The Association Between Proton Pump Inhibitor Use and Gastroenteropancreatic Neuroendocrine Tumors: A Systematic...

This systematic review evaluated the site-specific association between long-term use of proton pump inhibitors (PPIs) and neuroendocrine tumors (NETs), with a primary focus on gastric and duodenal NETs.

Eight non-randomized studies involving about 1273 cases from the USA, Mexico, and Italy were included and reviewed. Definitions of PPI exposure and comparator groups varied across studies, and methodological quality was assessed with the ROBINS-I tool. Due to heterogeneity in design and outcomes, results were narratively synthesized.

The findings were site-specific. For gastric NETs (G-NETs), an association was noted with indolent tumors-generally small, confined to the mucosa or submucosa, and rarely metastatic. In contrast, for pancreatic and ileal NETs, the main impact of PPIs is related to interference with the diagnostic biomarker chromogranin A (CgA) rather than tumorigenesis. Several studies indicated a biological link between prolonged PPI therapy, enterochromaffin-like (ECL) or parietal cell hyperplasia, and tumor development, whereas others emphasized chronic atrophic or autoimmune gastritis as major contributors. PPIs were also found to elevate circulating CgA, potentially confounding diagnosis, while vasostatin-1 (VS-1) emerged as a more specific biomarker.

The association between PPI use and GEP-NETs is site-specific. PPI-associated G-NETs appear to represent a distinct subgroup with low malignant potential, whereas links to non-gastric NETs seem more related to diagnostic confounding. Hypergastrinemia plays a central role in pathogenesis, but co-factors such as atrophic gastritis, autoimmune gastritis, and Helicobacter pylori infection likely contribute. The association is multifactorial, and large prospective studies are needed to establish causality.