Theories of endometrial carcinogenesis: A multidisciplinary approach

Historical observations have suggested that endometrial carcinomas vary in histopathologic appearance and clinical features. More recent, systematic s tudies have provided epidemiologic, clinicopathologic, and molecular suppor t for these observations. Specifically, studies suggest that the most commo n type of endometrial carcinoma, endometrioid adenocarcinoma, develops from endometrial hyperplasia in the setting of excess estrogen exposure and usu ally pursues an indolent clinical course, In contrast, a minority of endome trial carcinomas, best represented by serous carcinoma, do not seem to be r elated to estrogenic risk factors or elevated serum hormone levels, and the se tumors seem to develop from atrophic rather than hyperplastic epithelium . We have proposed that serous carcinomas develop from "endometrial intraep ithelial carcinoma," a lesion representing malignant transformation of the endometrial surface epithelium. Whereas endometrioid carcinoma and endometr ial hyperplasia are associated with microsatellite instability and ras and PTEN mutations, serous carcinoma and endometrial intraepithelial carcinoma are associated with p53 mutations and abnormal accumulation of p53 protein. Based on these data regarding the pathogenesis of endometrioid and serous carcinoma, we have proposed a dualistic model of endometrial carcinogenesis incorporating a "classic" estrogen-driven pathway and an "alternative" pat hway seemingly unrelated to hormones. It is hoped that further studies may permit the extension and modification of this model and that these advances will lead to improved diagnosis, management, and prevention.