Chapter
Types of Gastritis
13 Tim Andrews and Fiona Campbell
Introduction
A wide variety of insults including infectious agents, medications,
and endogenous and environmental chemical substances may
cause injury to the gastric mucosa. This may take the form of
inflammation (gastritis), reactive changes without inflammation
(termed gastropathy by some authors), or a combination of the
two. The histological appearances may be a ‘pattern’ of injury that
is non-specific and can be seen in association with several aetiol-
ogies, or there may be histological features that are highly char-
acteristic of a single injurious agent. In this chapter, ‘gastritis’ is
considered in three sections: patterns of injury (with many poten-
tial causes), specific types of gastritis, and gastric mucosal injury
related to medical therapies. A practical approach to diagnosis
including potential diagnostic pitfalls is emphasised, as is the need
for accurate endoscopic and clinical information when interpret-
ing these specimens. Common entities, such as Helicobacter pylori
gastritis and reactive gastritis, as well as rare conditions and other
infections are considered. The discussion focuses on endoscopic
biopsies (the most common specimen seen in practice) but these
changes may be present in the resected stomach in the setting of
both benign and malignant disease and also, increasingly, in
specimens removed at the time of bariatric surgery.
Patterns of Gastritis
There are many different types of gastritis, which can be classi-
fied according to aetiology (Table 12.3) or morphological pat-
tern (Table 12.4). Recognising these different patterns of
gastritis can guide the pathologist towards suggesting the aetiol-
ogy. Chronic gastritis with a marked, typically mononuclear,
inflammatory infiltrate in the lamina propria is usually caused
Table 13.1 Atrophic gastritis
Helicobacter gastritis
Site Antral predominant
Chronic inflammation Superficial
Neutrophils Mild to severe
Helicobacter Present
IELs May be present
Inflammation in atrophy Minimal inflammation
ECL-cell hyperplasia (corpus) Absent
ECL, enterochromaffin-like; IELs, intraepithelial lymphocytes.
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by H. pylori infection or autoimmune gastritis (see the section
on specific gastritides). However, some patterns of gastritis
result from a larger number of aetiological factors, which is
why clinicopathological correlation is essential for reaching a
final diagnosis. These patterns of gastritis and their potential
aetiologies are discussed in more detail in this section.
Atrophic Gastritis
Gastric atrophy refers to the loss of gastric glands from the
antrum and/or corpus, with or without metaplasia. Atrophy
may be very localised and follow discrete erosion or ulceration.
Atrophic gastritis, where chronic inflammation leads to wide-
spread damage and atrophy, occurs with Helicobacter gastritis,
autoimmune gastritis, and atrophic autoimmune pangastritis.
Atrophic gastritis in the antrum, usually characterised by
intestinal metaplasia (see Figure 12.1), is most commonly
related to Helicobacter gastritis. Atrophic gastritis in the corpus
is typically a result of autoimmune gastritis. The atrophy in the
corpus is characterised by loss of parietal cells/oxyntic glands
accompanied by extension of mucous neck cells into the deep
gastric glands (so-called mucous neck cell metaplasia, pseudo-
pyloric metaplasia, or spasmolytic polypeptide-expressing
metaplasia)1 (Figure 12.2) with or without intestinal metapla-
sia and pancreatic acinar metaplasia. Atrophic autoimmune
pangastritis is much less common than either Helicobacter
gastritis or autoimmune gastritis. It is characterised by lym-
phoplasmacytic inflammation in the deep lamina propria of
the antrum and corpus, which (in contrast to Helicobacter
gastritis and autoimmune gastritis) persists even when there
is severe atrophy (Table 13.1).
Autoimmune gastritis Atrophic autoimmune pangastritis
Corpus restricted Antrum and corpus
Deep Deep
Minimal Mild to severe
Absent Absent
Absent Present
Minimal inflammation Persistent intense inflammation
Present Absent
 Chapter 13: Types of Gastritis

Gastric atrophy can be assessed non-invasively by measur-
ing serum pepsinogen I (PgI), which is produced and secreted
by chief cells, and pepsinogen II (PgII), which is produced by
oxyntic and antral mucosa. Patients with gastric atrophy have a
lower PgI/PgII ratio.2 Assessment of serum pepsinogen, gas-
trin, and antibodies against Helicobacter, parietal cells, and
intrinsic factor can be combined with endoscopy and histology
(of separately identified antral and corpus biopsies) in evaluat-
ing the distribution and aetiology of atrophic gastritis. When
corpus atrophy is associated with normal antral biopsies, a
diagnosis of autoimmune gastritis is suggested and can be
confirmed clinically by the detection of antibodies to parietal
cells and intrinsic factor. In contrast, if the antral biopsies also
show atrophy, then Helicobacter gastritis is the likely cause of
the corpus atrophy, unless there is concurrent autoimmune
gastritis and Helicobacter gastritis. Intense inflammation
accompanying the atrophy in the antrum and corpus suggests
atrophic autoimmune pangastritis.
(GI) bleeding. On endoscopy, there are multiple 2–15 mm
diameter superficial round gastric erosions, mucosal oedema,
and petechial haemorrhages, typically in the gastric body.
Biopsies of acute gastritis are not common. Histology may
show acute congestion, superficial fibrin thrombi, superficial
lamina propria haemorrhage, and mucosal necrosis (Figure
13.1). Neutrophils are rare unless there is erosion. Iron pill
gastritis is accompanied by grey/brown iron deposition in the
superficial lamina propria, which can be confirmed on Perls
stain.
Collagenous Gastritis
Collagenous gastritis is an extremely rare condition that may
affect children or adults, with a female preponderance reported
in adults. Patients may be asymptomatic or may present with
epigastric or abdominal pain, diarrhoea, and anaemia. The

Hypertrophic Gastritis
Florid foveolar hyperplasia and gastritis may be apparent in a
lymphocytic gastritis, H. pylori gastritis, or cytomegalovirus
gastritis (see later discussion). This should be distinguished
from the non-inflamed hypertrophic gastric mucosa resulting
from diffuse hyperplasia of oxyntic mucosa in Zollinger–
Ellison syndrome, florid foveolar hyperplasia without gastritis
in Ménétrier disease, and mucosal infiltration by adenocarci-
noma or lymphoma.

Acute Erosive, Haemorrhagic, or Stress Gastritis

Acute gastric injury may occur with ingestion of drugs (e.g.
ferrous sulphate, non-steroidal inflammatory drugs [NSAIDs],
or immune checkpoint inhibitors such as Nivolumab),3
alcohol,4 or corrosives; following trauma or hypoperfusion;
and in patients with uraemia. Patients present with acute
onset of epigastric pain, nausea, vomiting, and gastrointestinal Figure 13.1 Erosive gastritis with superficial mucosal necrosis.

(A) (B)

Figure 13.2 Collagenous gastritis with (A) a thickened collagen plate highlighted on (B) Masson trichrome.

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disease may be restricted to the stomach, but patients may also Focally Enhanced Gastritis (Focally Active Gastritis)
have coeliac disease, collagenous sprue, and/or collagenous
Focally enhanced gastritis (also known as focally active gastri-
colitis.5 It may also occur following olmesartan therapy.6
tis) is characterised by discrete foci of lymphocytes, plasma
According to some reports, corpus involvement is more com-
cells, and macrophages around and within gastric foveolae and
mon in children and antrum involvement more common in
glands, particularly in the deep mucosa, in a background of
adults,7 but this is not a consistent finding.6
normal mucosa.13,14 Occasional eosinophils and neutrophils
On histology, there is surface epithelial damage, thickening
may also be present. It is more frequently present in the
of the subepithelial collagen plate (to >10 μm) with entrapped
antrum and has been described in patients with Crohn’s dis-
capillaries and inflammatory cells in the collagen plate, and an
ease or ulcerative colitis15–17 as well as in patients without
associated lymphoplasmacytic inflammatory cell infiltrate in
idiopathic inflammatory bowel disease (e.g. Helicobacter gas-
the lamina propria (Figure 13.2A). There may be prominent
tritis and following bone marrow transplantation).15,18 When
eosinophils, increased intraepithelial lymphocytes, occasional
focally enhanced gastritis is accompanied by granulomas that
neutrophils, and, uncommonly, corpus mucosal atrophy.
are not associated with disrupted glands, the possibility of
Masson trichrome stain or tenascin immunohistochemistry7
Crohn’s disease can be suggested. In children, focally enhanced
can be used to highlight the thickened collagen plate (Figure
gastritis may predict inflammatory bowel disease. However,
13.2B) and, along with Congo red, distinguishes this from gastric
focally enhanced gastritis alone should not be interpreted as a
amyloid. Lamina propria fibrosis may be seen in radiation gas-
specific marker of idiopathic inflammatory bowel disease.15
tritis or ischaemic gastritis, but in these conditions the fibrosis
diffusely involves the lamina propria and is not confined to the
subepithelial zone. Patients may respond to gluten-free diet, Granulomatous Gastritis
steroids, or withdrawal of triggering drugs (e.g. olmesartan), but Granulomas may occur in the stomach in a wide variety of
the success of current treatment options appears to be limited. diseases (Figure 13.3) (Fact Sheet 13.2). Crohn’s disease is the
most common cause in the Western world.19,20 Other causes
Eosinophilic (Allergic) Gastritis include sarcoidosis, infection (tuberculosis, syphilis,
Mycobacterium avium intracellulare, histoplasmosis, mucor-
This is a rare entity characterised by a prominent eosinophil
mycosis, anisakiasis, schistosomiasis, Whipple’s disease), reac-
infiltrate in the wall of the stomach. It may be isolated to the
tion to foreign or endogenous materials, vasculitis, chronic
stomach, but often occurs as part of an eosinophilic
granulomatous disease, Langerhans cell histiocytosis, and
gastroenterocolitis.8 Patients may have a history of allergic
malignancy. A proposed association with Helicobacter
disease such as asthma, food intolerance or atopic eczema, a
infection21,22 is questioned by many authors.19,23,24
peripheral eosinophilia, and raised serum IgE.
In Crohn’s disease, the granulomas may be associated with
The eosinophil infiltrate is maximal and diffuse in the
focally enhanced gastritis (see above). In sarcoidosis, the com-
antrum, whereas corpus involvement is less frequent and
pact epithelioid granulomas may be present in the absence of
tends to be patchy if present.9 The eosinophil infiltrate is
any other inflammation. Central necrosis may be seen in the
typically predominantly submucosal but may involve any
granulomas of mycobacterial or fungal infection, eosinophils
layer of the stomach wall. Patients present with nausea and
may be prominent with parasitic infection, and food debris
vomiting, abdominal pain, diarrhoea, failure to thrive, or
(when there is involvement of the muscularis propria) gastric
outlet obstruction. Fact Sheet 13.1 Some Causes of Gastric Eosinophil
When there is gastric mucosal involvement, there is a Infiltrates
marked eosinophil infiltrate (20–30 eosinophils per high-
• Eosinophilic/allergic gastroenterocolitis
power field) in the lamina propria with intraepithelial eosino-
• Parasitic infection
phils and eosinophil gland abscesses.10 There may be epithelial
damage and erosions, but there are few, if any, other inflamma- • Helicobacter gastritis
tory cells. • Other infections
Eosinophils may be present in the gastric mucosa in other • Drug reactions
conditions (Fact Sheet 13.1) such as parasitic infection, • Autoimmune gastritis
Helicobacter gastritis, autoimmune gastritis, Crohn’s disease, • Collagenous gastritis
connective tissue disorders, drug reactions, inflammatory • Crohn’s disease
fibroid polyp, and malignancy (e.g. adenocarcinoma, lym- • Connective tissue disorders
phoma, Langerhans cell histiocytosis, systemic mastocytosis).11 • Inflammatory fibroid polyp
In these entities, the eosinophils are a component of a mixed • Neoplasia
inflammatory cell infiltrate, rather than a ‘pure’ infiltrate as seen
• Adenocarcinoma
in eosinophilic gastritis. However, it is always prudent to con-
• Lymphoma
sider and exclude these other possibilities before making a
diagnosis of eosinophilic gastritis. Therapeutic options for eosi- • Langerhans cell histiocytosis
nophilic gastritis include dietary restriction, antihistamines, • Systemic mastocytosis
steroids, and (for persistent gastric outlet obstruction) surgery.12
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 Chapter 13: Types of Gastritis

(A) (B)

Figure 13.3 Granulomatous gastritis with (A) antral mucosal and (B) corpus mucosal granulomas.

Fact Sheet 13.2 Some Causes of Gastric Granulomas

Crohn’s disease
Sarcoidosis
Infection
• Tuberculosis
• Syphilis
• Mycobacterium avium intracellulare
• Histoplasmosis
• Mucormycosis
• Anisakiasis
• Schistosomiasis
• Whipple’s disease
• Helicobacter infection (controversial)

Reaction to foreign or endogenous materials

Vasculitis
Chronic granulomatous disease Figure 13.4 Ischaemic gastritis with gland loss, hyalinised lamina propria, and
regenerative epithelial atypia.
Langerhans cell histiocytosis
Malignancy

anastomotic blood vessels that arise from branches of the coeliac

may be present in foreign body type granulomas. However, in
most cases, definitive morphological diagnosis is not possible,
even after further levels and special stains for microorganisms.25
The term ‘idiopathic granulomatous gastritis’, when the aetiol-
ogy of the granulomas is unknown, is no longer an appropriate
pathological diagnosis.23 Ultimately, diagnosis depends on
extensive clinicopathological correlation, and potentially on
clinical follow-up.
Ischaemic Gastritis
Gastric ischaemia and infarction are extremely uncommon
because the stomach is supplied by an extensive network of
trunk. Acute ischaemia may result from arterial occlusion (by
thrombus, emboli, or atherosclerosis), systemic hypotension,
acute gastric dilatation, volvulus, or previous gastric surgery.26–28
Ischaemia may also complicate phlegmonous gastritis. Chronic
ischaemia is typically associated with progressive atherosclerotic
occlusion of the coeliac artery. Patients may present with acute or
chronic abdominal pain, nausea and vomiting, or GI bleeding.29
Endoscopy may reveal discrete ulcers or more extensive mucosal
necrosis. The histological features of ischaemia include gland
withering, gland loss, hyalinised lamina propria, and coagulative
necrosis (Figure 13.4). Submucosal vessels may show a vasculitis,
thromboemboli, or cholesterol emboli. With severe ischaemia,
there may be transmural infarction, necrosis, and perforation.

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 Tim Andrews and Fiona Campbell
Ischaemic features can be seen in mucosal biopsies taken from
the vertical linear erosions (so-called Cameron lesions) that occur
in large sliding hiatus hernias and result from vascular compres-
sion of the hiatus hernia by the diaphragm.30 Clinicopathological
correlation is required to distinguish these erosions from other
potentially life-threatening causes of ischaemic gastritis.
Lymphocytic Gastritis
Lymphocytic gastritis, characterised by increased intraepithe-
lial lymphocytes (IELs), is not a distinct entity but a type of
gastritis that has numerous aetiologies (Fact Sheet 13.3).31 It is
uncommon and occurs more frequently in women.32 Patients
may be asymptomatic or may present with anorexia, epigastric
pain, and sometimes weight loss and a protein-losing gastro-
enteropathy. The stomach may be endoscopically normal,
hypertrophic with thickened folds, or show numerous ‘vol-
cano-like’ erosions (given the term varioliform gastritis), par-
ticularly in the corpus. On histology, there are more than 25
IELs/100 epithelial cells in the surface and foveolar epithelium
(Figure 13.5A), while the deeper epithelium is spared.33,34
These intraepithelial lymphocytes express CD3 and CD8 on
immunohistochemistry (Figure 13.5B). There is accompanying
chronic inflammation (lymphocytes, plasma cells, eosinophils,
and mast cells) in the lamina propria, which can be minimal or
quite marked, and there may be neutrophils, particularly when
erosions are present. Lymphocytic gastritis commonly involves
the whole stomach but may be restricted to the corpus or
antrum. Patients with evidence of protein loss may have hyper-
trophic lymphocytic gastritis, characterised by hypertrophic
gastric folds and florid foveolar hyperplasia resembling
Ménétrier disease.
Lymphocytic gastritis is associated with Helicobacter pylori
infection in 20% of cases and coeliac disease in up to 40% of
cases.32,34,35 Conversely, 4% of patients with H. pylori infection
will have a lymphocytic gastritis that is corpus predominant,
(A)
Figure 13.5 Lymphocytic gastritis with chronic inflammation in the lamina propria and (A) increased intraepithelial lymphocytes confirmed on (B) CD3
immunohistochemistry.
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and up to 30% of patients with coeliac disease will have lym-
phocytic gastritis that is antral predominant.34,36 The associa-
tion between H. pylori and lymphocytic gastritis seems to be
restricted to those cases in which there is a significant neutro-
phil infiltrate.37 Whenever there is a lymphocytic gastritis, the
pathologist should look for H. pylori (with special stains or
immunohistochemistry, if necessary) and when the lymphocy-
tic gastritis is antral-predominant, it is prudent to suggest that
a duodenal biopsy should be performed to exclude coeliac
disease.
Lymphocytic gastritis may also be associated with a lym-
phocytic enterocolitis,38 Crohn’s disease, Ménétrier disease,
HIV, common variable immunodeficiency, medication (e.g.
toclopidine or olmesartan),39,40 and gastric malignancy (lym-
phoma or adenocarcinoma).26 However, many cases are idio-
pathic, with no known association.
Lymphocytic gastritis may resolve spontaneously but can
persist for many years. Some patients may respond to a gluten-
free diet41 or H. pylori eradication, while those with medica-
tion-induced lymphocytic gastritis may respond to withdrawal
of the medication.
Reactive Gastritis
The terms reactive gastritis or gastropathy, chemical gastritis
or gastropathy, and reflux gastritis or gastropathy have typi-
cally been used interchangeably to describe the appearance
seen when the gastric mucosa is subjected to a range of insults,
most usually reflux of alkaline duodenal contents / bile or
drugs in the form of NSAIDs. Other rarer associations, includ-
ing with ischaemia, have been noted.42
The histological features of reactive gastritis are foveolar
hyperplasia (with or without reactive epithelial changes), vas-
cular congestion, oedema, smooth muscle fibres in the super-
ficial lamina propria between the foveolae, and little or no
accompanying inflammation (Figure 13.6).43 In some cases,
(B)
 Chapter 13: Types of Gastritis

Fact Sheet 13.3 Lymphocytic Gastritis

General
• Uncommon; female > male
• Characterised by increased intraepithelial lymphocytes
(IELs)
• Not a distinct entity; has numerous aetiologies
Endoscopy
• Normal/hypertrophic with thickened folds/numerous
‘volcano-like’ erosions (varioliform gastritis), particularly in
the corpus
Histology
• Often involves whole stomach; may be restricted to corpus
or antrum
• 25 IELs/100 epithelial cells in surface and foveolar
epithelium; deeper epithelium is spared
• IELs: CD3+ CD8+
• Lamina propria chronic inflammation (lymphocytes, plasma Figure 13.6 Reactive gastritis with typical corkscrew foveolar hyperplasia.
cells, eosinophils, mast cells)
• Neutrophils, particularly when erosions are present
• Hypertrophic lymphocytic gastritis (LG) may occur: erosion with associated inflammation, infection with H. pylori,
hypertrophic gastric folds and florid foveolar hyperplasia or intestinal metaplasia.45
resembling Ménétrier disease; protein loss common
The diagnosis of reactive gastritis should not usually present
Associations a significant challenge histologically. However, pathologists
• Helicobacter pylori infection in 20% of LG have different thresholds for calling a biopsy ‘mild reactive
• Coeliac disease in up to 40% of LG gastritis’ rather than normal. Different mucin immunohisto-
• 4% of patients with Helicobacter pylori infection have LG chemical profiles have been demonstrated between reactive
(corpus-predominant) gastritis and H. pylori gastritis, but the clinical utility of this
• 30% of patients with coeliac disease have LG (antral- investigation is uncertain.46 Distinguishing reactive gastritis
predominant) from a hyperplastic polyp may be difficult if endoscopic findings
• Lymphocytic enterocolitis are not available. Up to 20% of hyperplastic polyps may show a
• Crohn’s disease reactive gastritis in the background stomach.47 Ménétrier dis-
• Ménétrier disease ease may also be included in the differential diagnosis. Florid
• HIV foveolar hyperplasia may resemble dysplasia.
• Common variable immunodeficiency
• Medication (e.g. toclopidine or olmesartan) Russell Body / Mott Cell Gastritis
• Gastric malignancy (lymphoma or adenocarcinoma) Russell body gastritis was first described by Tazawa and
• No demonstrable association in many cases Tsutsumi in 1998.48 The lamina propria of the gastric mucosa
is infiltrated by abundant Mott cells, i.e. plasma cells containing
Russell bodies (spherical eosinophilic intracytoplasmic inclu-
sions resulting from the accumulation of immunoglobulins
Practice Points 13.1 Lymphocytic Gastritis within the rough endoplasmic reticulum) (Figure 13.7). The
plasma cells do not show cellular atypia or mitotic figures, and
• If LG is observed, Helicobacter pylori should be sought by
do not show Ki67-immunopositivity. Most cases have H. pylori
the pathologist (with special stains or
immunohistochemistry, if necessary).
gastritis with accompanying lymphocytes, eosinophils, neutro-
phils, and organisms in the surface mucus. In other cases, the
• When LG is antral predominant, a duodenal biopsy to
exclude coeliac disease is advisable.
Mott cells are the only inflammatory cells in the lamina propria.
In initial reports, the Mott cells were shown to be polyclonal.
However, several more recent reports describe monoclonal Mott
cells (typically kappa light chain restricted) while the plasma
tablet debris or bile entrapped adjacent to the surface may cells that lack Russell bodies are polyclonal.49,50
identify the aetiology. The diagnostic criteria have not changed Patients may present with dyspepsia and epigastric pain,
significantly since their initial description, and a more recent and, on endoscopy, have erosive or nodular gastritis or a
study using a visual analogue scale scoring system has again discrete lesion (the latter due to a localised accumulation of
revalidated them.44 Reactive gastritis may be complicated by Russell body-containing plasma cells). The antrum is the most

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 Tim Andrews and Fiona Campbell
(A)
Figure 13.7 Russell body gastritis with (A) abundant Mott cells in the lamina propria (B) more readily visible at higher power.
common site of involvement. Despite the monoclonal nature
of the Mott cells in some cases, Russell body gastritis is con-
sidered a benign reactive condition and may regress with H.
pylori eradication therapy if associated with H. pylori gastritis.
The differential diagnosis includes lymphoplasmacytic
lymphoma (which may also have splenomegaly and lympha-
denopathy), mucosa-associated lymphoid tissue (MALT) lym-
phoma (characterised by lymphoepithelial lesions and
proliferation of centrocyte-like cells or monocytoid B cells),
plasmacytoma (with osteolytic lesions on CT and paraprotei-
naema), or possibly signet ring cell adenocarcinoma. There are
occasional case reports of Russell body gastritis and Mott cell
proliferation coexisting with gastric adenocarcinoma.51,52
Xanthogranulomatous Gastritis
This very rare form of gastritis, of uncertain aetiology, is
characterised by xanthogranulomatous inflammation in the
submucosa and deeper layers of the stomach wall. The mor-
phological features resemble those seen more commonly in the
kidney and gallbladder. Indeed, primary xanthogranuloma-
tous cholecystitis may extend into the stomach wall.53
On endoscopy, there is a submucosal lesion, mimicking a
GI stromal tumour or gastric cancer.54 The resection specimen
reveals a soft yellow lesion, which, on histology, has the char-
acteristic infiltrate of lipid-laden macrophages admixed with
multinucleate (Touton type) giant cells, lymphocytes, and
fibroblasts.
Specific Gastritides
The following entities have histological features that are char-
acteristic of a single specific aetiology. However, it is worth
remembering that more than one type of gastritis may occur at
the same time. Differential diagnoses and potential pitfalls are
also discussed.
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(B)
Autoimmune Gastritis
Autoimmune gastritis (also known as autoimmune metaplastic
atrophic gastritis) is caused by autoantibodies to intrinsic
factor, which is required for vitamin B12 absorption, and auto-
antibody-mediated destruction of parietal cells, resulting in
decreased acid production. Vitamin B12 deficiency may result
in pernicious anaemia, while loss of acid production leads to
decreased iron absorption and concomitant iron deficiency
anaemia.55 Autoimmune gastritis is more common in females,
and patients often have other autoimmune diseases such as
autoimmune thyroiditis, coeliac disease, and type 1 diabetes
mellitus.56 Patients may be asymptomatic or present with
dyspepsia. Iron deficiency anaemia is a common presentation.
Pernicious anaemia is present only in advanced disease.
In early disease, there is chronic inflammation in the cor-
pus mucosa with minimal atrophy and no evidence of meta-
plasia. As the disease progresses, the chronic inflammation in
the corpus (characterised by lymphoplasmacytic inflammation
and eosinophils extending into the deep mucosa and lymphoid
aggregates) is accompanied by loss of parietal cells and muco-
sal atrophy (Figure 13.8A), together with mucous neck cell
metaplasia (also called pseudopyloric metaplasia or spasmoly-
tic polypeptide-expressing metaplasia,1) intestinal metaplasia
(Figure 13.8B), and pancreatic acinar metaplasia (Figure
13.9).57,58 Neutrophils are scanty in autoimmune gastritis.
With advanced atrophy, the chronic inflammatory cell infil-
trate subsides. The antrum mucosa is either normal or shows
the features of a reactive gastropathy, unless there is concomi-
tant Helicobacter infection.
Loss of parietal cells and decreased acid production leads to
antral G-cell hyperplasia and hypergastrinaemia, which, in turn,
causes enterochromaffin-like (ECL)-cell proliferation in the
corpus.59 The ECL-cell hyperplasia in the corpus can be demon-
strated by immunohistochemistry (with synaptophysin and
chromogranin) initially as linear ECL-cell hyperplasia, then

(A)
Figure 13.8 Autoimmune gastritis with (A) chronic inflammation, loss of parietal cells, and mucosal atrophy and (B) pseudopyloric metaplasia and intestinal
metaplasia.
Figure 13.9 Autoimmune gastritis with pancreatic acinar metaplasia.
micronodular ECL-cell hyperplasia (Figure 13.10), adenomatoid
ECL-cell hyperplasia (when there are clusters of five or more
micronodules), ECL-cell dysplasia (when micronodules fuse
together), and type 1 neuroendocrine (carcinoid) tumours
when these fused nodules form a lesion >5 mm in diameter.
As well as neuroendocrine tumours, patients with autoim-
mune gastritis can develop other types of polyp.60 The inflam-
matory changes and atrophy can be patchy, resulting in islands
of residual normal oxyntic mucosa (Figure 13.11) that may give
the impression of polyps.61 Hyperplastic polyps, intestinal type
adenomas, and pyloric gland adenomas may also occur.62
Patients with pernicious anaemia have an increased risk of
gastric (intestinal type) adenocarcinoma,63,64 but the increase
may be related to coexistent H. pylori infection.65
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Chapter 13: Types of Gastritis
(B)
Figure 13.10 Autoimmune gastritis with linear and nodular ECL-cell
hyperplasia on synaptophysin immunohistochemistry.
The differential diagnosis for autoimmune gastritis
includes H. pylori gastritis and atrophic autoimmune pan-
gastritis (Table 13.1). The inflammation in Helicobacter
gastritis is typically predominantly antral, in a superficial
location in the mucosa, includes neutrophils, and not
accompanied by ECL-cell hyperplasia. However, H. pylori
may lead to autoantibodies against parietal cells.66 Atrophic
autoimmune pangastritis involves the antrum as well as the
corpus, and is also characterised by transmucosal inflam-
mation, but may have abundant neutrophils as well as
increased intraepithelial lymphocytes. The inflammation in
autoimmune atrophic pangastritis persists even when there
is severe atrophy, in contrast to autoimmune gastritis and
Helicobacter gastritis. Lymphoplasmacytic infiltration of the
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 Tim Andrews and Fiona Campbell
deep lamina propria of the stomach may also be a manifes-
tation of IgG4-related disease, according to recent reports.67
Atrophic Autoimmune Pangastritis
In contrast to autoimmune gastritis, atrophic autoimmune pan-
gastritis (first described by Jevremovic et al. in 2006)68 involves
the antrum as well as the corpus. Patients present with nausea and
vomiting, abdominal pain, diarrhoea, and protein loss. Patients
may have other systemic autoimmune diseases (e.g. systemic
lupus erythematosus, coeliac disease, or autoimmune haemolytic
anaemia) and/or autoimmune enteropathy with anti-goblet cell
and anti-enterocyte antibodies.69 It is characterised by intense
lymphoplasmacytic inflammation that involves the superficial
and deep lamina propria and is accompanied by neutrophils,
including gland microabscesses, increased intraepithelial
Figure 13.11 Autoimmune gastritis with residual normal oxyntic mucosa
which may give the endoscopic impression of a polyp.
(A)
Figure 13.12 Atrophic autoimmune pangastritis with (A) transmucosal chronic inflammation, loss of parietal cells and (B) gland microabscesses and increased
intraepithelial lymphocytes.
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lymphocytes, prominent apoptotic bodies, and loss of parietal
cells (Figure 13.12). There may be ulceration, but there is no
evidence of H. pylori. In contrast to autoimmune gastritis, the
intense inflammation persists even when there is severe atrophy
and there is no ECL-cell hyperplasia. Treatment comprises
immunosuppressive therapy.
Infectious Gastritis
Helicobacter pylori infection is the most common cause of
bacterial gastritis. However, bacterial infection may also lead
to the rare entities of emphysematous gastritis and phlegmo-
nous gastritis. Gastric viral, fungal, or parasitic infections, as
well as tuberculosis and syphilis, are also uncommon and are
usually a manifestation of disseminated infection.
Helicobacter pylori Gastritis
Helicobacter pylori infection typically causes a superficial
chronic active gastritis (Figure 13.13) that may be complicated
by atrophic gastritis and also by gastric adenocarcinoma and
MALT lymphoma (hence the designation of H. pylori as a
carcinogen).70,71 The prevalence of H. pylori infection, which
is transmitted through the faeco-oral and oro-oral routes,
varies widely throughout the world, with a high prevalence in
developing countries.72,73 With the emergence of antibiotic-
resistant H. pylori strains and the knowledge that eradication of
infection does not always prevent the progression of gastric
pathology, current research is using in vivo and ex vivo models
to investigate the mechanisms underlying H. pylori–induced
gastric pathology and to evaluate new therapeutic strategies.73
Acute H. pylori infection is usually self-limited and, conse-
quently, endoscopy and biopsy are not usually performed.
Endoscopy in chronic infection may detect antral predominant
erythema, nodules, erosions, or ulceration.
On histology, chronic H. pylori gastritis is characterised by
a superficial, chronic active gastritis in the antrum with a
(B)

Figure 13.13 Helicobacter pylori gastritis with superficial chronic
inflammation, in contrast to the transmucosal inflammation of autoimmune
gastritis and atrophic autoimmune pangastritis.
lamina propria mixed inflammatory infiltrate that includes
lymphocytes, plasma cells, eosinophils, and neutrophil poly-
morphs. Lymphoid aggregates and germinal follicles are often
present and the term ‘follicular gastritis’ has been used when
this is particularly striking. This corresponds to the endoscopic
entity of ‘nodular gastritis’ and is more common in the pae-
diatric population. The hyperplastic lymphoid tissue regresses
with eradication therapy, and care must be taken not to over-
diagnose a MALT lymphoma in this setting.74 The inflamma-
tion may be accompanied by mucin depletion and degenera-
tive changes in the epithelium. H. pylori are identified
entrapped within the surface and foveolar mucus and adherent
to the surface epithelium.
Although H. pylori gastritis is typically antral-predominant,
a corpus-predominant form of H. pylori gastritis may occur in
patients taking long-term proton pump inhibitors, when the
bacteria move from the antrum to the corpus75 and are present
in the deep oxyntic glands. In this setting gastric atrophy is
more common. H. pylori pangastritis affects the antrum and
corpus equally and is associated with widespread atrophy and a
higher risk of progression to gastric adenocarcinoma than
other forms of Helicobacter gastritis.
Gastric biopsies with H. pylori gastritis should always be
assessed for the known complications, i.e. intestinal metapla-
sia, atrophy, dysplasia, adenocarcinoma, and MALT lym-
phoma. The latter is characterised by expansion of the lamina
propria by an atypical lymphoid infiltrate that also infiltrates
the muscularis mucosae, and the presence of lymphoepithelial
lesions with subsequent loss of glands.
Identification of Helicobacter pylori There is significant
debate around the role of histopathology in the detection of
H. pylori and whether this ‘expensive’ method can be justified
compared to other, less expensive tests including the rapid
urease test, faecal antigen testing, and serological detection of
anti–H. pylori antibody. One commonly cited reason for taking
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Chapter 13: Types of Gastritis
Fact Sheet 13.4 Ancillary Methods for Detecting
Helicobacter pylori in Biopsies
• Histochemical stains such as Giemsa and Warthin–Starry are
inexpensive and readily available even in resource-poor
settings, although they are less sensitive and specific than
immunohistochemistry and the time taken to search for
sparse organisms can be increased compared to
immunohistochemistry.
• Immunohistochemistry (Figure 13.14) is sensitive and
specific, can detect organisms deep in the oxyntic glands
when patients are taking proton pump inhibitors, and can
detect the coccoid forms, but clearly has a resource
implication if performed on all gastric biopsies on a reflex
basis.
• Culture of biopsy specimens (with subsequent antibiotic
sensitivity testing) may be useful in cases of treatment
failure but are not justified in routine practice.81
• Polymerase chain reaction (PCR) for H. pylori may be
performed on fresh tissue or formalin-fixed, paraffin-
embedded samples,82 although arguably there is a
difference between detecting H. pylori DNA and proving
the presence of pathogenic organisms.
a biopsy is that the patient is using a proton pump inhibitor,
which increases the likelihood of a false-negative urease test.
There is some evidence that the same factors that reduce
organism density and impact on the sensitivity of urease also
affect histology.76 Current UK National Institute for Health
and Care Excellence (NICE) guidelines recommend the use of
either a urea breath test, faecal antigen test, or serology to
establish a patient’s H. pylori status, and a repeat urea breath
test at an appropriate interval to monitor treatment.77
However, a recent British Society of Gastroenterology position
statement suggests that a non-invasive test, urease test, or
histology can establish H. pylori status in the patient presenting
to hospital services.78 Therefore, a significant number of gas-
tric biopsies inevitably are sent to the pathologist with a clinical
query of whether H. pylori are present or not, and the pathol-
ogist should have an appropriate range of ancillary tests avail-
able to detect the organisms (see Table 12.1).
When present, H. pylori is detectable on a routine haema-
toxylin and eosin (H&E) stain in around 70% of cases.79 In the
authors’ laboratory, the use of additional tests is restricted to
cases showing typical morphological features of H. pylori gas-
tritis but no H. pylori organisms on H&E (often following
eradication therapy). This pragmatic approach, as opposed to
a reflex approach on all cases, is supported by others, but the
subject remains controversial.80 The ancillary methods com-
monly used are summarised in Fact Sheet 13.4.
When the typical inflammatory changes of H. pylori gas-
tritis are present, but no organisms are detectable, it is worth
considering whether the patient has been treated for H. pylori
prior to biopsy or whether there has been inadvertent eradica-
tion by antibiotics that were given for another indication.83
Some cases of reactive gastritis may show inflammation as a
consequence of ulceration, but the inflammation is usually less
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 Tim Andrews and Fiona Campbell

Figure 13.14 Helicobacter pylori demonstrated by immunohistochemistry. Figure 13.15 Helicobacter heilmannii are much larger organisms than
Helicobacter pylori and do not adhere to the epithelial cells.

intense than that seen in H. pylori gastritis. However, reactive

Fact Sheet 13.5 Helicobacter pylori Gastritis
gastritis and H. pylori gastritis can coexist and the pathologist
should always consider the possibility of dual pathology. General
In the immunocompromised host, inflammation may be • Common worldwide
identified in association with a range of infectious agents other • Acute Helicobacter pylori infection is usually self-limited
than H. pylori, including cytomegalovirus (CMV) and Epstein–
Barr virus (EBV) infection. The clinical history should guide • Endoscopy and biopsy rare
appropriate further work-up in these cases. There is some • Endoscopy in chronic infection
evidence that H. pylori may be less pathogenic in HIV-positive
• Antral predominant erythema, nodules, erosions, or
patients, possibly due to the requirement for a functioning
ulceration
immune system to facilitate the interaction with the gastric
mucosa.84 Complications
• Atrophic gastritis
Other Helicobacter Species There are descriptions of many
• Gastric adenocarcinoma
non–H. pylori Helicobacter species that are associated with
gastritis in humans, including Helicobacter heilmannii, • MALT lymphoma
Helicobacter felis, and Helicobacter suis. Typically, they may Distribution
result in milder inflammation when present as a single infec- • Typically antral-predominant
tion (without H. pylori coinfection). Helicobacter heilmannii • Corpus-predominant H. pylori gastritis may occur in
may be recognised on routine H&E stain because the bacteria patients taking long-term proton pump inhibitors
are twice as large as H. pylori, have a helical/spiral structure, do • Pangastritis affects the antrum and corpus equally,
not adhere to the gastric epithelial cells, and are far less numer- with widespread atrophy and a higher risk of
ous in biopsy specimens (Figure 13.15). The histochemical adenocarcinoma
stains and immunohistochemistry used to detect H. pylori
Histology
can also detect H. heilmannii, and there may be some cross-
• Superficial, chronic active gastritis in the antrum
reaction with other tests such as the rapid urease test.
Treatment is with antibiotics. Given that these non–H. pylori • Lamina propria mixed inflammatory infiltrate that includes
lymphocytes, plasma cells, eosinophils, and neutrophil
Helicobacter species often coexist with H. pylori infection, they
polymorphs
may go unrecognised in many cases or be eliminated unde-
• Lymphoid aggregates and germinal follicles often
tected following empirical antibiotic treatment.85
present
Helicobacter pylori in the Setting of Weight Loss Surgery • Mucin depletion and degenerative changes in the
The increasing use of sleeve gastrectomy to manage obese epithelium
patients has resulted in many studies evaluating the necessity • Helicobacter pylori within the surface mucus and adherent
for preoperative endoscopy and examination of the surgical to the surface and foveolar epithelium
specimen in these patients. Two recent studies have shown that

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Practice Points 13.2 Helicobacter pylori
• Avoid overdiagnosing prominent lymphoid tissue as
lymphoma
• Assess all biopsies that show Helicobacter pylori gastritis for
intestinal metaplasia, atrophy, dysplasia, adenocarcinoma,
and MALT lymphoma.
H. pylori and non–H. pylori gastritis are common in such
specimens.86,87 There are no specific special recommendations
for dealing with preoperative biopsies or the resected speci-
mens other than establishing if H. pylori are present or not.
Emphysematous Gastritis
Emphysematous gastritis is a rare and commonly fatal disease
caused by invasion of the gastric wall by gas-producing organ-
isms such as Clostridium, Escherichia coli, Streptococcus,
Enterobacter, and Pseudomonas aeruginosa.88 Patients present
with an acute abdomen and systemic toxicity and may have
haematemesis and melaena. Imaging reveals intramural gas
bubbles. Emphysematous gastritis may result from a septic
focus in the gastric wall as a consequence of alcohol abuse,
ingestion of NSAIDs or corrosive agents, recent abdominal
surgery, or pancreatitis, and is more common in immunocom-
promised patients. Whether the bacteria enter the stomach
wall through mucosal ulceration and/or by haematogenous
spread to the stomach is uncertain.
Macroscopically, the gastric wall feels crepitant because of
the presence of the intramural gas bubbles. On histology, there
may be ulceration, mucosal necrosis, transmural oedema,
transmural neutrophils, and numerous gas-filled spaces with
or without a giant cell reaction. In advanced disease, the entire
stomach wall may be gangrenous and necrotic. Treatment is
either conservative or by surgical resection.89
The differential diagnosis includes gastric emphysema, when
gas enters the stomach wall following gastric mucosal trauma
(e.g. vomiting, endoscopy, or nasogastric tube insertion) or
ruptured pulmonary emphysematous blebs, and phlegmonous
gastritis (see the section that follows). Patients with gastric
emphysema are not septic, do not have transmural oedema
and neutrophils, and have a good prognosis.90 Although phleg-
monous gastritis is characterised by predominantly submucosal
oedema and neutrophilic inflammation, there is no intramural
gas.
Phlegmonous Gastritis
This is an extremely rare form of gastritis, is often fatal, and is
caused by suppurative bacterial infection of the submucosa of
the stomach. The most common organism is haemolytic strep-
tococcus. Predisposing factors include mucosal injury (e.g.
following endoscopy), diabetes mellitus, chronic alcoholism,
and immunocompromise, but phlegmonous gastritis may also
occur in previously healthy individuals.91,92 Patients present
with acute epigastric pain, nausea and vomiting, fever, and
signs of sepsis. Occasional patients may present with pus in
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Chapter 13: Types of Gastritis
the vomitus, which may be pathognomonic.91 Imaging reveals
diffuse thickening of the gastric wall. On endoscopy, there is
enlargement or flattening of the rugal folds with marked sub-
mucosal oedema.
Histologically, the mucosa is usually intact and there is
florid oedema and neutrophil infiltration of the submucosa
with microabscesses. A Gram stain will demonstrate the bac-
teria in the submucosa. Thrombosis in the mural vessels can
lead to secondary ischaemic necrosis with transmural inflam-
mation, necrosis of the muscularis propria, and sometimes
perforation.93 The recommended treatment is either conserva-
tive (with antibiotics) and/or localised or total resection.
Phlegmonous gastritis can be distinguished from emphy-
sematous gastritis by the lack of gas bubbles in the wall of the
stomach.
Viral Gastritis
Cytomegalovirus (CMV) is the most common viral infection
of the stomach and occurs in young children and immuno-
compromised adults (e.g. those with HIV or post-transplant)
(see also Chapter 4). It may coexist with graft-versus-host
disease (GvHD) and may also occur in immunocompetent
patients. Patients may be asymptomatic or present with epi-
gastric pain, nausea and vomiting, or haematemesis. On endo-
scopy, the mucosa may be normal or there may be nodules,
erosive gastritis, and ulcers. Gastric outlet obstruction, per-
foration, and gastrocolic fistula formation have also been
described.94,95 Children may have a hypertrophic gastropathy
and protein-losing enteropathy resembling Ménétrier disease.96
On histology, the gastric mucosa may be normal but contain
occasional CMV inclusions, or there may be marked inflamma-
tion and ulceration with abundant CMV inclusions (Figure
13.16A). CMV inclusions may be intranuclear (with classical
‘owls’ eye’ appearance) or intracytoplasmic (eosinophilic and
granular) and can be found in epithelial, endothelial (Figure
13.16B or stromal cells either on routine H&E staining or
immunohistochemistry.
Herpes simplex virus gastritis is rare97 and occurs in
immunocompromised individuals. On endoscopy, there may
be oedematous nodules or ulcers. On histology, there is acute
and chronic inflammation with ulceration. Herpes simplex viral
inclusions are found in the gastric epithelial cells and are
demonstrable on H&E staining or with immunohistochemistry.
Herpes varicella zoster viral infection may occur in the
stomach and may be detected by immunohistochemistry or
molecular testing.98
Epstein–Barr virus (EBV) infection rarely affects the sto-
mach, where it may be misdiagnosed as lymphoma. Patients
with acute EBV infection may not have GI symptoms or may
present with epigastric pain and nausea. Gastric ulcers are
apparent on endoscopy.99,100 On histology, there is ulceration
and expansion of the lamina propria by a diffuse atypical
lymphoid infiltrate composed of small, intermediate-sized,
and large lymphocytes with immunoblast-like cells.
Neutrophils are scanty, even when ulceration is present, and
there are no lymphoid follicles or H. pylori. On immunohisto-
chemistry, this lymphoid infiltrate is composed of a mixture of
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 Tim Andrews and Fiona Campbell

(A) (B)

Figure 13.16 Cytomegalovirus gastritis with (A) abundant viral inclusions in granulation tissue and (B) occasional inclusions in mucosal endothelial cells.

B lymphocytes and, predominantly, T lymphocytes. There is a

normal kappa to lambda light chain ratio. In situ hybridisation
for EBV-encoded small RNA-1 (EBER-1) shows diffuse posi-
tivity. EBV is a self-limiting ulcerative gastritis, and this also
aids in the distinction from malignant lymphoma.

Fungal Gastritis
Fungal infection of the stomach is rare and may be localised to
the stomach or occur as part of a disseminated infection.
Candida is the most common cause of fungal gastritis and
occurs as an opportunistic infection in immunocompromised
individuals and in patients with chronic alcoholism, malnutri-
tion, malignancy, or severe atrophic gastritis and
achlorhydria.101,102 Candida may also colonise chronic peptic
ulcers in immunocompetent individuals.103 On endoscopy,
there may be pale yellow/white mucosal membranes, warty
nodules, or ulceration. On histology, fungal hyphae and spores
are present within ulcer slough and hyphae are seen infiltrating
the ulcer base. Hyphae may invade vessel walls leading to Figure 13.17 Gastric giardia seen on the surface of the antral mucosa.
thrombosis or rupture and haemorrhage. Other gastric fungal
infections include mucormycosis (see Figure 18.17), where the
broad, non-septate branching hyphae may infiltrate the ulcer immunocompromised patients. In the stomach the organisms
base and vessel walls;104 Histoplasma capsulatum (see Figure are apparent on the luminal border, with accompanying
18.19), where the organisms are present in macrophages;105,106 inflammation in the lamina propria. Involvement of the
Cryptococcus neoformans (see Figure 4.2);107,108 and antrum is more common than in the corpus.110 Gastric tox-
Pneumocystis jiroveci (see Figure 4.3).109 Fungal gastritis may oplasmosis has been described in immunocompromised
occasionally be associated with granulomas. Special histo- patients with disseminated disease111 and as isolated gastric
chemistry may highlight the fungal elements, e.g. periodic infection.112 Infected patients may have a normal endoscopy or
acid–Schiff diastase (PASD) and Grocott–Gomori methena- thickening of the gastric folds. The trophozoites can be identi-
mine silver for histoplasmosis, and Masson–Fontana for fied in epithelial, endothelial, or stromal cells. Anisakiasis
Cryptococcus. (which may be associated with granulomatous inflammation),
Strongyloides (Figure 18.26), Schistosoma (Figures 18.27 and
22.8), and Ascaris lumbricoides (Figure 18.24) infections have
Parasitic Gastritis all been described in the stomach. Giardia can occasionally be
Patients with parasitic infections of the stomach may have a present in the surface mucus of gastric antrum (Figure 13.17),
non-specific active chronic gastritis or abundant mucosal eosi- which may be normal or have intestinal metaplasia, in patients
nophils. Cryptosporidiosis (Figure 18.22) occurs in with duodenal infection.113

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Tuberculosis
Gastric involvement in pulmonary or systemic tuberculosis is
uncommon, and isolated gastric tuberculosis is extremely
rare.114 Gastric tuberculosis typically involves the antrum and
may lead to gastric outlet obstruction and fistula formation.
Patients present with epigastric pain, nausea and vomiting, or
haematemesis. On endoscopy, there are ulcers in the antrum,
and the gastric wall may be thickened. On histology, there is
granulomatous inflammation with confluent granulomas that
may or may not have caseous necrosis (Figures 18.12, 19.7,
22.5, and 27.4). Acid- and alcohol-fast bacilli may be detected
on special histochemistry (e.g. Ziehl–Neelsen) or by polymer-
ase chain reaction (PCR); the latter is useful for speciation.
Syphilis
Gastric syphilis is extremely rare.115,116 Patients may present
with epigastric pain and haematemesis. On endoscopy, there
may be multiple erosions and ulcers, hypertrophic gastric
folds, or a nodular mucosa. The antrum is most commonly
affected, and involvement can lead to gastric outlet obstruc-
tion. On histology, there is a diffuse plasma cell-rich infiltrate
with neutrophils, lymphocytes, lymphoid follicles, and
destruction of the glands. Poorly formed granulomas may be
present. The differential diagnosis includes H. pylori gastritis.
Syphilis can be diagnosed either by identification of
Treponema pallidum on immunohistochemistry or PCR
(Figure 22.3F) or by serology.
Gastritis Related to Medical Therapy
Drugs can produce a wide range of appearances within the
gastric mucosa. Some are specific for a given drug or class of
drugs, but most are non-specific and fall within the differential
diagnosis of other patterns of gastritis (see Table 12.6). Follow-
up biopsies of drug-induced gastritis are rare and the improve-
ment of symptoms following cessation of a suspected culprit
medication (and/or the addition of steroids as treatment in
cases where drug cessation is not a clinical option) is usually
considered proof of cure. The exception is with some of the
newer immunomodulating agents/immunosuppressive drugs,
where further biopsies may be indicated either to monitor
treatment response or, in the setting of a clinical trial, for the
purposes of data gathering.
This section will discuss drugs associated with the various
common patterns of gastritis, the major classes of drugs known
to be gastro-toxic (including NSAIDs), and the small molecu-
lar immunotherapy type drugs which appear to be creating a
range of novel GI tract pathology that the practising histo-
pathologist needs to consider in the differential diagnosis of an
inflamed gastric biopsy.
Virtually any histological change may be associated with
drug administration, and there are few clues to aid the diag-
nosis apart from history, clinical suspicion, and, ultimately,
exclusion of other causes. Features that are said to occur
commonly are foveolar hyperplasia, erosions, ulcers, strictures,
crystal/tablet deposition, and reactive epithelial changes
mimicking dysplasia (see also Chapter 5).
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Chapter 13: Types of Gastritis
Gastritis Associated with Deposition of Tablets and
Crystals, with Emphasis on Iron Pill–Associated
Gastritis
Oral iron tablet therapy is common in those with iron defi-
ciency anaemia and is seen increasingly often in the ageing
population. Issues with swallowing and gastric motility, and a
failure to consume adequate fluids, all predispose elderly and
debilitated patients to the side effects of tablet residue/debris
becoming lodged adjacent to the mucosal surface, where it acts
as an irritant producing a range of mucosal changes including
erosions, inflammation, and regenerative changes. These can
be particularly florid and may be mistaken for dysplasia by the
unwary. Similar issues are encountered at other sites, including
the oesophagus.117 The classical picture of iron pill associated
gastritis comprises focal erosion and regeneration/reactive
changes associated with deposition of grey-brown crystalline
material in the superficial mucosa. This material is Perls posi-
tive on histochemical staining (Figure 13.18). In the absence of
typical features or a definite history of iron tablet use, it is
important to distinguish these changes from other types of iron
deposition within the stomach118 and also from the effects of
other medications. Iron deposition within stromal cells is typi-
cally associated with iron tablet ingestion or some other form
of previous mucosal injury with haemorrhage. Deposition of
iron within epithelial cells, typically in a diffuse distribution, is
associated with systemic iron overload disorders such as hae-
mochromatosis. Many other tablets or deposits may mimic
iron pill gastritis, and it is worth noting that some of these
compounds may also be weakly Perls positive.
A recently described mimic of iron pill gastritis occurred
following the administration of OsmoPrep, a tablet form of
sodium phosphate bowel preparation taken by patients under-
going simultaneous upper and lower GI endoscopy. The gastritis
was characterised by the presence of purple to black granular
deposits in the superficial mucosa with prominent reactive epithe-
lial changes. However, these deposits were Perls negative, von
Kossa positive, and Alizarin red negative, confirming that they
were sodium phosphate deposits rather than iron deposition.119
Deposition of Kayexalate crystals associated with necrosis
is described in the stomach (and more commonly in the lower
GI tract) in uraemic patients receiving this treatment for
hyperkalaemia.120 Mucosal calcinosis in the stomach may
occur in patients with renal disease and those taking antacids
and sucralfate.121 Bile acid sequestrant crystals and uncommon
compounds such as Lanthanum, a rare earth metal used in the
treatment of hypophosphataemia, have also given rise to
deposits in the stomach.122
Gastritis Associated with NSAIDs
NSAIDs are commonly used to good effect in the treatment of
a wide range of conditions. However, there is recognition that
their usage is associated with a significant burden of GI muco-
sal injury, especially gastric mucosal pathology (see also
Chapter 5). The histological features may range from a mild
reactive gastritis to erosions and florid ulceration. The latter
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 Tim Andrews and Fiona Campbell
(A)
Figure 13.18 Iron pill gastritis with (A) grey-brown crystalline material on the surface that is (B) Perls positive.
has been described in association with fatal upper GI haemor-
rhage. However, the histological changes are non-specific.123
There is debate about the most effective way to administer
NSAIDs (including whether they should be taken with food,
the need for additional gastro-protective medications, and the
most appropriate drug and formulation to use), and whether
there is an association (positive or negative) between NSAIDs
and coexisting H. pylori infection.124 There is also interest in
the evolving field of pharmacogenomics where the presence or
absence of a certain polymorphism in a metabolising enzyme
may be associated with the side-effect profile of a given drug
such as NSAIDs.125 These are all clinically important consid-
erations but do not influence the histological picture, and the
reader is directed to the relevant literature.
Other Drugs Associated with Specific Inflammatory
Changes in the Gastric Mucosa
Doxycycline is a tetracycline antibiotic that has been asso-
ciated with ulceration in the upper GI tract. Several studies
have described a characteristic pattern of injury, including
vascular degeneration in superficial capillaries with associated
perivascular oedema, endotheliitis, and fibrin microthrombi.
These findings have not been reported in patients with other
forms of ulceration.126,127
Olmesartan is an angiotensin II inhibitor used in the treat-
ment of hypertension and appears to cause significant GI side
effects more often than other agents in this class. The effects are
typically duodenal (mimicking collagenous sprue / coeliac dis-
ease) or ileocolonic, but rare associations with lymphocytic/
collagenous gastritis have been reported.6,40
Gastritis Associated with Immunosuppressive
Agents
Mycophenolate mofetil is an immunomodulatory drug used
in several conditions including in patients who have
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(B)
undergone renal transplant. In the stomach, it may cause a
florid reactive gastritis with associated granuloma formation.
The GvHD-like changes reported at other sites have not been
identified in the gastric mucosa.128–130
Infliximab is a tumour necrosis factor-α inhibitor used in
the treatment of inflammatory conditions, including rheuma-
toid arthritis and Crohn’s disease. It may cause lymphocytic
gastritis and eosinophilic gastritis.131
Gastritis Associated with Novel
Immunomodulatory Agents
Several ‘novel’ agents which target a range of immune func-
tions, including specific T-cell surface molecules, are now used
commonly to treat a range of solid tumours such as malignant
melanoma and non–small-cell lung cancer. These agents seem
to be responsible for a range of deleterious effects on the GI
tract mucosa, and commonly cause diarrhoea. While much of
the literature focuses on changes in the lower GI tract, small
studies and case reports have described changes in the gastric
mucosa. These include inflammation with prominent neutro-
phils and, in some cases, gland abscesses (associated with
Ipilimumab, Pembrolizumab, and Nivolumab),132 lymphocy-
tic gastritis (Pembrolizumab and Durvalumab),133 and acute
haemorrhagic/erosive gastritis (Nivolumab).134 Increased
apoptotic debris may be seen in some cases.134a The possibility
that gastric mucosal changes could be therapy-related should
always be considered when there is such a drug history.
Radiotherapy- and Chemotherapy-Associated
Gastric Mucosal Injury
Radiation for upper abdominal neoplasia such as oesophageal
cancer or pancreatic cancer135,136 may lead to gastric injury,
which can take the form of acute gastritis, deep acute ulcers, or
chronic ulceration (see also Chapter 3).137–140
 Chapter 13: Types of Gastritis

Acute radiation gastritis may occur a few days to a few
months after radiation exposure and is characterised by degen-
erative changes in the gastric epithelium, oedematous and
hyalinised lamina propria, telangiectasia, and submucosal
oedema. There is swelling of endothelial cells, a reduction in
the size of the vessel lumina, coagulative mucosal necrosis, and
superficial ulceration. This usually resolves within 2–3 months
with regeneration of the mucosa, but there may be residual
atrophy, fibrosis, atypical radiation fibroblasts, and
endarteritis.
Deep acute ulcers may develop 1–2 months after radiation
exposure as a consequence of vascular damage ischaemia with
endothelial proliferation, fibrinoid necrosis, and radiation
fibroblasts. Chronic ulceration may occur a few months to
several years after radiation exposure and is a result of ischae-
mia caused by fibrous obliteration of blood vessels. The
chronic ulcers resemble peptic ulcers, are usually solitary,
and occur more frequently in the antrum. There is fibrosis,
which may be glassy/hyalinised, bizarre radiation fibroblasts,
telangiectasia, atypical endothelial cells in capillaries, and hya-
linised arterial walls.
Intra-arterial radiation therapy (where yttrium-90–contain-
ing microspheres are implanted permanently into primary or
secondary malignant tumours in the liver, via the hepatic artery)
may lead to gastric ulceration in up to 30% of patients.141
Ectopic radioembolic 90Y microspheres in the gastric mucosal
and submucosal vessels produce ulceration as a consequence of
localised chronic ischaemic injury.
‘Conventional’ chemotherapy agents such as 5-flurouracil
(5-FU) are also associated with a range of mucosal changes
including florid ulceration. The appearances are drug and dose
dependent and there may be degenerative and regenerative
changes that are florid enough to create a diagnostic dilemma
with relationship to dysplasia/malignancy.142 So-called ‘radia-
tion recall’ gastritis describes the situation where previous
radiation therapy results in more severe damage than would
otherwise have been expected when chemotherapy is subse-
quently administered.
Recreational Drugs
The literature related to illicit and recreational drugs is extre-
mely sparse, perhaps because their effects do not come to
medical attention or because there are effects more cata-
strophic than those on the stomach. ‘Gastritis’ not otherwise
specified may occur in association with inhalational ketamine
use (with symptoms resolving on drug cessation).143 Gastric
perforation associated with crack cocaine use is also well
described.144

7. Arnason T, Brown IS, Goldsmith JD, with Crohn’s disease. Gastroenterology.

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