Ovarian cancer pathogenesis: a model in evolution

Abstract

Ovarian cancer is a deadly disease for which there is no effective means of early detection. Ovarian carcinomas comprise a diverse group of neoplasms, exhibiting a wide range of morphological characteristics, clinical manifestations, genetic alterations, and tumor behaviors. This high degree of heterogeneity presents a major clinical challenge in both diagnosing and treating ovarian cancer. Furthermore, the early events leading to ovarian carcinoma development are poorly understood, thus complicating efforts to develop screening modalities for this disease. Here, we provide an overview of the current models of ovarian cancer pathogenesis, highlighting recent findings implicating the fallopian tube fimbria as a possible site of origin of ovarian carcinomas. The ovarian cancer model will continue to evolve as we learn more about the genetics and etiology of this disease.

Figure 1

The major histologic subtypes of ovarian carcinoma. Serous carcinomas resemble fallopian tube epithelium, endometrioid carcinomas resemble endometrial glands, and mucinous carcinomas resemble endocervical epithelium. Photographs show representative tumor sections stained with hematoxylin and eosin. The shaded circle represents the general anatomical location from which ovarian carcinomas are thought to arise. The pink and blue entities within the cross-sected ovary represent maturing ovarian follicles.

Figure 2

Pathologic features of the morphological continuum from normal fallopian tube epithelium to invasive serous carcinoma. Normal fallopian tube epithelium (FTE), containing both secretory (thick arrow) and ciliated (thin arrow) cells, is typically immunonegative for p53, γ-H2AX (a marker of DNA damage), and MIB1 (antibody against Ki67; a proliferation marker). The benign “p53 signature” is composed of a stretch of secretory cells exhibiting strong p53 expression and evidence of DNA damage (i.e., nuclear γ-H2AX foci), but showing no signs of proliferation. Upon progression to TIC, there is an acquisition of proliferative capacity, as evidenced by gain of MIB1 immunoreactivity. High levels of p53, γ-H2AX, and MIB1 typically persist after a TIC develops into invasive serous carcinoma.

Figure 3

Diagram of a fimbrial plica, illustrating the stepwise progression of normal fallopian tube epithelium to invasive serous carcinoma. The fallopian tube epithelium (FTE) is composed of a single layer of ciliated and secretory cells that are exposed to ovulation-associated inflammatory cytokines and reactive oxygen species (ROS). Repetitive genotoxic stress causes DNA damage and induces p53 mutation, leading to the clonal expansion of normal looking FTE cells of secretory phenotype. This stretch of damaged cells—termed a “p53 signature”—stains strongly for p53 and γ-H2AX. Further genetic “hits” enable cells to acquire a proliferative capacity, giving rise to tubal intraepithelial carcinoma (TIC). As a TIC progresses to invasive serous carcinoma, malignant cells are exfoliated from the fimbria, whereupon they may spread rapidly to the surface of the peritoneum and/or ovary. Exfoliation may also occur from TICs prior to fimbrial invasion.