Diverse tumorigenic pathways in ovarian serous carcinoma

Abstract

This study was undertaken to analyze genetic alterations in 108 sporadic serous ovarian neoplasms to elucidate ovarian serous carcinogenesis. Our results demonstrate that K-ras mutations occur in approximately 50% of serous borderline tumors (SBTs), non-invasive micropapillary serous carcinomas (MPSCs), and invasive micropapillary serous carcinomas, which represent a morphological continuum of tumor progression. Moreover, progressive increase in the degree of allelic imbalance of chromosomes 1p, 5q, 8p, 18q, 22q, and Xp was observed comparing serous borderline tumors to noninvasive and invasive micropapillary serous carcinomas. In contrast, high-grade (conventional serous carcinoma) tumors contained wild-type K-ras in all 23 cases studied and a high frequency of allelic imbalance even in small (early) primary tumors similar to that found in advanced stage tumors. Based on these findings, we propose a dualistic model for ovarian serous carcinogenesis. One pathway involves a stepwise progression from SBT to noninvasive and then invasive MPSC. The other pathway is characterized by rapid progression from the ovarian surface epithelium or inclusion cysts to a conventional (high-grade) serous carcinoma.

Figure 1.

A: Morphological features of the different ovarian serous neoplasms. i: SBT with focal transition to a micropapillary area (asterisk). These focal micropapillary areas are not infrequent in SBTs. ii: Noninvasive MPSC completely replaces an ovary. The tumor is characterized by broad fibrotic papillae from which numerous long delicate micropapillary projections emanate. iii: Noninvasive MPSC (in the upper field) with an area of early invasion (invasive MPSC; right lower field with arrows). iv: Invasive MPSC. The low-grade nuclear features in the invasive carcinoma are the same as in the noninvasive counterpart. Original magnification, ×250. B: Morphological features of conventional serous carcinoma. i: Small (early) conventional serous carcinoma. The tumor measures 0.7 cm and appears to arise from the overlying ovarian surface epithelium. ii: Conventional serous carcinoma. In this area the tumor is composed of solid masses. iii: Conventional serous carcinoma. Spaces within the masses create a pseudopapillary structure as a result of cellular necrosis and processing artifact. The tumor cells contain highly atypical nuclei. Original magnification, ×400.

Figure 2.

Summary of the results of allelic status in ovarian serous tumors. Each panel represents a group of serous tumors: SBT, noninvasive MPSC, invasive MPSC, and conventional serous carcinoma. Chromosomal arms in which the SNP markers are located are indicated on the left of each panel. In the vertical columns, each column represents one case. Black squares represent chromosomal arms in which allelic imbalance is identified based on the digital SNP analysis, while gray squares represent chromosomal arms in which both alleles were in balance. Blank squares indicate chromosomal arms that cannot be evaluated because the allelic ratio in the SPRT analysis does not achieve a statistical significant difference or because all SNP markers tested are uninformative in the normal tissue. The very small conventional serous carcinomas (maximal dimension 0.6 and 0.7 cm) are marked with asterisks.

Figure 3.

Schematic representation of the dualistic model depicting the development of ovarian serous carcinomas, the most common type of ovarian cancer. In one pathway invasive MPSC develops in a stepwise fashion from a SBT through a noninvasive stage of MPSC before becoming invasive. These tumors are associated with frequent K-ras mutations. Increased allelic imbalance of chromosome 5q is associated with the progression from SBT to MPSC and increased allelic imbalance of chromosome 1p with the progression from noninvasive to invasive MPSC. In the second pathway, conventional serous carcinoma, a high-grade neoplasm, exhibits a solid and/or pseudopapillary morphology and develops from the ovarian surface epithelium without morphologically recognizable intermediate stages. K-ras mutations have not been found in all these neoplasms tested.