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Introduction to the ISGYP Symposium on Endometrial Hyperplasia

In recent years investigators have attempted to refine and improve the criteria for the diagnosis of the putative, noninvasive precursors of endometrioid carcinoma, the most common type of endometrial cancer. The most recent World Health Organization classification of endometrial hyperplasia, published in 1994, divides noninvasive endometrial proliferations into four categories: simple hyperplasia, complex hyperplasia, simple atypical hyperplasia, and complex atypical hyperplasia (1). Based on follow-up studies, the most important clinical cut point from the standpoint of progression to carcinoma is the distinction between hyperplasia and atypical hyperplasia (2). Unfortunately, two recent studies have shown that the reproducibility of the diagnosis of atypical hyperplasia is only moderate (3,4). These studies have given investigators further impetus to determine whether adjunctive techniques, including morphometric (5) and more recently molecular biologic methods (6), can assist and potentially replace morphologic evaluation in the diagnosis of these lesions. The objective of this symposium is to review the current “state of the art” of morphology and molecular biology of endometrial hyperplasia to determine whether the time is right to incorporate some of the new adjunctive techniques into clinical practice and whether the classification of endometrial hyperplasia should be changed to reflect these advances. Dr. George Mutter reviews studies that he and his colleagues have done correlating clonality of endometrial proliferations using molecular techniques with morphometric analysis that have in turn been linked to microscopic findings. Based on these data, Mutter and colleagues have proposed a new classification of endometrial hyperplasia. The next discussant, Dr. Lora Hedrick Ellenson, reviews what is currently known about the molecular events involved in endometrial carcinogenesis with an emphasis on the relationship of atypical endometrial hyperplasia to endometrioid carcinoma. Finally, Dr. Richard Zaino contributes an overview of the morphology and molecular biology of endometrial hyperplasia from the perspective of the practicing surgical pathologist, focusing on problems with the current classification and speculating on the role of the molecular data in influencing our approaches to diagnosis and classification. The key problem in the evaluation of noninvasive endometrial proliferations is the recognition of cytologic atypia. At times the distinction of hyperplasia from atypical hyperplasia can be very difficult and is not reliably reproducible. Because the morphologic changes of atypia in the endometrium are subtle and depend not only on subjective interpretation by pathologists but also on the vagaries of fixation and tissue processing, it is doubtful that we can anticipate much improvement based solely on morphology. Molecular and morphometric analyses show promise of providing a more objective assessment of endometrial hyperplasia. However, the current methodology employed to identify morphologic surrogates of clonal proliferations that are thought to be the immediate precursors of endometrial carcinoma also require a determination of cytologic atypia. Advances in our understanding of the molecular pathogenesis of hyperplasia will hopefully permit more highly reproducible and meaningful parsing of endometrial proliferations with a significantly increased risk of progression to carcinoma. As our understanding of the molecular mechanisms that underlie endometrial carcinogenesis become more comprehensive, the current morphologic classification will evolve into one based on morphologic and molecular features. The remaining question is when?