Assessing the Relationship between Gastrointestinal and Pancreatic Neuroendocrine Tumor Grade and Overall Survival: A Systematic Review and Meta-Analysis

Background: Neuroendocrine tumors (NET) are a rare group of epithelial neoplasms present in the gastrointestinal tract (GI) (67.5%) and bronchopulmonary tree (25.3-30%), and in 15% of cases, their primary sites cannot be identified. Although endoscopic screening, improvements in pathological techniques, and early detection have shown improvements in NET survival rates, the prognosis of advanced, metastatic, and poorly differentiated NET is very poor. In this study, we aimed to evaluate the effect of gastrointestinal and pancreatic (GEPs) NETs' grade on overall survival. Method: We searched observational studies describing the overall survival or prognostic factors of primary GEP NETs from May 2011-May 2021 following the PRISMA guidelines. Studies describing the effect of primary grade 3 GEP NETs on overall survival were included. A meta-analysis was performed, and a pooled hazard ratio and their 95% confidence interval (95% CI) were obtained. Forest plots were created using random effects models and a sensitivity analysis was performed to account for the heterogeneity. Results: Seven studies with 7692 confirmed patients were included. In our meta-analysis, grade 3 GEP NETs were associated with higher odds of poor survival (pooled HR: 2.73; 95% CI: 1.36-5.47; p = 0.005), with a 92% heterogeneity between studies (p < 0.0001). To account for this heterogeneity, a sensitivity analysis was performed by removing two outlying studies (Fathi et al. and Foubert et al.) on funnel plots. The results after the sensitivity analysis did not change and still showed a significant association of grade 3 with a poor survival (pooled HR: 4.53; 95% CI: 3.54-5.78; p < 0.00001), with no heterogeneity between studies (p = 0.72; I-2 = 0%). Conclusions: Our meta-analysis found that grade 3 GEP NETs are associated with poor survival and additional future studies are needed to identify other risk factors associated with poor survival in GEP NETs to improve their mortality.