Cutaneous metastases. Thaddeus Mully. University of California, San Francisco Professor, Departments of Pathology and Dermatology

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1 Cutaneous metastases Thaddeus Mully University of California, San Francisco Professor, Departments of Pathology and Dermatology

2 DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY Thaddeus Mully Course C005 Essential Dermatopathology: What You Need to Know for Clinical Practice: Neoplastic DISCLOSURES I do not have any relevant relationships with industry.

3 Introduction Cutaneous metastases are uncommonly encountered and present a diagnostic challenge for clinicians and pathologists alike They may not be suspected and can clinically and histopathologically mimic other entities Communication with the submitting clinician is often necessary to obtain relevant clinical history as this is a big diagnosis Histopathologic and immunohistochemical results can be helpful in suggesting a primary source, but further work up is always necessary

4 General principles (Clinical) The overall incidence of cutaneous metastasis from a variety of internal malignancies is about 2-12% Rarely (< 1%) is skin metastasis the presenting sign of internal malignancy Poor prognosis; mean survival following a cutaneous metastasis is 7.5 months By definition these are all late stage patients

5 General principles (Clinical) In adults the most common primary sources are: Breast CA, melanoma, head and neck SCC, lung CA, colorectal CA, renal CA In women, most common primary sources are: Breast (69%), large intestine (9%), melanoma (5%) and ovary (4%) In men, most common primary sources are: Lung (24%), large intestine (19%), melanoma (13%), squamous cell CA of oral cavity (12%), kidney (6%) In neonates the most common sources are neuroblastoma and less commonly rhabdomyosarcoma

6 Clinical presentation Most common is solitary or small grouped nodule(s), firm, often rapidly growing Erythematous patch (inflammatory carcinoma, carcinoma erysipeloides) Firm indurated plaque (carcinoma en cuirasse) Grouped hemorrhagic papules (carcinoma telangiectoides)

7 General principles (Clinical) Often localize to same general vicinity as primary malignancy: Lung primary: Chest wall and proximal upper extremities GI and GU primaries: Abdominal wall Oral cavity and esophageal primaries: Head and neck Bladder and prostate: Abdominal wall or penis Sometimes develop at site of scars from prior surgeries, prior procedures (thoracentesis, paracentesis) and colostomy sites Scalp metastases are usually from breast, lung, or renal primaries

8 Sister Mary Joseph Nodule (umbilical met) Most often metastatic adenoca from stomach, large bowel, and less often ovary, pancreas, urinary bladder, endometrium

9 Histopathologic patterns Large nodular aggregate(s) centered in the dermis, without connection to the overlying epidermis; rare epidermotropic met seen with melanoma, prostate, and some squamous cell CA s Small nests, strands, or single cells arranged interstitially between collagen bundles; sometimes in a single file pattern (especially for breast CA) Lymphatic and vascular invasion

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13 Distinguishing between a cutaneous metastatic adenoca and a primary skin (adnexal) neoplasm Metastatic AdenoCA Adnexal neoplasm p p D2-40 (podoplanin) - + CK 5/6 - + Exception is mucinous eccrine CA of skin which is typically p63 negative Plaza, et al: JCP 37:403,2010 Liang, et al: AJSP 31:304,2007

14 Cytokeratin-7 (CK7) and cytokeratin-20 (CK20) expression profiles Breast Lung (SCC) Lung (nonsmall cell) Lung (small cell) Colon/ Rectal Gastric Pancrea s/biliary Bladder/ Urotheli al Renal Ovary CK CK20 / Reference: Applied Immunohistochemistry 3:99-107, 1995.

15 Breast (Mammary) Small nests, strands, or single neoplastic cells arranged interstitially between collagen bundles, often in a single file pattern

16 Breast (Mammary) Neoplastic cells filling lymph-vascular spaces; Inflammatory CA ; carcinoma erysipeloides

17 D2-40

18 Breast (Mammary) Small nests and strands of neoplastic cells with surrounding desmoplasia and fibrosis; carcinoma en cuirasse

19 Breast (Mammary) Scalp hair follicles overrun by nests of poorly differentiated breast CA; alopecia neoplastica

20 Breast (Mammary) Cytokeratin-7 Positive and Cytokeratin-20 Negative (CK7+/CK20 ) CAM5.2 + (low molecular weight cytokeratin) CEA + GCDFP-15 + (Gross cystic disease fluid protein) Mammaglobin + ER and PR variably + (NOT useful as a breast marker) Rarely S100 + with melanin pigment (mimic of melanoma)

21 Lung Squamous cell CA CK7 /CK20 CK5/6+ Non-small cell adenocarcinoma CK7 +/CK20 TTF-1 + Small cell adenocarcinoma CK7 /CK20 (usually) TTF-1 +

22 Lung (small cell oat cell carcinoma) Small round blue cells Salt and pepper chromatin Fragile cells with crush artifact DDx is with primary cutaneous neuroendocrine CA (Merkel Cell CA) Merkel cell Met Small Cell CK20 + /+ TTF-1 +

23 Colon AdenoCA with dirty necrosis CK7 /CK20 + CEA + CDX2 + Villin +

24 Renal Nodular aggregates of clear cells Richly vascular CK7 /CK20 EMA + CD10+ RCC-ma + PAX8 + PAX2 + **PAX8 and PAX2 are also + in ovarian and other gyn tumors

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27 Melanoma Nodular or nested aggregates May lose ability to produce melanin pigment S100 + Melan-A + MITF + HMB-45 +/ Some met melanomas may lose all melanocytic markers Ref: AJSP 40: , 2016

28 Immunohistochemical stains for less common cutaneous mets Ovarian Prostate Gastric Pancreatic Bladder/Urothelial Thyroid CK7+/CK20, CA-125, WT-1 (serous), PAX8, PAX2 PSA, PSAP CK7+/CK20+, CDX2 CK7+/CK20+, CA19.9, CA125 CK7+/CK20+, p63, CK5/6 TTF-1+, thyroglobulin, calcitonin (medullary)

29 References Wang NP, et al: Coordinate expression of cytokeratins 7 and 20 defines unique subsets of carcinomas. Applied Immunohistochemistry 3:99-107, Alcaraz I, et al: Cutaneous metastases from internal malignancies: a clinicopathologic and immunohistochemical review. American Journal of Dermatopathology 34: , Plaza JA, et al: Value of p63 and podoplanin (D2-40) in the distinction between primary cutaneous tumors and adenocarcinomas metastatic to the skin. Journal of Cutaneous Pathology 37:403-10, Liang, et al: Podoplanin is a highly sensitive and specific marker to distinguish primary skin adnexal carcinomas from adenocarcinomas metastatic to the skin. American Journal of Surgical Pathology 31:304-10, Agaimy A, et al: Metastatic malignant melanoma with complete loss of differentiation markers. American Journal of Surgical Pathology 40:181-91, Lee JJ, et al: p40 exhibits better specificity than p63 in distinguishing primary skin adnexal carcinomas from cutaneous metastases. Human Pathology 45(5):

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