Origins and molecular pathology of ovarian cancer

Abstract

Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. Current data indicate that each of these histologic subtypes is associated with distinct morphologic and molecular genetic alterations: high-grade serous and possibly endometrioid carcinomas most probably arise from surface epithelial inclusion glands with TP53 mutations and dysfunction of BRCA1 and/or BRCA2; low-grade serous carcinomas probably arise in a stepwise fashion in an adenoma-borderline tumor-carcinoma sequence from typical to micropapillary borderline tumors to low-grade invasive serous carcinoma via activation of the RAS-RAF signaling pathway secondary to mutations in KRAS and BRAF; mucinous carcinomas arise via an adenoma-borderline tumor-carcinoma sequence with mutations in KRAS; low-grade endometrioid carcinomas arise from endometriosis via mutations in CTNNB1 (the gene encoding b-catenin) and PTEN. Although the morphologic data strongly support an origin of clear cell carcinoma from endometriosis, there is limited data on the genetic alterations in these uncommon tumors. Thus it is likely that most low-grade, relatively indolent ovarian carcinomas of serous, mucinous and endometrioid type arise from pre-existing cystadenomas or endometriosis whereas most high-grade serous carcinomas arise without an easily identifiable precursor lesion. Modern Pathology (2005) 18, S19-S32. doi:10.1038/modpathol.3800306Keywords: ovarian cancer; ovarian borderline tumors; histogenesis; molecular pathology Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. 1,2 Two types of ovarian surface epithelial lesions have been described as possible precursors of these carcinomas: lesions that appear in situ in surface epithelium or surface epithelial inclusion glands (SEIG); and preexisting benign epithelial ovarian tumors and endometriosis. The morphologic and genetic data implicating each as a precursor lesion of the major histologic subtypes of ovarian carcinoma are discussed. Surface epithelium and surface epithelial inclusion glands as precursor lesions Morphologic DataTwo types of morphologic data are available regarding the malignant potential of ovarian surface epithelium and inclusion glands, alterations in these structures and studies on microscopic ovarian carcinoma.Surface epithelium and surface epithelial inclusion glands Despite the widespread acceptance of the origin of surface epithelial cancers from the ovarian surface epithelium and its inclusion glands, only rarely have putative precursor lesions been described at these sites. Two...

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