Endometrial cancer in women with HNPCC

Abstract

Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC) is a cancer susceptibility syndrome. Germline mutations in mismatch repair genes (MLH1, MSH2, or MSH6) account for a majority of families with HNPCC. With the availability of clinical genetic testing, the estimates of cancer risk have become more precise. Women with HNPCC have a 40–60% lifetime risk for endometrial cancer and a 40–60% lifetime risk for colon cancer. In two recent studies, risk of endometrial cancer exceeded risk of colon cancer(1,2). While much is known about HNPCC-associated colon cancer, considerably less is known about HNPCC-associated endometrial cancer. Earlier studies have suggested that HNPCC-associated endometrial cancers are predominantly low grade and of endometrioid histology. However, these data were obtained from women who fulfilled clinical criteria for HNPCC, prior to the availability of genetic testing. A recent study examined a small series of endometrial cancers from patients with known germline mutations in MLH1 or MSH2 and reported an association with poorly differentiated tumors and lymphangioinvasive growth(3). We are currently conducting a pathologic review of a larger series of endometrial cancers in known mutation carriers and preliminarily note a wide spectrum of endometrial cancers including papillary serous and clear cell tumors. Of 47 tumors that were reviewed, 7 (14%) were nonendometrioid. Of the 40 tumors with endometrioid histology, 17 (42.5%) were Grade 1, 16 (40%) were Grade 2, and 7 (17.5%) were Grade 3. In our studies as well as others, tumor loss of staining by immunohistochemistry of MLH1 or MSH2 correlates well with the patient's known germline mutation. However, microsatellite instability patterns differ between HNPCC-associated endometrial and colon cancers, with HNPCC-associated endometrial cancers having a lower proportion of unstable loci than HNPCC-associated colon cancers. It is unclear whether HNPCC-associated endometrial cancers progress through a step-wise progression from normal endometrium to complex atypical hyperplasia to endometrial cancer. Clearly, understanding the natural history of HNPCC-associated endometrial cancer is necessary in order to formulate reasonable screening and prevention programs. Current screening guidelines include an annual transvaginal ultrasound and endometrial biopsy. We are currently conducting an NCI funded chemoprevention trial for this cohort, examining both Depo-Provera and the oral contraceptive. A secondary endpoint of this study is to establish the point estimate of endometrial abnormalities in asymptomatic women with HNPCC. Of 20 women enrolled thus far, 2 have had complex atypical hyperplasia on baseline endometrial biopsy despite normal ultrasound evaluation of their endometrial lining. Both have chosen to undergo hysterectomy, and both had complex atypical hyperplasia admixed with Grade 1 cancer on final pathology. Clearly endometrial cancer screening and prevention recommendations for women with HNPCC will continue to evolve as more information on the natural history of this disease develops.