Gall Bladder Disease and the Risk of Small Bowel Cancer—Results from a Nationwide Swedish Cohort Study

SIMPLE SUMMARY: Gallbladder disease (GBD) has been linked to small bowel cancer, but earlier reports have been based on a few cancer cases and no previous studies have adjusted for potential confounders. We report a 1.4-fold increased risk of small bowel adenocarcinoma, 1.8-fold increased risk of adenomas, and a 2.1-fold increased risk of carcinoids in patients with GBD compared to matched comparators. Absolute risks were low, however (<1 per 1000 patients followed for 10 years) for all three outcomes. We lacked detailed data on body mass index, cigarette smoking, and GBD biomarkers. Further results from an observational study, like ours, cannot establish a causal relationship or rule out the presence of residual confounding. The increased risk of carcinoid, seen 11–16 years after GBD diagnosis, may represent an etiologically plausible causal link to carcinoid development and warrants further study. The reported low absolute risks argue against targeted surveillance for small bowel cancer after GBD diagnosis. In conclusion, this study reports a moderately increased relative risk of small bowel cancers and adenomas in patients with GBD; absolute risks were however low. ABSTRACT: Background and aims: Small bowel cancer is a rare but rising malignancy. The etiology is poorly understood and there is a need for large-scale studies. Gallbladder disease (GBD), inducing localized inflammation, has been suggested to increase small bowel cancer risk. Methods: We retrieved nationwide data from Sweden’s 28 pathology departments on all adults (age 20–79) with pathology-confirmed GBD diagnosed in 1965–2017. In total 156,390 GBD patients were matched with up to 5 matched comparators from the general population and follow-up started one year after GBD diagnosis. We used stratified Cox regression to calculate hazard ratios (HRs) for small bowel adenocarcinoma, adenomas, and carcinoids. Results: During a median follow-up of 12 years, we identified 92 small bowel adenocarcinomas, 132 adenomas, and 81 carcinoid tumors in the GBD cohort. Corresponding incidence rates were 4.8, 6.9, and 4.2 per 100,000 person-years (PY), compared to 3.2, 3.2, and 1.8 in matched comparators. The adjusted HR was 1.42 (95% CI = 1.08–1.87) for small bowel adenocarcinoma, 1.79 (95% CI = 1.41–2.27) for adenoma, and 2.07 (95% CI = 1.52–2.81) for carcinoid. The excess cancer risk was most pronounced during the first year of follow-up for adenocarcinomas and during the first six years for adenomas while for carcinoids the HR peaked 10–15 years after start of follow-up. Conclusions: In this nationwide cohort study, GBD was associated with an increased risk of small bowel cancer. The excess risk of small bowel adenocarcinoma was mainly seen during the first years of follow-up while small bowel carcinoid risk peaked 11–16 years after GBD diagnosis.