Ovarian cancer: 2012 Update Srini Prasad MD Univ Texas MD Anderson Cancer Center

Ovarian cancer: 2012 Update Srini Prasad MD Univ Texas MD Anderson Cancer Center

Ovarian cancer is not a single disease

Ovarian Epithelial Tumors: Histological Spectrum* Type Frequency Histology High-Grade Serous Carcinoma 60-65% Low-Grade Serous Carcinoma 5% Endometrioid Carcinoma 10-15% Clear cell Carcinoma 10% *2002 World Health Organization Classification of Ovarian Tumors

Ovarian Epithelial Tumors: Histological Spectrum* Type Frequency Histology Transitional Carcinoma 5% Mucinous Carcinoma <5% *2002 World Health Organization Classification of Ovarian Tumors

10% ovarian cancers are hereditary

Ovarian Carcinoma: Hereditary syndromes Hereditary forms: Distinct clinicopathological features Mutations of tumor-suppressor genes BRCA 1 & 2 (90%) Ovarian cancer syndrome Breast & Ovarian cancer syndrome Mutations of DNA MisMatch Repair (MMR) genes hmlh1 & hmsh2 (10%) Hereditary non-polyposis colorectal cancer HNPCC (Lynch-II) Finch et al. Gynecol Oncol 2006;100:58-64

Ovarian Carcinoma: Risk Stratification Sporadic HNPCC BRCA1 BRCA2 Syndrome mutation Mutation Lifetime risk for Ovarian Ca 1-2% 12% 40-50% 20-30% Finch et al. Gynecol Oncol 2006;100:58-64

BRCA-1 syndrome: Ovarian cancer

BRCA 2 syndrome: Ovarian cancer

Adnexal carcinomas?

Adnexal carcinomas? The era of indifference to the fallopian tube has passed Pauerstein & Woodruff. Txt on Fallopian Tube.1969

High-grade Ovarian Serous Carcinoma

Ovarian cancers develop from microscopic & macroscopic precursor lesions

Serous Ovarian Carcinoma: Step-wise progression Cystadenoma Serous borderline tumor Low-grade serous carcinoma

Ovarian Carcinoma: Carcinogenesis Histology High-grade Serous Carcinoma Precursor lesions Serous tubal intraepithelial carcinoma Low-grade Serous Carcinoma Serous cystadenoma, adenofibroma Serous Borderline Tumor Mucinous Carcinoma Mucinous cystadenoma Mucinous Borderline Tumor

Ovarian Carcinoma: Carcinogenesis Histology Endometrioid Carcinoma Clear cell Carcinoma Precursor lesions Endometriosis Endometrioid borderline tumor or adenofibroma Endometriosis Clear cell adenofibroma, Borderline Tumor Malignant Brenner neoplasm Brenner neoplasm Borderline Brenner Tumor

Endometriosis Associated Ovarian Carcinoma 40% of endometrioid carcinomas are associated with endometriosis 50% of clear cell carcinomas are associated with endometriosis

Endometriosis Associated Ovarian Carcinoma 1-2% of endometriosis show malignant change Sequential genetic changes cause malignant transformation EAOC is typically low stage/low grade, predominantly clear-cell (most common subtype) or endometrioid type, & portend a better prognosis

Endometriosis Associated Ovarian Carcinoma Endometrium β-catenin,il-6 ER,PR Endometriosis PTEN,hMLH1 LOH 9p,11q,22q Atypical Endometriosis PTEN, TP53 β-catenin, LOH 6q,5q Endometrioid / Clear Cell Cancer *Sequential Cytogenetic March of Endometriosis to Endometriosis-Associated Ovarian Carcinoma

Metastatic mucinous cancer from the appendix

Metastatic mucinous cancer from sigmoid colon primary

Ovarian Epithelial Carcinoma: Histogenesis?Fallopian tube/ Ovary? Epithelial inclusion cysts? Secondary Mullerian system Endometriosis TP53 & BRCA mutations BRAF/KRAS mutations PTEN/β-catenin mutations PTEN/PI3KCA mutations Borderline Tumor High Grade Serous Ca Low Grade Serous Ca Endometrioid Carcinoma Clear cell Carcinoma Katre R. Am J Roentgenol; Lalwani N. Radiographics

Each ovarian cancer subtype shows distinctive genetics & biology

Molecular Genetics in Clinical Practice The Devil is in the DNA *Chanock, Thomas. Nat Genet 2007;39(3):283-4

Ovarian Carcinoma: Carcinogenesis Histology Precursor lesions Mutations High-grade Serous Carcinoma Low-grade Serous Carcinoma Mucinous Carcinoma Serous tubal intraepithelial carcinoma Serous cystadenoma, adenofibroma Serous Borderline Tumor Mucinous cystadenoma Mucinous Borderline Tumor TP-53 (60-80%) HER2/neu gene (10-20%) AKT2 gene (12-18%) B-raf, K-ras (>2/3 tumors) K-ras (>60%)

Ovarian Carcinoma: Carcinogenesis Histology Precursor lesions Mutations Endometrioid Carcinoma Clear cell Carcinoma Malignant Brenner neoplasm Endometriosis Endometrioid borderline tumor or adenofibroma Endometriosis Clear cell adenofibroma, Borderline Tumor Brenner neoplasm Borderline Brenner Tumor CTNNB-1 (>1/3 cancers) PTEN/PI3KCA (40%) MSI ( Up to 20%) PI3KCA (33%) HNF-1β/IL6-STAT/HIF- 1α HER2/neu gene Not well characterized

Ovarian carcinoma: Chemotherapy Cancers are like cockroaches; both are difficult to kill.

Ovarian cancer: Conclusions Ovarian cancers are histo-pathologically heterogeneous Most ovarian cancers likely arise from outside the ovary Biological diversity: type 1 are indolent, usually confined to the ovary; type 2 are widely metastatic High grade serous is platinum sensitive; low grade serous, mucinous & clear cell cancers are chemo-resistant?changes in screening, prophylaxis, prognosis &treatment paradigms