Risk and Protective Factors for Small Intestine Neuroendocrine Tumours: A Prospectivecase-Control Study

Background: The incidence of small intestine neuroendocrine tumours is increasing, but few studies have investigated risk factors for their occurrence, suggesting that family history of any cancers, smoking, and previous cholecystectomy are associated with an increased risk. Such studies investigated small series, or examined cancer registries without direct interviews. Aim: We therefore aimed at clarifying risk and protective factors for the occurrence of sporadic small intestine neuroendocrine tumours (SI-NETs). Patients and Methods: Multicentre case-control study. Patients prospectively evaluated with histologic diagnosis of SI-NETs, excluding familial syndromes. Controls with non-neoplastic/non-chronic disorders seen at GI outpatients clinics, matched (4:1) for sex and age. All directly interviewed by means of a specific questionnaire on potential risk and protective factors. Cases and controls compared by Fisher test or Student's t test for categorical or continuous variables. Explanatory variables analysed by simple logistic regression analysis, with multivariate stepwise variable-selection procedure performed; p <0.05 was significant. Results: 215 SI-NETs and 860 controls enrolled. Family history (FH) of colorectal cancer (8.8 vs. 5%), and breast cancer (10.2 vs. 4.8%), heavy smoking (24.7 vs. 14.8%) and drinking >21 alcohol units per week (7.4 vs. 3.8%), were all significantly more frequent in SI-NETs than controls. Multivariate analysis showed that FH of colorectal cancer (OR 2.23; 95% CI 1.29-3.84, p = 0.003), FH of breast cancer (OR 2.05; 95% CI 1.13-3.69, p = 0.01) and smoking (OR 1.47; 95% CI 1.07-2.03, p = 0.01) and in particular heavy-smoking (OR 1.94; 95% CI 1.29-3.84, p = 0.0008) were associated with an increased risk for carcinoid occurrence, while use of aspirin was a protective factor (OR 0.20; 95% CI 0.06-0.65, p = 0.008). Conclusion: Family history of colorectal and breast cancer, and smoking seem to be risk factors for the development of small intestine neuroendocrine tumours, while use of aspirin might to be a protective factor. These factors partially overlap with those associated with colorectal cancer, but are different from those previously associated with pancreatic neuroendocrine tumours. These findings may suggest that the mechanisms of carcinogenesis for endocrine cells in different sites can be specific, and similar to those of their exocrine counterparts.