Association Between Long-Term Proton Pump Inhibitor Use and Low-Risk Gastric Neuroendocrine Tumors

Gastric neuroendocrine tumors (NETs) account for approximately 2% of all gastric neoplasms and develop from enterochromaffin-like cells in the gastric mucosa. Types 1 and 2 develop because of hypergastrinemia; type 3 typically occurs sporadically, tends to be more aggressive, presents metastatically in over 50% of cases, and has normal fasting gastrin levels. Although the long-term use of proton pump inhibitors (PPIs) has been known to lead to chronic hypergastrinemia, only a small number of gastric NETs associated with PPI use have been reported, and the classification of these cases remains undefined.

This was a retrospective study of all gastric NETs seen at H. Lee Moffitt Cancer Center and Research Institute between January 2008 and August 2023. Patients with type 1 or type 2 gastric NETs and poorly differentiated neuroendocrine carcinomas were excluded. Data were collected from patients with "sporadic" gastric NETs, including PPI use, gastrin levels (both on and off PPI), pathologic features, and disease stage.

A total of 90 patients met the eligibility criteria: 50% had long-term PPI use (≥5 years of consecutive treatment). All had well-differentiated tumors: 34 grade 1, 45 grade 2, 6 grade 3, and 5 with an unknown grade. Among 45 patients who received long-term PPI, none developed distant metastatic disease; among the remaining patients without long-term PPI use, 62% had metastatic disease (p < 0.0001).

Gastric NETs diagnosed in patients with long-term PPI use tend to be less aggressive than those occurring sporadically in the absence of long-term PPI therapy. We propose that PPI-associated gastric NETs be considered a fourth category (type 4) with a prognosis more similar to type 1 than to type 3.