Advancing our understanding of endometrial cancer histologic subtypes: Should we lump or split?

Abstract

The significance of the various histologic subtypes of endometrial adenocarcinoma has been debated in the epidemiologic and clinical literature for years. The most common subtype, endometrioid, is thought to arise from the type I pathway as the result of atypical hyperplasia induced by estrogen excess. It is generally associated with a lower age, stage, and grade at diagnosis. Serous endometrial cancer, on the other hand, is the result of the type II pathway, where the endometrium commonly is atrophic and may proceed through intraepithelial carcinoma as a precursor lesion. Patients with serous tumors tend to be older and present at a higher stage and grade [ [1] Irvin W.P. Rice L.W. Berkowitz R.S. Advances in the management of endometrial cancer: a review. J. Reprod. Med. 2002; 47: 173-189 PubMed Google Scholar ]. With the advent of molecular techniques, we recognized that the phenotypic differences between the pathways also were associated with genetic differences; while type I tumors commonly have PTEN, ras, and β-catenin mutations, serous tumors often display p53 mutations [ 1 Irvin W.P. Rice L.W. Berkowitz R.S. Advances in the management of endometrial cancer: a review. J. Reprod. Med. 2002; 47: 173-189 PubMed Google Scholar , 2 Shedden K.A. Kshirsagar M.P. Schwartz D.R. Wu R. Yu H. Misek D.E. et al. Histologic type, organ of origin, and Wnt pathway status: effect on gene expression in ovarian and uterine carcinomas. Clin Cancer Res. 2005; 11: 2123-2131 Crossref PubMed Scopus (35) Google Scholar ]. The pathogenesis of clear cell endometrial cancer is the least understood, displaying features of both pathways. Despite limited insight into their development, however, clear cell tumors have the most distinct signature of any of the histologic subtypes with genomic profiling [ 3 Risinger J.I. Maxwell G.L. Chandramouli G.V.R. Jazaeri A. Aprelikova O. Patterson T. et al. Microarray analysis reveals distinct gene expression profiles amog different histolgoic types of endometrial cancer. Cancer Res. 2003; 63: 6-11 PubMed Google Scholar , 4 Zorn K.K. Bonome T. Gangi L. Chandramouli G.V.R. Awtrey C.S. Gardner G.J. et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005; 11: 6422-6430 Crossref PubMed Scopus (317) Google Scholar ]. The challenge currently lies in correlating the emerging molecular data with recommendations to patients regarding prevention, diagnosis, and management of endometrial cancer.