Ovarian cancer update: lessons from morphology, molecules, and mice

Abstract

Ovarian carcinomas are a heterogeneous group of neoplasms. Pathologists currently employ a morphology-based classification system to divide ovarian carcinomas into major subgroups based on degree (tumor grade) and type of differentiation (eg, serous, endometrioid, clear cell, or mucinous). Molecular studies have shown that specific genetic defects are likely to be present in certain histologic types of ovarian carcinomas and unlikely to be present in others. Within the serous and endometrioid carcinomas, the molecular defects in low-grade versus high-grade tumors also appear to be largely distinct. Recently, mouse models of ovarian carcinoma have been developed that recapitulate many of the morphologic features and biologic behavior of selected subtypes of ovarian cancer. It is expected that these mouse models will yield new insights into ovarian cancer pathogenesis and prove useful for preclinical testing of novel strategies for ovarian cancer treatment.

Figure 1

Representative photomicrographs of the four major histopathologic types of ovarian carcinoma. A) Serous carcinomas comprise approximately 70% of ovarian carcinomas and frequently harbor TP53 mutations. B) Mucinous carcinomas are rarest (approximately 3%) and often harbor KRAS mutations. C) Endometrioid carcinomas (≈10–15%) have relatively frequent mutations of CTNNB1, PIK3CA, KRAS and TP53. D) Clear cell carcinomas (≈10%) have the highest frequency of PIK3CA mutations. All sections stained with hematoxylin & eosin; original magnification X200.

Figure 2

Gene expression profiling of primary ovarian carcinomas. A) Principal component analysis (PCA) of 99 ovarian carcinomas using all probe sets on the U133A array; the first two principal components are shown. Individual tumors are annotated with histopathologic type as indicated (green-OS, serous; blue-OM, mucinous; yellow-OC, clear cell; and red-OE, endometrioid); B) Same PCA plot showing only serous carcinomas; C) Same PCA plot showing only serous and clear cell carcinomas; D) Same PCA plot showing only serous and mucinous carcinomas; E) Same PCA plot showing only serous and endometrioid carcinomas; F) Same PCA plot showing only endometrioid carcinomas annotated with mutational status of CTNNB1, APC, PTEN and PIK3CA as indicated; G) Same PCA plot showing only endometrioid carcinomas annotated with mutational status of CTNNB1, APC, PTEN, PIK3CA, and TP53 as indicated. ****Figure (modified version) reprinted from Cancer Cell, 11:321–333, 2007 (R Wu et al., Mouse Model of Human Ovarian Endometrioid Adenocarcinoma Based on Somatic Defects in the Wnt/β-Catenin and PI3K/Pten Signaling Pathways) with permission from Elsevier.