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Bethesda Guidelines for Lynch Syndrome Screening Appear to Improve the Amsterdam Criteria
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman is a consultant to GlaxoSmithKline, Eli Lilly Co., Abbott Laboratories, Sanofi-Aventis, and Pfizer, and serves on the speakers bureau for GlaxoSmithKline, Eli Lilly Co., and OrthoBiotech.
Synopsis: The 1996 Bethesda guidelines (revised 2002), which were added to the Amsterdam criteria to improve screening sensitivity and specificity for Lynch syndrome, were evaluated relative to a diagnostic algorithm in two gynecologic populations supporting their utility.
Source: Walsh CS, et al. Lynch syndrome among gynecologic oncology patients meeting Bethesda guidelines for screening. Gynecol Oncol 2009 Dec 22; Epub ahead of print.
Lynch Syndrome (LS) is a familial colorectal cancer syndrome, which occurs as a result of autosomal dominant inheritance of DNA mismatch repair genes. It is characterized by a high lifetime incidence of colorectal cancer, as well as gynecologic malignancies, such as endometrial and ovarian cancer. Successful screening has been associated with decreased colorectal cancer mortality. The original 1996 Bethesda guidelines added two gynecologic populations for whom further evaluation should be entertained: those with endometrial cancer before the age of 45 years and those with two LS-related cancers (e.g., synchronous endometrial and ovarian cancer). Prevalence of LS and genomic characteristics for these populations is not well described and were the endpoints of the study. To address these endpoints, a diagnostic algorithm was constructed that included immunohistochemistry for mismatch repair protein expression, followed by selective evaluation for microsatellite instability and MLH1 gene promoter methylation. Among 72 eligible patients, 9 (12%) had molecular findings consistent with LS: 6/50 (12%) in the early-onset endometrial cancer group and 3/22 (14%) in the synchronous primary cancer group. In an additional 3 cases, MLH1 silencing was due to promoter methylation: 1/50 (2%) in the early-onset endometrial cancer group and 2/22 (9%) in the synchronous primary cancer group. Of the 9 women with molecular criteria suggesting LS, only 3 had pedigrees meeting the Amsterdam criteria. The authors conclude that a diagnostic algorithm can identify patients with LS and those who warrant further genetic testing. Their findings reinforce the recommendation that women diagnosed with endometrial cancer before the age of 45 years and women with synchronous endometrial and ovarian cancer be screened for LS, irrespective of family history.
The lifetime risk of developing endometrial or ovarian cancer in patients with Lynch syndrome is estimated at 60% and 12%, respectively. Despite the syndrome's relative rarity (annual incidence about 1/1000-2000), the identification of potentially affected individuals before a cancer diagnosis can lead to effective screening, which has not only been associated with reduction in LS-associated cancer, but also reduced mortality. In 1991, the Amsterdam criteria, commonly referred to as the "3-2-1 criteria" (i.e., 3 first-degree relatives with LS cancers, in 2 generations, 1 of whom developed cancer before age 50), were developed to assist patients and health care providers in identifying individuals and families at high risk for LS. In light of its low performance sensitivity, the guidelines were amended in 1996 and again in 2002 to add other "at-risk" populations, including those individuals developing endometrial cancer at an early age and those with dual, or "synchronous," primaries, such as in the uterus and ovaries simultaneously. While believed to improve specificity and sensitivity, the prevalence of genomic changes in these populations has been infrequently described and was evaluated in the current study. Young age at diagnosis and synchronous primaries in the uterus and ovary have been previously represented by a small, but important fraction (5%-15%) of LS-associated genomic changes. The current study also demonstrates the latter group is frequently associated with MLH1 epigenetic change, notably promoter methylation, and as such, alone, would not require further evaluation for LS in family members. This indicates that patients found with tumors lacking immunohistochemical staining for MLH1 protein should be additionally screened for epigenetic change. Finally, in this, as in other recent studies, family history proved to be an unreliable triage tool, suggesting heightened clinical awareness be exercised in identifying potential subjects.