Serous carcinoma has been studied less intensively than endometrioid carcinoma owing largely to its relative infrequency, accounting for only 10-15% of all endometrial carcinomas. Further complicating the issue is that many studies in the past did not recognize it as a distinct entity. Although a number of cancer-causing genes have been studied, only the TP53 tumor suppressor gene is altered in a significant number of cases. Some studies have detected TP53 mutations in almost 90% of cases making it one of the small number of adult solid tumors with such a high frequency of mutation in a single gene (18). Furthermore, approx 75% of endometrial intraepithelial carcinomas, the putative precursor of serous carcinoma, have mutations in TP53 implicating a role for its inactivation early in the development of this aggressive tumor type. This is in contrast to endometrioid carcinoma in which TP53 mutations are relatively uncommon and are largely confined to Grade 3 tumors. Thus, it is possible that the mutation of TP53 early in the pathogenesis of serous carcinoma is an important factor in determining its aggressive behavior. In addition, the fact that TP53 mutations occur most commonly in Grade 3 endometrioid and serous carcinomas may provide an explanation for overexpression and mutation of TP53 as an independent indicator of poor prognosis.
In contrast to endometrioid carcinoma, mutations in KRAS and PTEN appear to be highly uncommon in serous carcinoma (14). Additionally, MSI has not been described. Studies have suggested that there is amplification and overexpression of c-myc and Her-2/neu; however, it is not clear from the literature what percent of serous carcinomas demonstrate these alterations.
As in other tumor systems, the molecular studies of endometrial cancer support the concept that epithelial-derived tumors develop from preinvasive lesions that accrue a constellation of genetic alterations, providing the cell with the attributes necessary for unregulated growth (Fig. 1). In endometrioid carcinoma, PTEN alterations appear to be central to the initiation of proliferative lesions that then acquire mutations in other cancer-causing genes (e.g., DNA mismatch repair genes, KRAS, TP53) in the progression to malignancy. Conversely, TP53 mutations appear to be critical in the conversion of relatively quiescent, atrophic endometrium into an intraepithelial form of serous carcinoma, which then sets the stage for the accumulation of alterations in as yet unidentified cancer-causing genes. Finally, although the dualistic model is valid, it may not adequately encompass the more uncommon types of endometrial carcinoma, including clear cell carcinoma, which will be briefly discussed next.
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