Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer

Abstract

Ovarian epithelial cancer is diagnosed in approximately 25,000 women yearly in the United States, accounting for approximately 12,500 deaths. Of these tumors, serous cancer is the most lethal, due to its capacity to spread beyond the reproductive tract and involve the peritoneal surfaces or distant organs. Conventional classification systems designate tumor origins principally on the location of the largest tumor. However, despite the fact that the largest tumors typically involve the ovaries, demonstrations of a precise starting point for these tumors, including precursor lesions, have been inconsistent. In recent years, a major effort to prevent serous cancer in genetically susceptible women with mutations in BRCA1 or BRCA2 has spawned the practice of prophylactic salpingo-oophorectomy. This practice has surprisingly revealed that many early cancers in these women arise in the fallopian tube, and further studies have pinpointed the distal (fimbrial) portion as the most common site of origin. Emerging studies that carefully examine the fallopian tubes suggest a high frequency of early cancer in the fimbria in unselected women with ovarian and peritoneal serous carcinoma, raising the distinct possibility that a significant proportion of these tumors have a fimbrial origin. The evidence for these discoveries and their relevance to serous cancer classification, early detection and prevention are addressed in this review. A model for pelvic serous cancer is proposed that takes into account five distinct variables which ultimately impact on origin and tumor distribution: (1) location of target epithelium, (2) genotoxic stress, (3) type of epithelium, (4) mitigating genetic factors, and (5) tumor spread pattern. Ultimately, this model illustrates the importance of identifying cancer precursors, inasmuch as these entities are useful as both surrogate endpoints for their respective malignancies in epidemiologic studies and natural targets for cancer prevention.

Figure 1.

Example of an ovarian tumor with a broad phenotypic range arising by a sequence of genetic events (so-called Type I tumor).^– (A) A large ovarian cyst contains evidence of preexisting endometriosis (small arrow) in which a clear cell carcinoma has developed (large arrow). Elsewhere in the cyst, (B) benign endometrial epithelium is juxtaposed with (C) a mucinous cystadenoma and (D) the malignant tumor. Type II high-grade serous carcinoma of presumably short duration frequently involve (E and F) the ovarian surface. However, many are associated with (G) an early carcinoma in the distal fallopian tube.^,

Figure 2.

Appearance of early serous cancer (intraepithelial carcinoma, arrow) arising in the fimbria of a BRCA+ woman and merging with invasion (A, left). These tumors are typically (but not necessarily) strongly positive for p53 protein by immunohistochemistry (B), reflecting in most cases a p53 mutation.

Figure 3.

Normal appearing salpingeal mucosa (A) with strong p53 positivity (B). p53 signatures share many similarities (e.g., cell type, location, p53 mutations) with serous carcinoma.

Figure 4.

This proposed model integrates the molecular models of ovarian cancer with the fimbrial model of serous carcinogenesis, further taking into account cell of origin and pattern of spread.^,,, The pathway on the right originates in the ovarian epithelial inclusions, giving rise to most Type I neoplasms (and less commonly, serous carcinomas) by step-wise mutations, and includes endometriosis, benign and borderline cystadenomas. The pathway on the left would arise in either the fimbrial mucosa or tubal epithelium that has become adherent to the ovarian cortex (endosalpingiosis). In this pathway, the initial step consists of a p53 mutation following genotoxic injury (the “p53 signature”). In the fimbria, a tubal intraepithelial carcinoma (TIC) develops in some instances and may invade locally or exfoliate to other peritoneal (e.g., ovary or pelvis) surfaces. Depending on the location and rate of tumor growth, the tumor might be presumed to originate from the tube, ovary, or peritoneum. This would explain many, but not all, high grade (Type II) tumors.