Pathology, hormonal aspects, and molecular genetics of the two types of endometrial cancer

Endometrial carcinomas can be classified into two clinico-pathological groups: estrogen-related (Type I) and estrogen-unrelated (Type II) tumors. Type I tumors are endometrioid adenocarcinomas and generally arise from their precursor, endometrial hyperplasia. The expression of hormone-related proteins such as sex steroid receptors, pS2 protein, LH/hCG receptor, heat shock protein 90kDa (HSP90), and bcl-2 protein is a characteristic of endometrial hyperplasias and well differentiated endometrioid adenocarcinomas, and may be implicated in the early development of the tumor. Transforming growth factor-α (TGF-α) and insulin-like growth factor-1 (IGF-1) are presumed to support the growth of endometrioid carcinoma under the influence of estrogens. In tumors undergoing the hyperplasia-carcinoma sequence, mutation of the K-ras oncogene or PTEN/MMAC tumor suppressor gene is an early event, followed only later by over-expression of p53 protein, cyclin D1, c-erbB-2 protein, and epidermal growth factor receptor (EGFR). Type II tumors are nonendometrioid adenocarcinomas, such as serous adenocarcinoma and clear-cell adenocarcinoma, both of which show biologically aggressive behavior. Most of these carcinomas do not express sex steroid receptors, and they may develop in a hormone-independent manner. Mutation and/or over-expression of p53 protein is significantly more common in serous and clear-cell tumors than in endometrioid carcinomas. The putative precursor of serous carcinoma, endometrial intraepithelial carcinoma (EIC), also shows p53 over-expression. Thus, p53 over-expression is an early event in the carcinogenesis of serous carcinomas. DNA aneuploidy and c-myc amplification are more frequent, but bcl-2 expression and microsatellite instability are less prevalent in serous carcinomas. Inherited endometrial carcinomas have recently been classed as Type III tumors. Most of these tumors exhibit microsatellite instability and a good prognosis. Finally, endometrial carcinomas induced by prolonged tamoxifen therapy in breast cancer patients are worthy of mention.