The current theory of carcinogenesis for the deadliest of “ovarian” cancers – high-grade serous carcinoma (HGSC) – holds that the malignancy develops first in the fallopian tube and spreads to the ovaries, peritoneum and/or regional lymph nodes. This is based primarily on the observation of early forms of serous neoplasia (serous tubular intraepithelial lesions (STILs), and serous tubular intraepithelial carcinomas (STICS)) in the fimbria of women undergoing risk reduction surgery. However, these lesions are uncommon in the general population, confer a low risk (5%) of HGSC following their removal in at-risk women with germ-line BRCA1/2 mutations and require 4 or more years to recur as intraperitoneal HGSC. These features suggest that isolated STILs and STICs behave as precursors with uncertain cancer risk rather than carcinomas. Their evolution to HGSC after escape from the tube could proceed step-wise with multiple biologic events; however, it is unclear whether immediately adjacent HGSCs in the setting of advanced disease evolved in the same fashion. The latter scenario could also be explained by a “catastrophic” model in which STICs suddenly develop with invasive and metastatic potential, overwhelming or obscuring the site of origin. Moreover, a similar model might explain the sudden emergence of HGSC in the peritoneal cavity following escape of precursor cells years before. Long term follow-up data from opportunistic or prophylactic salpingectomy should shed light on where malignant transformation occurs, as well as the time-line from precursor to metastatic HGSC.
