Risk factors for neuroendocrine neoplasms: A systematic review and meta-analysis

Background: Neuroendocrine neoplasms (NENs) are rare cancers mainly of lung and digestive tract. Little is known on risk factors. The aim of this work is to define the risk factors for NEN development by extensive review and meta-analysis of published data. Methods: The search was conducted on Medline, Scopus, and Web of Science following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The Newcastle-Ottawa scale was used for study quality. Meta-analyses were conducted by primary site. Odds ratio (OR), hazard ratio, risk ratio, standardized incidence ratio, and associated 95% confidence intervals (CIs) were abstracted. Data were combined and analyses carried out for risk factors considered by at least two studies. Random-effects model was adopted for study variation. Results: Of 1535 extracted articles, 24 were enrolled. Meta-analyses were possible for pancreas, small intestine, and rectum. Risk for NEN associated with: (i) family history of cancer at all investigated sites (lung, stomach, pancreas, small intestine, appendix, and colon; OR 2.12 [95% CI 1.40-3.22, I2 = 0.0%, P = 0.681] at meta-analysis in pancreas); (ii) body mass index (BMI) or diabetes (stomach, pancreas, and small intestine; OR of 2.76 [95% CI 1.65-4.64, I2 = 58.5%, P = 0.090] for diabetes at meta-analysis in pancreas); (iii) cigarette smoking (lung, stomach, pancreas, and small intestine; OR of 1.34 [95% CI 1.10-1.63, I2 = 0.0%, P = 0.780] and of 1.59 [95% CI 1.07-2.37, I2 = 32.9%, P = 0.225] for smokers versus never-smokers at meta-analysis for pancreas and small intestine); (iv) alcohol consumption (pancreas and rectum; OR of 2.44 [95% CI 1.07-5.59, I2 = 65.8%, P = 0.054] and of 1.53 [95% CI 0.99-2.35, I2 = 0.0%, P = 0.630] for heavy drinkers versus never-drinkers at meta-analysis for pancreas and rectum). Conclusions: Family history of cancer is the most relevant risk factor for NEN development at all investigated sites, followed by BMI and diabetes. Cigarette smoking and alcohol consumption are potential risk factors for selected anatomical sites.