GENETIC DISPARITY BETWEEN MORPHOLOGICALLY BENIGN CYSTS CONTIGUOUS TO OVARIAN CARCINOMAS ACID SOLITARY CYSTADENOMAS

Background: Ovarian carcinomas occasionally contain large, histologica lly benign cysts contiguous to the clearly malignant areas (cystadenoc arcinomas). The question of whether such cysts are remnants of pre-exi sting benign tumors (cystadenomas) or constitute integral components o f the carcinomas is important in clarifying the role of cystadenomas i n ovarian carcinogenesis. It is also important for our general underst anding of tumor heterogeneity, a phenomenon thought to result from the gradual accumulation of genetic abnormalities in initially homogeneon s tumors. This question is also pertinent to the clinical management o f ovarian cystadenomas, which are frequent in women of childbearing ag e and are usually treated surgically based on the possibility that the y may give rise to carcinomas. Purpose: Reasoning that molecular marke rs of ovarian malignancy would be confined to the histologically malig nant portions of cystadenocarcinomas if the morphologically benign por tions are in fact pre-existing typical cystadenomas, we sought to veri fy that mutations in the p53 tumor suppressor gene are markers of mali gnancy in ovarian tumors and to determine the distribution of such mut ations in cystadenocarcinomas. Methods: We used immunohistochemical an d DNA-sequencing techniques to analyze 46 ovarian carcinomas, 21 ovari an tumors of low malignant potential, and 16 solitary cystadenomas for the presence of p53 mutations. We then used similar techniques to exa mine the distribution of such mutations in different portions of cysta denocarcinomas. The observed differences in mutation frequencies were analyzed by the two-tailed Fisher's exact test. Results: Mutations in the p53 gene were present in 24 (52%) of the 46 carcinomas, but they w ere absent in the 21 tumors of low malignant potential (P<.0001) and t he 16 solitary cystadenomas (P = .0002). Six of six cystadenocarcinoma s with p53 mutations showed the presence of the same mutations in the adjacent, histologically benign cysts. The mutations were seen not onl y in cells immediately adjacent to the carcinomas, but also throughout the morphologically benign cysts. Twenty (83%) of the 24 cases showin g mutation of one p53 allele also showed loss of genetic heterozygosit y, suggesting that the other p53 allele was deleted. Such allelic loss , if present in morphologically malignant portions of cystadenocarcino mas, was also observed in the contiguous cysts. Conclusions: Ovarian c arcinomas can be distinguished from ovarian cystadenomas and tumors of low malignant potential by p53 mutations. The fact that the mutations were present in histologically benign cysts contiguous to ovarian car cinomas suggests that such cysts are not typical cystadenomas and may carry a genetic predisposition to carcinogenesis that is not present i n ordinary cystadenomas.