Case provided by Mirela Stancu, MD

Case History

A 65 year old man with history of gastroesophageal reflux disease (GERD) on long term proton pump inhibitor therapy, presented for surveillance endoscopy. Esophago-gastro-duodenoscopy (EGD) showed mild reflux changes at esophago-gastric junction (EGJ) and thick gastric folds in the cardia. A biopsy was obtained from EGJ and from cardial mucosa.

Microscopic Findings

The histologic sections demonstrate numerous mucosal fragments with hyperplastic, reactive gastric pits (foveolae), edema and minimal predominantly chronic inflammation, indicative of reactive/reflux gastritis. In some of the fragments, small clusters or linear proliferations of uniform, basophilic cells with bland nuclei and moderately abundant amphophilic cytoplasm were noted lying within the deeper gastric glands and not exceeding the diameter of the normal glands. In other areas, compact round-to-oval micronodules of similar cells, forming a distinct collection of less than 150m in maximum size are present in the lamina propria, some abutting the deeper aspect of the gastric glands. The chromogranin A stain shows strong cytoplasmic staining of the cells, confirming their neuroendocrine origin.




Enterochromaffin cell-like (ECL) hyperplasia is a benign, but potentially pre-neoplastic condition associated with hypergastrinemic states.

Hypergastrinemia may be induced by:

  1. potent inhibitors of acid secretion (H2-blockers or proton pump inhibitors omeprazole, lansoprazole, pantoprazole);
  2. loss of parietal cells in chronic atrophic gastritis (either due to autoimmune gastritis/pernicious anemia or due to chronic H. pylori gastritis); and
  3. diversion of acid from antrum by surgical transplantation. Primary hypergastrinemia occurs in Zollinger-Ellison syndrome either isolated, or part of the multiple endocrine neoplasia type I (MEN type I) syndrome.

Gastrin release from antral G cells is regulated by the following mechanisms:

  1. luminal regulation:
    • amino acids (particularly phenylalanine and tryptophan) are responsible for food-induced gastrin release.
    • acidity of the gastric content is another major factor (alkaline pH is stimulatory and acidic pH is inhibitory).
  2. H. pylori:
    • by producing an alkaline pH by acid-neutralizing ammonia catalyzed by the bacterial urease.
    • by production of stimulatory cytokines (interleukin-1 beta and TNF-alpha) released from the T lymphocytes and monocytes present in the gastric inflammatory infiltrate.
    • another possible mechanism is through inhibition of somatostatin that normally provides an inhibitory feedback to gastrin release.
  3. Neural and peptidergic regulation:
    • gastrin release is stimulated by activation of preganglionic vagal fibers, and is resistant to atropine. Paradoxically, the intraluminal stimulation (by a protein meal) of gastrin release is inhibited by low doses of atropine.
    • Bombesin and bombesin-like peptide (GRP) potently stimulate gastrin release which thereafter results in acid secretion.

ECL cells are the main neuroendocrine cells of the stomach, comprising approximately 70% of the gastric NE cells, and represent the major histamine source of the gastric mucosa. They are located in the body/fundic glands, in the basal third of the glands in close proximity with the parietal cells. The histamine-synthesizing enzyme (histidine decarboxylase, HDC) can be identified within ECL cells; they also have CCK receptors on their surface that bind gastrin at physiological dosages, which, in turn, activates HDC resulting in histamine synthesis and secretion. The released histamine is a potent stimulant of hydrochloric acid secretion, exerting a direct stimulatory effect on H2 receptors of the parietal cells. The feedback loop is completed by the inhibitory effect exerted by the released hydrochloric acid on the antral G cells, probably via a somatostatin-regulated mechanism.

ECL hyperplasia may be a precursor of gastric carcinoid tumors, going initially through the intermediary step of endocrine cell dysplasia. The ECL hyperplasia - dysplasia - carcinoid tumor sequence occurs in approximately 4% of patients with pernicious anemia-associated chronic atrophic gastritis after an average of 19-year clinical course. It can also occur in patients with Zollinger-Ellison syndrome almost exclusively associated with MEN type I syndrome (autosomal dominant syndrome characterized by endocrine tumors of the pituitary gland, pancreatic islets and parathyroid gland, due to germline mutation of tumor suppressor gene MEN1, located on chromosome 11q13).

Potent inhibitors of acid secretion such as proton pump inhibitors are associated with hypergastrinemia and ECL hyperplasia. Such patients have serum gastrin levels 2- to 3-fold over the normal values (50-70pg/mL), comparable to patients with proximal gastric vagotomy, and 3- to 6-fold lower that the levels present in the patients with pernicious anemia. Plasma gastrin levels generally peak within the first 4 months of treatment with a proton pump inhibitor and stabilize without further increase thereafter. Gastrin levels generally return to baseline values within the first month after cessation of therapy. The incidence of high gastrin levels, defined as 400pg/mL or higher, was 11% in one large study (see ref). In long-term studies (greater than 10 years of treatment) in humans on proton pump inhibitor therapy, no evidence of gastric carcinoid formation has been noted. In contrast, in rat models, prolonged hypergastrinemia due to acid-suppressive agents is associated with gastric carcinoid tumors, most likely due to higher density of gastric ECL cells and higher ECL response to gastrin stimulation than humans.

Histologically, the benign/pre-neoplastic gastric endocrine proliferations are classified as:

  1. endocrine (ECL) hyperplasia
    • diffuse or simple hyperplasia - characterized by an increase (>2 fold) in ECL number.
    • linear hyperplasia - characterized by a chain of at least 5 ECL cells, growing in a sleeve-like manner within the gastric glands.
    • micronodular hyperplasia - micronodular clusters of at least 5 cells not exceeding the diameter of gastric glands, lying within the gastric glands, or within the lamina propria at the deep aspect of the oxyntic glands. These collections do not exceed 150 microns in maximum size.
  2. adenomatoid endocrine (ECL) hyperplasia
    • defined as compact collections of 5 or more ECL micronodules, lying close to each other, in the deep lamina propria.
    • nbo more than 150 microns in maximum size.
  3. endocrine (ECL) dysplasia
    • defined as large confluent micronodules of ECL cells lying deep in the mucosa, ranging from 150 to 500 microns in size.
    • microinfiltration of the lamina propria may be present.
    • newly formed stroma is occasionaly noted.
    • when the nodules are larger than 0.5 mm and confined to the mucosa, they are classified as microcarcinoids (or intramucosal carcinoid tumors).

In conclusion, the histologic changes observed in gastric endocrine cells after long-term daily administration of proton pump inhibitor drugs are minimal, self-limiting, non-dysplastic and non-neoplastic.


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2. Freston JW. Long-term Acid Control and Proton Pump Inhibitors: Interactions and Safety Issues in Perspective. Am J Gastroenterol 1997;92:51S-57S.
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Chromogranin stain highlights the endocrine cells lining the gastric glands in a cuff-like manner. A few ECLs are arranged in small cluster and lye within the lamina propria (immunoperoxidase, medium power magnification).
One ECL micronodule expands the gastric gland of origin (chromogranin A immuoperoxidase stain, high power magnification).
One ECL micronodule expands the gastric gland of origin (chromogranin A immuoperoxidase stain, high power magnification).
Low power magnification of multiple small ECL micronodules meeting the criteria for the diagnosis of adenomatoid ECL hyperplasia (chromogranin A, low power magnification).
Chromogranin stain highlights the endocrine cells lining the gastric glands in a cuff-like manner (immunoperoxidase, low power magnification).
Another example of endocrine cell hyperplasia. Note that the endocrine cell micronodules lye within the gastric gland extending into the neck portion (H&E, high power magnification).
Gastric cardial type mucosa with reactive foveolar hyperplasia and edema of the lamina propria. Indistinct predominantly intraepithelial and extraepithelial clusters of basophilic cells are noted in the center of the image.
Large nodules of basophilic small cells resembling gastric chief cells are present at the base of the gastric pits.
Endocrine cell hyperplasia is defined as micronodular clusters of 5 or more cells, not exceeding the diameter of gastric glands, present within gastric glands or adjacent to them within lamina propria (H&E, high power magnification).
Gastric cardial type mucosa with reactive foveolar hyperplasia and edema of the lamina propria. Indistinct predominantly intraepithelial clusters of basophilic cells are noted in the left half of the image (H&E, low power magnification).