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 widespread 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, pseudopyloric metaplasia, or spasmolytic polypeptide-expressing metaplasia)¹ (Figure 12.2) with or without intestinal metaplasia and pancreatic acinar metaplasia. Atrophic autoimmune pangastritis is much less common than either Helicobacter gastritis or autoimmune gastritis. It is characterised by lymphoplasmacytic 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).

Gastric atrophy can be assessed non-invasively by measuring 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, gastrin, and antibodies against Helicobacter, parietal cells, and intrinsic factor can be combined with endoscopy and histology (of separately identified antral and corpus biopsies) in evaluating 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.

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 adenocarcinoma 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 (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.

Figure 13.1 Erosive gastritis with superficial mucosal necrosis.

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 disease may be restricted to the stomach, but patients may also have coeliac disease, collagenous sprue, and/or collagenous colitis.⁵ It may also occur following olmesartan therapy.⁶ According to some reports, corpus involvement is more common in children and antrum involvement more common in adults,⁷ but this is not a consistent finding.⁶

On histology, there is surface epithelial damage, thickening of the subepithelial collagen plate (to>10 μm) with entrapped capillaries and inflammatory cells in the collagen plate, and an associated lymphoplasmacytic inflammatory cell infiltrate in the lamina propria (Figure 13.2A). There may be prominent eosinophils, increased intraepithelial lymphocytes, occasional neutrophils, and, uncommonly, corpus mucosal atrophy.

Masson trichrome stain or tenascin immunohistochemistry⁷ can be used to highlight the thickened collagen plate (Figure 13.2B) and, along with Congo red, distinguishes this from gastric amyloid. Lamina propria fibrosis may be seen in radiation gastritis 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, steroids, or withdrawal of triggering drugs (e.g. olmesartan), but the success of current treatment options appears to be limited.

(A) A thickened collagen plate highlighted on

(B) Masson trichrome.

Figure 13.2 Collagenous gastritis with

Eosinophilic (Allergic) Gastritis

This is a rare entity characterised by a prominent eosinophil infiltrate in the wall of the stomach. It may be isolated to the stomach, but often occurs as part of an eosinophilic gastroenterocolitis.⁸ Patients may have a history of allergic disease such as asthma, food intolerance or atopic eczema, a peripheral eosinophilia, and raised serum IgE.

The eosinophil infiltrate is maximal and diffuse in the antrum, whereas corpus involvement is less frequent and tends to be patchy if present.⁹ The eosinophil infiltrate is typically predominantly submucosal but may involve any layer of the stomach wall. Patients present with nausea and vomiting, abdominal pain, diarrhoea, failure to thrive, or (when there is involvement of the muscularis propria) gastric outlet obstruction.

When there is gastric mucosal involvement, there is a marked eosinophil infiltrate (20–30 eosinophils per high-power field) in the lamina propria with intraepithelial eosinophils and eosinophil gland abscesses.¹⁰ There may be epithelial damage and erosions, but there are few, if any, other inflammatory cells.

Eosinophils may be present in the gastric mucosa in other conditions (Fact Sheet 13.1) such as parasitic infection, Helicobacter gastritis, autoimmune gastritis, Crohn’s disease, connective tissue disorders, drug reactions, inflammatory fibroid polyp, and malignancy (e.g. adenocarcinoma, lymphoma, Langerhans cell histiocytosis, systemic mastocytosis).¹¹ In these entities, the eosinophils are a component of a mixed inflammatory cell infiltrate, rather than a ‘pure’ infiltrate as seen in eosinophilic gastritis. However, it is always prudent to consider and exclude these other possibilities before making a diagnosis of eosinophilic gastritis. Therapeutic options for eosinophilic gastritis include dietary restriction, antihistamines, steroids, and (for persistent gastric outlet obstruction) surgery.¹²

Focally Enhanced Gastritis (Focally Active Gastritis)

Focally enhanced gastritis (also known as focally active gastritis) is characterised by discrete foci of lymphocytes, plasma cells, and macrophages around and within gastric foveolae and glands, particularly in the deep mucosa, in a background of normal mucosa.^{13, 14} Occasional eosinophils and neutrophils may also be present. It is more frequently present in the antrum and has been described in patients with Crohn’s disease or ulcerative colitis^15–17 as well as in patients without idiopathic inflammatory bowel disease (e.g. Helicobacter gastritis and following bone marrow transplantation).^{15, 18} When focally enhanced gastritis is accompanied by granulomas that are not associated with disrupted glands, the possibility of Crohn’s disease can be suggested. In children, focally enhanced gastritis may predict inflammatory bowel disease. However, focally enhanced gastritis alone should not be interpreted as a specific marker of idiopathic inflammatory bowel disease.¹⁵

Granulomatous Gastritis

Granulomas may occur in the stomach in a wide variety of diseases (Figure 13.3) (Fact Sheet 13.2). Crohn’s disease is the most common cause in the Western world.^{19, 20} Other causes include sarcoidosis, infection (tuberculosis, syphilis, Mycobacterium avium intracellulare, histoplasmosis, mucormycosis, anisakiasis, schistosomiasis, Whipple’s disease), reaction to foreign or endogenous materials, vasculitis, chronic granulomatous disease, Langerhans cell histiocytosis, and malignancy. A proposed association with Helicobacter infection^{21, 22} is questioned by many authors.^{19, 23, 24}

(A) Antral mucosal

(B) Corpus mucosal granulomas.

Figure 13.3 Granulomatous gastritis with

In Crohn’s disease, the granulomas may be associated with focally enhanced gastritis (see above). In sarcoidosis, the compact epithelioid granulomas may be present in the absence of any other inflammation. Central necrosis may be seen in the granulomas of mycobacterial or fungal infection, eosinophils may be prominent with parasitic infection, and food debris 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 aetiology 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 anastomotic blood vessels that arise from branches of the coeliac 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.

Figure 13.4 Ischaemic gastritis with gland loss, hyalinised lamina propria, and regenerative epithelial atypia.

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 compression 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 intraepithelial 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 gastroenteropathy. The stomach may be endoscopically normal, hypertrophic with thickened folds, or show numerous ‘volcano-like’ erosions (given the term varioliform gastritis), particularly 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 hypertrophic lymphocytic gastritis, characterised by hypertrophic gastric folds and florid foveolar hyperplasia resembling Ménétrier disease.

(A) Increased intraepithelial lymphocytes confirmed on

(B) CD3 immunohistochemistry.

Figure 13.5 Lymphocytic gastritis with chronic inflammation in the lamina propria

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, and up to 30% of patients with coeliac disease will have lymphocytic gastritis that is antral predominant.^{34, 36} The association between H. pylori and lymphocytic gastritis seems to be restricted to those cases in which there is a significant neutrophil 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 lymphocytic 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 lymphocytic enterocolitis,³⁸ Crohn’s disease, Ménétrier disease, HIV, common variable immunodeficiency, medication (e.g. toclopidine or olmesartan),^{39, 40} and gastric malignancy (lymphoma or adenocarcinoma).²⁶ However, many cases are idiopathic, 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 medication-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 typically 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, including with ischaemia, have been noted.⁴²

The histological features of reactive gastritis are foveolar hyperplasia (with or without reactive epithelial changes), vascular congestion, oedema, smooth muscle fibres in the superficial lamina propria between the foveolae, and little or no accompanying inflammation (Figure 13.6).⁴³ In some cases, tablet debris or bile entrapped adjacent to the surface may identify the aetiology. The diagnostic criteria have not changed significantly since their initial description, and a more recent study using a visual analogue scale scoring system has again revalidated them.⁴⁴ Reactive gastritis may be complicated by erosion with associated inflammation, infection with H. pylori, or intestinal metaplasia.⁴⁵

Figure 13.6 Reactive gastritis with typical corkscrew foveolar hyperplasia.

The diagnosis of reactive gastritis should not usually present a significant challenge histologically. However, pathologists have different thresholds for calling a biopsy ‘mild reactive gastritis’ rather than normal. Different mucin immunohistochemical profiles have been demonstrated between reactive gastritis and H. pylori gastritis, but the clinical utility of this investigation is uncertain.⁴⁶ Distinguishing reactive gastritis from a hyperplastic polyp may be difficult if endoscopic findings are not available. Up to 20% of hyperplastic polyps may show a reactive gastritis in the background stomach.⁴⁷ Ménétrier disease may also be included in the differential diagnosis. Florid foveolar hyperplasia may resemble dysplasia.

Russell Body / Mott Cell Gastritis

Russell body gastritis was first described by Tazawa and 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 inclusions resulting from the accumulation of immunoglobulins within the rough endoplasmic reticulum) (Figure 13.7). The plasma cells do not show cellular atypia or mitotic figures, and do not show Ki67-immunopositivity. Most cases have H. pylori gastritis with accompanying lymphocytes, eosinophils, neutrophils, and organisms in the surface mucus. In other cases, the 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 cells that lack Russell bodies are polyclonal.^{49, 50}

(A) Abundant Mott cells in the lamina propria

(B) More readily visible at higher power.

Figure 13.7 Russell body gastritis with

Patients may present with dyspepsia and epigastric pain, and, on endoscopy, have erosive or nodular gastritis or a discrete lesion (the latter due to a localised accumulation of Russell body-containing plasma cells). The antrum is the most common site of involvement. Despite the monoclonal nature of the Mott cells in some cases, Russell body gastritis is considered 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 lymphadenopathy), mucosa-associated lymphoid tissue (MALT) lymphoma (characterised by lymphoepithelial lesions and proliferation of centrocyte-like cells or monocytoid B cells), plasmacytoma (with osteolytic lesions on CT and paraproteinaema), 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 morphological features resemble those seen more commonly in the kidney and gallbladder. Indeed, primary xanthogranulomatous 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 characteristic infiltrate of lipid-laden macrophages admixed with multinucleate (Touton type) giant cells, lymphocytes, and fibroblasts.

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 autoantibody-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 corpus mucosa with minimal atrophy and no evidence of metaplasia. 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 mucosal atrophy (Figure 13.8A), together with mucous neck cell metaplasia (also called pseudopyloric metaplasia or spasmolytic 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 infiltrate subsides. The antrum mucosa is either normal or shows the features of a reactive gastropathy, unless there is concomitant Helicobacter infection.

(A) Chronic inflammation, loss of parietal cells, and mucosal atrophy

(B) Pseudopyloric metaplasia and intestinal metaplasia.

Figure 13.8 Autoimmune gastritis with

Figure 13.9 Autoimmune gastritis with pancreatic acinar metaplasia.

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 demonstrated by immunohistochemistry (with synaptophysin and chromogranin) initially as linear ECL-cell hyperplasia, then 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.

Figure 13.10 Autoimmune gastritis with linear and nodular ECL-cell hyperplasia on synaptophysin immunohistochemistry.

As well as neuroendocrine tumours, patients with autoimmune gastritis can develop other types of polyp.⁶⁰ The inflammatory 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

Figure 13.11 Autoimmune gastritis with residual normal oxyntic mucosa which may give the endoscopic impression of a polyp.

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

The differential diagnosis for autoimmune gastritis includes H. pylori gastritis and atrophic autoimmune pangastritis (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 inflammation, 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 deep lamina propria of the stomach may also be a manifestation of IgG4-related disease, according to recent reports.⁶⁷

Atrophic Autoimmune Pangastritis

In contrast to autoimmune gastritis, atrophic autoimmune pangastritis (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 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.

(A) Transmucosal chronic inflammation, loss of parietal cells

(B) Gland microabscesses and increased intraepithelial lymphocytes.

Figure 13.12 Atrophic autoimmune pangastritis with

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 phlegmonous 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

Figure 13.13 Helicobacter pylori gastritis with superficial chronic inflammation, in contrast to the transmucosal inflammation of autoimmune gastritis and atrophic autoimmune pangastritis.

Acute H. pylori infection is usually self-limited and, consequently, 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 lamina propria mixed inflammatory infiltrate that includes lymphocytes, plasma cells, eosinophils, and neutrophil polymorphs. 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 paediatric 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 inflammation may be accompanied by mucin depletion and degenerative 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 metaplasia, atrophy, dysplasia, adenocarcinoma, and MALT lymphoma. 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 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 gastric biopsies inevitably are sent to the pathologist with a clinical query of whether H. pylori are present or not, and the pathologist should have an appropriate range of ancillary tests available to detect the organisms (see Table 12.1).

When present, H. pylori is detectable on a routine haematoxylin 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 gastritis 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 commonly used are summarised in Fact Sheet 13.4.

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.

Figure 13.14 Helicobacter pylori demonstrated by immunohistochemistry.

When the typical inflammatory changes of H. pylori gastritis 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 eradication 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 intense than that seen in H. pylori gastritis. However, reactive gastritis and H. pylori gastritis can coexist and the pathologist should always consider the possibility of dual pathology.

In the immunocompromised host, inflammation may be identified in association with a range of infectious agents other than H. pylori, including cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infection. The clinical history should guide appropriate further work-up in these cases. There is some evidence that H. pylori may be less pathogenic in HIV-positive patients, possibly due to the requirement for a functioning immune system to facilitate the interaction with the gastric mucosa.⁸⁴

Other Helicobacter Species

There are descriptions of many non–H. pylori Helicobacter species that are associated with gastritis in humans, including Helicobacter heilmannii, Helicobacter felis, and Helicobacter suis. Typically, they may result in milder inflammation when present as a single infection (without H. pylori coinfection). Helicobacter heilmannii may be recognised on routine H&E stain because the bacteria are twice as large as H. pylori, have a helical/spiral structure, do not adhere to the gastric epithelial cells, and are far less numerous in biopsy specimens (Figure 13.15). The histochemical stains and immunohistochemistry used to detect H. pylori can also detect H. heilmannii, and there may be some cross-reaction with other tests such as the rapid urease test. Treatment is with antibiotics. Given that these non–H. pylori Helicobacter species often coexist with H. pylori infection, they may go unrecognised in many cases or be eliminated undetected following empirical antibiotic treatment.⁸⁵

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

Helicobacter pylori in the Setting of Weight Loss Surgery

The increasing use of sleeve gastrectomy to manage obese patients has resulted in many studies evaluating the necessity for preoperative endoscopy and examination of the surgical specimen in these patients. Two recent studies have shown that 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 specimens other than establishing if H. pylori are present or not.

Fact Sheet 13.5 Helicobacter pylori Gastritis

General

• 
  

  Common worldwide

  
  
• 
  

  Acute Helicobacter pylori infection is usually self-limited

  
  
  
  
  • 
    

    Endoscopy and biopsy rare

  
  
  
  
• 
  

  Endoscopy in chronic infection

  
  
  
  
  • 
    

    Antral predominant erythema, nodules, erosions, or ulceration

  
  

Complications

• 
  

  Atrophic gastritis

  
  
• 
  

  Gastric adenocarcinoma

  
  
• 
  

  MALT lymphoma

Distribution

• 
  

  Typically antral-predominant

  
  
• 
  

  Corpus-predominant H. pylori gastritis may occur in patients taking long-term proton pump inhibitors

  
  
• 
  

  Pangastritis affects the antrum and corpus equally, with widespread atrophy and a higher risk of adenocarcinoma

Histology

• 
  

  Superficial, chronic active gastritis in the antrum

  
  
• 
  

  Lamina propria mixed inflammatory infiltrate that includes lymphocytes, plasma cells, eosinophils, and neutrophil polymorphs

  
  
• 
  

  Lymphoid aggregates and germinal follicles often present

  
  
• 
  

  Mucin depletion and degenerative changes in the epithelium

  
  
• 
  

  Helicobacter pylori within the surface mucus and adherent to the surface and foveolar epithelium

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Chapter 4 – Transplantation, Immunodeficiency, and Immunosuppression Chapter 5 – Drug-Induced Gastrointestinal Disease Chapter 14 – Duodenitis Chapter 25 – Ileal Pouch Anal Anastomosis Chapter 20 – Microscopic Colitis Chapter 21 – Inflammatory Bowel Disease Diagnosis

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