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Radiogenomics of Ovarian cancer Srini Prasad MD Univ Texas MD Anderson Cancer Center Ovarian Epithelial Carcinoma: Facts and Figures • Most lethal gynecological malignancy; 90% of adult ovarian cancers; Second most common GYN cancer (US) • Estimated 22,430 new cancers with 15,280 deaths in 2007 • Lifetime-risk is 1-2% (United States) • Approx. 80% of cancers: Stage 2-4 @ Diagnosis – 70% die within 5 years of diagnosis Kurman RJ. Am J Surg Pathol 2010;34(3):433-443 Ovarian cancer is not a single disease Ovarian Carcinoma: Current Concepts • Histologically and biologically diverse disease • Characteristic histology, cytogenetics & metabolic pathways determine biology, treatment response & prognosis Ovarian Epithelial Tumors: Histological Spectrum* Type High-Grade Serous Carcinoma Low-Grade Serous Carcinoma Endometrioid Carcinoma Frequency 60-65% Clear cell Carcinoma 10% Histology 5% 10-15% *2014 World Health Organization Classification of Ovarian Tumors Ovarian Epithelial Tumors: Histological Spectrum* Type Frequency Transitional Carcinoma 5% Mucinous Carcinoma <5% Histology *2014 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 Lifetime risk for Ovarian Ca Sporadic HNPCC Syndrome BRCA1 mutation BRCA2 Mutation 1-2% 12% 40-50% 20-30% Finch et al. Gynecol Oncol 2006;100:58-64 Ovarian Cancer: BRCA 1 / 2 associated syndromes • • • • Predominantly serous carcinomas; High-grade, high-stage Better response to platinum chemotherapy; longer survival OC pill prophylaxis, prophylactic salpingo-oophorectomy? Annual GYN surveillance Finch et al. Gynecol Oncol 2006;100:58-64 Ovarian cancers develop from microscopic & macroscopic precursor lesions 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 Precursor lesions Endometrioid Carcinoma Endometriosis Endometrioid borderline tumor or adenofibroma Clear cell Carcinoma Endometriosis Clear cell adenofibroma, Borderline Tumor Malignant Brenner neoplasm Brenner neoplasm Borderline Brenner Tumor 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 Serous tubal intraepithelial carcinoma TP-53 (60-80%) HER2/neu gene (10-20%) AKT2 gene (12-18%) Low-grade Serous Carcinoma Serous cystadenoma, adenofibroma Serous Borderline Tumor B-raf, K-ras (>2/3 tumors) Mucinous Carcinoma Mucinous cystadenoma Mucinous Borderline Tumor K-ras (>60%) Nik NN et al. Annu. Rev. Pathol. Mech. Dis. 2014 Ovarian Carcinoma: Carcinogenesis Histology Precursor lesions Mutations Endometrioid Carcinoma Endometriosis Endometrioid borderline tumor or adenofibroma CTNNB-1 (>1/3 cancers) PTEN/PI3KCA (40%) MSI ( Up to 20%) Clear cell Carcinoma Endometriosis Clear cell adenofibroma, Borderline Tumor PI3KCA (33%) HNF-1β/IL6-STAT/HIF-1α HER2/neu gene Malignant Brenner neoplasm Brenner neoplasm Borderline Brenner Tumor Not well characterized Ovarian Carcinoma: HNPCC syndrome • Autosomal dominant disorder; mutations of DNA MisMatch Repair (MMR) genes hMLH1 & hMSH2 (70%) • Defective MMR genes lead to microsatellite instability & inactivation of genes that regulate cell cycle • Characterized by right colon cancers (without polyps), endometrial and ovarian cancers • Stage I/II ovarian cancers at an early age • Serous or endometrioid histopathology Prat J. Hum Pathol. 2005;36(8):861-70 Endometriosis Associated Ovarian Carcinoma • 1-2% of endometriosis shows 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 Ovarian Carcinoma: Clinical Implications • Histology determines tumor biology/stage, prognosis & response to chemotherapy – Mucinous, low-grade serous & clear cell cancers: chemoresistant • High grade & low-grade serous cancers respond differently – Platinum vs Pathway specific chemotherapy • Endometriosis predisposes to endometrioid & clear cell Ca • Endometrioid carcinoma is associated with endometrial Ca • 85% of patients with serous carcinoma have advanced disease; 5-year survival is a dismal 10-20% Kurman RJ. Am J Surg Pathol 2010;34(3):433-443 Ovarian Carcinoma: Clinical Implications • Screening – Type I vs Type II cancers (Low stage vs low volume disease) • Prophylactic salpingectomy vs salpingo-oophorectomy – Hereditary cancer syndromes • Treatment – Pathway specific vs platinum chemotherapy – Her2/Neu upregulated in clear cell carcinoma: may respond to anti- Her2/Neu antibody (Herceptin) therapy – Drugs aimed at MAPK/BRAF: ?Help in low-grade serous Ca Kurman RJ. Am J Surg Pathol 2010;34(3):433-443 Ovarian Carcinoma: Conclusions • • • • Most ovarian ‘cancers’ likely arise from outside the ovary ?Changes in screening, prophylaxis and treatment paradigms Imaging: A major role in diagnosis, staging & management Molecular imaging: Help in early/recurrent disease, drug development? Thank you all