HYPERTROPHIC GASTROPATHIES:
ALL THAT THICKENS…IS NOT MÉNÉTRIER 'S DISEASE
Kay Washington, MD, PhD
Professor of Pathology
Vanderbilt University Medical Center
Rodger C. Haggitt Gastrointestinal Pathology Society
March 3, 2013
The endoscopic observation of thickened gastric folds may reflect a variety of pathologies in the
stomach, from common conditions to the very rare, such as Ménétrier's disease and poorly
characterized polyposis syndromes. The pathophysiology and etiology of many of these
conditions are not well understood, although many clinical associations have been made over
the years. Because diagnosis of some of these disorders required examination of the full
thickness of an often very thick gastric mucosa, standard forceps biopsies may not be adequate
and the endoscopist should be encouraged to obtain full-thickness snare biopsies. For
instance, superficial biopsies of hyperplastic foveolar epithelium may show similar findings in
focal foveolar hyperplasia, hyperplastic polyp, hamartomatous polyps, Ménétrier's disease, in
mucosa adjacent to gastric ulcers. Pathologic diagnosis therefore requires knowledge of the
endoscopic findings including the location of the lesion in the stomach, adequate sampling, and
careful clinical correlation.
Table 1: Morphologic Approach to Hypertrophic/Hyperplastic Gastropathies
Hyperplastic Mucosal Compartment
Differential Diagnosis
Foveolar epithelium
Focal foveolar hyperplasia
Hyperplastic polyp
Hamartomatous polyp
Ménétrier’s disease
Parietal cells
Zollinger-Ellison syndrome
All layers
Hypertrophic Hypersecretory gastropathy
MÉNÉTRIER'S DISEASE
Clinical and demographic features. First described in 1888, Ménétrier’s disease is a rare
acquired protein-losing gastropathy characterized by giant rugal folds with massive foveolar
hyperplasia and loss of parietal cells. The classic clinical features are hypoalbuminemia with
peripheral edema, abdominal pain, and nausea and vomiting. Two distinct forms occur: a
chronic form with insidious onset seen in adults, and a spontaneously resolving form with abrupt
onset associated with cytomegalovirus infection in children. The average age at diagnosis in
adults is 55, and the disorder is more commonly reported in men. A number of patients with
Ménétrier’s disease also have ulcerative colitis, although the association remains enigmatic.
We have also seen a case associated with primary pulmonary hypertension. Ménétrier’ disease
in adults is associated with an increased risk of gastric cancer, estimated at 2-15% lifetime risk.
1
Endoscopic features. Ménétrier’s disease primarily involves the gastric corpus and the antrum
is often spared. At endoscopy, the enlarged gastric folds resemble cerebral convolutions.
Gastric pH is neutral or alkaline due to decreased parietal cells, and copious thick mucus is
often noted. Serum gastrin levels are usually normal or near-normal despite the hypoacidity.
Full-thickness snare biopsies are essential for evaluating the pathologic features.
Table 2: Differential Diagnosis of Thickened Gastric Folds
Location in
Endoscopic
Clinical
stomach
Features
Findings
Ménétrier's
Corpus; may
Cerebriform
Nausea,
disease
also involve
thickened folds
vomiting,
antrum
peripheral
edema
Zollinger-Ellison
Corpus
Folds thickened
Refractory
syndrome
up to 8 mm
peptic ulcer
disease
Hypertrophic
Corpus
Diffuse
Peptic ulcer
hyperplastic
cobblestone
disease
gastropathy
nodularity
Hyperplastic polyp Antrum; also in Polyp(s), single
Associated with
corpus and
or multiple
chronic atrophic
cardia
gastritis
Condition
Polypoid gastritis
Antrum and
corpus
Nodularity
Epigastric pain
Polyposis
syndrome
Antrum and
corpus
Variable; diffuse
nodular
enlargement of
gastric folds or
discrete polyps
Juvenile
polyposis,
Peutz-Jaeger
syndrome, other
undefined
polyposis
syndrome
Usually found in
operated
stomach
Gastritis cystica
Body & antrum;
profunda/polyposa gastric remnant
in operated
stomach
Lymphoma
Antrum and
corpus
Usually localized
Thickened folds
Variable
Carcinoma
Thickened folds
Variable
Antrum and
corpus
2
Pathologic
Feature
Massive
foveolar
hyperplasia
Parietal cell
hyperplasia
Hyperplasia of
all glandular
elements
Foveolar
hyperplasia with
architectural
disarray
Chronic active
gastritis with H.
pylori
Features
overlap with
hyperplastic
polyp
Entrapped
cystic glands in
submucosa or
deeper layers
Effacement of
gastric mucosal
architecture by
neoplastic
lymphoid
infiltrate
Infiltrating
carcinoma, noncohesive type
Other rare causes of thickened gastric folds include metastatic carcinoma [1], eosinophilic
gastroenteritis [2, 3], and gastric involvement by syphilis [4].
Pathologic features of Ménétrier’s disease
 Massive foveolar hyperplasia, with mucosal thickness of 1 cm or more
 Decreased or absent parietal cells
 Corkscrew morphology of foveolar epithelium, although overall linear architecture is
primarily maintained
 Cystically dilated glands in deep mucosa
 Variable lamina propria inflammatory infiltrate, but often including eosinophils
 Smooth muscle strands in lamina propria
Variants of Ménétrier’s disease reported include localized cases [5], spontaneously resolving
forms and a form characterized by numerous intraepithelial lymphocytes and known as
hypertrophic lymphocytic gastritis [6]. The latter condition may also present with giant folds in
the body of the stomach sparing the antrum. The mucosal inflammation in hypertrophic
lymphocytic gastritis is severe and diffuse, with a striking increase in intraepithelial lymphocytes.
Uninflamed mucosa in a study of 13 cases did not show foveolar hyperplasia and loss of
parietal cells was not seen [6]. In comparing these 13 cases with 10 cases of classic
Ménétrier’s disease with massive foveolar hyperplasia and little inflammation, the investigators
concluded that hypertrophic lymphocytic gastritis should be considered as part of the spectrum
of lymphocytic gastritis and not a form of Ménétrier’s disease.
The spontaneously-remitting form of Ménétrier’s disease primarily occurs in the setting of
cytomegalovirus (CMV) infection, but has also been reported in H. pylori gastritis. Spontaneous
resolution generally occurs in children over 4 to 6 weeks [7]. CMV-associated Ménétrier’s
disease may also be seen in adults [8].
Familial cases of Ménétrier’s disease have been reported; while some appear to represent
Ménétrier’s disease, others likely represent polyposis syndromes involving the stomach.
Inherited Ménétrier’s disease-like cases appear to be transmitted in an autosomal dominant
fashion. In one reported family, affected individuals had anemia, not protein loss, and no
increase in TGF- α was demonstrated by RT-PCR or immunohistochemistry [9].
Pathophysiology. TGF-α, one of the seven mammalian ligands that active the epidermal
growth factor receptor (EGFR), stimulates gastric epithelial repair and renewal while inhibiting
acid secretion. Twenty years ago, studies in MT- TGF- α overexpressing mice [10] showed a
phenotype of foveolar hyperplasia with decreased parietal cells similar to Ménétrier’s disease,
and increased levels of TGF- α were demonstrated in the hyperplastic foveolar epithelium in
humans with this disorder [11]. While the cause of the sustained increase in gastric mucosal
TGF-α has not been defined in Ménétrier’s disease, it is possible that subclinical gastric injury
may trigger appropriate TGF-α release and activation of downstream EGFR signaling.
Ménétrier’s disease may result from failure of the normal feedback loop, which would also
explain durable remission seen with cetuximab. CMV-dependent EGFR activation may explain
the association of CMV infection with Ménétrier’s disease, as CMV infects human cells by
interacting with EGFR. Similarly, H. pylori infection causes overexpression of amphiregulin and
3
heparin-binding EGF-like growth factor, other members of the EGFR ligand family, and may
lead to a similar increase in EGFR signaling. Ruthenium red data suggests that defective tight
junction barrier function may be related to protein loss in Ménétrier’s disease, although the
signaling pathways responsible have not been defined.
Clinicopathologic Decision-Making Tree for Diagnosis of Ménétrier’s Disease
Treatment. The mainstay of treatment for debilitating Ménétrier’s disease is gastrectomy.
Evidence for the benefit of most medical treatments, including octreotide, which may modulate
EGFR signaling, antibiotics, prednisone and non-steroidal anti-inflammatory agents, is
inconsistent. Based on the observation of increased EGFR signaling as an underlying event in
4
Ménétrier’s disease, a clinical trial of cetuximab, a partially humanized antibody directed at
EGFR that blocks ligand binding, was initiated in 1999 at Vanderbilt [12, 13]. All seven patients
completing a one-month course of treatment showed improvement in clinical symptoms and
gastric histology, with four showing near-total histologic remission [14]. However, the increased
risk of gastric cancer remains a concern in this population, and four individuals elected to
undergo gastrectomy despite durable response to therapy.
Distinction from gastric involvement by polyposis. Juvenile polyposis and other polyposis
syndromes sometimes involve the stomach, and distinction from Ménétrier’s disease may be
difficult on histologic grounds alone. Clinical features, such as anemia and protein loss, can
also mimic Ménétrier’s disease, and it is likely that some cases reported in the literature as
Ménétrier’s disease represent juvenile polyposis. In the Vanderbilt series of 48 patients
evaluated for possible Ménétrier’s disease, 3 were diagnosed with juvenile polyposis, 1 with
Cronkhite-Canada Syndrome, and 4 others with hamartomatous polyps or an uncharacterized
polyposis syndrome [15]. Histologic features favoring juvenile polyp over Ménétrier’s disease
are disorderly architecture and “cap-like” appearance of the hyperplastic foveolar epithelium,
preservation of parietal cells, and lack of lamina propria smooth muscle.
Gastric Polyposis Syndrome Mimics of Ménétrier’s Disease
Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder, manifested by
hamartomatous polyps in the colon in 98% of patients; hamartomatous polyps are found in the
stomach 14% and in small bowel in 7%. Roughly half of JPS cases are due to germline
mutations in SMAD4 or BMPR1A, with the remainder due to as-yet-uncharacterized genetic
alterations. SMAD4 mutations are associated with more severe gastric phenotypes [16], and an
exclusively gastric form of JPS has been described [17], associated with a nonsense mutation
resulting in a stop codon [c.1527 G>A] in exon 11 of SMAD4 in one case, and a four base pair
deletion in exon 9 at codon 415 in another. Such cases have been described as showing a
mixed hyperplastic/polypoid gastropathy, mainly in the gastric corpus, with thick adherent
mucus. Gastric juvenile polyps may be difficult to classify with certainty in the absence of a
known diagnosis of JPS, and the morphology overlaps with hyperplastic polyps and that of other
hamartomatous lesions [18]. In our experience, the non-polypoid background gastric body
mucosa in JPS cases sometimes shows a subtle foveolar hyperplasia, and it has been
speculated that disruption of the TGFβ/SMAD signaling pathway can lead to TGF α
overexpression, especially in the setting of H. pylori infection [19], which could explain the
similarities of gastric JPS polyps to Ménétrier’s disease in some cases.
Other polyposis syndromes that should be considered in the differential diagnosis include
Peutz-Jaegers [18], Cronkhite-Canada, or Cowden’s syndrome [20, 21] and newly-described
syndromes such as proximal polyposis of the stomach [22].
Gastritis cystica profunda/polyposa, an uncommon lesion more often found in previously
operated stomachs, consists of displaced or herniated dilated glandular elements in the
submucosa or deeper layers of the gastric wall. When the glands are primarily located deep in
the gastric wall, the lesion is termed profunda; when an exophytic component is present, the
term polyposa is used. It is often associated with chronic bile reflux and probably represents a
reactive proliferation of entrapped herniated mucosal elements. While gastritis cystica profunda
5
may present as giant gastric folds [23], it more often presents as a localized lesion [24]. Cases
of gastritis cystic profunda in the setting of Ménétrier’s disease [25] most likely represent
herniation of cystically dilated mucosa often found in Ménétrier’s disease. The major
significance of gastritis cystica profunda is the occasional difficulty in distinguishing the
herniated glands from well differentiated adenocarcinoma [26].
Table 3. Diagnostic features of Ménétrier’s disease in patients with chronic symptoms
Clinical
Endoscopic
Histologic
↓serum albumin
Diffusely enlarged folds in corpus
Massive foveolar hyperplasia
peripheral edema
↓gastric acidity
Decreased parietal cells
Normal serum
Increased mucin production
Maintenance of mucosal
gastrin
architecture
ZOLLINGER-ELLISON SYNDROME
Clinical features. The most severe gastric hypersecretory state is Zollinger-Ellison syndrome
(ZES), characterized by refractory peptic ulcer disease due to ectopic release of gastrin by a
neuroendocrine tumor. From 20% to 60% of patients with ZES have MEN-1 syndrome. Given
that gastric acid secretion is increased up to five times normal in ZES, it is not surprising that the
most common symptom is abdominal pain (83%). The gastrinoma is usually located in the
duodenum (70 to 90% in recent studies) or pancreas in the gastrinoma triangle, but may be
primary at many unusual sites, including lymph nodes, liver, heart, and ovaries [27]. Elevated
serum gastrin is found in up to 99% of ZES patients, but it is important to measure gastric pH at
the same time to rule out hypochlorhydric states. Because proton pump inhibitors (PPIs) can
cause hypergastrinemia, fasting gastrin and secretin tests should be performed after stopping
PPIs to avoid delay in diagnosis.
Endoscopy. Almost all patients with ZES (92%) have prominent gastric folds. Ulcers in
esophagus (14%), stomach (18%), duodenum (6%) are now seen infrequently at baseline
endoscopy but are routine-appearing when present.
Pathology. The mucosa of the gastric body is thickened, with measurements of up to 5-8 mm
reported [28], due to parietal cell hyperplasia. In addition to expanding the mucosa, parietal
cells also extend to the base of the glands, in zones normally occupied by chief cells. The
foveolar compartment is not expanded. ECL cell hyperplasia is more common in the gastric
body in MEN1/ZES patients compared to sporadic ZES cases.
Treatment and outcome. The peptic ulcer symptoms and complications of ZES respond well
to PPI treatment [29]. Even patients with metastatic disease may have a relatively indolent
course, although a subset have more aggressive disease, and the extent of liver metastases is
an important factor influencing survival [30, 31]. Patients with sporadic gastrinomas may have a
worse prognosis than those with MEN-1; median survival in one series was 7 years for nonsyndromic patients [29].
Pseudo-Zollinger-Ellison Syndrome. Gastric acid hypersecretion may occur in the absence
of gastrinomas and may be related to vagal hyperactivity. Such cases have been called ZESlike hypersecretion or pseudo-ZES, and are distinguished from ZES by negative secretin
6
stimulation testing. Most of the patients in one series were middle-aged white men with normal
serum gastrin [32]. Some reported cases show primary G cell hyperplasia in the gastric antrum
[33, 34]. Patients generally respond to treatment with proton pump inhibitors.
HYPERTROPHIC HYPERSECRETORY GASTROPATHY
This condition is defined as hyperplasia of all glandular compartments of the gastric body with
hypersecretion of acid, pepsin, and mucoprotein. Many of the published reports predate
recognition of H. pylori gastritis, and it is possible that some cases represent polypoid gastritis.
Most reported cases had duodenal or gastric ulcers, with 70% having documented peptic ulcer
disease in one series [35]. The gastric body mucosa is described as diffusely nodular, with
normal or atrophic antral mucosa on endoscopy [36] . In addition to parietal cell and foveolar
hyperplasia, the gastric glands may be cystically dilated. As in Ménétrier’s disease, serum
albumin levels are low and gastrin levels are normal.
HYPERPLASTIC POLYPS
One of the most commonly encountered lesions with foveolar hyperplasia is the gastric
hyperplastic polyp. In a recent large survey, the prevalence of gastric polyps in a private
practice setting was 6%, with 17% of polyps representing hyperplastic polyps or foveolar
hyperplasia [37]. Some pathologists distinguish between focal or polypoid foveolar hyperplasia,
defined as a sharply localized focus of superficial foveolar hyperplasia, without cystic change or
architectural distortion, and hyperplastic polyps, characterized by marked elongation of the pit
region, with a corkscrew appearance, branching and cystic dilatation of foveolar epithelium with
architectural disarray, and lack of a glandular component [38]. These lesions may represent the
continuum of a response to injury, supported by the observation that the surrounding mucosa is
rarely normal, generally showing reactive or chemical gastropathy, or chronic gastritis with or
without H. pylori. While in older reports hyperplastic polyps are most commonly seen in the
antrum [39], in some series they are also found in the gastric body [38]. They also tend to be
associated with intestinal metaplasia in the surrounding mucosa and atrophic gastritis, and
inversely associated with active H. pylori infection, consistent with long-standing H. pyloriinduced atrophic gastritis. Hyperplastic polyps are found more proximally in atrophic mucosa in
autoimmune gastritis. Risk of neoplastic transformation is proportional to polyp size, with
resection recommended for those measuring over 1.5 cm.
Features of gastric hyperplastic polyps[39]:
 Most common in antrum, but may be found in body and cardia
 Variable in size, with polyps measuring up to 9 cm reported
 Multiple in 20% of patients
 Almost always associated with abnormal background mucosa, often atrophic gastritis
 Intestinal metaplasia is found in up to 16% of hyperplastic polyps, and is more common in
the non-polypoid mucosa
 1.5 to 4.5% contain neoplastic areas, either dysplasia or carcinoma. Overall risk of
neoplasia is low and likely related to underlying condition.
7
DIFFERENTIAL DIAGNOSIS OF THICKENED GASTRIC FOLDS: NEOPLASIA
Two of the important causes of thickened gastric folds are neoplastic: lymphoma and
diffuse gastric carcinoma.
Gastric lymphomas, especially marginal-zone B-cell lymphomas, affect the same population,
older adults, as Ménétrier’s disease. Because the lesion is usually confined to the mucosa, the
gastric folds may be diffusely thickened. Erosions and shallow ulcers may also be seen.
However, the microscopic features of gastric lymphoma do not include epithelial hyperplasia,
and while the condition may be confused with gastritis, it is not typically mistaken for the
hypertrophic gastropathies. On microscopic examination, a diffuse of vaguely nodular infiltrate
of B cells with infiltration and disruption of gastric glands (lymphoepithelial lesions) is seen.
Prominent plasmacytoid differentiation may also occur.
Diffuse (non-cohesive) gastric carcinoma may also cause generalized thickening of the
gastric folds and may be missed with small forceps biopsies [40]. Clinical features such as
anemia and abdominal pain may overlap with those of hypertrophic gastropathies, and a high
index of suspicion must be maintained. Gastric carcinoma arising in Ménétrier’s disease may
be particularly difficult to detect, given the difficulty in identifying localized lesions at endoscopy
in a background of diffusely thickened mucosa.
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