Risk of Metachronous Colorectal Neoplasm after a Segmental Colectomy in Lynch Syndrome Patients According to Mismatch Repair Gene Status

Background Because of increased risk of metachronous colorectal cancer (CRC), all patients with Lynch syndrome (LS) are offered a total colectomy. However, because metachronous CRC rate by mismatch repair (MMR) gene is uncertain, and total colectomy negatively impacts quality of life, it remains unclear whether segmental resection is indicated for lower penetrance MMR genes. We evaluated metachronous CRC incidence according to MMR gene in LS patients who underwent a segmental colectomy. Study Design Single-center, retrospective cohort study in patients with an earlier colectomy for CRC and an MMR germline mutation in MLH1, MSH2, MSH6, or PMS2 followed prospectively in a hereditary CRC family registry. All patients underwent surveillance colonoscopy. Metachronous CRC was defined as one detected more than 1 year after index resection. Primary end point was cumulative incidence of metachronous CRC overall and by MMR gene. Results One hundred and ten patients were included: 35 with MLH1 likely pathogenic/pathogenic (LP/P) variants (32%), 42 MSH2 (38%), 20 MSH6 (18%), and 13 PMS2 (12%). Median follow-up 4.26 years (range 0.53 to 19.92 years). Overall, metachronous CRC developed in 22 patients (20%). At 10-year follow-up, incidence was 12% (95% CI 6% to 23%), with no metachronous CRC detected in patients with a PMS2 or MSH6 LP/P variant. Conclusions After index segmental resection, metachronous CRC is less likely to develop in LS patients with MSH6 or PMS2 LP/P variant than in MLH1 or MSH2 carriers. Our data support segmental resection and long-term colonoscopic surveillance rather than total colectomy in carefully selected, well-informed LS patients with MSH6 or PMS2 LP/P variant.