Implementation of tumor testing for lynch syndrome in endometrial cancers at a large academic medical center

Highlights

• There were no differences in age, histology, grade, stage, or BMI in patients with Lynch syndrome versus sporadic tumors.

• Universal screening in endometrial cancers is practical and eliminates the chance for missing eligible cases.

• Lynch syndrome screening in endometrial cancer is successfully implemented with collaboration among genetic counselors, gynecologic oncologists, and pathologists.

Abstract

Objectives

Lynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. Recognizing women at risk for LS based on personal/family history is burdensome and imprecise. Tumor testing using microsatellite instability (MSI) testing and immunohistochemistry (IHC) for mismatch repair protein expression can be an effective strategy for identifying potential LS in patients presenting with colorectal or endometrial cancer. Here we describe our experience implementing a screening program for endometrial cancers.

Methods

Endometrial cancers diagnosed ≤ 50 years or those with suspicious personal history or histopathologic features were screened with MSI/IHC, June 2009–June 2011. Criteria were later (July 2011–July 2012) expanded to patients diagnosed < 60 years, or at any age with suspicious features, and finally (after August 2012) universal screening was implemented. Screening techniques began with both MSI and IHC for every tumor, and later converted to IHC for two proteins, and MLH1 promoter methylation analysis when indicated. A genetic counselor contacted patients directly to offer genetic counseling appointments.

Results

Two hundred and forty-five endometrial cancers (average age, 57 years) were screened. Sixty-two patients (25%) had abnormal results, and 42 patients were referred for genetic counseling. Of the 42 patients, 34 underwent genetic counseling, 28 pursued genetic testing, and 11 were diagnosed with LS. When age and pathology criteria were used, 27 eligible cases were overlooked for screening and 3 cases of LS were found only because a clinician requested screening.

Conclusions

Universal screening of endometrial cancers for LS is practical and successfully implemented with collaboration among genetic counselors, gynecologic oncologists, and pathologists.

Introduction

Lynch syndrome (LS) is an autosomal dominant disorder, caused by germ line mutations in the four mismatch repair (MMR) pathway genes, MLH1, MSH2, MSH6, and PMS2, and EPCAM deletion (resulting in MSH2 promoter methylation), which increase the risk of endometrial, colorectal, ovarian, gastric, small bowel, and other cancers. LS confers up to a 60% risk of endometrial cancer and accounts for 2%–6% of all endometrial cancers [1], [2]. Nearly 50% of women with LS and multiple malignancies present with endometrial cancer as their first primary cancer [3]. It is therefore essential to identify endometrial cancer patients with LS to guide medical management and to help reduce the risk of additional cancers for the patient and relatives.

Traditional methods of identifying LS, including the Amsterdam criteria, have proven to be ineffective for endometrial cancer patients, with sensitivity < 40% [1]. Tumor testing with microsatellite instability (MSI) testing and immunohistochemistry (IHC) for MMR protein expression are more sensitive methods of identifying LS. Over 90% of endometrial cancers caused by LS demonstrate MSI [1]. IHC for the MMR proteins has a sensitivity of approximately 94% and can be used alone or in conjunction with MSI to identify patients who for whom directed germ line testing is indicated [1].

Several large institutions across the United States have implemented universal screening using MSI and/or IHC in colorectal cancers due in part to the recommendation from the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, stating that all newly diagnosed colorectal cancer patients should be offered testing for LS [4]. However, the only guidelines for MSI/IHC screening for LS in endometrial cancer state that testing should be considered for women diagnosed before the age of 50 years [5]. Since most women with LS are diagnosed with endometrial cancer after the age of 50 years and are more likely to be diagnosed with endometrial cancer than with colon cancer, there is a need for a better screening strategy in this population [6]. A few hospitals have begun screening endometrial cancers; however, the best screening criteria and methodology are not well established. Here we report on implementing and evaluating universal screening of endometrial cancers for LS at a large academic medical center.