Pathogenesis of Ovarian Cancer

Abstract

The received view of ovarian carcinogenesis is that carcinoma begins in the ovary, undergoes progressive "dedifferentiation" from a well to a poorly differentiated tumor and then spreads to the pelvic and abdominal cavities before metastasizing to distant sites. It has therefore been reasoned that survival for this highly lethal disease could be improved by developing screening methods that detect disease when it is confined to the ovary. To date, however, no prospective, randomized trial of any ovarian cancer screening test(s) has demonstrated a decrease in mortality. We believe that one of the main reasons for this is that the dogma underlying ovarian carcinogenesis is flawed. Based on studies performed in our laboratory over the last decade we have proposed a model of ovarian carcinogenesis that takes into account the diverse nature of "ovarian cancer" and correlates the clinical, pathologic and molecular features of the disease. In this model, ovarian tumors are divided into two groups designated Type I and Type II. Type I tumors are slow growing, generally confined to the ovary at diagnosis and develop from well established precursor lesions that are termed "borderline" tumors. Type I tumors include low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell carcinomas. They are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN, and beta-catenin. Type II tumors are rapidly growing, highly aggressive neoplasms for which well defined precursor lesions have not been described. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas) and undifferentiated carcinomas. This group of tumors has a high level of genetic instability and is characterized by mutation of TP53. The model helps to explain why current screening techniques, aimed at detecting stage I disease, have not been effective. Tumors that remain confined to the ovary for a long period of time belong to the Type I group but they account for only 25% of the malignant tumors. The vast majority of what is considered "ovarian cancer" belongs to the Type II category and these are only rarely confined to the ovary. Although the reasons for this are not entirely clear, it appears that some tumors evolve rapidly and spread to extra-ovarian sites early in their development. In addition, a significant number of Type II "ovarian carcinomas" develop outside the ovary, specifically, the peritoneum and fallopian tube, and involve the ovary secondarily. These tumors are advanced stage at their inception. Therefore, a more realistic endpoint for the early detection of ovarian carcinoma may be volume and not stage of disease. Thus, the model which correlates the clinical and pathologic features of "ovarian cancer" with the specific molecular genetic events that play a role in tumor progression can lead to a more rational approach to early detection and to more targeted therapeutic intervention.The received view of ovarian carcinogen...

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