Heterogeneity of the precursor lesions of endometrial carcinoma, according to the histologic subtype

Endometrial carcinoma is a constellation of different types of carcinomas, each exhibiting different morphology, genetic abnormalities, and clinical outcomes and developing via a different carcinogenesis process. Atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN) is a precursor of endometrioid carcinoma. AEH/EIN is a noninvasive proliferation of atypical epithelium, which frequently harbors mutations in the PTEN, KRAS, CTNNB1, or ARID1A genes that are observed in endometrioid carcinoma. Microsatellite instability caused by epigenetic suppression of DNA mismatch repair protein MLH1 is also observed in AEH/EIN. These genetic abnormalities constitute early events of endometrioid carcinogenesis. As serous carcinoma without stromal invasion shows aggressive behavior, noninvasive serous neoplasia is designated as serous endometrial intraepithelial carcinoma (SEIC). Mutation of TP53 is detected in most cases of serous carcinoma and SEIC. Mutation of TP53 occurs in normal-appearing epithelium and is designated as p53 signature. Some clear cell carcinomas have associated intraepithelial lesions exhibiting less atypia than carcinoma. Although this lesion is a putative precursor lesion of clear cell carcinoma, further study is necessary.