Histopathology of genetically defined endometrial precancers

Endometrial precancers are monoclonal, benign neoplasms prone to malignant transformation. A type collection (deposited at www.endometrium.org) of confirmed precancers has been identified by their monoclonal growth and continuity of acquired genetic markers that occur between premalignant and malignant phases of tumorigenesis. Computerized morphometry of these premalignant lesions, designated endometrial intraepithelial neoplasia (EIN), has disclosed new architectural criteria and revised cytologic criteria for their diagnosis. EIN lesions originate focally and expand in size over time, in keeping with a proliferative monoclonal origin. They are characterized by closely packed glands (volume percentage stroma < 55%) with cytology that is clearly demarcated from that of the adjacent field. A minimum homogeneous field of cytologically demarcated glands is required to accurately assess the architecture diagnostic of EIN, and morphometry-diagnosed lesions with a largest diameter of at least 1 to 2 mm have previously been shown to predict the relevant clinical outcome of concurrent or future endometrial adenocarcinoma. Nonphysiologic loss of the PTEN protein, a tumor suppressor gene mutated in many endometrioid adenocarcinomas, is seen in individual glands of endometrium exposed to unopposed estrogens and in packed clusters of EIN glands. The isolated PTEN-free glands in anovulatory endometria may be the earliest stage of endometrial tumorigenesis, but they are not readily distinguishable by routine histology, nor do they have a defined natural history.