Gynecological Tumors in Hereditary Nonpolyposis Colorectal Cancer: We Know They Are Common—Now What?

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, is one of the most common familial cancer syndromes, affecting 1/1000 individuals. The molecular basis for HNPCC is a defect in a DNA mismatch repair gene, usually a germline mutation in hMLH1 or hMSH2. Such a defective DNA mismatch repair causes microsatellite instability, the molecular hallmark of HNPCC-associated malignancies. Individuals with HNPCC are at increased risk for colon and endometrial cancers, as well as malignancies of the ovary, stomach, small intestine, hepatobiliary tract, ureter, brain, and skin. Traditionally, HNPCC has been considered a colon-cancerdominated syndrome. Therefore, gastroenterologists, GI surgeons, and GI oncologists have to date played a major role in the identification, care, and management of these patients. Data from recent studies suggest that the gynecologic oncology community needs to play a greater role in the identification and management of women with HNPCC. The two most recent reports on HNPCC and cancer risk found that women who carry a germline mutation in hMLH1 or hMSH2 have a higher lifetime risk of endometrial cancer than of colon cancer [1, 2]. Aarnio et al. [1] reported a 60% lifetime risk of endometrial cancer, and Dunlop et al. [2] estimated a 43% lifetime risk of endometrial cancer. The lifetime risk for ovarian cancer is substantially lower, at 10–12%. These new estimates of endometrial cancer risk are based on true mutation carriers, or obligate carriers, in contrast to prior estimates that were based on a more heterogeneous, clinically defined group of individuals. With the availability of commercial genetic testing for MLH1 and MSH2, geneticists and the GI community are identifying unaffected women who are at substantial risk for the development of gynecologic cancers. Therefore, it is crucial that we develop rational endometrial and ovarian cancer screening and prevention strategies. Currently, there are no established guidelines. To devise screening strategies for these individuals, we need to know more about the clinicopathologic characteristics of HNPCC-associated endometrial and ovarian cancer. In contrast to HNPCC-associated colon cancer, we still know very little about the basic clinicopathologic and molecular features of