International Society of Gynecological Pathologists Symposium on Endometrial Hyperplasia II. The Molecular Biology of Endometrial Tumorigenesis: Does It Have a Message?*

Uterine endometrioid carcinoma (UEC) is thought to arise from a proliferative endometrium caused by the stimulus of unopposed estrogen through a continuum of histopathologic abnormalities demonstrating increasing glandular complexity and cytologic atypia. A clinicopathologic study of such lesions found that the risk of developing carcinoma is associated more closely with the presence of cytologic atypia than architectural complexity (1). Historically, numerous light microscopic classification systems have been developed in an attempt to predict the clinical behavior of these putative precursor lesions. In 1994, the World Health Organization defined four diagnostic categories of endometrial proliferative lesions: simple hyperplasia, simple hyperplasia with atypia, complex hyperplasia, and complex atypical hyperplasia (CAH), with the intent of providing a unifying nomenclature (2). Recent studies have shown that there is considerable lack of reproducibility in the diagnosis of endometrial hyperplasia using the World Health Organization classification (3,4). Furthermore, it has been documented that the most significant lack of both intraobserver and interobserver agreement is in the diagnosis of cytologic atypia. Because atypia denotes a high-risk category and often determines patient management, the inability to reliably identify its presence is problematic. In response, some investigators have proposed further refining the light microscopic features of atypia, while others have suggested changing the current World Health Organization classification system. Both groups proposing a change in classification have suggested a simplified system, but unfortunately there is no agreement in the terminology or how the lesions should be classified within the new terminology. In addition, concern has already been raised about the loss of important information in oversimplification of this complex biologic process. Clearly it is appropriate to change classification systems when increased knowledge allows for refinement in our understanding of, or substantially changes the way in which we view, a disease process. The goal of this discussion is to explore the current relevant knowledge of the molecular biology of endometrial hyperplasia and carcinoma and to determine its possible contribution to classification. The majority of the molecular studies on endometrial tumorigenesis have focused on frankly invasive lesions; only a limited number of publications have been aimed at uncovering genetic alterations that occur in endometrial hyperplasia. The two most common types of genetic alterations yet identified in UEC are mutations in the tumor suppressor gene PTEN and microsatellite instability (MSI), and these alterations have recently been studied in endometrial hyperplasia. For these reasons, they will be the focus of this discussion.