Adnexal primary or Melanocy+c prolifera+ons in sundamaged metastatic carcinoma?

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Ralf Butler
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1 Adnexal primary or Melanocy+c prolifera+ons in sundamaged metastatic carcinoma? skin Jane L. Messina, MD Interna0onal Melanoma Pathology Working Group 4 th annual mee0ng Tampa, Florida November 14, 2011 # Kenneth Y. Tsai, MD, PhD September 16, 2017

2 I have no conflicts of interest to declare Many of these slides were created by Jane Messina, MD

3 Goals Scope of the issue Cost of the issue Specific workups Case presenta+ons / gallery

Metastases to the skin ~5 % (1-10%) of all oncology pa+ents will develop skin metastases <1% of oncology pa+ents will PRESENT with skin metastases Primary

4 Metastases to the skin ~5 % (1-10%) of all oncology pa+ents will develop skin metastases <1% of oncology pa+ents will PRESENT with skin metastases Primary cancer origin BREAST 69% COLON 9% MELANOMA 5% LUNG 4% OVARY 4% LUNG 24% COLON 10% MELANOMA 13% ORAL CAVITY 12% Wong et al. N Am J Med Sci Sept. 5(9):

5 Adnexal carcinoma SEER: 5 cases/1 million person years 1984 cases in 12 years Es+mated number of cases in US annually: 661 Incidence rose 150% from compared to Demographics and distribu+on suggest UV-related cases for subset Blake et al. Arch Dermatol. 2010;146(6):

6 Schwartz, J Am Acad Dermatol 1995; 33: Saeed S et al. J Cutan Pathol 2004 Jul; 31(6): Clinical features Adnexal Metasta0c carcinoma Incidence 0.5% popula+on 2.5% of popula+on Median age at diagnosis M:F 1.5:1 1:2 Loca+on Head and neck 70% Face>scalp>extremi+es> trunk Number of lesions Dura+on of lesions 1 mul+ple >6 months <6 months M: H&N>ant. chest>abdomen F: ant chest/abdomen Morphology Dome-shaped nodule Dome-shaped nodule> kerato+c, clustered, inflammatory Outcome 5 year survival 96-97% Median 2-36 months

7 Scalp tumors Omen late sign in metasta+c carcinoma Lung and kidney in males Breast in females Therefore, more likely to represent adnexal carcinoma

Primary adnexal versus metasta0c carcinoma: the heavy liners p63 CK5/6 D2-40 p63 + in 91-100% primary adnexal tumors but only posi+ve in 8% of metasta+c adenocarcinomas CK 5/6 + 71% primary adnexal

8 Primary adnexal versus metasta0c carcinoma: the heavy liners p63 CK5/6 D2-40 p63 + in % primary adnexal tumors but only posi+ve in 8% of metasta+c adenocarcinomas CK 5/6 + 71% primary adnexal tumors but can be posi+ve in up to 25% of metasta+c adenocarcinomas D in all 100% of 9 adnexal carcinoma (may be focal) absent in 42 metasta+c adenocarcinomas Plaza et al. J Cutan Pathol (2010); 37: Lee et al. Human Pathology (2014) 45,

9 P63 and CK5/6 piualls Non-cutaneous primaries known to be posi+ve: Squamous cell carcinomas (esophageal, lung, head and neck) Urothelial carcinoma Salivary gland carcinoma p63 also found in rare lung, pancreas, GI, endometrial tumors

10 Primary adnexal carcinoma: new kid on the block: p40 p40 recognizes only the ΔNp63 isoform of p63 highly specific for squamous or basal epithelia 80% of adnexal carcinoma posi+ve staining, and only found in 8% of metasta+c adenocarcinoma (salivary gland and bladder primaries only) PPV: 90% NPV: 84% Lee et al. Human Pathology (2014) 45,

11 Most common dilemma: metasta0c breast vs primary adnexal carcinoma Sweat gland carcinoma p63 91% 6-8% CK5/6 71% 6% Mammaglobin 5%-18% 45-66% GATA-3 15% 90% Breast carcinoma ER/PR are found in up to 25% of sweat gland carcinomas Mammaglobin is more sensi+ve but less specific than GCDFP-15 Tumor marker CA15.3 expressed by but not reported to be elevated in serum of adnexal carcinomas Mentrikoski and Wick, Am J Clin Pathol 2015; 143: Rollins-Raval et al. Arch Pathol Lab Med 2011; 135:

2% most specific D2-40 44% 4% nes+n 37 8 calre+nin

12 Metasta0c adenocarcinoma vs adnexal Sweat gland carcinoma Cutaneous metastasis p63 91% 8 % CK15 40% 2% most specific D % 4% nes+n 37 8 calre+nin Mahalingam et al. Modern Pathology 2010; 23:

13 Carcinoma of unknown primary Median survival 2-4 months Workup expensive, +me-consuming 56 pa+ents presen+ng to MCC with CUP: Primary site found in 7% 20% survived >1 year (mean 8 months) Average cost of diagnosis $17,973 Schapira and Garreq Arch Int Med 1995 Oct 23; 155(19):

14 Workup of CUP: NCCN guidelines H&P, blood panel, CT chest/abdomen/pelvis, sitedirected endoscopy, biopsy Biopsy Immunohistochemical analysis- exhaus+ve panels have not been shown to increase diagnos+c accuracy Tier 1: +ssue lineage (carcinoma v sarcoma v lymphoma v melanoma) Tier 2: puta+ve primary site Tier 3: biomarkers (e.g. RAS, HER2, ALK) Gene signature profiling for +ssue of origin is not recommended for standard management at this +me

15 CK7 / CK20 Arch Pathol Lab Med. 2016;140:

16 CUP: most useful an0bodies Prostate Lung Breast PSA NKX3.1 + TTF-1 or napsin A GCDFP-1 5 or mamma globin WT-1 PAX8 ER CA-125 Mesoth elin CK Ovary serous CK20 or CDX2 Pancreas Stomach Colon +/- +/- + -/+ +/- -/+ -/+ + Other notable stars: RCC, PAX8 (renal), HepPar-1, glypican-3, arginase (hepatocellular), GATA-3 (urothelial)

17 Molecular profiles to assess tumor origin DNA-based gene expression profiling (Cancer TYPE ID) and mirna profile (Roseqa Cancer Origin test) commercially available, accuracy in valida+on sets ~85% Accuracy of blinded tes+ng in pa+ents with latent/ known primary GEP: ~75% IHC: ~65% Hainsworth JD and Greco FA. Virchows Arch (2014) 464:

GEP v IHC in assessing CUP In five series of 117 pa+ents, IHC predicts single site of origin in ~55% of cases GEP predic+on iden+cal in 78% of these Direc+ng treatment with GEP diagnosis: no

18 GEP v IHC in assessing CUP In five series of 117 pa+ents, IHC predicts single site of origin in ~55% of cases GEP predic+on iden+cal in 78% of these Direc+ng treatment with GEP diagnosis: no evidence of beqer survival compared to IHC in a single prospec+ve study Greco et al J Natl Cancer Inst. Doi: /jnci/djt099 Hainsworth JD and Greco FA. Virchows Arch (2014) 464:

19 The next fron0er - epigenomics 485K probes DNA methyla+on assay from FFPE Trained on large datasets Skin was the source for about 5% of the cases Coupled to specific therapy with enhanced survival Lancet Oncol 2016; 17:

20 68 year old woman with 6-month history of forehead mass

21 CK 5/6 p63 CK7 Diagnosis: Metasta+c breast adenocarcinoma ER mammaglobin

22 68 year old male with new scalp lesion

23 68 year old male with new scalp lesion

24 68 year old male with new scalp lesion CK5/6 p63 p63 calponin Preserva+on of myoepithelium=carcinoma in situ Diagnosis: Primary apocrine adenocarcinoma

25 GALLERY

27 ER CK7 GCDFP-15

30 Esophageal carcinoma

32 Renal cell carcinoma

34 Serous ovarian carcinoma

36 Thyroid carcinoma

37 Sister Mary Joseph Nodule

38 Pancrea+c adenocarcinoma

39 Summary Metasta+c carcinoma more commonly encountered than adnexal carcinoma H/N loca+on sta+s+cally more likely to be adnexal primary, chest/abdomen favors metasta+c Directed panel (p40/p63, CK5/6) helps iden+fy adnexal origin up to 90% of +me When in doubt, lineage-specific IHC very useful Play the odds For breast mammaglobin, GCDFP-15

The clinically challenging entity of liver metastasis from tumors of unknown primary

The clinically challenging entity of liver metastasis from tumors of unknown primary Xuchen Zhang, MD, PhD Associate Professor of Pathology Department of Pathology Yale University School of Medicine Liver