death Inhibit β-(1,3)-D-glucan synthase → ↓ glucan production → disrupt cell wall synthesis

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• Ketoconazole –– AE: High rate of hepatic toxicity (not used systemically) –– Do not use w/: cisapride, terfenadine, astemizole (↑ QT syndrome) • Voriconazole –– Indications: Invasive aspergillosis, Fusarium, Candida –– Severe phototoxicity (pseudoporphyria) –– XP-like lentigines, ↑ risk SCC, QT prolongation • Terbinafine –– Metabolized liver (CYP2D6 inhibitor) –– Indications: tinea, histoplasmosis, chromoblastomycosis, endothrix –– AE: GI #1, rash, HA, ↑ LFT, taste/smell disturbance, SJS/TEN, exacerbation of SLE, drug-induced SCLE –– Caution w/: doxepin, amitriptyline –– Use with caution in patients with liver or kidney disease –– Can prolong QT interval when used with thioridazine –– Caution with: cimetidine—increased terbinafine levels –– Caution with: rifampin—decreased terbinafine levels • Griseofulvin –– Indications: Tinea capitis (ectothrix esp) –– AE: GI#1, HA, fixed drug eruption, photosensitivity, exacerbate porphyria, SLE –– Do not use in patients with porphyrias, liver failure, pregnant women –– Caution with: warfarin—decreases levels and efficacy of warfarin –– Caution with: alcohol—potentiates disulfiram-like reaction –– Caution with: OCPs—increases estrogen-metabolizing liver enzymes, making OCPs less effective, can cause menstrual irregularities • Caspofungin –– Indications: invasive candida, aspergillus –– AE: facial swelling, ↑ alk P, ↓ K, hematuria/proteinuria • Amphotericin B –– Indications: severe fungal infections (disseminated candidiasis, cryptococcal meningitis, blastomycosis, disseminated histoplasmosis, extra cutaneous sporotrichosis, coccidioidomycosis, paracoccidioidomycosis, mucormycosis, aspergillosis) –– AE: fever, chills, nausea, vomiting, HTN, exfoliative dermatitis, FDE, flushing, urticaria

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• Caspofungin –– Indications: invasive aspergillosis in pts. refractory or intolerant to other antifungals, candidemia, esophageal candidiasis –– Caution with: cyclosporine—leads to increased caspofungin levels –– Caution with: tacrolimus—leads to decreased tacrolimus levels –– Caution with: phenytoin, rifampin, dexamethasone, carbamazepine— leads to decreased caspofungin levels –– AE: HA, N/V, fever, infusion rxns, phlebitis, flushing, facial swelling, urticaria, rashes, pruritus IV.  Antiparasitics • See Box 7.11

Box 7.11 Antiparasitics (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) Ivermectin

Albendazole

MoA Binds glutamategated Cl-channel

Stops tubulin polymerization

Thiobendazole Inhibit fumarate reductase

Permethrin

Maalathion

Spinosad

Lindane

Disables Na + transport channels → paralysis Organophosphate that inhibits ach-esterase Instigates arthropod motor neurons → paralysis Organochlorine → paralysis

Indications Onchocerciasis, scabies, cutaneous larva migrans, pediculosis Neurocysticercosis, hookworms, scabies, Giardia, Strongyloides Strongyloides, cutaneous larva migrans, trichinosis, ascariasis Scabies, pediculosis capitis

AE Mazzotti reaction— systemic sx in patients with onchocerciasis

Pediculosis capitis

Flammable Organophosphate poisoning

BM suppression, aplastic anemia, agranulocytosis Can ↑ theophylline levels Can ↑ theophylline levels Hepatotoxicity, SJS, GI

Pediculosis capitis

Scabies, pediculosis capitis

7.6  Other Miscellaneous I. Antimalarials • Hydroxychloroquine, chloroquine, quinacrine –– Can add Q to either to enhance effect

Seizures if ingested

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• MoA: –– inhibit UV-induced cutaneous rxn, –– ↓macrophage ability to express MHC complex antigens, –– impair chemotaxis, –– inhibit platelet aggregation/adhesion • HCQ/CQ have long half lives—steady state at 3–4 months • Useful in disorders with lymphocytic infiltrates –– SLE, malaria, RA, PMLE, Lupus panniculitis, discoid LE, PCT • AEs: –– Yellow pigmentation (Q) –– Drug-induced LP –– Morbilliform HS eruption –– ↑ in DM (31%) > lupus (3%) –– Psoriasis exacerbation (CQ) –– Hyperpigmentation (looks like minocycline type II) –– Nail hyperpigmentation –– Ocular toxicity (NOT in Q) II. Dapsone • MoA: –– Inhibits myeloperoxidase –– ↓oxidative damage to normal tissue in neutrophilic dermatoses –– ↓chemotaxis of neutrophils • Used for DH, leprosy –– Off-label: neutrophilic dermatoses, vasculitides • AEs –– Check G6PD –– Caution in those with significant cardiopulmonary, liver, renal disease, pre-­existing neuropathy –– Hemolytic anemia, methemoglobinemia ◦◦ Dose-dependent, occurs in all to some degree ◦◦ Cimetidine, vitamin E may protect ◦◦ Tx methylene blue –– Agranulocytosis ◦◦ Serious idiosyncratic reaction—occurs at 7  weeks, fever pharyngitis, sepsis –– Peripheral neuropathy (distal motor)

Chapter 8

Dermatologic Surgery

8.1  Anesthetics • Work by reversibly interrupting nerve conduction • Diffuse across nerve membrane, binds to sodium channel, prevents sodium influx into cell, prevents generation of action potential • Three components: aromatic, intermediate, amine –– Aromatic—lipophilic, determines potency and duration of action ◦◦ Facilitates diffusion through membrane ◦◦ Lower pKA → faster onset ◦◦ Higher lipid solubility → higher potency –– Amine—hydrophilic, determines onset of action ◦◦ Binds Na channel, prevents depolarization ◦◦ Higher protein binding → increased duration –– Intermediate—determines amide or ester • Amides: lidocaine, mepivacaine, prilocaine, etidocaine, bupivacaine –– Contraindicated in end-stage liver disease –– Metabolized through CYP 3A4 –– Longer duration, not easily hydrolyzed • Esters: procaine, benzocaine (topical), tetracaine, chloroprocaine, cocaine –– Contraindicated in renal disease –– Metabolized by plasma pseudocholinesterase –– Use with caution in myasthenia gravis, PABA allergy, pseudocholinesterase deficiency –– Shorter duration

© Springer Nature Switzerland AG 2020 W. W. Huang, C. S. Ahn, Clinical Manual of Dermatology, https://doi.org/10.1007/978-3-030-23940-4_8

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Box 8.1 Anesthetics Amides

Lidocaine Mepivacaine Prilocaine Etidocaine Bupivicaine

Esters

Procaine Benzocaine Tetracaine Cocaine

Fastest onset Anesthetic of choice in pregnancy Slowest onset Fetal bradycardia Risk of methemoglobinemia Longest duration of action Highest risk of cardiac toxicity Fetal bradycardia Shortest acting (30–90 min) Used on mucous membranes Used for ocular anesthesia Longest acting ester (240–480 min) Only vasoconstrictor

• Lidocaine dosage: –– Maximum dose adults: 5  mg/kg without epinephrine, 7  mg/kg with epinephrine –– Maximum dose children: 1.5–2 mg/kg without epinephrine, 3–4 mg/kg with epinephrine –– Tumescent anesthesia: 55 mg/kg (of 0.1%) • See Box 8.1 • Adverse reactions to anesthetics –– Vasovagal reaction ◦◦ ◦◦ ◦◦ ◦◦

Most common ↓ heart rate, ↓ blood pressure Sweating nausea Tx: cold compress, Trendelenburg

–– Epinephrine reaction ◦◦ ↑ heart rate, ↑ blood pressure ◦◦ Sweating, headache ◦◦ Tx: self-limited, propranolol –– Anaphylactic reaction ◦◦ ↑ heart rate, ↓ blood pressure ◦◦ Tx: epinephrine

8.2 Suture

265

–– Lidocaine overdose ◦◦ Early lidocaine toxicity: normal heart rate and blood pressure, circumoral/ digital paresthesia, restless, euphoria, lightheaded ◦◦ Middle lidocaine toxicity: normal heart rate and blood pressure, nausea, vomiting, twitching, tremors, slurred speech (tx: diazepam) ◦◦ Late lidocaine toxicity: ↓ heart rate and ↓ blood pressure, seizures, cardiopulmonary depression (tx: requires respiratory support)

8.2  Suture I. Suture properties • See Box 8.2 II. Suture types • Natural materials (gut, silk), degraded by proteolysis • Synthetic sutures degraded by hydrolysis Box 8.2 Suture Properties Capillarity

• Ability to wick fluid from immersed end to dry end • Multifilament have ↑ capillarity → ↑ infxn • Silk has increased capillarity Coefficient of • Numeric value assigned that quantifies how easily suture passes friction (COF) through tissue • Braided has ↑ COF, polyprolene has low COF (also translates to poorer knot security) Pliability • Ease of use of suture—translates to greater ease in creating knot • Braided has ↑ pliability Memory • Tendency to retain original configuration • Nylon and polyproline have good memory Plasticity • Ability to retain tensile strength after being stretched • Polyprolene has highest plasticity (accommodate postop swelling) Elasticity • Ability to stretch (with wound edema) and return to original length • Polybutester and poliglecaprone 25 exhibit elasticity • Polybutester, poliglecaprone-25 have ↑ plasticity (good for swollen tissues) Configuration • Monofilament: single strand, less risk of bacterial contamination, less resistance when passing through tissue, tie down easily, easier to crush/ crimp/or break • Polyfilament (braided): increased chance of harboring bacteria (capillarity), good pliability, ease of handling and good knot security Knot strength • Force required to cause knot slippage • Depends on COF and memory of suture • Polyglycolic acid has one of highest knot strengths Tissue • Inflammatory response in tissue elicited by suture reactivity • Monofilament/synthetic suture have less ractivity than polyfilament and natural suture • Surgical gut and silk have high reactivity

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(a) Absorbable • Fast-absorbing gut: 3–5 days –– Heat treated for more rapid degradation –– Can be used for facial wound closures or placement or skin grafts • Plain gut: 7–10 days (#1 tissue reactivity) • Monocryl (poliglecaprone-25): 7–10 days –– –– –– –– ––

Monofilament synthetic Pliable with good knot strength Retains 60% tensile strength at 7 days, 30% at 2 weeks Better handling and knot security than other monofilaments Relatively low tissue reactivity

• Dexon (polyglycolic acid): 14 days • Chromic gut: 21–28 days –– Treated with chromate salts to resist enzymatic degradation • Vicryl (polyglactin 910): 30–40 days –– Braided, multifilament with synthetic coating –– Low tissue reactivity • PDS (polydioxanone): 30–50 days –– Monofilament synthetic –– Easier passage through tissue, decreased tissue reactivity, decreased risk of wound infection –– Decreased handling, knot strength due to decreased COF –– Retains 70% tensile strength at 2 weeks, 50% at 4 weeks, 25% at 6 weeks –– Useful for wounds under higher tension or wounds requiring prolonged dermal support to decrease scar spreading (b) Non-absorbable • Silk: gold standard ease of handling (#2 tissue reactivity) –– Multifilament made of braided fibers of protein harvested from cocoon of silkworm larva –– Usually coated with wax or silicone –– Soft, lies flat—useful in mucosa or intertriginous areas –– High tissue reactivity and low tensile strength –– Increased potential for wound infection –– Degrades slowly over time (2 years) • Nylon –– Monofilament and polyfilament forms –– High tensile strength

8.3 Preoperative Considerations

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• Polyprolene: least inflammatory, ↓ coefficient of friction –– Monofilament synthetic –– Good tensile strength and plasticity –– Memory may compromise knot security • Ethibond (polyester): highest tensile strength, used on mucosal skin • Novafill (polybutester): high elasticity (c) Suture alternatives • Staples –– Strong with decreased risk of tissue strangulation and reactivity in comparison to suture –– Associated with higher risk of flap necrosis • Skin closure tapes –– Microporous material with acrylate adhesive –– Use for small surgical wounds with little tension • Octyl cyanoacrylate, n-butyl-2-cyanoacrylate –– Adhesive used to close superficial lacerations or incisions –– Polymerizes in 2–5 min, giving wound strength equivalent to 5–0 nylon suture or subcuticular absorbable suture

8.3  Preoperative Considerations I. Sterilization (a) Steam autoclave • • • •

Most commonly used in office setting (easiest, safest) High pressure, high temperature Cannot use with heat-sensitive plastics Corrosive (dulls instruments)

(b) Chemical autoclave • • • •

Uses heated chemical vapor Mix of formaldehyde, methyl ethyl ketone, acetone, alcohol Less dulling of instruments Requires protective gear and ventilation due to chemical use

(c) Dry heat • Inexpensive • No corrosion or dulling but cannot be used for paper, cloth, or plastic • Requires high temperature and longer times

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(d) Gas • • • •

Use ethylene oxide or formaldehyde Used mostly in hospital setting—expensive but good for large volume Effective for heat-sensitive and moisture-sensitive instruments Gas is toxic and mutagenic

(e) Cold/chemical immersion • • • •

Immersion in glutaraldehyde or aqueous formaldehyde Not always effective against spores, hepatitis B Can cause contact dermatitis Not considered adequate as single metod for sterilizing surgical instruments

II. Antiseptic agents • See Box 8.3 Box 8.3 Antiseptic Agents (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) Alcohol

Chlorhexidine

Chloroxylenol

Hexachlorophene

Iodine/Iodophors

Quaternary ammonium (Benzalkonium) Triclosan

Flammable Fastest onset of action Optimal strength 70% alcohol Broad spectrum Inactive against spores, protozoan oocysts Disrupts cell membranes #1 overall (avoid around eyes/ears) Rapid onset of action Broad spectrum Inactive against spores Causes ototoxicity, keratitis, conjunctivitis Deactives enzymes, Ineffective against pseudomonas unless alters cell walls combined with EDTA Slow onset Inactivates enzymes Not used—Neurotoxic, teratogenic Slow onset Effective only against staphylococcus Irritation, inactivated by blood and Oxidation disrupts protein synthesis and cell sputum Rapid onset of action membranes Broad spectrum Induces leaks in Used in eyedrops cytoplasm membranes Inactivated by organic materials and cotton gauze Slow onset Not as effective Alters cytoplasmic membrane and synthesis Binds enoyl acyl carrier protein reductase in bacteria of RNA, fatty acids, Rapid onset of action proteins Denatures cell walls (100% alcohol less effective than 70%)

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Box 8.4 Electrical Hemostasis (Adapted from Alikhan A, Hocker TLH. Review of Dermatology, 1st Ed. Elsevier. 2017) Electrodessication Electrofulgaration Electrocoagulation Electrosection Electrocautery

Voltage Hi Hi Low Low –

Amperage Low Low Hi Hi –

Waveform Markedly damped Markedly damped Moderately damped Undamped None

Terminal Mono Mono Bi Bi

III. Electrosurgery • Electrical hemostasis—caution should be utilized with any implantable device • ICDs more sensitive than pacemakers • Relatively safet o use biterminal with forceps • Electrosection associated with highest risk (avoid) • See Box 8.4 IV. Preoperative considerations • Preoperative evaluation: –– Discuss bleeding tendencies, anticoagulant use, history of hypertension, alcohol use, smoking/nicotine use, diabetes

8.4  Cryosurgery, Excision, Flaps, and Grafts I. Cryosurgery • Application of low temperature causing cellular injury, sloughing of damaged tissue → subsequent healing • Boiling point of liquid nitrogen: −196 °C • Hand-held unit used with spray-tip accessory or closed cryoprobe (contact therapy) • Cell death for melanocytes: −5 °C • Cell death for keratinocytes: −25° to −30 °C • Cell death for fibroblasts: −35 to 40 °C • Mechanism of action via intracellular ice crystal formation and membrane rupture • Freezing tissue (direct effect) –– Extracellular dehydration: ice crystal formation in extracellular space causes extracellular hyperosmotic gradient that dehydrates adjacent cells

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–– Membrane rupture: occurs with continued freezing, causing intracellular ice crystal formation –– Vasoconstriction: due to initial freezing, causes further damage through anoxia –– Vasodilation: after thawing, compensatory vasodilation raises harmful free radicals into affected tissue • Cooling • Thawing—should be slow • Optimal action is rapid freezing and slow thawing (factors intracellular ice formation) • Maximum destructive effects achieved with repeated freeze-thaw cycles • Indicated for actinic keratosies, actinic cheilitis, lentigo maligna, SCCIS (Bowen’s disease), erythroplasia of Queyrat, multiple benign lesions/ conditions II. Excisions • Designed to remove lesion for histopathologic examination and surgical cure • Margin of normal-appearing skin taken and depth of excision depend on diagnosis Shape of excision is fusiform—optimal angle at apices varies 30–75°, length should be 3× width to minimize standing cone formation • M-plasty: used to shorten length of excision, ideal near free margins • S-plasty: increases total length of scar, redistributes tension along vectors, good for convex surfaces (forearm, shin) and excision crossing over joint (elbow, knee) • Margins: –– –– –– –– –– –– –– ––

BCC—typical margins 3–4 mm, 6–10 mm for high risk SCC—typical margins 3–4 mm, 6 mm or Mohs for high risk Atypical nevi—3–4 mm DFSP—2–3 cm extending to fascia Melanoma in situ—5 mm Malignant melanoma, Breslow 2 mm–2 cm to fascia

III. Flaps (a) Flap components • See Box 8.5 (b) Axial • • • •

Flaps based on named vessel = most reliable Paramedian forehead → supratrochlear Dorsal nasal rotation (Rieger) → angular Abbe cross-lip → labial

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Box 8.5 Flap Components (Adapted from Bolognia JL, Schaffer JV, Cerroni. Dermatology, 4th Ed. Elsevier. 2018) Flap body Pedicle Primary defect Secondary defect Primary movement Secondary movement Primary tension vector Secondary tension vector Burow’s triangle Primary Burow’s triangle Secondary Burow’s triangle Subunit

Skin being advanced, transposed, rotated, interpolated or imported into the primary defect Vascular base of the flap that maintains vascularization in the early post-op period Area deficient in skin that will be reconstructed by movement of body (i.e. wound that requires closure) Area devoid of skin created by movement of body of flap (i.e. wound resulting from closure of primary defect) Movement of flap body into defect Tissue movement necessary to close donor site defect Direction of force counteracting movement of body Direction of force created by closure of donor site defect Dog-ear or standing cone Redundant skin removed as wounds are closed Standing cone directly connected to primary defect Standing cone connected to secondary defect Surface area demarcated by either natural or arbitrary lines that have unique textural, cosmetic, or functional features

(c) Random pattern • Unnamed musculocutaneous arteries • ↑ portion of flap perfused by anastomotic subdermal and dermal vascular plexuses (d) Advancement flaps • Random-pattern flaps where primary flap movement is LINEAR, provides least mobility • Examples: unilateral Burow’s triangle, O-U advancement, bilateral A-T and O-T advancement, bilateral O-H advancement, island pedicle (V-Y) (e) Rotation flaps • Random or axial-pattern flap where donor tissue pivots in curved or arc-like motion • Examples: unilateral rotation, unilateral Rieger variant (axial using angular artery), unilateral Mustarde/Tenzel variant, bilateral O-Z

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(f) Transposition flaps • Either rotation or advancement flap where donor tissue is nearby but not directly adjacent to defect, thus must move across and over intervening segment of normal skin to close defect • Examples: rhombic transposition flap, bilobe transposition flap, Banner transposition flap, nasolabial/melolabial transposition flap, Z-plasty (g) Interpolation flaps • Subset of transposition flap used for larger defects, usually requires 2 stages separated by 3 weeks • Examples: paramedial forehead, Abbe lip switch, nasolabial/melolabial, retroauricular flap IV. Grafts (a) Graft types • Full-thickness skin graft (FTSG) –– Contains entire epidermis and full thickness dermis (includes adnexal structures) –– Good tissue matching –– High nutritional and vascularity requirement (higher rate of graft failure) –– Less contraction • Split-thickness skin graft (STSG) –– Full-thickness epidermis and partial dermis –– low nutritional and vascularity requirement –– High contraction with poor adnexal function • Composite graft –– Composed of at least 2 different tissues (skin, cartilage) –– High nutritional and very high vascular requirements • Free cartilage graft –– Cartilage with overlying perichondrium –– Moderate nutritional and high vascularity requirements (b) Stages of graft • Imbibition –– –– –– –– ––

24–48 h Fibrin attaches graft to bed Passive diffusion of nutrients from plasma exudate of wound bed Edematous, gains up to 40% weight Fibrin replaced by granulation tissue with attaches graft permanently to bed

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• Inosculation –– 48–72 h –– Lasts 7–10 days –– Revascularization linking dermal vessels between graft and recipient wound bed • Neovascularization –– Day 7 –– Partly occurs during inosculation –– Capillary and lymphatic ingrowth (revascularization)—should be complete by day 7 • Reinnervation/maturation –– 2–4 weeks –– Graft reinnervation and (partial) return of sensory nerve function V. Surgical complications (a) Wound healing considerations • • • • • •

Factors that contribute to decreased vascular supply: cigarette smoking Hematoma/seroma, infection, mechanical shear forces Diabetes Protein deprivation Severe trace element or vitamin deficiencies Systemic medications: corticosteroids, chemotherapeutics, immunosuppressive drugs, anticoagulants

(b) Short-term • Dehiscence (due to tension, hematoma formation, poor wound healing, or infection) • Pain • Infection (2 weeks

Edema, bruising, erythema, nodularity, vaso-occlusion Edema, lymphedema, persistent bruising, nodules (Tyndall effect) Infection, inflammatory nodules, granuloma formation

9.3 Chemical Peels

9.3  Chemical Peels I. Superficial depth peels • Targets epidermis to papillary dermis • TCA (5–25%) –– –– –– ––

Does not require neutralizer No frost—indicates depth to stratum corneum Irregular light frost—indicates depth to superficial epidermis Uniform frost with pink—indicates full thickness epidermis

• Jessner’s solution –– Resorcinol, salicylic acid, lactic acid, 95% ethanol –– Resorcinol can cause syncope and thyroid suppression • Salicylic acid –– –– –– –– ––

Typically 20–30% concentration Does not need neutralizer—β hydroxy acid peel Used for comedonal acne Contraindicated in pregnancy, breastfeeding, allergy to aspirin Salicylism characterized by nausea, disorientation, tinnitus

• Alpha hydroxy acid peels –– Glycolic acid, lactic acid –– No frosting observed –– Glycolic acid requires neutralizer with sodium bicarbonate II. Medium depth peels • Targets papillary to upper reticular dermis III. Deep peels • Targets reticular dermis • Phenol –– Nephrotoxic, cardiotoxic –– Requires fluid hydration before and after peel –– Cardiac monitoring during peel • Baker Gordon peel –– Phenol, septisol, croton oil –– Septisol (triclosan) and croton oil enhance penetration of phenol

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9.4  Sclerotherapy • • • •

Use of sclerosant causes endothelial damage and fibrosis of vein Compression after sclerotherapy facilitates fibrosis Deep venous system: femoral and popliteal vein Superficial venous system: small saphenous vein, great saphenous vein –– Connected to deep system via perforator veins

• Lateral source—most common source of telangiectasias • Hyperosmotic agents: dehydrate, damage endothelial cells • Detergents: induce injury by altering surface tension around endothelial cells –– Examples: sodium morrhuate, ethanolamine—both can produce severe necrosis, higher risk of allergic reactions • Chemical irritants: induce injury via corrosive action • Foaming can decrease treatments and increase efficacy in treatment of larger veins • Contraindications: sapheno-femoral reflux, sapheno-popliteal reflux, history of DVT, pregnancy –– Duplex ultrasound gold standard imaging modality for reflux –– Doppler ultrasound can assess veins to depth of 2 cm • FDA-approved agents: sodium morrhuate, sodium tetradecyl sulfate • Others: hypertonic saline, chromated glycerin, polyiodinated iodine, ethanolamine oleate, polidocanol • See Box 9.4

Box 9.4 Sclerotherapy Agents Osmotic agents Hypertonic saline Detergents

Chemical agents

Sodium tetradecyl sulfate Polidocanol

Sodium morrhuate Ethanolamine oleate Glycerin Polyiodide iodine

Most painful, associated with cramping, necrosis Highest risk for hyperpigmentation Disulfiram-like reaction Overall well-tolerated (less pain, necrosis, hyperpigmentation) Highest risk for anaphylaxis Acute renal failure, Lowest risk for hyperpigmentation but weak agent Anaphylaxis, iodinine hypersensitivity

9.5 Hair Transplantation

281

9.5  Hair Transplantation • Usually >25 follicular units/cm2 transferred • Two methods: –– Strip—taken from occipital scalp, removes 100 follicular units/cm2 –– Follicular—punch removal, each unit has 2–3 hair shafts ◦◦ Preferred method in patients with short hair, risk of scar, and younger patients • Post-transplant telogen effluvium • New hair growth 10–20 weeks post-surgery • Overall effect observed at 6–9 months

Index

A Absorbable sutures, 266 Absorption spectrum, 20 Acne cosmetica, 54 Acne excoriee, 146 Acne keloidalis, 60 Acne mechanica, 56 Acne variants, 55 Acne vulgaris, 53–56 Acquired elastotic hemangiomas, 149 Acquired generalized lipodystrophy, 120–121 Acral persistent papular mucinosis, 129 Acrodermatitis enteropathica, 144 Actinic keratosis, 157 Actinic prurigo, 147 Actinomycosis, 187 Action spectrum, 20 Acute cutaneous lupus (ACLE), 63 Acute intermittent porphyria, 138 Acute porphyrias, 138–145 Acyclovir, 257 Adalimumab, 248 Adams-Oliver syndrome, 214 Adenoid cystic carcinoma, 166 Adnexal glands, biology of, 11–12 Adnexal neoplasms follicular neoplasms, 163–170 sebaceous neoplasms, 163–170 sweat gland neoplasms, 163–170 Adnexal structures, 2 Adult-Onset Still Disease, 74 Aicardi-Goutières syndrome, 65 ALA-D deficiency porphyria, 138 Alezzandrini syndrome, 95 Allergic contact dermatitis, 36, 40–42 Alopecia areata, 90, 91

Amyloidosis, 128–134 Anacardiaceae family, 41 Anagen, 15 Anakinra, 248 Androgenetic alopecia, 89, 90 Angiokeratoma corporis diffusum, 235 Angiosarcoma, 176 Anhidrotic ectodermal dysplasia, 230 Animal-related gram-negative infections, 191 Annular elastolytic giant cell granuloma, 109 Annular lipoatrophy, 121 Anthrax, 186 Antibiotics, 251 bactrim, 254 cephalosporins, 252, 253 clindamycin, 255 daptomycin, 255 fluoroquinolones, 253, 254 linezolid, 255 macrolides, 253 penicillins, 251, 252 quinupristin & dalfopristin, 255 rifampin, 254 tetracyclines, 254 topical, 255–256 vancomycin, 253 Antifungals amphotericin B, 259 caspofungin, 259, 260 fluconazole, 258 griseofulvin, 259 itraconazole, 258 ketoconazole, 259 mechanisms of action, 258 terbinafine, 259 voriconazole, 259

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284 Antihistamines, 243 Anti-inflammatory effects, 21 Antimalarials, 260, 261 Antimicrobial peptides, 24 Antimicrobials, 251 Antiparasitics, 260 Antiphospholipid syndrome (APLS), 100, 102 Antiseptic agents, 268 α1-Antitrypsin deficiency panniculitis, 124 Antiviral, 256 therapy, 257 Aphthous stomatitis, 117–118 Aplasia cutis congenita, 214 Apocrine glands, 3, 11–13 Apremilast, 247 Asteatotic eczema, 36 Asteraceae family, 41, 42 Atopic dermatitis, 31–35 Atrophic connective tissue panniculitis, 121 Atypical fibroxanthoma, 173 Autoimmune connective tissue disease, 139 Avelumab, 250 B Bacterial infections atypical mycobacteria, 198 Bartonella infections, 188 Borrelial infections, 193 Corynebacterial infections, 185 cutaneous tuberculosis, 195 diseases from flea, mite, louse, and tick vectors, 193–194 filamentous bacteria, 187 gram-negative infections, 188–191 leprosy, 195–197 non-syphilis treponemes, 192 polymicrobial and gram-positive infections, 183–186 Pseudomonas infections, 187 Rickettsia infections, 188 staphylococcal infections, 183 streptococcal infections, 183, 184 syphilis, 192 Bacterial venereal infections, 194, 195 Balloon cell nevus, 159 Barraquer-Simons syndrome, see Acquired partial lipodystrophy syndrome Bart syndrome, 214 Bartonella infections, 188 Bart-Pumphrey syndrome, 224 Basal keratinocyte, 8 Base excision repair, 21

Index Basement membrane, biology of, 7–9 BCC, 18, 158 B cells, 28 Becker’s melanosis, 158 Beckwith-Wiedmann syndrome, 233 Behçet’s disease, 104 Benign cephalic histiocytosis, 110 Benign keratinocytic neoplasms, 155 epidermal nevus, 156 Flegel disease, 157 nevus comedonicus, 156 seborrheic keratosis, 155 Warty dyskeratoma, 157 Benign nodular calcification, 140 Benign vascular lesions, 174, 176 Bexarotene, 245 Binimetinib, 250 Biologic agents, 248 Birt-Hogg-Dubé syndrome, 239 Bleomycin, 257 Blistering disorders dermatitis herpetiformis, 78–86 epidermolysis bullosa, 87–88 linear IgA bullous dermatosis, 86–87 pemphigoid, 78–88 pemphigus, 78–89 Blisters, causes of, 89 Blue vitiligo, 95 Blue-rubber bleb nevus, 234 Body dysmorphic disorder, 145 Borrelial infections, 193 Botulinum toxin, 276–279 Bowel-associated dermatosis-arthritis syndrome, 104 Bowen’s disease, 157 Branchial cleft cyst, 155 Brodalumab, 248 Bronchogenic cyst, 154 Brooke-Spiegler syndrome, 239 Bullous pemphigoid, 82–84 C Calciphylaxis, 140 Calcium oxalate, 39 Canakinumab, 248 Candida folliculitis, 58 Cantharidin, 257 Carcinogenesis, 17–19 Carvajal syndrome, 223 Catagen, 15 Cellulitis, 186 Central centrifugal cicatricial alopecia, 92

Index Cheilitis glandularis, 118 Chemical burn, 117 Chemical irritant dermatitis, 39, 40 Chemical peels, 279 Chilblain lupus, 65 CHILD syndrome, 220 Childhood flexural comedones, 56 Chloracne, 56 Chlorambucil, 249 Chronic actinic dermatitis, 148 Chronic cutaneous lupus erythematosus variants, 62 Cidofovir, 257 Clostridium, 186 Clouston syndrome, 224 CMTC, 235 Cobb syndrome, 235 Cobimetinib, 250 Collagen, 9 processing, 10 of skin, 10 Colloid milium, 149 Comèl-Netherton syndrome, 220 Common acquired nevi, 159 Complement deficiency, 25 Complement proteins, 23 Composite graft, 272 Congenital atrichia with papules, 91 Congenital dermal melanocytosis, 158 Congenital erythropoietic porphyria (CEP), 137 Congenital ichthyosiform erythroderma (CIE), 218 Congenital infections associated with extramedullary hematopoiesis, 214 congenital candidiasis, 216 congenital HSV, 216 congenital syphilis, 215, 216 congenital varicella, 216 viral exanthems, 215, 217 Congenital lymphedema, 234 Congenital nevus, 158 Connective tissue disorders dermatomyositis, 65–78 lichen sclerosus, 61–73 lupus erythematosus, 61–65 morphea, 61–73 rheumatologic disorders and autoinflammatory diseases, 74–77 systemic sclerosis, 61–78 Conradi-Hünermann-Happle syndrome, 220 Corneal envelope defects, 218

285 Corynebacterial infections, 185 Cosmetic dermatology aging and skin, 275 botulinum toxin, 276–279 chemical peels, 276–279 dermal fillers, 276–278 hair transplantation, 281 sclerotherapy, 279–280 Cowden syndrome, 239 Cryosurgery, 269–270 Cutaneous hematolymphoid neoplasms cutaneous T cell lymphomas, 177–180 leukemia cutis, 181 primary cutaneous B-cell lymphoma, 180 Cutaneous mucinosis of infancy, 129 Cutaneous neoplasms, pathogenesis of, 17–19 Cutaneous small vessel vasculitis (CSVV), 99 Cutaneous T cell lymphomas, 177–180 Cutaneous tuberculosis, 195 Cutis rhomboidalis nuchae, 149 Cylindroma, 163 Cylophosphamide, 249 Cysts, 153–158 Cytokines, 24, 25 Cytophagic histiocytic panniculitis, 128 Cytotoxic agents, 249 D Dabrafenib, 250 Dapsone, 261, 262 Deep peels, 279 Degos disease, 102 Demodex folliculitis, 58 Depigmentation, 96 Depositional and metabolic disorders, 128–145 amyloidosis, 128–145 calcifying and ossifying disorders, of skin, 128–145 mucinoses, 128–145 nutritional diseases, 128–145 porphyria, 135–145 Dermal duct tumor, 164 Dermal fillers adverse events, 278 autologous fat, 277 calcium hydroxyapatite, 277 hyaluronic acid, 277 poly-L-lactic acid, 277 polymethylacrylate, 277 Dermatitis artefacta, 146 Dermatitis herpetiformis, 78–86

286 Dermatofibroma, 172, 173 Dermatofibrosarcoma protuberans, 173 Dermatologic surgery absorbable sutures, 265–266 adhesives, 267 advancement flaps, 271 anesthetics, 263–264 axial flaps, 270 cryosurgery, 269–270 excisions, 270 flap components, 270, 271 grafts, 272–273 interpolation flaps, 272 long-term complications, 273 non-absorbable sutures, 266 preoperative considerations, 267–269 antiseptic agents, 268 electrosurgery, 269 sterilization, 267–268 random-pattern flaps, 271 rotation flaps, 271 short-term complications, 273 skin closure tapes, 267 staples, 267 suture properties, 265 synthetic sutures, 265 transposition flaps, 272 wound healing considerations, 273 Dermatomyositis, 65–78 antibodies, 66 variants, 68 Dermatopathia pigmentosa reticularis, 229 Dermatopharmacology antibiotics (see Antibiotics) antifungals (see Antifungals) antihistamines, 243 antimalarials, 260, 261 antimicrobials, 251 antiparasitics, 260 antivirals, 256 biologic agents, 248 corticosteroids, 245–246 cytotoxic agents, 249 dapsone, 261, 262 immunomodulators, 247 oncolytic agents, 249–250 retinoids, 243–244 Dermatophyte folliculitis, 58 Dermatophytoses, 199–203 Dermis and subcutaneous tissue, 1, 2 Dermo-epidermal junction, 2 ultrastructural subregion components, 8 Dermoid cyst, 153

Index Desmoplastic trichoepithelioma, 167 Desquamative gingivitis, 116 Diclofenac, 251 Discoid lupus erythematosus (DLE), 62 Discrete papular lichen myxedematosus, 129 Disorders of cornification ichthyoses (see Ichthyoses) keratodermas, 222–226 Disorders of pigmentation hereditary dyschromatoses, 229 hyperpigmentation, 226, 228 Lentigines syndromes, 228 oculocutaneous albinism, 226 silvery hair syndromes, 226, 227 White forelock syndromes, 226, 227 Dissecting cellulitis, 92 Disseminate and recurrent infundibulofolliculitis, 59 Disseminated superficial actinic porokeratosis, 156 DNA repair, disorders of, 241 Dowling-Degos disease, 228 DRESS, 152 Drug-induced acne, 54 Drug-induced pemphigus, 81 Drug-induced psoriasis, 44 Drug-induced SCLE, 64 Drug-induced SLE, 64 Drug-induced solar urticaria, 148 Drug reactions acute generalized exanthematous pustulosis, 152 DRESS, 152 erythema multiforme, 150–152 Stevens-Johnson syndrome/toxic epidermal necrolysis, 150–151 Drug-related gingival hyperplasia, 117 Dyschromatosis symmetrica hereditarian, 229 Dyschromatosis universalis hereditaria, 229 Dyskeratosis congenita, 229 Dystrophic calcification, 139–140 E Eccrine glands, 3, 11, 12 Ectodermal dysplasia, 230 due to p63 mutations, 5, 230 Ectrodactyly ectodermal dysplasia-cleft lip/ palate syndrome, 230 Eczema, asteatotic, 36 Eczematous dermatoses, 31–42 allergic contact dermatitis, 36 asteatotic eczema, 36

Index atopic dermatitis, 31–35 irritant dermatitis, 37 nummular dermatitis, 36 plant dermatoses, 116 seborrheic dermatitis, 35–36 Eczematous disorders, regional, 36 Elastic fibers, 9–10 Electrical hemostasis, 269 Electrosurgery, 269 Embryology adnexal structures, 2 dermis and subcutaneous tissue, 1, 2 dermo-epidermal junction, 2 epidermis, 1 Encorafenib, 250 Endemic treponematoses, see Non-syphilis treponemes Eosinophilic dermatoses, 105–106 Eosinophilic folliculitis, 59–61 Eosinophilic pustular folliculitis, of infancy, 59 Eosinophilic ulcer of oral mucosa, 118 Eosinophils, 26 Ephelides, 149 Epidermal hyperplasia, 21 Epidermal nevus, 156 Epidermis, 1 benign and malignant tumors of benign keratinocytic neoplasms, 153–158 cysts, 153–158 premalignant/malignant keratinocytic neoplasms, 153–158 cells of, 5–7 granules in, 4 Epidermoid inclusion cyst, 153 Epidermolysis bullosa, 78–88 Epidermolytic ichthyosis, 218 Erdheim-Chester disease, 114 Erosive gingivostomatitis, see Desquamative gingivitis Erosive pustular dermatosis, 149 Eruptive disseminated porokeratosis, 156 Erysipeloid, 186 Erythema dyschromicum perstans, 53 Erythema induratum, 125 Erythema multiforme, 41, 150–152 Erythema nodosum, 124 Erythema toxicum neonatorum, 213 Erythematotelangiectatic rosacea, 57 Erythrasma, 185 Erythrokeratoderma, 218, 221, 222 variabilis, 221

287 Erythropoietic protoporphyria (EPP), 136 Essential fatty acid deficiency, 143 Etanercept, 248 Eulanin fibers, 10 Excoriation disorder, 146 Exogen, 15 Extracellular matrix, 9–11 Extrafibrillar matrix, 10 F Famciclovir, 257 Familial Mediterranean fever, 134 Favre-Racouchot syndrome, 149 Felty syndrome, 77 Fibroblastic proliferations, 173, 174 Fibrofolliculoma, 168 Fibroma, 117 Fibrous histiocytoma, see Dermatofibroma Filamentous bacteria, 187 Fissured tongue, 116 Fixed solar urticaria, 148 Flaps, 270–272 Flegel disease, 157 5-Fluorouracil, 249 Follicular and apocrine diseases acne vulgaris, 53–56 folliculitis and follicular disorders, 58–61 rosacea, 53–58 Follicular mucinosis, 131 Folliculitis eosinophilic, 59 infundibulofolliculitis, 59 superficial, 58–59 Foscarnet, 257 Free cartilage graft, 272 Full-thickness skin graft (FTSG), 272 Fungal infections dermatophytoses, 199–203 opportunistic systemic mycoses, 203, 204 subcutaneous mycoses, 202 superficial mycoses, 199–202 systemic (dimorphic) mycoses, 203 G Galli-Galli disease, 228 Gardner syndrome, 240 Gavokizumab, 248 Generalized eruptive histiocytoma, 111 Generalized Myxedema, 130 Geographic tongue, 115 Giant cell reticulohistiocytoma, 113

288 Glaucoma, 232 Glochids, 39 Glogau Photoaging Scale, 275 Glomulovenous malformations, 234 Gorlin syndrome, 238 Gram-negative folliculitis, 58 Granular parakeratosis, 49 Granuloma annulare, 107–109 Granuloma faciale, 105 Granulomatous disorders annular elastolytic giant cell granuloma, 109 granuloma annulare, 107–109 necrobiosis lipoidica, 110 sarcoidosis, 107–109 Granulomatous rosacea, 57 Gunther disease, see Congenital erythropoietic porphyria (CEP) Guselkumab, 248 H Haber’s syndrome, 58 Hair cycle, 15 Hair diseases alopecia areata, 90, 91 androgenetic alopecia, 89, 90 non-scarring alopecias, 91, 92 scarring alopecia, 89–93 telogen effluvium, 90 trichotillomania, 91 Hair follicle anatomy, 14–15 Hair follicle development, 13 Hair follicle morphogenesis, stages of, 14 Hair follicle nevus, 166 Hair shaft abnormalities, 93 Hair transplantation, 281 Hairy tongue, 116 Halo nevus, 159 Harlequin ichthyosis, 218 Hay-Well’s syndrome, 230 Hematoma-associated retiform purpura, 103 Heme biosynthetic pathway, 135 Hemodialysis-associated amyloidosis, 134 Hepatoerythropoietic porphyria (HEP), 137 Hereditary coproporphyria, 138 Hereditary dyschromatoses, 229 Hereditary progressive mucinous histiocytosis, 114 Herpes simplex folliculitis, 58 Herpetiform pemphigus, 80 Hidradenitis suppurativa, 60, 61 Hidradenoma, 164, 165

Index Hidradenoma papilliferum (HPAP), 165 Hidroacanthoma simplex, 164 Hidrocystoma, 154 Hidrotic ectodermal dysplasia, 224, 230 High-grade vascular lesions, 174–176 H. influenza cellulitis, 190 Histiocytosis indeterminate, 115 Langerhans cell, 110 non-Langerhans cell, 110–115 HIV/AIDS dermatology, 206–210 HIV/ART-associated lipodystrophy, 122–128 HIV-associated eosinophilic pustular folliculitis, 59 Hot tub folliculitis, 58 Howel-Evans syndrome, 223 HPV infections, 203–206 HSV infections, 206 Hydroa vacciniforme, 147 Hydroxyurea, 249 Hydroxyurea-associated vascular occlusion, 102 Hypereosinophilic syndromes, 106 Hyperlipoproteinemias, 122, 123 Hyperpigmentation, 226, 228 Hyperpigmentation disorders, 96, 97 Hyperpigmented macules, 161 Hypervitaminosis D, 141 Hypochromic vitiligo, 95 Hypohidrotic ectodermal dysplasia, 230 Hypopigmentation, 96 Hypotrichosis simplex of the scalp, 134 I Iatrogenic calcification, 141 Ichthyoses, 218 erythrokeratodermas, 221, 222 non-syndromic, 218, 219 syndromic, 220, 221 Ichthyosis en confetti, 220 Ichthyosis hystrix Curth-Macklin, 220 Ichthyosis vulgaris, 218 Idiopathic calcification, 141 Idiopathic facial aseptic granuloma, 56 Idiopathic guttate hypomelanosis, 149 IgA pemphigus, 81 Imatinib mesylate, 250 Imiquimod, 249 Immunoglobulins, 27 Immunologically-mediated photodermatoses, 146–148 Immunologic contact urticaria, 38

Index Immunomodulators, 247 Incontinentia pigmenti, 235–238 Infantile acne, 214 Infection-induced panniculitis, 127 Infectious dermatoses, 209 Inflammatory dermatoses, 208, 209 Inflammatory vitiligo, 95 Infliximab, 248 Infundibulofolliculitis, 59 Ingenol mebutate, 251 Inherited amyloidosis, 134 Innate immunology, 23–26 Interferon-associated cutaneous necrosis, 103 Intermediate vascular lesions, 175–177 Involutional lipoatrophy, 121 Ipilimumab, 250 Irritant contact dermatitis (ICD), subtypes, 38 Isotretinoin, 245 Ixekizumab, 248 J Jackson-Lawler syndrome, 223, 230 Jadassohn-Lewandowski syndrome, 223, 229 Juvenile xanthogranuloma, 110 K KA, 158 Kabuki syndrome, 95 Kaposi sarcoma, 175 Kaposiform hemangioendothelioma, 175 Kasabach-Merritt phenomenon, 231 Keratin defects, 218 Keratin intermediate filaments, 6 Keratinocyte cell junctions, 6 Keratinocytes, 5 Keratitis-ichthyosis-deafness (KID) syndrome, 221 Keratodermas, 222 diffuse PPKs, 223, 225 focal PPKs, 223, 225 Keratosis lichenoides chronica, 53 Keratosis pilaris atrophicans, 59 Klippel-Trenaunay syndrome, 233 Kwashiorkor’s, 142 L Lamellar ichthyosis, 218 Lamina densa, 8 Lamina lucida, 8 Langerhans cell histiocytosis, 110, 111

289 Langerhans cells, 7, 27 Large vessel vasculitides, 101 Large vessel vasculitis, 98 Lawrence syndrome, see Acquired generalized lipodystrophy Leishmaniasis, 211, 212 Lentigines syndromes, 228 Leprosy, 195–197 Leser-Trelat sign, 155 Leukemia cutis, 181 Lichen amyloidosis, 132 Lichen myxedematosus, 129 Lichen nitidus, 53 Lichenoid dermatoses erythema dyschromicum perstans, 53 keratosis lichenoides chronica, 53 lichen nitidus, 53 lichen planus, 50–52 lichen striatus, 52 Lichen planopilaris, 92 Lichen planus, 50–52 Lichen sclerosus, 73 Lichen spinulosus, 59 Lichen striatus, 52 Linear IgA bullous dermatosis, 86–89 Linear porokeratosis, 156 Lipedematous alopecia, 91 Lipid disorders lipodystrophies, 119–128 panniculitis, 119–128 xanthomas, 119–128 Lipoatrophia semicircularis, 121 Lipodermatosclerosis, 127 Lipodystrophia centrifugalis abdominalis infantilis, 121 Lipodystrophies acquired, 120–122 characterization, 119 congenital/familial, 119–121 HIV/ART-associated, 122–128 Lipoproteins, 123 Listeria infection, 186 Livedoid vasculopathy, 102 Lobular panniculitis, 139 Localized lichen myxedematosus in HIV-infected patients, 129 in “toxic” syndromes, 129 Localized lipoatrophy, 121 Lucio phenomenon, 197 Lumbar/sacral syndrome, 231 Lupus erythematosus tumidus, 64 Lupus panniculitis, 65, 126 Lupus profundus, 65

290 M Macrocephaly capillary malformation syndrome, 233 Macrocystic lymphatic malformations, 234 Macular amyloidosis, 132 Maffuci syndrome, 233 Majocchi granuloma, 58 Mal de Meleda, 224 Malakoplakia, 190 Malassezia (Pityrosporum) folliculitis, 58 Malignant atrophic papulosis, 102 Malnutrition, 142 Marasmus, 142 Mast cells, 26 McCune-Albright syndrome, 226 Mechanical irritant dermatitis, 39 Mechlorethamine hydrochloride, 250 Median raphe cyst, 155 Median rhomboid glossitis, 116 Medium depth peels, 279 Medium vessel vasculitides, 100, 101 Medium vessel vasculitis, 98 Melanocytes, 6, 16 Melanocytic neoplasms melanoma, 158–161 nevi, 158–163 Melanoma, 18–19 management, 160 mutations, 159 pathogenesis, 159–160 staging, 160, 162 systemic therapies, 162 MEN tumor syndromes, 240, 241 Menkes disease, 144 Merkel cells, 7 Metastatic calcification, 140–141 MHC, 29 Microcystic adnexal carcinoma, 163 Microcystic lymphatic malformations, 234 Microfibrils, 9 Milk-Alkali syndrome, 141 Mixed connective tissue disease, 76 Mononuclear phagocytes, 25 Morbihan’s disease, 57 Morphea, 61–73 Morphea/scleroderma panniculitis, 124 Morsicatio buccarum, 117 MTX, 247 Mucinoses associated with altered thyroid function, 130 follicular mucinosis, 131 lichen myxedematosus, 129

Index papulonodular mucinosis, 131 reticular erythematous mucinosis, 131 scleredema, 130 scleromyxedema, 128 self-healing cutaneous mucinosis, 129 urticaria-like follicular mucinosis, 131 Muckle-Wells syndrome, 134 Mucocele, 118 Mucous membrane pemphigoid, 84–89 Multicentric reticulohistiocytosis, 113 Multiple mucosal neuroma syndrome, 241 Mycophenolate mofetil, 247 Mycosis fungoides, 177–178 Myiasis, 210 N Naegeli-Franceschetti-Jadassohn syndrome, 229 Nail anatomy, 15 Nail disorders, 93, 94 Natural killer (NK) cells, 24 Naxos disease, 224 Necrobiosis lipoidica, 110 Necrobiotic xanthogranuloma, 113 Necrotizing fasciitis, 186 Necrotizing sialometaplasia, 118 Necrotizing ulcerative gingivitis, 116 Neisseria meningitidis, 188 Neonatal cephalic pustulosis (neonatal acne), 214 Neonatal hemangiomatosis, 231 Neonatal lupus erythematosus (NLE), 65 Neoplasms, 209 Neural tumors, 170, 171 Neurocutaneous syndromes incontinentia pigmenti, 235–238 neurofibromatosis, 235–236 tuberous sclerosis, 237–238 Neurofibromatosis, 235–236 Neurotoxins, 277 See also Botulinum toxin Neutrophilic dermatoses, 103–105 Behçet’s disease, 104 bowel-associated dermatosis-arthritis syndrome, 104 pyoderma gangrenosum, 103–104 SAPHO syndrome, 104, 105 Sweet syndrome, 103 Neutrophils, 26 Nevus comedonicus, 156 Nevus of Ito, 158 Nevus of Ota, 158

Index Nevus sebaceous, 169 Nevus spilus, 159 Newborn vs. adult skin, 2 Nivolumab, 250 Nocardiosis, 187 Nodular amyloidosis, 133 Nodular lichen myxedematosus, 129 Non-absorbable sutures, 266 Non-acute porphyrias, 136–137 Non-infectious granulomas, 108 Non-Langerhans cell histiocytosis, 110–115 Non-scarring alopecias, 91, 92 Non-syndromic ichthyoses, 218, 219 Non-syphilis treponemes, 192 Nucleotide excision repair (NER), 21 Nummular dermatitis, 36 Nutritional diseases, 128–145 O Occupational acne, 54 Ocular rosacea, 57 Oculocutaneous albinism (OCA), 226 Ofuji disease, 59 Omalizumab, 249 Omphalomesenteric duct cyst, 155 Oncogenes, 18 Oncolytic agents, 247–250 Onychomycosis, 200, 201 Opportunistic systemic mycoses, 203, 204 Ossifying disorders, 141 Oxytalan fibers, 10 P Pachynonychia congenita, 229–230 Pancreatic panniculitis, 125 Panniculitis, 119–128 of dermatomyositis, 126 lobular, 139 Papillary dermis, 9 Papillary digital carcinoma, 166 Papillary eccrine adenoma, 166 Papillon-Lefevre syndrome, 224 Papular xanthoma, 114 Papuloerythroderma of Ofuji, 105 Papulonodular mucinosis associated with autoimmune connective tissue disease, 131 Papulopustular rosacea, 57 Papulosquamous dermatoses granular parakeratosis, 49, 50 pityriasis lichenoides, 48, 49

291 pityriasis rosea, 49 pityriasis rotunda, 49 pityriasis rubra pilaris, 47 psoriasis, 42–47 Papulosquamous lesions, 44 Paraneoplastic pemphigus, 81 Parasitic infections, 210 Parkes-Weber syndrome, 234 Partington amyloidosis, 134 Pediatric dermatology congenital infections, 214–216 DNA repair, disorders of, 241 inherited disorders disorders of cornification, 218–225 disorders of pigmentation, 226–229 of hair and nails, 229–231 inherited tumor syndromes, 238–241 neurocutaneous syndromes, 235–238 newborn injuries, 213 newborn rashes, 213–214 vascular disorders, 231–235 Peg/conical teeth causes, 231 Pembrolizumab, 250 Pemphigoid variants, 83 Pemphigus erythematosus, 80 Pemphigus foliaceus, 80 Pemphigus vegetans, 80 Pemphigus vulgaris, 79 Penciclovir, 257 Periodontal disease, 115–116 Periorificial dermatitis, 57 PHACE syndrome, 231 Phakomatosis pigmentokeratotica, 233 Phakomatosis pigmentovascularis, 232 Photoaging, 21 in darker skin types, 149 in fair-skinned patients, 149 Photocarcinogenesis, 21, 150 Photodermatoses, 146–150 Phrynoderma, 60 Phymatous rosacea, 57 Phytophotodermatitis, 40 Piedra, 201 Pigment darkening, 21 Pigmentation disorders, 116 Pilar cyst, see Trichilemmal cyst Pilomatrical carcinoma, 169 Pilomatricoma, 167 Pitted keratolysis, 185 Pityriasis folliculorum, 58 Pityriasis lichenoides, 48, 49 Pityriasis rosea, 49 Pityriasis rotunda, 49

292 Pityriasis rubra pilaris, 47 Pityriasis versicolor, 201 Pityrosporum folliculitis, 202 Plant dermatoses, 116 PMLE, 146 Podofilox, 257 Podophyllin, 257 Poikiloderma of Civatte, 149 Polymicrobial and gram-positive infections, 186 Pomade acne, 54 Porocarcinoma, 165 Porokeratosis of Mibelli, 156 Porokeratosis palmaris, plantaris, et disseminate (PPPD), 156 Porokeratosis ptychotropica, 156 Poroma, 164 Porphyria cutanea tarda (PCT), 136 Porphyrias, 135 acute, 138–145 non-acute, 136–145 pseudoporphyria, 137 Port wine stains, disorders with, 232 Post-steroid panniculitis, 126 Premalignant/malignant keratinocytic neoplasms, 153–158 Pretibial myxedema, 130 Primary cutaneous amyloidosis, 132–133 Primary cutaneous B-cell lymphoma, 180 Primary systemic amyloidosis, 132, 133 Progressive nodular histiocytoma, 114 Progressive symmetric erythrokeratoderma, 221 Pro-inflammatory effects, 21 Proliferating pilar tumor, 169 Proliferating trichilemmal cyst, 154 Protein contact dermatitis, 39 Proteus syndrome, 233 Protothecosis, 210 Protozoan infections, 210–212 PRP, clinical subtypes of, 48 Pseudoacne of nasal crease, 56 Pseudocyst of the auricle, 155 Pseudofolliculitis barbae, 60 Pseudomonas infections, 187 Pseudoporphyria, 137 Psoriasiform alopecia, 91 Psoriasis associated systemic manifestations, 42 biologic treatments, 47 clinical variants, 44, 45 drug-induced, 44 histopathology, 44 immunologic factors, 43 moderate-severe, 43

Index treatment, 46, 47 trigger factors, 44 Psoriatic arthritis, 46 variants, 44 Psychocutaneous disorders, primary, 145 acne excoriee, 146 body dysmorphic disorder, 145 delusions of parasitosis, 145 dermatitis artefacta, 146 excoriation disorder, 146 trichotillomania, 146 Punctate porokeratosis, 156 Pustular psoriasis, 45 Pyoderma gangrenosum, 103–104 R Radiation acne, 56 Rapp-Hodgkin syndrome, 230 Refsum disease, 220 Regional eczematous disorders, 36 Relapsing polychondritis, 75 Reticular dermis, 9 Reticular erythematous mucinosis, 131 Reticulate acropigmentation of Kitamura, 228 Retinoids, 244 Rheumatoid arthritis, 77 skin findings, 77 Rhinoscleroma, 190 Rhinosporidiosis, 210 Richner-Hanhart syndrome, 223 Rickettsia infections, 188 Rilonacept, 248 Rituximab, 249 Rosacea, 56–58 conglobata, 57 fulminans, 57 Rosaceiform dermatitis, 58 Rosai-Dorfman disease, 113 S Sabra dermatitis, 39 Salivary gland diseases, 118 Salmonellosis, 190 SAPHO syndrome, 104, 105 Sarcoidosis, 107–109 variants, 109 Scabies, 210 Scarring alopecia, 92–93 SCC, 18, 157 SCLE drug-induced, 64 syndromes, 63 Scleredema, 130

Index Sclerema neonatorum, 125, 213 Scleromyxedema, 128 Sclerotherapy, 279–280 Sea-blue histiocyte syndrome, 115 Sebaceoma, 170 Sebaceous adenoma, 170 Sebaceous carcinoma, 170 Sebaceous glands, 2, 12 Sebaceous hyperplasia, 169 Seborrheic dermatitis, 35–42 Seborrheic keratosis, 155 Secondary amyloidosis, 133 Secondary systemic amyloidosis, 134 Secukinumab, 248 Self-healing cutaneous mucinosis, 129 Senear-Usher syndrome, 80 Sezary syndrome, 178 Silvery hair syndromes, 226, 227 Sinecatechins, 257 Sipple syndrome (MEN2A), 134, 240 Sjögren-Larsson syndrome, 220 Sjögren’s syndrome, 75, 76, 118 Skin pigmentation, determinants of, 7 SLE, drug-induced, 64 Small vessel vasculitides, 100 Small vessel vasculitis, 97, 98 Smooth muscle neoplasms, 172 Sneddon syndrome, 102 Soft tissue tumors, 170–174 Solar (actinic) elastosis, 149 Solar lentigo, 149 Solar purpura, 149 Solar urticaria, 148 Spiradenocarcinoma, 164 Spiradenoma, 163 Split-thickness skin graft (STSG), 272 Staphylococcal infections, 183 Steatocystoma, 154 Stevens-Johnson syndrome, 150–151 Stratum basale, 4 Stratum corneum, 4 Stratum granulosum, 4 Stratum lucidum, 4 Stratum spinulosum, 4 Streptococcal infections, 183, 184 Sturge-Weber syndrome, 232 Subacute cutaneous lupus erythematosus (SCLE), 63 Subacute nodular migratory panniculitis, 124 Subcutaneous fat necrosis, 213 of newborn, 125 Subcutaneous mycoses, 202 Sublamina densa, 8 Sunburn, 21 Sun exposures, effects of, 20

293 Superficial depth peels, 279 Superficial epidermolytic ichthyosis, 218 Superficial folliculitis, 58–59 Superficial mycoses, 199–202 Sweat gland neoplasms adenoid cystic carcinoma, 166 cylindroma, 163 dermal duct tumor, 164 hidradenoma, 164, 165 hidradenoma papilliferum, 165 hidroacanthoma simplex, 164 microcystic adnexal carcinoma, 163 papillary digital carcinoma, 166 porocarcinoma, 165 poroma, 164 spiradenocarcinoma, 164 spiradenoma, 163 syringocystadenoma papilliferum, 165 syringofibroadenoma, 165 syringoma, 163 tubular apocrine adenoma/papillary eccrine adenoma, 166 Sweet syndrome, 103 Syndromic ichthyoses, 220, 221 Syphilis, 183–192 Syringocystadenoma papilliferum (SPAP), 165 Syringofibroadenoma, 165 Syringoma, 163 Systemic (dimorphic) mycoses, 203 Systemic retinoids, 244 Systemic sclerosis, 61–78 Systemic-Onset juvenile idiopathic arthritis, 74 T T cell, 28 subtypes, 29 Telogen, 15 effluvium, 90 Temporal triangular alopecia, 91 Th1 and Th2 disease states, 30 Thyroglossal duct cyst, 155 Tinea barbae, 200 Tinea capitis, 200 Tinea corporis, 199 Tinea cruris, 199 Tinea faciei, 200 Tinea manuum, 200 Tinea nigra, 201 Tinea pedis, 200 Tinea unguium, 200, 201 Toll-like receptors, 24, 26 Tongue, benign conditions of, 115 Toxic epidermal necrolysis, 150–151

294 Toxin-mediated (non-immunologic) contact urticaria, 39 Traction alopecia, 93 Trametinib, 250 Transient neonatal pustular melanosis, 213 Traumatic panniculitis, 127 Traumatic ulcer, 117 Treatment-associated dermatoses, 209, 210 Trichilemmal cyst, 153 Trichilemmoma, 168 Trichoadenoma, 168 Trichoblastoma, 167 Trichodiscoma, 168 Trichoepithelioma, 167 Trichofolliculoma, 167 Trichomes, 39 Trichomycosis axillaris, 185 Trichothiodystrophy, 220 Trichotillomania, 91, 146 Trichrome vitiligo, 95 Tropical acne, 56 Trypanosomiasis, 211 Tuberous sclerosis, 235–238 Tubular apocrine adenoma, 166 Tumor biology and pathways, 16–19 Tumor of follicular infundibulum, 168 Tumor suppressors, 18 Tungiasis, 210 Turcot syndrome, 240

Index angiokeratoma corporis diffusum, 235 arteriovenous malformations, 234–235 capillary malformations, 231–235 CMTC, 235 lymphatic malformations, 234 vascular tumors, 231–235 venous malformations, 231–234 Vascular neoplasms, 174–177 Vascular occlusion syndromes, 100–103 Vasculitis, 98 cutaneous small vessel, 99 small and medium, 100 Vellus hair cyst, 154 Vemurafenib, 250 Verrucous carcinoma, 157 Viral exanthems, 217 Viral infections HPV, 203–206 HSV, 206 Poxviruses, 206, 208 Vismodegib, 250 Vitamin D3 synthesis, 21 Vitiligo, 95–96 Vogt-Koyanagi-Harada syndrome, 95 Vohwinkel syndrome, 223 Vörner type PPK, 223

U Unna-Thost PPK, 223 Urticaria-like follicular mucinosis, 131 Ustekinumab, 248 UV light, 20

W Warty dyskeratoma, 157 Wells syndrome, 105, 106 Wermer syndrome, 240 White forelock syndromes, 226, 227 Wilson disease, 145 Wound healing, 19–20

V Valacyclovir, 257 Variegate porphyria, 138 Vascular biology, 16–17 Vascular diseases, 97–103 Vascular disorders, pediatric

X Xanthoma disseminatum, 114 Xanthomas, 119–128 X-linked dominant protoporphyria, 137 X-linked recessive ichthyosis, 218 X-linked reticulate pigmentary disorder, 134