New insights into the pathogenesis of serous ovarian cancer and its clinical impact

Abstract

There are only a handful of concepts concerning cancer and carcinogenesis that are currently beyond dispute. One such dogma is the adenoma-carcinoma sequence and that a multistep accumulation of genetic alterations is required for transformation from a benign to a neoplastic tissue. The inevitable derivative of this dogma is that every invasive carcinoma is in fact a missed intraepithelial tumor, and furthermore, a late evolutionary stage in the sequence of development from a precursor lesion. Until fairly recently, high-grade serous ovarian carcinoma seemed to be one of the only known deviants of these concepts. In this article, we discuss the emergence of the fallopian tube fimbria as a field of origin for high-grade serous carcinomas and present a binary model of ovarian cancer pathogenesis that takes into consideration prior epidemiologic, morphologic, and genetic data. With the rise of the fallopian tube secretory epithelial cell as a cell of origin for high-grade pelvic serous carcinomas, the need to develop tools and model systems to characterize the biology and physiology of this cell is recognized.

Fig 1.

Transformation of ovarian surface epithelium (OSE). The OSE undergoes cyclic ovulation-induced rupture, leading to formation of cortical inclusion cysts (CICs). Entrapped within the ovarian cortex, the OSE undergoes Müllerian metaplasia, and is exposed to hormone and inflammatory stimuli that induce replicative stress and DNA damage which can lead to defined mutations and transformation into mucinous, endometrioid, and low-grade serous carcinomas.

Fig 2.

Pathologic features of the fallopian tube (FT) carcinogenesis spectrum. While normal FT epithelium contains both ciliated and secretory cells, p53 signature—the proposed precursor lesion—is characterized by normal tissue morphology with p53-positive secretory cells harboring DNA damage (γ-H2A.X staining). Tubal intraepithelial carcinoma (TIC) shares these features but has acquired a proliferative advantage (increased Ki-67/MiB1 staining). Invasive serous carcinoma shows increased proliferation and disruption of the basement membrane.

Fig 3.

High-grade serous carcinogenic sequence. The spectrum of fallopian tube (FT) epithelial transformation ranges from normal epithelium, through p53 signature, an intraepithelial, and eventually, an invasive carcinoma. Exfoliation into the peritoneal cavity is an early event. This model suggests that all types of pelvic serous tumors are the same entity, the majority of which originate from the FT fimbria. TIC, tubal intraepithelial carcinoma.

Fig 4.

An integrated model of high-grade serous carcinogenesis. This model integrates the data about the stepwise development of serous carcinoma in the fimbria of the fallopian tube (FT) and in the ovarian surface epithelium (OSE) –derived cortical inclusion cysts (CICs). The hormone stimulation and the inflammatory mediators involved in ovulation are believed to have similar carcinogenic effect in both pathways.