How Should Women With Early-Onset Endometrial Cancer Be Evaluated for Lynch Syndrome?

In a 1990 meeting in Amsterdam, the Netherlands, the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer established criteria for recruiting families into collaborative studies to identify the genetic causes and elucidate the natural history of hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome. These initial so-called Amsterdam criteria required that at least three cases of colorectal cancer occur in first-degree relatives of each other, that the predisposition span at least two generations, and that one of the colorectal cancers occurs at younger than age 50 years. Although these guidelines were useful to identify families for participation in research studies, it became evident that these criteria were overly restrictive for clinical use and did not reflect the fact that HNPCC/ Lynch syndrome was actually a multiorgan-system disease in which extracolonic malignancies account for a great proportion of the total cancer burden. In 1999, recognizing these limitations, the International Collaborative Group on HNPCC revised the Amsterdam criteria to include extracolonic cancers, especially endometrial cancer. These Amsterdam II criteria are listed in Table 1. Although the revised criteria are quite specific, only 13% to 36% of patients with molecularly confirmed Lynch-associated colorectal cancer meet these criteria. To better identify individuals who could be at risk for Lynch syndrome and to reflect the emerging understanding that this syndrome was due to defects in the mismatch repair pathway, the Early Detection Branch of the National Cancer Institute convened a conference in Bethesda in 1996 to identify clinicopathologic criteria that could lead to the identification of patients with Lynch syndrome who were not identified by the original Amsterdam criteria. The guidelines that emerged from this conference, which have become known as the Bethesda criteria, identified individuals with colorectal or endometrial cancer whose tumor should undergo evaluation for mismatch repair defects by microsatellite instability (MSI) testing. These criteria specifically included a recommendation that tumors from individuals with endometrial cancer diagnosed at younger than age 45 years be tested for MSI. In the subsequent 5 years, it became apparent that the sensitivity and specificity of the original Bethesda guideline could be improved, and a follow-up conference in 2002 created the Revised Bethesda guidelines (listed in Table 2) that have become the standard for offering testing for mismatch repair defects in colorectal cancer. However, the revised criteria do not provide guidelines for which endometrial tumors should undergo mismatch repair defect evaluation, despite a 40% to 60% lifetime risk of endometrial cancer in women with a mismatch repair mutation associated with Lynch syndrome. In the current issue of Journal of Clinical Oncology (JCO), Lu et al attempt to provide some guidance for which women with endometrial cancer younger than age 50 years should be offered genetic risk assessment to consider the possibility of HNPCC. In this series, women with endometrial cancer diagnosed at younger than age 50 years were identified prospectively at one of three centers. Participants underwent germline testing for mutations in MLH1, MSH2, and MSH6 as well as immunohistochemical (IHC) analysis of mismatch repair protein expression and MSI testing. Patients with loss of MLH1 protein expression in which no germline MLH1 mutation was identified also underwent methylation analysis of the MLH1 promoter. In this series of 100 patients, nine patients had clearly identified deleterious mutations. Four additional patients had MSI, IHC, or methylation results suggestive of the possibility of a germline mutation, though no additional mutations were identified on screening. The authors then correlated clinical information with mutation status and found that having either a low body mass index (BMI) or a first-degree relative with a Lynch syndrome–associated cancer were highly associated with the presence of a germline mutation. The authors go on to conclude that women with endometrial cancer diagnosed at younger than age 50 years in combination with a BMI greater than 30 and no first-degree relative with a Lynch syndrome–associated cancer are unlikely to have Lynch syndrome. While the results of the current study are provocative and are in general agreement with results from a smaller study by Berends et al published in JCO in 2003, it is reasonable to ask if the study design led to a self-fulfilling conclusion with regard to the impact of family history. Only 58% of the 172 patients with endometrial cancer diagnosed at younger than age 50 years at the three study sites chose to participate in the study protocol. Of these 100 participants, two had metachronous colon cancers; nine had synchronous ovarian cancers; 16 had a parent with colon, uterine, or ovarian cancer; and 10 had a sibling with a colon, uterine, or ovarian cancer. In this cohort, which appears to be overrepresented for Lynch syndrome–associated malignancies in the probands and their first-degree relatives, the possibility of a bias leading to the preferential enrollment of individuals with personal or familial features of Lynch syndrome must be considered. It is JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 33 NOVEMBER 2