Lynch Syndrome Screening Tests in Uterine Cancer Patients >50 Years Depends on Clinical and Tumor Morphology Criteria: Evidence Against Universal Testing
Sarah M Calkins, Anthony N Karnezis, Peggy G Conrad, Lee-May Chen, Joseph T Rabban. UCSF, San Francisco, CA
Background: Controversy exists about which uterine cancer patients should undergo Lynch syndrome (LS) screening testing by mismatch repair (MMR) immunohistochemistry (IHC). Bethesda Guidelines (BG), designed for colon cancer patients, use age <50 and personal/family cancer pedigree as criteria but sensitivity is low for uterine cancer. Tumor morphology suggestive of MMR deficiency (TM-MMR) may also serve as screening criteria (tumor infiltrating or peritumoral lymphocytes, undifferentiated histology, lower uterine segment origin, concurrent ovarian tumor). Optimal integration of age, cancer pedigree and TM-MMR into an algorithm to determine who should get MMR IHC remains to be defined. Our institution has prospectively used BG and TM-MMR to trigger MMR IHC. In this algorithm uterine cancer patients without BG or TM-MMR do not get tested; such untested patients are all age >50. In this study, we retrospectively asked whether the protocol missed any abnormal MMR cases among untested patients, with the aim of determining whether universal testing should be implemented.
Design: We retrospectively performed MMR IHC on all untested uterine cancer patients age >50 from mid 2007 to mid 2011. These patients lacked BG criteria and lacked TM-MMR. IHC for MLH1, MSH2, MSH6 and PMS2 was performed using triplicate tumor samples in a tissue microarray; all abnormal results were validated by repeat IHC on whole slide sections from individual tumor blocks. MLH1 promoter methylation was evaluated for cases of MLH1 loss. Results were compared to those from the prospectively tested uterine cancer patients >50 years who had BG criteria and/or TM-MMR.
Results: Among 182 uterine cancers (89% pure endometrioid type) in patients >50 years, lacking BG and TM-MMR, only 5 (2.7%) had abnormal MMR: 4 had loss of MLH1/PMS2 (3 of 3 tested for MLH1 promoter methylation were positive) and 1 had loss of MSH6. In comparison, abnormal MMR was detected in 47% (35/74) of patients >50 years with TM-MMR and in 20% (4/21) of patients with BG criteria but lacking TM-MMR. Germline testing in 5 patients with abnormal MMR in the prospective cohort identified 1 patient with a PMS2 mutation.
Conclusions: In uterine cancer patients over 50 years, LS screening by 4 protein MMR IHC is of questionable value unless the patient fulfills Bethesda Guideline criteria or the cancer exhibits TM-MMR. The role of universal MSH6 screening in older patients deserves further study.
Category: Gynecologic & Obstetrics
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 137, Wednesday Morning