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enterochromaffin-like cell hyperplasia

Friday 8 February 2013

hyperplasia of enterochromaffin-like cells; gastric endocrine cell hyperplasia; gastric enterochromaffin-like cell hyperplasia; ELC hyperplasia

Endocrine cells of the gastric oxyntic mucosa, and especially the enterochromaffin-like cells (ECL), are the progenitors of gastrin-promoted proliferative lesions whose tumorigenic potential largely depends on the background condition in which they arise.

Originating from the histamine-containing enterochromaffin-like (ECL) cells of the embryologic foregut, gastric carcinoid tumors represent approximately 1.8% of all gastric neoplasms and approximately 7% of all carcinoids.


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

Hypergastrinemia may be induced by:
- potent inhibitors of acid secretion (H2-blockers or proton pump inhibitors omeprazole, lansoprazole, pantoprazole);
- loss of parietal cells in chronic atrophic gastritis (either due to autoimmune gastritis/pernicious anemia or due to chronic H. pylori gastritis); and
- 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.

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.

ECL hyperplasia - dysplasia - carcinoid tumor sequence

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).

Types - Synopsis

  • diffuse hyperplasia of enterochromaffin-like cells
  • linear hyperplasia of enterochromaffin-like cells
  • micronodular hyperplasia of enterochromaffin-like cells
  • adenomatoid hyperplasia of enterochromaffin-like cells

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

- 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.
  • adenomatoid endocrine (ECL) hyperplasia
    • defined as compact collections of 5 or more ECL micronodules, lying close to each other, in the deep lamina propria.
    • no more than 150 microns in maximum size.

- 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).

Enterochromaffin-like cell lesions

The endocrine cell lesions have been classified as:
- pseudohyperplasia : cell clustering unassociated with cell proliferation.
- hyperplasia of enterochromaffin-like cells
- dysplasia of enterochromaffin-like cells

  • enlarged
  • adenomatous or fused micronodules of enterochromaffin-like cells
  • microinfiltration of enterochromaffin-like cells
  • nodular growth of enterochromaffin-like cells

- neoplasia of enterochromaffin-like cells (intramucosal carcinoid tumor or invasive carcinoid tumor).

The entire spectrum of endocrine cell proliferation, from hyperplasia to dysplasia and neoplasia, has been observed in MEN-ZES and diffuse type ACAG.

Both hyperplastic and pseudohyperplastic changes occur with some frequency in the Helicobacter pylori-related chronic gastritis associated with ulcer disease or dyspepsia.

However, because no progression to dysplastic or neoplastic lesions has thus far been documented in these latter conditions, their role in gastric endocrine cell tumorigenesis appears negligible. (7762735)

Endocrine cell nodules

Endocrine cell nodules comprised a similar mixture of endocrine cells, sometimes communicating with glands of pseudopyloric metaplasia and proving to be reversible in one case, provides evidence that these nodules are hyperplastic, but finally may lead to gastric carcinoid tumors in AGA.

Size less than 150 micron (0.150 mm), basal location, and mixed hormone content may be helpful criteria for the distinction of hyperplastic endocrine cell nodules from small carcinoid tumors.


- hypertrophic gastropathy due to the familial multiple endocrine neoplasia-associated Zollinger-Ellison syndrome ( (MEN1-associated ZES),
- hypertrophic gastropathy due to the sporadic Zollinger-Ellison syndrome (ZES),
- diffuse chronic atrophic gastritis restricted to the corpus-fundus (type autoimmune metaplastic atrophic gastritis or ACAG) or autoimmune metaplastic atrophic gastritis (AMAG), with or without associated pernicious anemia,
- Helicobacter pylori-associated chronic atrophic gastritis (Helicobacter pylori-related multifocal chronic atrophic gastritis)

Case reports



- Bordi C, et al. Hypergastrinemia and gastric enterochromaffin-like-cell proliferations of the gastric mucosa: classification and histogenesis. Am J Surg Pathol 1995;19(Suppl):S8-S19.

- Hyperplastic, dysplastic, and neoplastic enterochromaffin-like-cell proliferations of the gastric mucosa. Classification and histogenesis. Solcia E, Fiocca R, Villani L, Luinetti O, Capella C. Am J Surg Pathol. 1995;19 Suppl 1:S1-7. PMID: 7762735

- Solcia E, et al. Enterochromaffin-like (ECL) cells and their growths: relationship to gastrin, reduced acid secretion and gastritis. Bailliere’s Clin Gastroenterol 1993;7:149-165.

- Gastric endocrine cell hyperplasia and carcinoid tumors in atrophic gastritis type A. Müller J, Kirchner T, Müller-Hermelink HK. Am J Surg Pathol. 1987 Dec;11(12):909-17. PMID: 3318512

- Harvey RF, et al. Multifocal gastric carcinoid tumors, achlorhydria, and hypergastrinemia. Lancet 1985;951-54.

- Moses RE, et al. The syndrome of Type A chronic atrophic gastritis, pernicious anemia, and multiple gastric carcinoids. J Clin Gastroenterol 1986;8:61-65.