- Selected Tumors of the Skin Appendages - Primary vs. Metastasis Napa Valley 2018

Victor G. Prieto, MD, PhD Chair of Pathology UT –MD Anderson Cancer Center [email protected] Napa Valley in May Introduction •“Threatening” field in Pathology •Relatively easy distinction between benign and malignant lesions: –Circumscription –Cytologic features •Not so important subclassification, except for same cases •Selected lesions •Primary vs. metastasis / •Solitary: sporadic in childhood or adolescence, flesh-colored, 2-8 mm papule or nodule, face •Uncommonly, autosomal dominant •Mutations of the region of the Drosophila patched gene (9p21) •Differential Dx: BCC Focally cystic pattern Well circumscribed Keratin pearls Cystic areas Central necrosis Rippled morphology More common on the head and neck Follicular differentiation Trichoepithelioma / trichoblastoma

Papillary mesenchymal body Dermal proliferation, desmoplastic stroma Some lesions with larger cysts Desmoplastic trichoepithelioma

Calcified cysts, rare perineural invasion BCC •Older individuals •Sun exposure •Clefting •Myxoid stroma •Perineural invasion Hamartomatous BCC (Infundibulocystic) •BCC with follicular differentiation, resembling trichoepithelioma •Clefting, myxoid stroma •Association with basal cell nevus syndrome Large dermal proliferation Papillary mesenchymal body Clefting, myxoid background TE BCC CD34 Diffuse Focal CD10 Stroma Tumor CK20 Scat. Neg Bcl-2 Periph Diff

CK20 TE CD10 TE CD34 TE

Bcl-2 BCC CK20 BCC CD10 BCC CD34 BCC PHLDA Trichoblastoma PHLDA BCC

Courtesy of Dr. Luis Requena

Key Points TE vs BCC • Age and sun damage • Cleft and myxoid stroma • Mitotic figures / apoptosis • Rare papillary mesenchymal bodies • CD34, bcl2, CK20, CD10, PHLDA • Hamartomatous BCC (mixed features) • Re-excision in case of doubt Microcystic Adnexal Ca • Solitary lesion, middle-age, upper lip, deeply infiltrative plaque • Recurrence • Similar lesion in mucosae Mills AM et al. Head and Neck Pathology, 2016; 1-8 Lesion on the face

• Deep invasion • Perineural invasion CK5/6

p63 Key Points

•Female, face •Dual differentiation •Deep and perineural invasion •Locally aggressive Sebaceous Lesions • Still controversy (all carcinoma?) • Solid or cystic lesions • Well circumscribed, lobular • Basaloid cells and sebocytes (“scalloping”) • Epithelioma (sebaceoma) / adenoma • Infiltrative, necrosis, mitotic figures Histologic clues for sebaceous lesions in Muir-Torre syndrome •Usually the lesions are hard to classify •Sebaceous adenomas or sebaceomas •Extraocular location (outside H&N) •Multiple lesions •Cystic appearance •Keratoacanthoma-like architecture Eccrine / Apocrine

• 40-year-old Caucasian male • “Benign” tumor in his right third digit 4 years ago (unavailable)

3rd recurrence Digital Papillary Adenocarcinoma • Originally described in 1987 • Variant of carcinoma occurring typically on fingers and toes, hands, feet • Usually solitary, asymptomatic or accompanied by pain • Male predominance (7:1) Digital Papillary Adenocarcinoma • Overall recurrence rate 30-40% but is significantly lower (5%) after re-excision or amputation • No longer “adenoma” • 14%distal metastases (lung, lymph nodes) • Sentinel lymph node biopsy? • BRAF-V600E mutation Bell, D., et al. Next-generation sequencing reveals rare genomic alterations in aggressive digital papillary adenocarcinoma. Ann Diagn Pathol 2015; 19(6): 381-384. Elderly male, face lesion Synaptophysin

Chromogranin Eccrine Mucinous Carcinoma (Neuro)Endocrine Type • 70 years, W>>M • Slow growth • Eyelid (inferior) • Circumscribed, multinodular • Good prognosis Zembowicz et al. Am J Surg Pathol 2005;29:1330–1339 •65 F Left eyelid

•Poorly circumscribed, dermis (subcutis and skeletal muscle) •Ducts •Hyperchromatic and pleomorphic •Extracellular mucin Mucinous Carcinoma •Slow growth •Face, scalp, axilla •Dermal tumor with basophilic mucin and small islands of epithelial cells •No “dirty necrosis” •Primary vs. metastatic? CK20 Metastatic GI

CDX2

Normal pattern P63 tumor Figure 3. Cytologic features. A and B, High-magnification view of squamous areas from cases 10 and 6, respectively. C and D, Clear cell areas from cases 5 and 7, respectively. The selected cases illustrate examples from either end of the spectrum of cytologic atypia. A and C show mild atypia; B and D show severe atypia, with numerous mitoses (hematoxylin-eosin, original magnifications ϫ40).

prominent intercellular bridges (Figure 3, A through D). All cases showed the presence of tumor necrosis form- Squamous pearls and single-cell keratinization could be ing variably sized ‘‘comedones’’ in the center of large tu- seen in 4 cases. The squamoid areas merged with the more mor aggregates. In 2 patients (cases 6 and 7) the tumor central zone of clear cells that occupied between 10% and necrosis was extensive, reaching geographic proportions. 90% of the tumor volume. Smaller tumor aggregates tend- In some tumors, the comedones showed concentric com- ed to be predominantly squamoid, whereas clear cell areas pact keratin with retention of degenerating nuclei. were most prominent in larger tumor nodules. Nuclear pleomorphism could be observed in both the Cytomorphology of clear cells varied from case to case squamoid and clear cells and varied from case to case, but and, to a lesser degree, within different parts of the same it was graded as moderate in most cases (Figure 3, A and lesion (Figure 3, A through D). In most cases, the neo- B). Occasional bizarre pleomorphic tumor giant cells were plastic clear cells had centrally placed nuclei with sur- encountered. The mitotic count ranged from 2 to 32/mm2 rounding optically clear cytoplasm and prominent cell (median, 8/mm2). membranes. Less often, signet ring forms were visualized, All tumors were carefully scrutinized for the presence with compressed crescent-shaped and laterally displaced of areas of specialized adnexal differentiation. There was Figure 1. A through C, The tumor shows infiltration of reticular dermis in discrete nests, lobules, tubules, or trabeculae of epithelial cells. A, Case 6; B, case 9; C, case 7 (hematoxylin-eosin, original magnifications ϫ2.5). Figure 3. Cytologic features. A and B, High-magnification view of squamousnuclei. areas In fromsome cases areas 10 and the 6, clear respectively. cells were C and D,columnar Clear cell in areas no evidence of ductal, cuticular, primitive germ (bas- Case 6; B, case 9; C, case 7 (hematoxylin-eosin, original magnifications ϫ2.5). from cases 5 and 7, respectively. The selected cases illustrate examples from either end of the spectrum of cytologic atypia. A and C show mild shape. The cytoplasmic clearing was due to accumulation aloid), apocrine, pilar, pilomatrical, or sebaceous differ- Figure 2. A through C, Zonal arrangement of tumor nests with the outer squamousatypia; and B and inner D showclear severecells with atypia, centrally with numerous located degenerating mitoses (hematoxylin-eosin, original magnifications ϫ40). ϫ ϫ of glycogen in all cases, which stained positive with pe- entiation in routine sections or immunohistochemical tumor cells showing pattern of comedonecrosis. A, Case 2; B, case 11; C, case 4 (hematoxylin-eosin, original magnifications ϫ20 [A], ϫ10 [B], ϫ and ϫ40 [C]). riodic acid–Schiff stain in a diastase-sensitive manner (Fig- studies in any of the cases analyzed. prominent intercellular bridges (Figure 3, A through D). ure 4,All A cases through showed C). No the koilocytic presence changesof tumor or necrosis any other form- Multiple sections revealed at least focal connection to Squamous pearls and single-cell keratinization could be histologicing variably changessized indicating ‘‘comedones’’ human in the papillomavirus center of large in- tu- the overlying epidermis in 8 cases (Figure 5, A and B). ing of outer layers of squamous cells and inner layers of ure 2,seen A through in 4 cases. C). The At squamoid the periphery, areas in mergeddividual with tumor the more fectionmor wereaggregates. seen. Evidence In 2 patients of intracytoplasmic (cases 6 and 7) lipid the tumor de- Four lesions showed multiple points of attachment of the ing of outer layers of squamous cells and inner layers of ure 2, A through C). At the periphery, individual tumor position or cytoplasmic microvacuolization, which would surface. In 8 cases, areas showing in situ carcinoma could clear cells often surrounding centrally located foci of de- lobulescentral showed zone squamous of clear cellsdifferentiation that occupied with between such cells 10% and necrosis was extensive, reaching geographic proportions. generating cells forming parakeratotic debris or inflamed having90% atypical, of the tumor round volume. to oval vesicularSmaller tumor nuclei, aggregates small nu- tend- suggestIn some sebaceous tumors, differentiat the comedonesion, was showed not conce identifiedntric com- in be identified (Figure 5, A). It was not apparent whether generating cells forming parakeratotic debris or inflamed having atypical, round to oval vesicular nuclei, small nu- any of the cases. the in situ carcinoma represented a true precursor lesion areas of tumor necrosis constituting comedonecrosis (Fig- cleoli,ed abundant to be predominantly pink cytoplasm, squamoid, polygonal whereas contours, clear cell and areas pact keratin with retention of degenerating nuclei. Arch Pathol Lab Med—Vol 131, November 2007 Adnexal Clear Cell Carcinomawere most With Comedonecrosis— prominent in largerChaudhry tumor & Zembowicz nodules. 1657 1658 NuclearArch Pathol pleomorp Lab Med—Volhism 131,could November be observed 2007 in bothAdnexal the Clear Cell Carcinoma With Comedonecrosis—Chaudhry & Zembowicz Arch Pathol Lab Med—Vol 131, November 2007 Adnexal Clear Cell CarcinomaCytomorphology With Comedonecrosis— of clearChaudhry cells varied & Zembowicz from case1657 to case squamoid and clear cells and varied from case to case, but and, to a lesser degree, within different parts of the same it was graded as moderate in most cases (Figure 3, A and lesion (Figure 3, A through D). In most cases, the neo- B). Occasional bizarre pleomorphic tumor giant cells were plastic clear cells had centrally placed nuclei with sur- encountered. The mitotic count ranged from 2 to 32/mm2 rounding optically clear cytoplasm and prominent cell (median, 8/mm2). membranes. Less often, signet ring forms were visualized, All tumors were carefully scrutinized for the presence with compressed crescent-shaped and laterally displaced of areas of specialized adnexal differentiation. There was nuclei. In some areas the clear cells were columnar in no evidence of ductal, cuticular, primitive hair germ (bas- shape. The cytoplasmic clearing was due to accumulation aloid), apocrine, pilar, pilomatrical, or sebaceous differ- of glycogen in all cases, which stained positive with pe- entiation in routine sections or immunohistochemical riodic acid–Schiff stain in a diastase-sensitive manner (Fig- studies in any of the cases analyzed. ure 4, A through C). No koilocytic changes or any other Multiple sections revealed at least focal connection to histologic changes indicating human papillomavirus in- the overlying epidermis in 8 cases (Figure 5, A and B). fection were seen. Evidence of intracytoplasmic lipid de- Four lesions showed multiple points of attachment of the position or cytoplasmic microvacuolization, which would surface. In 8 cases, areas showing in situ carcinoma could suggest sebaceous differentiation, was not identified in be identified (Figure 5, A). It was not apparent whether any of the cases. the in situ carcinoma represented a true precursor lesion 1658 Arch Pathol Lab Med—Vol 131, November 2007 Adnexal Clear Cell Carcinoma With Comedonecrosis—Chaudhry & Zembowicz Adnexal Clear Cell Carcinoma with Comedonecrosis • Elderly, M=W • Head and neck, scalp • Quick growth • Erythematous, tan color • Solitary papules/nodules (cm) • Possibility of recurrence Chaudry and Zembowicz. Arch Pathol Lab Med. 2007;131:1655–1664 Carcinoma with Comedonecrosis • Multilobular pattern • Squamous and central clear cells • Comedonecrosis, NO ducts • IHC: EMA, CK17, CEA focal

CEA Squamoid Ductal Eccrine SCC

• Solitary dermal nodule • Sometimes ulcerated • Head, neck, extremities or trunk • Middle-aged or elderly

Wong TY, Suster S, Mihm MC. Squamoid eccrine ductal carcinoma. Histopathology. 1997;30:288–293 van der Horst MP1, Garcia-Herrera A, Markiewicz D, Martin B, Calonje E, Brenn T. Am J Surg Pathol. 2016 Jun;40:755-60 Summary • Relatively easy distinction benign vs malignant • Not so important subclassification (eccrine, sebaceous) • Sebaceous (Muir Torre) • Acral lesions • Mucinous-neuroendocrine • Adnexal clear cell ca. with comedo Cutaneous Metastases • 0.7 to 10% of patients with visceral tumors • Important topic?: –Poor prognosis –First sign of disease Cutaneous Metastases Women Men •Breast (60-70%) •Lung •GI •GI •Lung •Head and neck •Ovary •GU Thyroid, adrenal, endometrium, prostate, mesothelioma Sariya et al. Arch Dermatol 2007; 143: 613 Cutaneous Met. Clinical Features

•Location: •Nodules –Anatomic proximity •Bullae (Zoster-like) –Chest, abdomen, •Cellulitis –Neck •Sclerosis –Scalp •Vasculitis-like Metastasis vs. Primary Clinical Features • (Met) Sudden appearance Multiple lesions Previous history Selected anatomic locations (umbilicus)

•(Primary) Previous, long-standing lesion Primary Cutaneous

Metastatic Breast Adenocarcinoma Primary Cutaneous Metastatic Breast Eccrine Carcinoma Adenocarcinoma

• p63 • Primary Adnexal eccrine carcinoma • CK5/6

• CK7

• Ducts • Necrosis

• Calretinin CK7 • Marked atypia

TTF1 p63

CK20 Practical Use of IPOX 1) Confirm diagnosis: 3) Origin: - Keratin - Mammaglobin - CEA (EMA) - CK20 2) Primary vs metastatic: - CDX2, villin - P63 (>25% cells) - CD19.9 - D2-40 - Calretinin - TTF1 - CK5/6 - CD10 (EMA) - CK7 - PSA / PSAP 4) Common sense and CPC! Primary vs. Metastatic Summary • Important differential diagnosis • Clinical and histologic features • IHC as an adjunct • Most important tool: Telephone Old train Napa Valley Thank you for your attention