Enterochromaffin-like Cell Hyperplasia–Associated Gastric Neuroendocrine Tumors May Arise in the Setting of Proton Pump Inhibitor Use

Abstract

Context.— Hypergastrinemia states such as achlorhydria from gastric mucosal atrophy or a gastrin-producing tumor in humans have been associated with the development of enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumors (GNETs). Whether drugs that can elevate serum gastrin levels, such as proton pump inhibitors (PPIs), can produce the same tissue effect is not known and there is no concrete evidence linking the use of PPIs to GNETs outside animal models and case reports. Objective.— To explore the clinicopathologic association for GNETs of presumed ECL cell origin that cannot be reliably placed into any of the 3 established categories currently recognized by the World Health Organization. Design.— This is a retrospective clinicopathologic study of GNETs in the body/fundus of a period of 15 years (2005–2019). Results.— Of a total of 87 cases, 57 (65.5%) were associated with atrophic gastritis, 2 (2.3%) were associated with Zollinger-Ellison syndrome, and 28 (32.2%) were unclassified. Of the latter, 11 were consistent with true sporadic/type 3 GNETs, while 17 had background mucosal changes of parietal cell and ECL cell hyperplasia but without underlying detectable gastrinoma, and 88.2% (15 of 17) of patients from this group had documented long-term PPI use. This subtype of GNETs was more commonly multifocal, and of higher grade (P = .03) than “true” sporadic GNETs. Conclusions.— A subset of GNETs arises in the background of gastric mucosal changes suggestive of hypergastrinemia, but without underlying gastrinoma, and could be linked to long-term PPI use.

Association of proton pump inhibitors with gastric and colorectal cancer risk: A systematic review and meta-analysis

“…It is well known that gastritis caused by H. pylori infection is an important factor leading to gastric cancer. Chronic H. pylori infection may induce gastric neuroendocrine tumours under the condition of hypergastrinemia ( Rais et al, 2022 ). Subgroup analysis showed that the use of PPI and the risk of gastric cancer increased nearly threefold after eradication of potential confounders of H. pylori infection.…”

The central role of gastrin in gastric cancer

“…It should be noted that nobody has explained why the inflammation has a selectively trophic effect on ECL cells. With the increasing acceptance of proton pump inhibitor-induced gastric NETs, we ( 82 ) and others ( 83 ) have come up with a new way to classify these tumors. We suggested that group 1 should comprise gastric NETs due to hypergastrinemia and that group 2 should comprise those not showing hypergastrinemia ( 82 ), whereas Rais et al.…”

Gastric Mucosal Protective Effects of Cinnamomum cassia in a Rat Model of Ethanol-Induced Gastric Injury

“…Clinical meta-analyses have demonstrated that long-term PPI use can exacerbate various conditions, including gastric cancer [ 11 ]. It can lead to hypergastrinemia due to potent gastric acid suppression, triggering intestinal chromaffin cell proliferation [ 12 ]. Prolonged PPI use, particularly in the presence of H. pylori infection, has been linked to the development of gastric cancer [ 12 ].…”

“…It can lead to hypergastrinemia due to potent gastric acid suppression, triggering intestinal chromaffin cell proliferation [ 12 ]. Prolonged PPI use, particularly in the presence of H. pylori infection, has been linked to the development of gastric cancer [ 12 ]. Consequently, exploring alternatives to mitigate these treatment side effects becomes imperative.…”