Mutational analysis of K-ras segregates ovarian serous carcinomas into two types: Invasive MPSC (low-grade tumor) and conventional serous carcinoma (high-grade tumor)

We previously proposed a dualistic model for ovarian serous carcinogenesis. One pathway involves the stepwise development of invasive micropapillary serous carcinoma (MPSC) from serous borderline tumor (atypical proliferative serous tumor) to noninvasive and then invasive MPSC. The carcinomas that develop in this fashion are characterized by low-grade nuclei and frequent K-ras mutations. They generally pursue an indolent course. In the other pathway conventional serous carcinoma (CSC) develops de novo from the ovarian surface epithelium without what appears to be intermediate stages. These tumors display high-grade nuclei, wild-type K-ras, and are very aggressive. Some of these CSCs display micropapillary architecture and simulate invasive MPSCs. This raises the possibility that these CSCs develop from an invasive MPSC. To address this question we reviewed 31 moderately and poorly differentiated CSCs and identified 7 with morphological features of invasive MPSC. These seven tumors exhibited micropapillary architecture in at least 25% of the tumor but contained high-grade nuclei. The 31 tumors were assessed for K-ras mutations using digital polymerase chain reaction-based analysis. Despite their micropapillary architecture, all 7 CSCs with micropapillary features contained wild-type K-ras as did the other 24 pure CSCs. The results indicate that CSCs with micropapillary features are not derived from invasive MPSCs. The molecular findings also support the view that ovarian serous carcinomas should be graded as low- and high-grade tumors.