Gastric and duodenal cancer in individuals with Lynch syndrome: a nationwide cohort study

Background Lynch syndrome increases the risk of gastric cancer (GC) and duodenal cancer (DC), particularly individuals with MLH1 and MSH2 pathogenic variants (PVs). To provide further insight into whether, and age, esophagogastroduodenoscopy (EGD) surveillance may be beneficial, we evaluated the cumulative incidence tumour characteristics of GC and DC in a large nationwide cohort of Dutch individuals with LS. Methods For this retrospective nationwide cohort study, clinical data of individuals with LS registered Hereditary Cancer Registry were matched with pathology reports filed by the Dutch Pathology registry. All registered between Jan 1, 1989 and Dec 31, 2021 with proven or putative PVs in one of the mismatch were included. Cumulative incidences of GC and DC were estimated for high-risk (MLH1, MSH2 and low-risk (MSH6 and PMS2) PVs using competing risk methodology (Fine and Gray method) with death causes as competing risk. Findings Among 1002 individuals with high-risk and 765 individuals with low-risk PVs, 29 GCs (1.6%) (2.2%) were diagnosed. Cumulative incidence of GC and DC under the age of 50 was very low (<= 1%) individuals. At age 70 and 75, cumulative incidence of GC was 3% [95% CI 1%-5%] and 5% [3%-8%] risk PVs and 1% [0%-2%] and 1% [0%-2%] for low-risk PVs (p = 0.006). For DC, cumulative incidence and 75 was 5% [3%-7%] and 6% [3%-8%] in high-risk, 1% [0%-1%] and 2% [0%-4%] in low-risk respectively (p = 0.01). Primary tumour resection was performed in 62% (18/29) of GCs and 77% (30/39) cases. Early-stage GC, defined as TNM stage I, was found in 32% (9/28) of GCs. Early-stage DC, defined stage I-IIa, was found in 39% (14/36) of DCs. Interpretation Individuals with MLH1, MSH2, and EpCAM PVs have an increased risk of developing GC the age of 70 years, but this risk is very low before the age of 50 years. The age of onset of surveillance, the and DC during EGD surveillance, and its cost-effectiveness should be subject of future studies.