Lynch syndrome-associated upper tract urothelial cancer: Assessment of clinical screening criteria and tissue-based point of care testing.

Abstract

371 Background: Lynch syndrome (LS) is an inherited syndrome that places patients at risk for upper tract urothelial carcinoma (UTUC). Our goal was to identify the most reliable means of screening for LS in patients with UTUC at the point of care (POC). Methods: Patient information was retrospectively collected in an IRB-approved protocol on UTUC patients. LS screening was universally performed on all patients presenting from 1/2013-7/2016. We evaluated patient and family history (Amsterdam I and II criteria; AMS1 and AMS2, respectively), tumor immunohistochemistry (IHC) for 4 mismatch repair proteins (MMRP), tumor and normal tissue polymerase-chain reaction for microsatellite instability (MSI), and clinical genetic analysis and counseling (GAC), in those with undiagnosed LS. Patients who were AMS 2 positive, MSI positive, or IHC positive were considered as presumed Lynch syndrome (PLS) and were referred for GAC. Results: 101 UTUC patients without a history of LS were universally screened during clinical follow-up. A total of 15/101 (15%) patients were PLS. 7/101 (7%) patients met AMS2 criteria. 4 patients meeting AMS2 criteria had intact expression of MMRP and no MSI instability. 11 (11%) patients had either loss of one or more MMRP. There were two cases of MSI high instability, both in patients with MMRP loss. There were no cases of MSI-high instability and negative IHC. Insufficient tissue was found in 1/101 (1%) of IHC and 8/88 (9%) of MSI tests (p=0.0164). All patients with any positive screen were referred for GAC, 5 followed-up and all 5 patients had a confirmed germline mutation. The remaining did not follow through with GAC because of financial/insurance barriers. Conclusions: We identified 15% of universally screened UTUC as PLS at the POC using IHC and AMS2 criteria. IHC and AMS2 criteria appear to provide the most reliable screening. MSI is limited by requirement for normal tissue, a greater amount of tumor tissue, and can miss cases of MMRP loss. There are significant barriers to GAC. Our findings of a 15% rate of LS-related UTUC is consistent with prior laboratory tissue studies and has significant implications for universal POC testing of UTUC patients.