Universal immunohistochemistry for Lynch Syndrome: a systematic review and meta-analysis of 58,580 colorectal carcinomas

Abstract Background and aims Lynch Syndrome is a form of hereditary colorectal cancer (CRC), caused by pathogenic germline variants (PV) in DNA mismatch repair genes. Currently, many Western countries perform universal immunohistochemistry testing on CRC to increase the identification of LS patients and their relatives. For a clear understanding of health benefits and costs, data on its outcomes are required: proportions of LS, sporadic MMR-deficient (MMRd) cases, and unexplained MMRd cases. Methods Ovid Medline, Embase and Cochrane CENTRAL were searched for studies reporting on universal MMR IHC, followed by MMR germline analysis, until March 20, 2020. Proportions were calculated, subgroup analyses were performed based on age and diagnostics used, and random effects meta-analyses were conducted. Quality was assessed using the Joanna Briggs Critical Appraisal Tool for Prevalence Studies. Results Of 2723 identified articles, 56 studies covering 58,580 CRCs were included. In 6.22% (95% CI 5.08%-7.61%; I2=96%) MMRd was identified. An MMR germline PV was present in 2.00% (95% CI 1.59%-2.50%, I2=92%), ranging from 1.80% to 7.27% based on completeness of diagnostics and age restriction. IHC outcomes were missing in 11.81%, germline testing was performed in 76.30% of eligible patients. In seven studies, including 6848 CRCs completing all diagnostic stages, germline PV and biallelic somatic MMR inactivation were found in 3.01% and 1.75%, respectively; 0.61% remained unexplained MMRd. Conclusion Age, completeness and type of diagnostics affect the percentage of MMR PV and unexplained MMRd percentages. Complete diagnostics explain almost all MMRd CRCs, reducing the amount of subsequent multi-gene panel testing. This contributes to optimising testing and surveillance in MMRd CRC patients and relatives.