Precancerous lesions of the endometrium:: A review of the molecular pathogenesis and problems in terminology

A dualistic model has been proposed for the pathogenesis of endometrial carcinoma. In this model, type-1 disease, represented by endometrioid carcinoma, denotes a slowly developing, indolent condition which develops in the setting of excess estrogen stimulation and which is associated with a comparatively favorable prognosis. Type-II disease, represented by serous carcinoma, is a more aggressive variant arising in a low-estrogen milieu. Pure serous carcinomas usually develop from atrophic endometrium in association with endometrial intraepithelial carcinoma (EIC) and are strongly associated with immunohistochemical detection of p53 protein and p53 gene mutations. Microsatellite instability and K-ras mutations are rare in serous carcinoma. Clear cell carcinoma of the endometrium is probably a type-it tumor. Microsatellite instability and K-ras mutations are common events in endometrioid carcinomas and are already present in its hyperplastic precursors. Tumors with microsatellite instability often show mutation of the PTEN gene. In contrast, p53 mutations are seen in only 10% to 20% of endometrial carcinomas, usually in poorly differentiated tumors. Endometrioid carcinomas are estrogen-dependent and frequently associated with endometrial hyperplasia. The nomenclature of these hyperplasias is in flux. Recent discussions have proposed distinguishing endometrial hyperplasia (glandular cystic hyperplasia and complex hyperplasia) and endometrioid neoplasia (atypical hyperplasia and well differentiated endometrioid carcinoma). Others have proposed a concept of endometrial intraepithelial neoplasia (atypical glandular cystic and complex hyperplasia). We recommend using the WHO classification until further clinicopathological and molecular studies are available to change the nomenclature based on scientific evidence and international consensus.