Abstract
BACKGROUND: Individuals with Lynch syndrome (LS) are advised to undergo pancreatic ductal adenocarcinoma (PDAC) surveillance if their lifetime risk is ≥5%, however, evidence is limited. This study quantifies lifetime risk and survival of three cancers relevant to PDAC surveillance, including PDAC, ampullary carcinoma (AC) and distal cholangiocarcinoma (dCC), to evaluate whether surveillance is justified. METHODS: This retrospective nationwide Dutch cohort study included individuals with LS pathogenic variants (PVs) in MLH1, MSH2, MSH6, PMS2 or EpCAM (identified between 1985 and 2024) and compared them to sporadic cases from the general population (diagnosed between 2000 and 2022). Cumulative incidence (CI) of PDAC, AC and dCC was estimated using Fine-and-Gray models for LS and a CI formula for sporadic cases. Relative risks (RRs) were calculated by comparing CIs. Survival of the cancers was compared between both cohorts using 1:10 matched analyses by age at diagnosis, sex, stage, and year of diagnosis. FINDINGS: In total, 2605 individuals with LS were included (median age 63.9 years; IQR 53.7-74.0), of whom 1515 (58.2%) were female. PVs were identified in MLH1 (723, 27.8%), MSH2 (895, 34.4%), MSH6 (731, 28.1%), PMS2 (233, 8.9%) and EpCAM (23, 0.9%). By age 75, the combined CI of PDAC, AC and dCC was 3.0% (95% CIs, 1.5-5.8) in MLH1, 3.4% (95% CIs, 2.0-5.8) in MSH2/EpCAM, 1.0% (95% CIs, 0.3-2.7) in MSH6 and 0% in PMS2. No familial-clustering of cancers was observed. Matched survival did not differ between PDACs in LS and sporadic cases. In contrast, survival was better for AC in LS (34.3 months; 95% CIs, 3.2-Inf) compared to sporadic cases (15.5 months; 95% CIs, 9.9-19.3). INTERPRETATION: In LS, the combined lifetime risk of PDAC, AC and dCC ranged from 0 to 3.4% across different genes, remaining below the 5% risk threshold for PDAC surveillance. Additionally, having an affected relative did not appear to increase risk. These findings suggest that current surveillance recommendations for individuals with LS should be re-evaluated. FUNDING: Lynch-Polyposis.