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.
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.
ADENOMATOID ENDOCRINE CELL HYPERPLASIA
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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