The evolving pathogenesis model of high-grade pelvic serous carcinoma.

Although high-grade serous carcinoma involving the ovary historically was thought to originate from the ovarian surface epithelium, a growing body of literature suggests that a large proportion may arise from fallopian tube secretory epithelial cells (FTSECs) and be better termed high-grade pelvic serous carcinoma (HGPSC). The clinical ramifications of clearly understanding tumorigenesis are highlighted in the successful screening, early detection, and treatment of colon cancer, inwhich there is awell-described sequenceofmutational events that characterize the transition fromnormal epithelium topremalignant adenoma and eventually invasive carcinoma. In stark contrast, the origins of ovarian cancer are only now being elucidated, and thus it remains themost aggressive gynecologicmalignancy,with themajority of women diagnosed at an advanced stage, in which treatment is more challenging. Developing a model of high-grade serous ovarian carcinoma pathogenesis is critical, and biomarkers of early tumorigenesis may guide effective screening and treatment. A model described by Bowtell and supported by others describes primary events that include early TP53 loss followed by BRCA loss, leading to chromosomal instability and widespread copy number changes [1–3]. Secondary and tertiary events then cause global changes in gene expression followed by mutations to facilitate tumor evolution. Importantly, most models incorporate early loss of TP53 and BRCA. Potential biomarkers or therapeutic targets must consider the driver mutations and genomic events in these models that take place before the full development of carcinoma, when a multitude of subsequent mutations and copy number alterations occur to shape each individual tumor. In support of FTSECs as the origin of HGPSC, Jarboe et al. and others have described a histologic continuum of epithelial changes that have been observed in the distal fallopian tube [4,5]. The transition is postulated to occur as follows: normal fallopian tube epithelium, overexpression of TP53, serous tubal intraepithelial carcinoma (STIC), and finally, invasive serous carcinoma. Clonality of the precursor cells in both the areas that overexpress TP53, so-called p53 signature, and the STICs provide the strongest support for the distal fallopian tube as a site of origin for HGPSC [6]. Other morphologic and anatomic evidence supports this hypothesis. However, a precursor lesionwithin the fallopian tube can only be identified in approximately half of all advanced cases of HGPSC. Therefore, the site of origin may lie outside of the fallopian tube in some cases, or premalignant cells may be shed onto the ovary or into the peritoneum prior to a neoplastic lesion developing within the distal fallopian tube. The data to suggest that the ovarian cortical inclusion cyst is a site of origin for some HGPSCs represent the union of these concepts, with FTSEC being shed onto the ovarian surface and subsequently undergoing invagination into a cortical inclusion cyst, which serves as a site for malignant transformation [2].