The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory

Abstract

Ovarian cancer is the most lethal gynecologic malignancy. Efforts at early detection and new therapeutic approaches to reduce mortality have been largely unsuccessful, because the origin and pathogenesis of epithelial ovarian cancer are poorly understood. Despite numerous studies that have carefully scrutinized the ovaries for precursor lesions, none have been found. This has led to the proposal that ovarian cancer develops de novo. Studies have shown that epithelial ovarian cancer is not a single disease but is composed of a diverse group of tumors that can be classified based on distinctive morphologic and molecular genetic features. One group of tumors, designated type I, is composed of low-grade serous, low-grade endometrioid, clear cell, mucinous and transitional (Brenner) carcinomas. These tumors generally behave in an indolent fashion, are confined to the ovary at presentation and, as a group, are relatively genetically stable. They lack mutations of TP53, but each histologic type exhibits a distinctive molecular genetic profile. Moreover, the carcinomas exhibit a shared lineage with the corresponding benign cystic neoplasm, often through an intermediate (borderline tumor) step, supporting the morphologic continuum of tumor progression. In contrast, another group of tumors, designated type II, is highly aggressive, evolves rapidly and almost always presents in advanced stage. Type II tumors include conventional high-grade serous carcinoma, undifferentiated carcinoma, and malignant mixed mesodermal tumors (carcinosarcoma). They displayTP53 mutations in over 80% of cases and rarely harbor the mutations that are found in the type I tumors. Recent studies have also provided cogent evidence that what have been traditionally thought to be primary ovarian tumors actually originate in other pelvic organs and involve the ovary secondarily. Thus, it has been proposed that serous tumors arise from the implantation of epithelium (benign or malignant) from the fallopian tube. Endometrioid and clear cell tumors have been associated with endometriosis that is regarded as the precursor of these tumors. As it is generally accepted that endometriosis develops from endometrial tissue by retrograde menstruation, it is reasonable to assume that the endometrium is the source of these ovarian neoplasms. Finally, preliminary data suggest that mucinous and transitional (Brenner) tumors arise from transitional-type epithelial nests at the tubal-mesothelial junction by a process of metaplasia. Appreciation of these new concepts will allow for a more rationale approach to screening, treatment, and prevention that potentially can have a significant impact on reducing the mortality of this devastating disease.

Figure 1

Serous tubal intraepithelial carcinoma (STIC). A. High magnification. Hematoxylin and eosin stain. B. Immunohistochemical stain for p53. An asterisk defines the boundary of the lesion.

Figure 2

Transfer of normal tubal epithelium to the ovary. A. Anatomical relationship of fallopian tube to the ovary at the time of ovulation. The fimbria envelops the ovary. B. Ovulation. The ovarian surface ruptures with expulsion and transfer of the oocyte to the fimbria. The fimbria is in intimate contact with the ovary at the site of rupture. C. Tubal epithelial cells from the fimbria are dislodged and implant on the denuded surface of the ovary resulting in the formation of an inclusion cyst.

Figure 3

Proposed development of low-grade (LG) and high-grade (HG) serous carcinoma. A. One mechanism involves normal tubal epithelium that is shed from the fimbria, which implants on the ovary to form an inclusion cyst. Depending on whether there is a mutation of KRAS/BRAF/ERRB2 or TP53 a low-grade or high-grade serous carcinoma develops respectively. Low-grade serous carcinoma often develops from a serous borderline tumor (SBT), which in turn arises from a serous cystadenoma. Another mechanism involves exfoliation of malignant cells from a serous tubal intraepithelial carcinoma (STIC) that implants on the ovarian surface resulting in the development of a high-grade serous carcinoma. B. A schematic representation of direct dissemination or shedding of STIC cells onto the ovarian surface where the carcinoma cells ultimately establish a tumor mass that is presumably arising from the ovary. Of note there may be stages of tumor progression that precede the formation of a STIC.

Figure 4

Proposed development of low-grade endometrioid and clear cell carcinoma. Endometrial tissue, by a process of retrograde menstruation, implants on the ovarian surface to form an endometriotic cyst from which a low-grade endometrioid or clear cell carcinoma can develop. EMC: low-grade endometrioid carcinoma of the ovary; CCC: clear cell carcinoma of the ovary.

Figure 5

Comparison of the immunohistochemical staining pattern for ovarian surface epithelium (mesothelium), normal fallopian tube epithelium, and high-grade serous carcinoma. PAX8 is a marker of mullerian-type epithelium such as fallopian tube epithelium and calretinin is a marker of mesothelium.