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
I have no conflicts of interest to declare Many of these slides were created by Jane Messina, MD
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 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. 2013 Sept. 5(9):499-504.
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 1978-82 compared to 2001-5 Demographics and distribu+on suggest UV-related cases for subset Blake et al. Arch Dermatol. 2010;146(6):625-632
Schwartz, J Am Acad Dermatol 1995; 33:161-82 Saeed S et al. J Cutan Pathol 2004 Jul; 31(6): 419-30 Clinical features Adnexal Metasta0c carcinoma Incidence 0.5% popula+on 2.5% of popula+on Median age at diagnosis 70 62 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
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 tumors but can be posi+ve in up to 25% of metasta+c adenocarcinomas D2-40 + in all 100% of 9 adnexal carcinoma (may be focal) absent in 42 metasta+c adenocarcinomas Plaza et al. J Cutan Pathol (2010); 37:403-410 Lee et al. Human Pathology (2014) 45, 1078 1083
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
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, 1078 1
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: 430-6 Rollins-Raval et al. Arch Pathol Lab Med 2011; 135:975-983.
Metasta0c adenocarcinoma vs adnexal Sweat gland carcinoma Cutaneous metastasis p63 91% 8 % CK15 40% 2% most specific D2-40 44% 4% nes+n 37 8 calre+nin 14 10 Mahalingam et al. Modern Pathology 2010; 23:713-719
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): 2050-4
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
CK7 / CK20 Arch Pathol Lab Med. 2016;140:508 523
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 CK7 + + + + + Ovary serous + + + + + + CK20 or CDX2 Pancreas Stomach Colon +/- +/- + -/+ +/- -/+ -/+ + Other notable stars: RCC, PAX8 (renal), HepPar-1, glypican-3, arginase (hepatocellular), GATA-3 (urothelial)
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) 464:393-402
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. 2013 J Natl Cancer Inst. Doi: 10.1093/jnci/djt099 Hainsworth JD and Greco FA. Virchows Arch (2014) 464:393-402
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: 1386 95
68 year old woman with 6-month history of forehead mass
CK 5/6 p63 CK7 Diagnosis: Metasta+c breast adenocarcinoma ER mammaglobin
68 year old male with new scalp lesion
68 year old male with new scalp lesion
68 year old male with new scalp lesion CK5/6 p63 p63 calponin Preserva+on of myoepithelium=carcinoma in situ Diagnosis: Primary apocrine adenocarcinoma
GALLERY
ER CK7 GCDFP-15
Esophageal carcinoma
Renal cell carcinoma
Serous ovarian carcinoma
Thyroid carcinoma
Sister Mary Joseph Nodule
Pancrea+c adenocarcinoma
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