Clinical History USCAP Specialty Conference. Gynecologic Pathology Case 3

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1 2010 USCA Specialty Conference Gynecologic athology Case Kathleen R. Cho, M.D. Department of athology Clinical History 46 yo woman presented with bilateral ovarian masses and elevated CA-125 TAH/BSO, pelvic and para-aortic lymph node dissection, optimal debulking performed Figure 1 Figure 2 Figure Figure 4

2 Figure 5 Figure 6 Do High Grade Carcinomas Exist? Features Favoring High Grade Carcinoma The morphological and molecular features of high-grade endometrioid and high-grade serous carcinomas overlap Some pathologists default the vast majority of gland forming or near-solid cytologically highgrade ovarian carcinomas to the serous category True high-grade endometrioid carcinomas are considered by some to be rare Round, punched out spaces rather than slit-like spaces Longer broader papillae Squamous differentiation Adenofibromatous growth pattern Endometriosis

3 ER p5 ER R R 85% serous CAs ER positive 77% endometrioid CAs ER positive 25% serous CAs R positive 64% endometrioid CAs R positive T5 mutations identified in 80+% serous CAs (Salani et al., 2008) T5 mutations identified in 51% endometrioid CAs; 17% FIGO1, 6% FIGO2/ (Wu et al., 2007). Lee et al., 2005 p16 WT1 92% serous CAs moderate/strong p16 staining (most 5+) 60% endometrioid CAs moderate/strong p16 staining (nearly half 5+) 66 78% serous CAs WT1 positive.9-20.% endometrioid CAs WT1 positive hillips et al., 2009 Gilks et al., 2008 First two principal components for 99 tumors, all probe-sets, log-transformed data (only endometrioid adenocarcinomas shown) OS 20 Wnt pathway defects: OM OC 10 Green = CTNNB1 mut Blue = AC mut IK/Akt pathway defects: = ten mut = IKCA mut 0 n = FIGO 1 26 FIGO 2/ First rincipal Component 25

4 First two principal components for 99 tumors, all probe-sets, log-transformed data (only endometrioid adenocarcinomas shown) 20 Green = CTNNB1 mut 10 Blue = AC mut = ten mut = IKCA mut p5 mutation First rincipal Component Characterization of the molecular differences between ovarian endometrioid carcinoma and ovarian serous carcinoma. Jason Madore et al., J athol, 2009 (Eub ahead of print) Do High Grade Carcinomas Exist? Molecular data suggest a small group of tumors may be true high-grade endometrioid carcinomas Morphological features allowing definitive distinction between high grade serous and endometrioid carcinomas remain uncertain Recognize potential pitfalls in using individual (or a few immunohistochemical stains) to definitively classify tumors as high grade endometrioid vs. serous Ovarian carcinomas arise through a multi-step process in which clonal selection acts on cells with somatic mutations and altered gene expression to allow outgrowth of progeny with increasingly aggressive growth properties we only see snapshots of tumors undergoing active evolution The genes mutated in cancer frequently encode proteins that function in conserved signaling pathways TWO ATHOGENETIC ATHWAYS TO OVARIAN SEROUS CARCINOMA TWO ATHOGENETIC ATHWAYS TO OVARIAN ENDOMETRIOID CARCINOMA? KRAS/BRAF mutations Ch1p LOH p16 loss Type I pathway Endometriosis Atypical Endometriosis Borderline Tumor Low Grade Adenocarcinoma Wnt pathway (β-catenin) defects IK/Akt pathway (TEN, IKCA) defects T5, other? Type II pathway? T5, other? Fallopian tube T5 Mutations + CIN Ie-Ming Shih, 2008 High Grade Adenocarcinoma

5 Case Summary Given currently available treatment options, distinction between high grade endometrioid and high grade serous carcinomas is of limited importance On the horizon.distinguishing amongst subsets of high grade tumors may have implications for personalized medicine using drugs that target specific molecular defects in tumor cells Clinical History: 46 yo woman presented with bilateral ovarian masses and elevated CA125 Differential Dx: High-grade endometrioid carcinoma High-grade serous carcinoma High-grade carcinoma with mixed differentiation Final Dx: High grade ovarian carcinoma with mixed endometrioid and serous differentiation, arising in the setting of endometriosis Keywords: Ovarian carcinoma Gene expression profiling Dualistic pathway model High-grade endometrioid carcinoma High-grade serous carcinoma Slide Legend Figure 1: Endometriosis adjacent to fallopian tube Figure 2: ortion of ovary with carcinoma involving endometriotic cyst Figures -6: hotomicrographs show carcinoma with features most pathologists associate with endometrioid differentiation: solid and near-solid areas of growth admixed with well formed glands, many with round/ovoid lumens Selected References 1. McCluggage WG: My approach to and thoughts on the typing of ovarian carcinomas, J Clin athol 2008, 61: Gilks CB, Ionescu DN, Kalloger SE, Kobel M, Irving J, Clarke B, Santos J, Le N, Moravan V, Swenerton K: Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma, Hum athol 2008, 9: Lee, Rosen DG, Zhu C, Silva EG, Liu J: Expression of progesterone receptor is a favorable prognostic marker in ovarian cancer, Gynecol Oncol 2005, 96: Wu R, Hendrix-Lucas N, Kuick R, Zhai Y, Schwartz DR, Akyol A, Hanash S, Misek DM, Katabuchi H, Williams BO, Fearon ER, Cho KR: Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/B-catanin and IK/ten signaling pathways, Cancer Cell 2007, 11: hillips V, Kelly, McCluggage WG: Increased p16 expression in high-grade serous and undifferentiated carcinoma compared with other morphologic types of ovarian carcinoma, Int J Gynecol athol 2009, 28: Stewart CJ, Brennan BA, Chan T, Netreba J: WT1 expression in endometrioid ovarian carcinoma with and without associated endometriosis, athology 2008, 40: Vang R, Shih Ie M, Kurman RJ: Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems, Adv Anat athol 2009, 16: Cho KR, Shih IM: Ovarian Cancer, Annu. Rev. athol. Mech. Dis. 2009, 4:287-1.