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Fortunately, as many as three-quarters of women with endometrial cancers present with localized disease and have an expected five year survival of 75%. The presence of abnormal vaginal discharge or bleeding (the most common symptoms of this disease) permits early detection and treatment, unlike the more asymptomatic ovarian tumors. Between 70-80% of carcinomas of the endometrium are gland-forming adenocarcinomas ("endometrioid adenocarcinomas"), with the remaining being comprised of high-grade clear cell, papillary serous and undifferentiated carcinomas. Approximately 5% of tumors are sarcomas, and are associated with a highly aggressive course. As with other cancers, stage remains the most important prognostic determinant in women with endometrial carcinomas. Other prognostic factors include histologic grade and the depth of myometrial invasion.
Our current understanding of the biology of uterine malignancies permits their dichotomy along two pathways. The first is the endometrioid adenocarcinomas that arise in relatively younger women, on a backdrop of simple and complex endometrial hyperplasia and have a strong etiologic association with unopposed estrogen exposure. The second group is comprised of the high-grade papillary serous and clear cell carcinomas, which arise in relatively older women, and are usually not preceded by a stage of endometrial hyperplasia or history of unopposed estrogen exposure. The latter tumors have a worse prognosis than the more common endometrioid adenocarcinomas. There is both epidemiologic and molecular evidence to suggest that endometrial hyperplasia represents a true precursor lesion for endometrioid adenocarcinomas, with complex hyperplasia resting on a histologic and genetic continuum in between simple hyperplasia and carcinoma.
Molecular analyses of endometrial cancers have also confirmed that distinct genetic differences also exist between the two previously described pathways of carcinogenesis. For example, p53 mutations are present in virtually all cases of high-grade papillary serous carcinomas of the endometrium. It has been shown that p53 abrogation occurs relatively early in the evolution of these tumors, and overexpression is present in 75% of endometrial intraepithelial carcinoma (EIC), considered the precursor lesion of papillary serous cancers. In contrast, p53 is mutated in only about a third of endometrioid adenocarcinomas, and in a minor proportion of endometrial hyperplasias, with complex hyperplasia demonstrating a higher frequency of abnormalities than simple hyperplasia. The latter tumors are more prone to arise on a background of microsatellite instability with loss of function of the DNA repair genes hMSH2 and hMLH1. Microsatellite instability is an uncommon feature in the high-grade endometrial carcinomas. Other commonly implicated genes include the PTEN/MMAC1 tumor suppressor gene on chromosome 10q23, inactivation of which is found in up to 50% of endometrial cancers (and an even higher frequency if the subset of tumors with microsatellite instability is considered), and the K-ras oncogene, activating mutations of which are found in 20-30% of endometrial adenocarcinomas. Studies have shown that the frequency of K-ras mutations rise progressively from simple through complex hyperplasia to carcinoma, and the presence of K-ras mutations in premalignant biopsy samples has been suggested as a marker of progression to malignancy. K-ras mutations have been shown to be associated with an adverse prognosis, independent of age or stage. Finally, overexpression of Her-2/neu oncoprotein has been reported in a proportion of endometrial adenocarcinomas, and it is associated in some studies with an adverse prognostic outcome. |
