Dermatopathology Primer of Cutaneous Tumors

Dermatopathology Primer of Cutaneous Tumors

Omar P. Sangueza, MD Parisa Mansoori, MD Professor of Dermatology Visiting Fellow in Dermatopathology Wake Forest University School of Medicine and Pathology Winston-Salem, North Carolina, USA Director of Dermatopathology Saleha A. Aldawsari, MD Wake Forest University Visiting Fellow in Dermatopathology Health Sciences Department of Pathology Winston-Salem, North Carolina, Wake Forest University School of Medicine USA Winston-Salem, North Carolina, USA Amir Al-Dabagh, MD Visiting Fellow in Dermatology Department of Dermatology Wake Forest University School of Medicine Sara Moradi Tuchayi, MD, MPH Winston-Salem, North Carolina, USA Research Fellow Department of Dermatology Amany A Fathaddin, MD Wake Forest University School of Medicine Visiting Fellow in Dermatopathology Winston-Salem, North Carolina, Wake Forest University School of Medicine USA Winston-Salem, North Carolina, USA Steven R. Feldman, MD, PhD Professor of Dermatology and Pathology Wake Forest University Health Sciences Winston-Salem, North Carolina, USA

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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com 3.1.4 Pilar sheath acanthoma 37 Contents 3.1.5 Tumor of the follicular Acknowledgements 7 infundibulum 38 Introduction 9 3.2 Sebaceous tumors 1 Tumors of the Epidermis 3.2.1 Benign neoplasms 1.1 Benign tumors 3.2.1.1 Sebaceous hyperplasia 39 1.1.1 Epidermal proliferations 3.2.1.2 Sebaceoma 40 1.1.1.1 Epidermal nevus 10 3.2.1.3 Sebaceous adenoma 41 1.1.1.2 Clear cell acanthoma 11 3.2.2 Malignant tumors 1.1.2 Warts and variants 3.2.2.1 Sebaceous carcinoma 42 1.1.2.1 Viral warts 12 3.3 Sweat gland neoplasms 1.1.2.2 Trichilemmoma 13 3.3.1 Benign neoplasms 1.1.2.3 Inverted follicular keratosis 14 3.3.1.1 Apocrine adenoma 43 1.1.2.4 Solar lentigo 15 3.3.1.2 Syringocystadenoma 1.1.2.5 Seborrheic keratosis 16 papilliferum 44 1.1.2.6 Warty dyskeratoma 17 3.3.1.3 Hidradenoma 45 1.2 Malignant tumors 3.3.1.4 Cylindroma 46 1.2.1 Basal cell carcinoma and variants 3.3.1.5 Apocrine hidrocystoma 47 1.2.1.1 Basal cell carcinoma and 3.3.1.6 Mixed tumor 48 variants 18 3.3.1.7 Spiradenoma 49 1.2.2 Squamous cell carcinoma and 3.3.1.8 Syringoma 50 variants 3.3.1.9 Poroma 51 1.2.2.1 Bowen’s disease 20 3.3.2 Malignant tumors 1.2.2.2 Keratoacanthoma 21 3.3.2.1 Adenoid cystic carcinoma 52 1.2.2.3 Squamous cell carcinoma 22 3.3.2.2 Microcystic adnexal carcinoma 53 3.3.2.3 Extramammary Paget’s disease 54 2 Melanocytic Neoplasms 3.3.2.4 Hidradenocarcinoma 55 2.1 Benign neoplasms 3.3.2.5 Porocarcinoma 56 2.1.1 Lentigo simplex 24 2.1.2 Melanocytic nevi 25 4 Tumors of Fibrous Tissue 2.1.3 Halo nevus 26 4.1 Benign tumors 2.1.4 Spitz nevus 27 4.1.1 Nodular fasciitis 57 2.1.5 Blue nevus 28 4.1.2 Dermatofibroma 58 2.2 Malignant lesions 4.1.3 Superficial fibromatosis 59 2.2.1 Malignant melanoma and variants 31 4.2 Malignant tumors 4.2.1 Fibrosarcomas 60 3 Tumors of Cutaneous Appendages 4.2.2 Dermatofibrosarcoma 3.1 Hair follicle tumors protuberans 61 3.1.1 Trichoepithelioma 33 4.2.3 Atypical fibroxanthoma 62 3.1.2 Trichoblastoma 35 3.1.3 Trichofolliculoma 36 5 Tumors of Fat 9 Cutaneous Cysts 5.1 Lipoma 63 9.1 Epidermoid cyst 91 5.2 Angiolipoma 64 9.2 Pilar cyst 92 5.3 Nevus lipomatosus superficialis 65 9.3 Dermoid cyst 93 9.4 Steatocystoma 94 6 Tumors of Smooth Muscle 9.5 Bronchogenic cyst 95 6.1 Benign neoplasms 9.6 Cutaneous ciliated cyst 96 6.1.1 Leiomyoma 66 9.4 Median raphe cyst 97 6.2 Malignant tumors 6.2.1 Leiomyosarcoma 67 10 Cutaneous Metastases 10.1 Cutaneous metastases 98 7 Neural Tumors 7.1 Nerve sheath tumors 11 Cutaneous Infiltrates: Non Lymphoid 7.1.1 Neurofibroma 68 11.1 Mast cell infiltrates 7.1.2 Schwannoma 69 11.1.1 Mastocytosis 100 7.1.3 Perineurioma 71 11.2 Histiocytic infiltrates 7.1.4 Palisaded and encapsulated 11.2.1 Juvenile xanthogranuloma 102 neuromas 72 11.2.2 Xanthomas 103 7.1.5 Cutaneous ganglioneuroma 73 11.2.3 Langerhans cell histiocytosis 104 7.1.6 Nasal glioma 74 11.3 Neuroendocrine infiltrates 7.1.7 Cutaneous meningioma 75 11.3.1 Merkel cell carcinoma 105 7.1.8 Granular cell tumor 76 12 Cutaneous Infiltrates: Lymphoid and 8 Vascular Tumors Leukemic 8.1 Hyperplasias 12.1 Pseudolymphomas 8.1.1 Pyogenic granuloma 77 12.1.1 Cutaneous pseudolymphomas 106 8.2 Benign neoplasms 12.2 Cutaneous lymphomas 8.2.1 Infantile hemangiomas 78 12.2.1 T-cell lymphomas 107 8.2.2 Cherry angiomas 79 12.2.2 Primary cutaneous CD30+ T-cell 8.2.3 Arteriovenous hemangioma 80 lymphoproliferative disorders 109 8.2.4 Microvenular hemangioma 81 12.2.3 B-cell lymphomas 110 8.2.5 Tufted angioma 82 12.3 Leukemic and miscellaneous infiltrates 8.2.6 Glomeruloid hemangioma 84 12.3.1 Leukemia cutis 111 8.2.7 Acquired elastotic hemangioma 85 References 112 8.2.8 Kaposiform hemangioendothelioma 86 Glossary of Terms 121 8.2.9 Glomus tumor and glomangioma 87 8.3 Malignant tumors 8.3.1 Kaposi sarcoma 88 8.3.2 Angiosarcoma 90 Acknowledgements

The second volume of Dermatopathology Primer is a complement to the first volume on inflammatory disease. This volume was produced in collaboration with many of the international fellows of the Section of Dermatopathology of the Wake Forest University School of Medicine.

We want to thank especially Professor Luis Requena from the Department of Dermatology of the Universidad Autonoma de Madrid for allowing us to use some of his wonderful material.

We also thank Mr. Charles P. Sangueza for his help in editing and critically reviewing many chapters of this manuscript.

7

Introduction

The second volume of the Dermatopathology Primer series deals with neoplastic diseases of the skin. This volume is a complement the first volume on inflammatory diseases.

As we noted in the first volume, the intent of these books is to introduce the basic concepts of dermatopathology to medical students and residents training in pathology and dermatology.

The book is organized into chapters discussing the differentiation of various neoplasms. These include cysts, epidermal, melanocytic lymphoid, and soft tissue neoplasms, both benign and malignant. For each neoplasm we have used illustrations and discussion demonstrating the most characteristic features. In addition, we have also included illustrations of the entities that enter in the differential diagnosis. Because of space limitations and the limited scope of the book, variations of the different neoplasms are not included. For further information the reader is encourage to consult any of several standard books of dermatopathology.

We hope that this book will fulfill the expectations of students beginning the study of dermatopathology.

9 TUMORS OF THE EPIDERMIS bENigN tumors • EpidErmal prolifEratioNs Epidemiology Epidermal nevus • Occurs in 1 in 1000 live births Introduction • 80% of lesions appear Epidermal nevus is a term that encompasses hamartomatous proliferations within the first year of of epithelium that originate from embryonal ectoderm. They are classified on life, with the majority the basis of the main histologic component: keratinocytes (epidermal nevus), of lesions appearing sebaceous gland (nevus sebaceous), pilosebaceous unit (nevus comedonicus), by age 14. There are eccrine gland (eccrine nevus), or apocrine gland (apocrine nevus). rare reports of epidermal nevi appearing in adults Histological • Mostly sporadic, however, some familial 2 cases have been documented Features 1. Acanthosis 1 Pathophysiology 2. Papillomatosis • Genetic mosaicism is thought to be the 3. Hyperkeratosis underlying cause, likely a postzygotic 4. Hyperpigmentation of the 4 somatic mutation basal layer may be seen • The mutation affects pluripotential cells giv- 5. Thickening of the granular ing rise to hamartomas of different cell lines layer Special Studies • Extensive epidermal nevi require further 3 work up. These patients require a complete examination, including the eyes, in order to 5 rule out cataracts and optic nerve hypoplasia; and neuroimaging and cardiac studies to rule out aneurysms and patent ductus arteriosus Clinical Features EpidErmal NEvus • The characteristic epidermal nevus presents as a linear, hyperpigmented, papillomatous plaque that can vary from pink to black, Histological velvety to verrucous, flat to thick, and can involve small or extensive areas of the skin Differential • The lesions are usually asymptomatic 1. Seborrheic keratosis: • The inflammatory linear verrucous • Well-circumscribed epidermal nevi (ILVEN) variant is pruritic neoplasm composed of and may be erythematous or scaly basaloid cells • The lesions are more common on the trunk • Basket weave orthokeratosis or extremities along the Blaschko lines, but • Horn pseudocysts may also occur on the face and neck • Approximately one-third of the patients develop the so-called epidermal nevus sEborrhEic KEratosis syndrome (ENS), an entity in where there is involvement of other systems including Important Things To Know the nervous, cardiovascular, urogenital, and/or skeletal • Neoplasms such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and keratoacanthoma are not usually associated with epidermal nevi Clinical Variants • Malignancy in epidermal nevus, when it does occur, develops after • The inflammatory linear verrucous epi- puberty dermal nevi (ILVEN) • Epidermal nevus syndrome (ENS) 10 clEar cEll acaNthoma (dEgos acaNthoma, palE cEll acaNthoma) Introduction Clear cell acanthoma (CCA) is a benign epidermal neoplasm composed of keratinocytes with ample pale cytoplasm and centrally placed nuclei. It consists EpidemiologyEpidemiology of a well-demarcated, solitary, shiny, and brown to orange papule or nodule. • • Middle-aged; mostly after the age of 40 Histological features • Male-to-female ratio is 1:1 1. Well-circumscribed lesions composed of uniform pale keratinocytes Pathophysiology 2. Distinct transition between the normal epidermis and the paler cells • It is unclear whether CCA is a 3. Parakeratosis with variable number of neutrophils true neoplasm or an inflammatory 4. Neutrophils are scattered within the acanthoma dermatosis 5. Absence of granular layer and epidermal melanin 6. Suprapapillary plate thinning, sparing of adnexal epidermis and dilated tortuous dermal blood vessels in the papillary dermis Clinical features • Solitary, slow-growing, well- demarcated, erythematous to brown 3 5 papule or nodule with moist eroded 6 surface. In some cases a collarette 1 of scale is present and produces a psoriasiform appearance 4 • The lesions are asymptomatic and slow 2 growing • Affects most commonly the legs, but it can be also seen on the thigh, face, Clear cell acanthoma forearm, trunk, and inguinal region • Almost completely blanches with pressure Histological differential • Size: 0.3–2 cm (giant clear cell acanthoma >5 cm) 1. Psoriasis vulgaris: 2. Trichilemmoma: • No clear cells with distinct • Neutrophils absent Special studies transition between the normal • Outlined by a thick eosinophilic epidermis and the clearer/paler basement membrane • Keratinocytes in the epidermis are cells in the epidermis • Peripheral palisading glycogen rich and stain with periodic • Numerous squamous eddies acid-Schiff, diastase labile

Important things to know • The clinical features can be confused with pyogenic granuloma and Clinical Variants seborrheic keratosis • None 11 bENigN tumors • Warts aNd variaNts viral Warts (vErrucaE) Introduction Verrucae are lesions caused by human papillomavirus (HPV), which produces various types of warts on different parts of the skin. Epidemiology Histological features 1. Exophytic neoplasm with finger-like projections; compact hyperkeratosis, • Verruca occurs predominantly in papillomatosis, hypergranulosis and acanthosis; inward turning of the children and adolescents although adults elongated rete ridges at the edge of the lesion are also frequently affected 2. Parakeratosis at the tips of the projections 3. Dilated blood vessels in papillary dermis Pathophysiology 4. Large vacuolated cells with small pyknotic nucleus (koilocytes) • Most verrucae vulgaris are induced • Flat warts or verruca plana show prominent hypergranulosis. The cytoplasm by HPV-2. Palmoplantar warts are of the cells shows blue-gray inclusions associated with HPV-1 or HPV-4 • Palmoplantar warts or myrmecia warts show red cytoplasmic inclusions infection. Verruca plana is associated • Epidermodysplasia verruciformis characterized by large cells with with HPV-3 and HPV-10 conspicuous perinuclear halo. The cytoplasm, which is blue-gray, contains • Epidermodysplasia verruciformis is a rare keratohyalin granules autosomal recessive genodermatosis due to mutation EVER1/TMC6 or EVER2/ TMC8 genes. Warts induced by different 2 types of HPV 1 • In condylomas, HPV-6 and 11 are most 3 commonly identified and are sexually 4 transmitted

Clinical features Wart 2 • Verruca vulgaris are hard papules found on Wart 3 exposed parts; mostly on the fingers • Palmoplantar warts are found on the palm or the sole and they are painful • Verrucae plana are multiple skin-colored Histological Differential or slightly elevated papules on face and extremities • Seborrheic keratosis: horn pseudocysts are seen and basket weave stratum • Condylomas are fleshy exophytic lesion corneum are seen of the anogenital region • Squamous cell carcinoma: atypical pleomorphic cells with mitoses are seen Special studies • In situ hybridization and immunohistochemistry to subtype HPVs

Seborrheic keratosis Verrucous squamous cell carcinoma Clinical Variants

Clinical Variants Important Things To Know • Patients with epidermodysplasia verruciformis show numerous flat • Flat warts (verruca plana) warts • Palmoplantar warts (myrmecia warts) • Condyloma 12 trichilEmmoma (tricholEmmoma) Introduction Trichilemmoma (tricholemmoma) is a form of benign adnexal neoplasm with differentiation mostly toward the follicular outer root sheath. These lesions are variants of warts and recently it has been demonstrated the presence of papillomavirus DNA in these lesions. Epidemiology • The majority of trichilemmoma occur Histological features between the age of 20 and 80 years, with 1. Small circumscribed and lobular or multilobular proliferation of pale a mean age of 30 years keratinocytes • Male-to-female ratio is approximately 1:1 2. Peripheral palisading of the nuclei • Trichilemmoma are not associated with 3. Outlined by a thick densely eosinophilic basement membrane morbidity or mortality 4. Numerous squamous eddies Pathophysiology • Trichilemmomas are induced by HPV • A mutation in the tumor suppressor gene PTEN/MMAC1, as observed in Cowden syndrome, may play a causative role

3 Clinical features 2 4 • Trichilemmomas appear as simple or 1 2 multiple small (3–8 mm in diameter) papules or nodules • Individual lesions may be keratotic or smooth-surfaced and coloration usually matches that of surrounding skin Trichilemmoma • Predominantly located on the central face, particularly around the nose and upper lip, but may occur at any non-glabrous site Histological differential • Most lesions are clinically misdiagnosed 1. Clear cell acanthoma: as BCC or benign keratosis • Glycogenated pale segment of epidermis is sharply demarcated from the • Multiple trichilemmomas typically present surrounding skin on the facial or genital skin. On genital • Neutrophils are noted throughout the lesion and in the overlying crust skin they simulate the clinical pattern of a • Absence of thickening of the basement membrane zone condyloma, especially if multiple • Multiple trichilemmomas can be associated with Cowden syndrome (an autosomal dominant condition distinguished by multiple trichilemmoma, sclerotic fibromas, acrokeratosis and adenocarcinoma of the breast, thyroid gland, or gastrointestinal tract) Special studies • Hematoxylin and eosin is the stain of choice • PAS-D (periodic acid-Schiff with diastase) stain may be used to highlight the Clear cell acanthoma thickened basement membrane • A CD34 stain may be used to differentiate between a desmoplastic Important Things To Know trichilemmoma and a BCC (CD34 positive in desmoplastic trichilemmoma and • Desmoplastic trichilemmoma is characterized by irregular extensions negative in BCC) of the outer root sheath which project into sclerotic collagen bundles and may simulate infiltrating squamous cell carcinoma Clinical Variants • None 13 iNvErtEd follicular KEratosis Introduction Inverted Follicular Keratosis (IFK) is an uncommon benign tumor of the follicular infundibulum that can be confused, both clinically and histologically, with several benign and malignant skin conditions. The lesion typically appears Epidemiology on the face as a solitary firm papule and is characterized histologically by an endophytic proliferation of keratinocytes with the formation of squamous eddies. • Middle-aged to elderly individuals • Male-to-female ratio is 2:1 Histological features Pathophysiology 1. Endophytic proliferation of follicular keratinocytes extending downward into the dermis in a well-demarcated, lobular configuration • The involved cells are thought to arise 2. Hyperkeratosis, parakeratosis and occasionally papillomatosis from the follicular infundibulum, 3. Squamous eddies although the reason for proliferation is 4. Mild inflammatory cell infiltrate, predominantly lymphohistiocytic is common unknown in dermis Clinical features • Solitary, flesh-colored or pink, firm papule which measures from 0.3–1 cm in diameter 1 • Most commonly found on face 2 4 3 (predilection for cheek, upper lip, eyelid) 3 • Asymptomatic, stable lesions with occasional regression Special studies Inverted follicular keratosis • In situ hybridization and immunohistochemistry to detect HPV Histological differential 1. Seborrheic keratosis (especially the 2. Squamous cell carcinoma irritated variant) • SCC is not well demarcated • Seborrheic keratosis are raised • Cellular atypia and abnormal above the surrounding skin mitoses • Absence of endophytic component • Absence of squamous eddies

Important Things To Know Clinical variants • IFK are essentially warts developing within a hair follicle • None 14 solar lENtigo Introduction Benign pigmented lesion with an increased number of pigmented keratinocytes. Histological features Epidemiology 1. Elongation of the rete ridges • Solar lentigo occurs on sun-exposed skin 2. Basal hyperpigmentation, sometimes quite heavy in more than 90% of the white population 3. Solar elastosis is almost always present older than age 60 years, but may be observed in much younger individuals as well

1 Pathophysiology • It has been suggested that solar lentigo 3 is induced by the mutagenic effect of repeated ultraviolet light exposure 2 • Carriers of one or two of the melanocortin-1-receptor (MC1R) gene variants have a 1.5- to 2-fold increased Solar lentigo risk for the development of numerous solar lentigines Histological differential Clinical features 1. Lentigo maligna: • Dark brown to black macules, 3–12 mm • Presence of irregular nests of melanocytes or more in diameter; often multiple • Single melanocytes in the upper layers of the epidermis • They are distinguished from common freckles by their persistence despite absence of sun exposure Special studies • Immunohistochemical analysis: S-100, HMB-45, Melan-A, and tyrosine kinase are negative in the pigmented keratinocytes, but highlight the presence of melanocytes

Lentigo maligna

Important Things To Know • Solar lentigos can be very large and simulate melanoma clinically Clinical Variants • Solar lentigo may show transition to reticulated seborrheic keratosis • Hypermelanotic or “ink spot” solar lentigo 15 sEborrhEic KEratosis Introduction Seborrheic keratoses are the most common benign skin tumor in older individuals characterized by well-demarcated papules with a verrucous surface. They appear “stuck-on” and increase in numbers with age. They are commonly Epidemiology found on the face, neck, and trunk (especially the upper back), as well as the extremities. • Common in elderly • Increase in number with age • Sunlight seems to play a role Histological features 1. Proliferation of basaloid cells with areas of acanthosis and papillomatosis Pathophysiology 2. Pseudo-horn cysts 3. Sharp demarcation of the base of the neoplasm • Monoclonal in origin, indicating clonal expansion of somatically activating 4. Basket weave hyperkeratosis mutations in a specific transmembrane • Histological variants include acanthotic, hyperkeratotic, clonal (Borst- tyrosine kinase receptor, fibroblast Jadassohn appearance), reticulated, irritated and melanoacanthoma variant growth factor receptor-3

4 Clinical features 2 • Sharply defined, tan to black, flat, 1 papular or nodular lesions with a velvety to verrucous surface 3 2 • “Stuck-on”, waxy appearance • Usually asymptomatic with minimal pruritis • Frequently located on sun-exposed areas; Seborrheic keratosis Pigmented seborrheic keratosis trunk, face, upper extremities Special studies Histological differential • None 1. Epidermal nevus: • Clinical history is helpful • Usually lack pseudocysts 2. Squamous cell carcinoma: • Atypical keratinocytes involving the entire epidermis, dyskeratosis and abundant mitoses

Epidermal nevus Squamous cell carcinoma

Clinical variants Important Things To Know • Dermatosis papulosa nigra • Leser-Trélat sign is the sudden onset of numerous seborrheic keratoses • Stucco keratosis and may indicate an underlying visceral neoplasm • Nevoid hyperkeratosis of the nipple • Oral melanoacanthoma 16 Warty dysKEratoma Epidemiology • Warty dyskeratoma occurs mostly in Introduction middle-aged to elderly adults Warty dyskeratoma is a benign papulonodular lesion characterized by an endophytic proliferation of squamous epithelium, typically occurring in relation Pathophysiology to a folliculosebaceous unit and showing prominent areas of acantholysis. • There are no known etiological factors Histological features Clinical features 1. Well-demarcated endophytic lesion characterized by prominent acantholytic • Most lesions are solitary flesh-colored to dyskeratosis brown papules, nodules or cysts with an 2. Suprabasal clefting with formation of villi umbilicated or pore-like center or central 3. Abundant keratin forming a plug within the center of the proliferation keratin plug 4. Corps rounds and grains, which are dyskeratotic keratinocytes present in • Most are 1–10 mm in size. Occasionally the stratum spinosum and granulosum the lesions are multiple • Most cases asymptomatic but can be pruritic and bleed 3 • Foul-smelling cheesy discharge possible 4 • The head and neck region is most 1 commonly involved 2 4 • Does not spontaneously regress Special studies Warty dyskeratoma • Excisional biopsy and immunofluorescent staining to rule out pemphigus vegetans Histological differential 1. Benign familial pemphigus (Hailey–Hailey disease) • Has more acantholysis • Acantholysis involving large areas of the epidermis 2. Darier’s disease • Needs clinicopathological correlation 3. Pemphigus vegetans • Large areas of acantholysis • Collections of eosinophils in the epidermis

Familial benign pemphigus Darier’s disease Pemphigus vegetans (Hailey–Hailey)

Important Things To Know • The diagnosis is rarely made clinically • Malignant degeneration has not been associated with warty dyskeratoma • HPV is not associated despite the warty dyskeratoma Clinical variants • None 17 maligNaNt tumors • basal cEll carciNoma aNd variaNts basal cEll carciNoma aNd variaNts Introduction Basal cell carcinoma (BCC) is the most common malignant neoplasm in humans. It is destructive locally and has a tendency to recur, but rarely metastasizes. BCC varies in aggressiveness and can be associated with multiple syndromes. Epidemiology Histological features • 75% of all diagnosed skin cancers in the United States are BCCs 1. Irregular collections of basaloid cells • Predisposing factors include a history of 2. Neoplastic keratinocytes with large oval basophilic nuclei and scant cytoplasm nonmelanoma skin cancer, Fitzpatrick 3. Clefts between the neoplastic cells and stroma (an artifact produced by the skin type I and II, prolonged sun exposure loss of mucin during processing) in youth, immunosuppression, exposure Other features: to arsenic, fiberglass dust, or dry cleaning • Necrotic tumor cells are present among the basaloid cells and sometimes form agents, and previous trauma (smallpox central pseudocystic spaces filled with mucinous debris vaccination site, burn scars) • BCC can be associated with xeroderma pigmentosum (XP), Gorlin’s syndrome 1 1 (basal cell nevus syndrome, BCNS), 1 Bazex syndrome (X-linked dominant 2 condition with features of follicular 3 atrophoderma, multiple BCCs, local anhidrosis, and congenital hypotrichosis) or Rombo syndrome (an autosomal dominant condition distinguished by Nodular basal cell carcinoma Basal cell carcinoma BCC, atrophoderma vermiculatum, trichoepitheliomas, hypotrichosis, milia, and peripheral vasodilation with cyanosis) Histological differential 1. Squamous cell carcinoma: Pathophysiology • Larger and more eosinophilic cells • BCCs develop from keratinocytes in the basal • No cleft artifact layer (stem cells) of hair follicles, sebaceous • No peripheral palisading glands, and interfollicular basal cells 2. Poroma: • A relationship to embryonic closure lines • Uniform cellular proliferation of basaloid may exist cells • The tumor suppressor genes p53 or • Lack necrotic cells PTCH1 are most commonly mutated • No clefting • XP and Gorlin’s syndrome have evidence • Lack of stromal changes seen in BCC Squamous cell carcinoma of PTCH1 mutations

Poroma Trichoepithelioma Clinical variants • Nodular • Superficial (multifocal) • Morpheaform (infiltrative) • Fibroepithelioma of Pinkus 18 Clinical features • Pearly red macule, papule, nodule or plaque most common in sun-exposed area especially the nose, face and ears BCC variants • Telangiectasia over the neoplasm Special studies • H&E is the stain of choice • BerEp-4 and cytokeratin 20 to differentiate Merkel cell carcinoma

superficial basal cell carcinoma Morpheaform or infiltrative basal cell carcinoma

Morpheaform or infiltrative basal cell carcinoma

Fibroepithelioma of Pinkus

Fibroepithelioma of Pinkus

Important Things To Know • Lichen planus like keratosis can mimic BCC clinically

19 maligNaNt tumors • squamous cEll carciNoma aNd variaNts boWEN’s disEasE Introduction Bowen’s disease is a clinical expression of squamous cell carcinoma in situ of the skin. Epidemiology Histological features • It occurs predominantly on sun-exposed 1. Full-thickness involvement of epidermis and sometimes the pilosebaceous skin of older white men, but both sexes epithelium by atypical keratinocytes, dyskeratotic cells, and mitoses are affected 2. Loss of the granular layer, parakeratosis, and hyperkeratosis • Invasive carcinoma can develop in up to • Several histological variants have been described: psoriasiform, atrophic, 8% of untreated cases verrucous hyperkeratotic, pigmented and pagetoid variant Pathophysiology 2 • The exact underlying cause remains 1 unclear; however, it is known that chronic sun damage disrupts normal keratinocytic maturation and causes mutation of the tumor suppressor gene mutation (TP53)

Clinical features Bowen Disease • The disease presents as an asymptomatic well-defined erythematous scaly plaque Histological differential Special studies 1. Bowenoid papulosis: • Immunohistochemical analysis: CK5/6+, • Multiple papules on the anogenital areas of young patients HMB-45–, CEA– 2. Extramammary Paget’s disease: • (CK7+, CEA+) • Sometimes difficult to distinguish from Pagetoid variant 3. Melanoma in situ • (S-100+, HMB-45+) • Sometimes difficult to distinguish from Pagetoid variant

Bowenoid papulosis Extramammary Paget’s disease Melanoma in situ

Clinical variants Important Things To Know • Bowenoid papulosis is indistinguishable from Bowen’s disease • Verrucous histologically • Ulcerated • Pigmented 20 KEratoacaNthoma Introduction Keratoacanthomas are rapidly growing variant of squamous cell carcinomas that may resolve spontaneously leaving an atrophic scar. Histological features Epidemiology 1. Invaginating epidermis with a keratin-filled crater. Adjacent epithelium • Keratoacanthomas develop in the older develops “lips” and shows orthokeratosis, acanthosis, hypergranulosis and age groups, particularly in the sixth and parakeratosis seventh decades, and there is a male 2. Strands of eosinophilic epidermis invade the dermis. Mitoses are present preponderance 3. Intraepidermal neutrophilic, eosinophilic microabscesses and horn pearls 4. Involuting lesions begin to take on a flattened, less crateriform appearance. Pathophysiology The inflammatory infiltrate becomes largely lichenoid • Exposure to excessive sunlight is the most frequently incriminated factor • DNA sequences of HPV of both genital and cutaneous types have been detected 1 in up to 55% of keratoacanthomas in 3 2 immunosuppressed patients Clinical features 4 • Solitary pink or flesh-colored dome- shaped nodule with a central keratin Keratoacanthoma Keratoacanthoma plug on the sun-exposed skin. Multiple keratoacanthoma can occur • It grows rapidly to a size of 1–2 cm, Histological differential followed by a stationary period. It has a tendency to involute spontaneously, 1. Squamous cell carcinoma: this takes 8–50 weeks. Giant • Intraepidermal microabscesses and tissue eosinophilia are more commonly keratoacanthoma is greater than 2 cm found in keratoacanthoma and has a predilection for the nose and 2. Warts: dorsum of the hand Do not show the degree of atypia seen in keratoacanthomas • • Abortive keratoacanthoma is a variant in • Tend to be exophytic which involution commences at an early stage • Keratoacanthoma centrifugum marginatum is a rare variant characterized by progressive peripheral growth with coincident central healing • Subungual keratoacanthomas grow rapidly; they are more destructive than squamous cell carcinoma in this site Special studies Squamous cell carcinoma • None

Clinical variants Important Things To Know • Subungual keratoacanthoma is an • Keratoacanthomas of the face and neck can metastasize aggressive carcinoma • Eruptive keratoacanthomas, which can appear suddenly and in crops 21 squamous cEll carciNoma Introduction Cutaneous squamous cell carcinoma (SCC) is the second most common cancer of the skin and accounts for 20% of cutaneous malignancies. Most squamous cell carcinomas are readily treated with few sequelae. Larger or more invasive lesions Epidemiology may require aggressive management and have the potential to metastasize. • SCC occurs in men about two to three Histological features times more frequently than it does in Histology will vary based on the different subtypes of SCC, however common women features are: • Predisposing factors include: Fitzpatrick 1. Acanthosis skin types I and II, being middle-aged or 2. Full-thickness intraepidermal proliferation of atypical keratinocytes, cellular elderly, multiple atypical keratinocytes atypia and mitoses (AK), a history of nonmelanoma skin 3. Atypical keratinocytes in the dermis (the main feature that distinguishes cancer, frequent UV light exposure invasive SCC from SCC in situ) • SCC is associated with 4. Keratinization results in the production of keratin pearls immunosuppressive therapy Other features: SCC is also associated with chronic • • Hyperkeratosis and parakeratosis skin ulcers, prior X ray treatment, • Atypical keratinocytes may be found in the basal layer and often extend HPV infection, arsenic ingestion, HIV deeply down hair follicles infection, smoking, genetic syndromes • Histological variants include: acantholytic, adenoid, spindle cell, clear cell type, such as xeroderma pigmentosum, and signet-ring cell type, verrucous carcinoma, sarcomatoid and pigmented type toxic exposure to tars and oils Pathophysiology • The primary cause of most SCC is cumulative lifetime UV light exposure; including PUVA • Inactivation of the tumor suppressor 4 gene TP53 occurs in up to 90% of all 1 cutaneous SCC lesions. Other tumor suppressor genes found to be mutated include P16 and P14 3 2 • Iatrogenic immunosuppression and DNA repair failure, such as in Squamous cell carcinoma xeroderma pigmentosum, have also been Squamous cell carcinoma associated with increased incidence of SCC

Clinical variants • Verrucous • Keratoacanthoma 22 Clinical features • Hyperkeratotic or ulcerated plaque with a red, inflamed base, a growing tumor, or a non-healing ulcer, often on sun-exposed areas such as the head and neck • SCC can also occur on the lips, inside the mouth, on the genitalia. It can be de Histological differential novo or arise from an AK • SCC is capable of locally infiltrative 1. Hypertrophic AK: growth, spread to regional lymph nodes, • Prominent orthokeratosis with alternating parakeratosis and distant metastasis, most often to the • Epidermis usually shows irregular psoriasiform hyperplasia and mild lung. It is usually asymptomatic unless papillomatosis perineural invasion is present • Atypical keratinocytes are confined to the basal layer • Presence of vertical collagen bundles and some dilated vessels in the papillary dermis Special studies 2. Keratoacanthomatous variant of SCC: • Immunoperoxidase staining for • Exoendophytic lesions with an invaginating mass of keratinizing, well- cytokeratin positivity differentiated squamous epithelium at the sides and bottom of the lesion • There is a central keratin-filled crater • Epithelial atypia and mitoses are not a usual features • There is a mixed infiltrate of inflammatory cells in the adjacent dermis. Eosinophils and neutrophils may be prominent, and these may extend into the epithelial nests to form small microabscesses

Hypertrophic atypical Keratoacanthoma keratinocytes

Important Things To Know • If the tumor is poorly differentiated it is associated with a higher risk of metastasis • Patients who develop one SCC have a 40% risk of developing another SCC within the next 2 years and should be evaluated with a complete skin examination every 6–12 months

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