Leticia Nogueira*, Neal D. Freedman, Eric A. Engels, Joan L. Warren, Felipe Castro, and Jill Koshiol * Correspondence to Dr. Leticia Nogueira, National Cancer Institute, 9609 Medical Center Drive, MSC 7248, Bethesda, MD 20892 (e-mail: leticia.nogueira@nih.gov). Initially submitted July 3, 2013; accepted for publication November 26, 2013.

Gallstones and cholecystectomy may be related to digestive system cancer through inflammation, altered bile flux, and changes in metabolic hormone levels. Although gallstones are recognized causes of gallbladder cancer, associations with other cancers of the digestive system are poorly established.

We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (1992–2005), which includes 17 cancer registries that cover approximately 26% of the US population, to identify first primary cancers (n = 236,850) occurring in persons aged ≥66 years and 100,000 cancer-free population-based controls frequency-matched by calendar year, age, and gender. Odds ratios and 95% confidence intervals were calculated using logistic regression analysis, adjusting for the matching factors. Gallstones and cholecystectomy were associated with increased risk of noncardia gastric cancer (odds ratio (OR) = 1.21 (95% confidence interval (CI): 1.11, 1.32) and OR = 1.26 (95% CI: 1.13, 1.40), respectively), small-intestine carcinoid (OR = 1.27 (95% CI: 1.01, 1.60) and OR = 1.78 (95% CI: 1.41, 2.25)), liver cancer (OR = 2.35 (95% CI: 2.18, 2.54) and OR = 1.26 (95% CI: 1.12, 1.41)), and pancreatic cancer (OR = 1.24 (95% CI: 1.16, 1.31) and OR = 1.23 (95% CI: 1.15, 1.33)). Colorectal cancer risk associated with gallstones and cholecystectomy decreased with increasing distance from the common bile duct (P-trend < 0.001).

Hence, gallstones and cholecystectomy are associated with the risk of cancers occurring throughout the digestive tract. cancer; cholecystectomy; digestive system; gallstones; gastric cancer; liver; pancreas


In conclusion, a history of gallstones and cholecystectomy were associated with an elevated risk of subsequent digestive tract cancers, including noncardia gastric cancer and smallintestine carcinoid, as well as auxiliary organ cancers, including hepatocellular carcinoma, cholangiocarcinoma, pancreatic cancer, and ampulla of Vater cancer. Both gallstones and cholecystectomy were associated with decreased colorectal cancer risk with increasing distance from the common bile duct. The results of this large US population-based study suggest that changes in bile flow (bile reflux into the stomach or continual excretion into the intestines), local inflammation (increased with gallstones and decreased with cholecystectomy), and changes in hormone levels (cholecystokinin in the pancreas) are important in the etiology of digestive system cancers.

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