Intercepting pelvic cancer in the distal fallopian tube: theories and realities

Abstract

The pathogenesis of high-grade serous carcinoma of the ovary has come into sharper focus as closer attention has been paid to the earlier phases of this disease. The study of patients with BRCA mutation has been of particular value, in as much as the examination of prophylactic salpingo-oophorectomies will reveal an early cancer in approximately 5% of individuals. Recently studies have shown that about 80% of these early carcinomas originate in the distal fallopian tube. This review summarizes the recent data supporting the distal fallopian tube as an important site for serous carcinogenesis, stressing both the presence of a novel precursor (the p53 signature) and the application of this model to all women irrespective of BRCA status. The challenges and unmet needs unmasked by this paradigm shift in ovarian cancer research are discussed.

Figure 1

– Morphologic and immunohistochemical correlates of a serous carcinogenic sequence in the distal fallopian tube. Step I, the p53 signature characterized by normal appearing epithelium with nuclear p53 immunostaining and a low proliferative index. Step II, an intermediate lesion, with increased proliferation and mild epithelial atypia. Step III, a tubal intraepithelial carcinoma, with neoplastic epithelium and high proliferative index.

Figure 2

– Schematic of the distal fallopian tube and two pathways to pelvic serous cancer. In one pathway, passive transfer of normal cells from the fimbria (green dots) leads to ovarian cortical inclusions that are usually quiescent but may ultimately evolve into serous malignancy via endometriosis or low‐grade tumors. In the second pathway, several tubal mucosal epithelial entities, including normal secretory cells (green), p53 signatures (yellow), and tubal intraepithelial carcinoma (STIC, red) are linked by a series of connected biologic events including unrepaired genotoxic injury, unregulated cell growth, and eventually, acquisition of a metastatic phenotype. The latter permits spread to the ovarian or peritoneal surfaces (red dots).