Comment

‘Mild (chronic) gastritis’ and similar non-specific terms are often used in endoscopic and histological reports. Furthermore, the term ‘gastritis’ is sometimes used by laypeople and physicians as a synonym for dyspeptic symptoms, sometimes associated to H. pylori infection and often relieved by its eradication.9 However, in most cases, endoscopic or histological findings are non-specific, do not suggest current H. pylori infection and cannot explain the symptoms. Making such unqualified diagnoses of gastritis may reinforce incorrect clinical assumptions and lead to unwarranted management strategies (eg, long-term proton pump inhibitor (PPI) treatment) or to unnecessary surveillance endoscopies. Therefore, a definition of the endoscopically and histologically normal gastric mucosa is crucial to prevent clinically irrelevant diagnoses (table 1).

Normal gastroscopy may be difficult to define, and the absence of lesions or changes is usually considered an adequate synonym. However, the regular arrangement of collecting (RAC) venules16 17 in the distal gastric body is seen by standard high-resolution–white-light or integrated endoscopy as regularly distributed red dots or starfish vascular structures.16 17 Its presence has a >90% positive predictive value for normal gastric oxyntic mucosa and reliably excludes H. pylori infection (figure 1).18 19

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Figure 1

Gastroscopy within normal limits. White-light gastroscopy: antral (A), angularis and corpus mucosa (B) within normal limits. Normal antrum (C) and corpus mucosa (D) in narrow-band imaging.

Histologically, there are two main types of gastric mucosa: oxyntic and mucosecreting pyloric.20 A third mucosal type lies distally to the oesophagogastric junction.15–17 This ‘cardia’ phenotype consists of foveolar epithelium with mucous glands and no parietal cells; its endoscopic landmarks and its nature (native vs metaplastic) are the subject of debate. The oxyntic mucosa of corpus and fundus covers more than two-thirds of the stomach. It contains oxyntic glands with short mucosecreting foveolae (synonym: pits). The mucosecreting antral and pyloric mucosa lines the distal stomach. The interface between oxyntic and antral mucosa consists of a ‘transitional phenotype’,21 with intermingling oxyntic and mucosecreting glands (see section 2.5.1). The presence of mucosecreting glands proximal to the incisura angularis raises the possibility of metaplastic pseudopyloric transformation (see section 2.5.3) of the native oxyntic mucosa extending distally beyond the incisura angularis.22–25

No inflammatory cells are present in either the epithelium (intraepithelial) or within the lumen of the glandular units, except for the extremely rare intraepithelial lymphocytes (≤1 per 100 epithelial cells).26 The normal lamina propria contains sparse resident lymphocytes, rare plasma cells and eosinophils, but no neutrophils (figure 2).20 In the absence of histological evidence of changes to the mucosal structure (including inflammatory infiltrates, lymphoid follicles, atrophy, intestinal or pseudopyloric metaplasia, detectable organisms, hyperplastic or neoplastic changes), a histopathological diagnosis of ‘gastric mucosa within normal limits’ should be made.27

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Figure 2

Gastric mucosa within normal limits. (A) The oxyntic mucosa covers two-thirds of the stomach (cranial portion). In sections stained with H&E, glandular pits are lined by surface mucous cells and, more in depth, by mucous neck cells of the proliferative zone. Deeper into the foveolae (commonly referred to as pits), closely packed tubular glands include parietal and peptic (chief) cells. Neuroendocrine cells (ie, enterochromaffin-like cells) are scattered through the oxyntic epithelium, primarily located in the deeper third of the glandular units. The deeper part of the oxyntic glands reaches the most superficial layer of the muscularis mucosae. Rare lymphocytes, plasma cells and eosinophils are restricted to the lamina propria of the interfoveolar zone; granulocytes are absent (H&E, original magnification 20×). (B) The distal stomach is lined by antral mucosecreting mucosa. The foveolae of the mucosecreting compound tubular glands cover approximately half the mucosa thickness; the mucus-secreting coils occupy the basal half of the mucosa. Each foveola dichotomises in two tubular branches; each branch further divides into four to five glandular coils involved in the mucous secretion. Coils are embedded in the loose connective tissue of the lamina propria, which is populated by scattered lympho-histiocytes, plasmacytes and rare eosinophils. Polymorphonuclear granulocytes are absent (H&E, original magnification 20×).

2.1.2 Acute gastritis clinically identifies a broad spectrum of short-lasting (usually self-limited) symptomatic inflammatory changes of gastric mucosa resulting from either non-transmissible or transmissible agents.

Comment

The definition of acute gastritis covers a broad spectrum of short-lasting (usually self-limited) inflammatory changes of the gastric mucosa.2 28

According to the Kyoto classification, the aetiology of so-called acute gastritis includes non-transmissible and transmissible agents (table 2).9 29 30

The clinical presentation largely depends on its aetiology.31 Epigastric pain, of variable severity, is the most frequent symptom, together with nausea, vomiting and post-prandial distress. General symptoms like fever, asthenia, sweating and hypotension may occur. Bleeding may originate from sparse petechiae, diffuse haemorrhagic gastritis and erosions.

Gastroscopy usually shows hyperaemia, oedema, friable mucosa, mucosal weals, erosions, gastric distension, bleeding and rarely phlegmon. Ulcers, when present, may also involve the parietal wall.

Biopsy sampling may yield aetiological clues. No dedicated biopsy protocols are currently suggested.15 32 The traditional histological distinction between acute (ie, short-lasting, usually self-limiting) and chronic (long-standing) gastritis based on the cellular population of the inflammatory infiltrate is not reliable. Lymphocytes (usually associated with chronic inflammation) may be prominent. Polymorphonuclear granulocytes (ie, PMN), typically associated with ‘acute’ inflammatory patterns, can be found in abundance in ‘long-lasting’ (clinically defined as ‘chronic’) inflammatory gastric diseases (eg, H. pylori gastritis). Different histological patterns according to the aetiology are summarised in table 3.

2.1.3 Chronic gastritis is clinically defined as long-lasting inflammation of the gastric mucosa.

Chronic gastritis often lasts lifelong in the persistent presence of underlying causes. Its most common aetiological agent is H. pylori.

Comment

Chronic gastritis is defined as long-lasting (usually non-self-limiting) inflammation of the gastric mucosa. Long-lasting gastritis is usually asymptomatic, although there is a weak correlation with dyspeptic symptoms.33 34

When the underlying causes persist, chronic gastritis is a lifelong condition, as in H. pylori infection. This is by far the most common cause of chronic (non-self-limiting) gastritis. Other causes include communicable (infectious) and non-communicable, host-related systemic conditions, such as autoimmune (ie, AIG) and immune-mediated conditions (eg, Crohn’s disease). Some of the gastritides classified by the Sydney System as ‘special forms’—and here referred to as ‘host related’ (eg, collagenous, eosinophilic and lymphocytic) may also be included in the category of long-standing immune-mediated gastritis (table 2; section 2.1.2).

The histological features consist of prominent inflammation of the gastric mucosal, which can be associated with a loss of native glandular structures resulting in mucosal atrophy. Depending on the aetiology, inflammation and atrophy may affect the two mucosal compartments (oxyntic corpus/fundus and mucosecreting antrum) unevenly.

Gastritis is distinguished as non-atrophic and atrophic.2 7 8 35 36 In non-atrophic gastritis, the inflammatory lesions may evenly involve both gastric compartments or predominate in either the antral or corpus/fundus mucosa. Mucosal atrophy is defined as the loss of native glands with or without metaplastic changes (intestinal and pseudopyloric metaplasia).37 Atrophy may occur in different topographical patterns: limited to the mucosecreting antrum, restricted to the oxyntic corpus/fundus or involving both compartments. This latter condition has also been equivocally referred to either as ‘multifocal atrophic gastritis’ or ‘atrophic pangastritis’. These definitions, however, describe two topographically distinct atrophic patterns: a patchy pattern, with scattered atrophic foci and neither antrum nor corpus predominance (ie, multifocal), and an extensive atrophy involving the entire gastric mucosa (‘pan’ meaning ‘whole’). The term ‘pangastritis’ should be exclusively used when referring to widespread atrophy of gastric mucosa, coexisting with inflammatory infiltrate (table 1, section 2.3.2; figure 3).

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Figure 3

Atrophy spreading throughout gastric mucosa according to the natural history of different aetiological models. Stomach opens along the greater curvature. The native mucosecreting (antral) compartment is depicted in light blue; the oxyntic (corpus/fundic) mucosa is green; the oxyntic–pyloric border is ideally between light blue and green compartments. Atrophic transformation is depicted in light orange. Three aetiopathogenetic models are shown (from top to bottom): (1) atrophy spreading in Helicobacter pylori (Hp) gastritis; (2) mucosal atrophy in autoimmune gastritis (AIG); (3) mucosal atrophy in Hp infection coexisting with AIG. In long-standing Hp gastritis, the earliest atrophic lesions involve the mucosecreting antrum (light blue changed into light orange) and they steadily spread cranially involving the oxyntic mucosa: closed (C1–C2–C3) and open (O1–O2–O3) patterns of Kimura and Takemoto atrophic gastritis are associated with the progressive cranialisation of the ‘atrophic border’ (see also figure 1). The concurrent atrophic involvement of antral and oxyntic mucosa may eventually result in pan-atrophic gastritis. In AIG, the atrophic lesions are restricted to the oxyntic compartment (original green changed into light orange/green). The progression of atrophy involves extensively the cranial stomach, sparing the mucosecreting compartment. Even in the most advanced atrophy, because of the unaffected mucosecreting antrum, the definition of pangastritis is semantically inappropriate (ie, the O3 pattern should require antral atrophy; see section 2.5.5). When Hp infection coexists with AIG (which targets the oxyntic mucosa), atrophic transformation may extensively involve both mucosal compartments, resulting in pan-atrophic disease.

A rigorous semantic approach distinguishes atrophic gastritis from gastric atrophy. The former results primarily from active H. pylori infection involving a PMN-rich inflammatory component; the latter consists of atrophic mucosa with absent or negligible inflammation, as seen after the eradication of H. pylori or its ‘spontaneous’ disappearance (table 1; sections 2.4.3 and 2.4.4).

The seminal studies of the pre-Helicobacter era, the current literature and clinical practice tend to use the term ‘atrophic gastritis’ to refer to a precancerous condition, irrespective of its inflammatory component. The two definitions, however, discriminate between clinicopathological diseases that differ in their risk of progression and require different clinical approaches. These divergent clinicobiological profiles represent the rationale for distinguishing the two atrophic phenotypes, particularly in clinical trials, where inflammation determines the patient’s management (table 1). As a rule, in post-eradication biopsy specimens, the cleansing of PMN inflammatory component precedes that of the lymphocytic infiltrate; the regression of atrophic changes is currently considered only possible in early atrophic disease (see section 2.4.3).

Because of the significant relationship between the topography of the lesions and both the aetiology and course of these conditions, both endoscopic and histological reports should explicitly refer to the topography of inflammatory and atrophic lesions.37 38

Since virtually all H. pylori-infected subjects harbour chronic active gastritis, non-invasive testing (serology, stool or breath tests; see section 2.2.2) may be used as non-invasive surrogate diagnostic markers. Atrophy can also be assessed non-invasively by means of serum gastrin and pepsinogen (Pg) I and II measurements, including the determination of the PgI/II ratio.39 40

The status of the gastric mucosa is optimally evaluated by gastroscopy with biopsy sampling. High-definition gastroscopy, in combination with image enhancement and magnification, allows the visualisation of many features of gastritis: mucosal nodularity, oedema, blurring of the appearance of connecting venules and enlarged folds. Endoscopic evidence of atrophy includes the disappearance of gastric folds and an enhancement of the mucosal vasculature. Intestinal metaplasia (IM) may appear as grey-white patches, and when narrow-band imaging (NBI) is used, light-blue lines or the so-called light-blue crests.41

Ideally, chronic gastritis (with and without atrophy) is managed by addressing the underlying aetiology. The withdrawal of specific drugs or other noxious agents results in improvement or disappearance of the inflammation. Eradication of H. pylori leads to an early disappearance of PMN infiltrate with progressive attenuation of lymphocytic inflammation; atrophy may to some extent regress, depending on its histological phenotype and extent (see section 2.4.3).7 42 43

2.1.4 A preneoplastic condition is defined as one that confers an increased risk of developing neoplasia. Gastritis is a preneoplastic condition with different levels of risk, depending on factors such as aetiology and stage.

Comment

Preneoplastic (synonym: precancerous) conditions are non-neoplastic diseases carrying an increased risk of developing malignancies.44–46 This definition distinguishes preneoplastic conditions from ‘lesions’. The latter refers more strictly to the anatomical background(s) involved in the histogenesis of malignancies (eg, epithelial abnormalities (intraepithelial neoplasia (IEN)) that may progress to invasive adenocarcinoma or enterochromaffin-like (ECL) gastric cell proliferation potentially progressing to type 1 neuroendocrine tumours (type 1 NETs) (see section 2.5.3).

Preneoplastic conditions involve host-related or environmental aetiological agents, also in association.47 48 Host-related preneoplastic conditions primarily include genetic abnormalities resulting in syndromic cancers.49–51 Aetiopathogenesis also includes gastric diseases due to immune-mediated mechanisms, potentially involving partially profiled genetic mechanisms.52

Environmental preneoplastic conditions result mainly from infectious diseases (eg, H. pylori, Epstein-Barr virus (EBV)) and—less commonly—from medical or surgical interventions (eg, gastric stumps).

Long-standing non-self-limiting H. pylori gastritis, particularly its atrophic variant, is the most prevalent environmental preneoplastic condition. Genotoxic infectious agents (EBV) may increase gastric cancer risk in non-atrophic stomachs (see section 2.6.5).

Functionally, mucosal atrophy is characterised by the impairment of acid production, lower PgI/II ratio and increased gastrin serological levels, all resulting from the loss of native acid-producing oxyntic cell population.14 Hypochlorhydria may activate ECL hyperplastic and dysplastic lesions which may result in type 1 NETs; the progression to NEC is very rare.53

Comment

Gastritis is an inflammation that occurs as a result of gastric mucosal injury. Nearly all H. pylori-infected individuals develop chronic gastritis, but the extent and grade of inflammation can be influenced by environmental factors, host genetics, time after infection and bacterial virulence factors.

Systematic reviews and meta-analyses have estimated that up to 4 billion people in the world were infected with H. pylori, 3 57 but the prevalence of H. pylori infection is declining in many developed countries, particularly in the younger populations.68 In addition to H. pylori, there are other infectious causes of gastritis including viruses, fungi and mycobacteria, particularly in immunocompromised hosts (see section 2.1.2). Currently, the role of other microorganisms within the gastric microbiota in the pathogenesis of gastritis and preneoplastic lesions remains uncertain (see section 2.7.2).69

In addition to H. pylori, other environmental agents such as bile reflux (usually mild)70 may also induce gastric mucosal inflammation. Medications are also an important aetiological agent, particularly non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin, through the depletion of mucosal prostaglandins (see section 2.6.3). Immune checkpoint inhibitors, which are increasingly used in various solid tumours, are also recognised as being able to induce immune-mediated gastritis as well as colitis (table 2).71

With the gradual decline in the prevalence of H. pylori infection due to both successful eradication and reduced acquisition of new infections, more epidemiological studies will be required to characterise the relative proportion and importance contributed by other agents to gastritis.48 72–74

2.2.2 H. pylori gastritis is a chronic active inflammation of the gastric mucosa, which—unless eradicated—can persist indefinitely. It presents with different phenotypes depending on its topographic distribution and the intensity of inflammation and atrophy. Both benign and malignant complications, related to the phenotype of gastritis, may eventually result.

Comment

H. pylori gastritis is an infectious, non-self-limiting disease with a wide spectrum of clinical and histopathological manifestations. Most infected subjects remain asymptomatic, while others develop dyspeptic symptoms or complications such as gastroduodenal ulcers or gastric neoplasia.60 75 76

H. pylori gastritis is defined, graded and staged as a distinct nosological entity (table 2). OGD with biopsies is the diagnostic gold standard as it allows the visualisation of the organisms, the assessment of the severity of gastritis, the topography of inflammation and atrophy, and the detection of other mucosal lesions (eg, erosion, ulcers, neoplasia).2

Based on topography and morphology of the microscopic feature, histology defines the intensity of the PMN infiltration (ie, activity), of lymphocytes and plasma cells (usually identified as chronic inflammatory infiltrate) and atrophy.2 Histology also allows determination of the gastritis phenotype and its potential risk of progressing to complications. While Helicobacters can be microscopically detected on H&E-stained slides, the highest sensitivity is obtained with histochemical and immunohistochemical techniques (figure 4).15 Molecular methods applied on intragastric fluid, fresh mucosal specimens or formalin-fixed paraffin-embedded biopsy samples detect the bacterial infection and the presence of H. pylori mutations resulting in antibiotic (ie, clarithromycin) resistance.75 77

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Figure 4

Non-atrophic Helicobacter pylori gastritis (OLGA/OLGIM gastritis staging: stage 0). (A) In antral non-atrophic mucosa, the population of the mucosecreting glands is easily recognisable with the glandular coils lying on the most superficial part of the muscularis mucosae. The interfoveolar area of the lamina propria is expanded by a low-grade inflammatory infiltrate, including lymphocytes, plasma cells, polymorphonuclear neutrophils (PMNs) and scattered histiocytes. PMNs also ‘invade’ some glandular units, being detectable within the columnar epithelia and within the gland lumen (ie, low-grade histological activity). An immunohistochemical stain for H. pylori (insert) shows few bacteria within the foveolar lumen. (B) The inflammatory lesions in the oxyntic biopsy specimen are less pronounced than those shown in the antral mucosa. Focal, low-grade inflammatory infiltrate, including lymphocytes, plasma cells, PMNs and scattered histiocytes, expands the lamina propria; few intraepithelial and intraglandular PMNs are present (low-grade ‘activity’). The native oxyntic epithelium shows ‘hypertrophic’ modifications (ie, plumped parietal cells), a characteristic feature of long-term therapy with proton pump inhibitors. OLGA/OLGIM, operating link for gastritis assessment/operating link for gastric intestinal metaplasia.

H. pylori gastritis can be diagnosed also by non-invasive tests, which are considered as surrogate markers.39 The ¹³C-urea breath test (¹³C-UBT) and stool antigen test (SAT) using monoclonal antibody-based ELISA are accurate, non-invasive tests that can be used in ‘test and treat’ strategies for patients aged <50 years with dyspepsia but no alarm symptoms.78 Their limitation is that, while they yield an accurate diagnosis of H. pylori, they do not provide information on the degree of gastric mucosal damage and atrophy.79 Serological tests for PgI and for the PgI/PgII ratio are non-invasive and with appropriately selected cut-off values may indicate severe oxyntic mucosa atrophy.39 80 81

Detailed information on H. pylori gastritis and whether severe gastric atrophy has already taken place is essential for the long-term management planning. There is ample evidence that H. pylori eradication cures gastritis and can arrest (and sometime revert) the progression to long-term complications, including gastric neoplasia.4 82

Comment

The original Sydney System and its updated Houston version recommended combining gastroscopy with at least two biopsy samples representative of the antral mucosecreting and two of the oxyntic mucosa.2 87 Later validation studies have suggested that the proposed sampling protocol was not inferior to other sites for the diagnosis of inflammatory and atrophic conditions.88–90 More extensive biopsy sampling protocols may be applied in clinically complex cases or when required by clinical research protocols.91 In such cases, elective attention has been paid to the gastric ‘transitional zones’92 (ie, gastro-oesophageal junction and oxyntic–pyloric border) (see sections 2.1.1, 2.3.4 and 2.5.1).88–96 In the healthy stomach, the accurate location of these border areas is highly affected by the topographical variability of the embryological patterning as well as by the accurate endoscopic recognition of the topographical landmarks.15 17 21

Stressing the need for a joint morphological assessment by merging the complementary information achievable through high-resolution virtual chromoendoscopy and histology, we recommend a ‘basic’ biopsy set including four biopsy samples: (a) two antral biopsies from either predefined sites (one from the lesser curvature and one from the greater curvature) or, if changes are observed endoscopically, targeting those suggesting either atrophy or IM; and (b) two biopsies from the oxyntic compartment, one from the lesser curvature and one from the greater curvature. Specimens from the two compartments, plus any additional samples from abnormal areas, should be topographically identified and submitted separately for histopathological examination.97

Currently, the expanded information achievable from high-resolution virtual chromoendoscopy prompts to prioritise the integration of the endoscopy and histology diagnostic messages, both of which require elective training of the specialists involved. In this interdisciplinary setting, the clinical management of patients should be modulated according to the most severe lesions detected by either endoscopy or histology.94

The currently validated endoscopic classifications for atrophy (Kyoto, Kimura-Takemoto) and IM (endoscopic grading of gastric intestinal metaplasia, EGGIM) are not standard at present, but if used in specialised endoscopic centres should likewise be incorporated into the endoscopic report that accompanies the request for histological examination.63 98–100 When in clinical use, AI-based endoscopy reports (see section 2.9) should also be included for additional information to pathologists. Focal lesions suspicious for neoplasia should always be sampled and submitted in separate, clearly labelled vials, for pathological analysis.

2.3.2 Diagnosis of atrophic gastritis should include data from gastroscopy, histology and serology.

Both phenotype and topography of atrophic changes must be reported and staged according to validated endoscopy and histology staging systems. The diagnosis should be based on data from endoscopy, histology, and include proven or suspected aetiology, whenever possible supported by serological data.

Comment

Gastric atrophy is a loss of appropriate (synonym: native) gastric glands in a given gastric mucosa compartment and is a precancerous condition.35–37 101–104 Different phenotypes of atrophic changes (non-metaplastic atrophy, IM, pseudopyloric metaplasia) may coexist and should be reported both endoscopically and histologically.7 42 105–107

Gastroscopy: Standard parameters have been established to determine high-quality endoscopic assessment of the upper gastrointestinal tract.108 109 High-resolution endoscopes with virtual chromoendoscopy increase accuracy in assessing the phenotype and topography of atrophic changes, particularly IM (figures 3 and 5).7 42 98 110 111 As for pseudopyloric metaplasia, the sensitivity of the endoscopic detection is significantly lower, particularly in the absence of coexisting IM.112 Validated endoscopic classifications (eg, Kimura-Takemoto for atrophy and EGGIM for IM, see section 2.3.4) have been shown to correlate with OLGA/OLGIM stages, gastric cancer risk and the risk of metachronous cancer after gastric endoscopic submucosal dissection (figures 3 and 5).113 114 Thus, it is recommended assessing the topography and extension of atrophic changes (particularly IM) using validated criteria (see section 2.1.1).42 98 115 Biopsies are not mandatory in patients under surveillance with no newly appearing mucosal lesions.

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Figure 5

Kimura and Takemoto classification of gastric mucosa atrophy. Kimura-Takemoto classification recognises two main atrophic topographical patterns: (1) closed (C type) and (2) open type (O type). Both patterns are further subdivided into three grades (C-1, C-2 and C-3; and O-1, O-2 and O-3). In C-1, atrophy is found only in the antrum, while in C-2 and C-3, the atrophic border (also known as pyloric–oxyntic border) starts from the greater curvature of the antrum, spreads to the anterior wall crossing the lesser curvature and enclosing the incisura almost symmetrically. In C-2, the location of the atrophic border is below the middle of the stomach on the lesser curvature, while in C-3, the atrophic border lies above it. In open types, the endoscopic atrophic area is more widespread, with the atrophic border lying between the lesser curvature and the anterior wall in type O-1, on the anterior wall in type O-2, and between the anterior wall and the greater curvature in type O-3. The severity of atrophy is often classified in three grades: mild (C-1; C-2), moderate (C-3; O-1) and severe (O-2; O-3). The figure is inspired by a drawing published by Nakajima et al.21

Histology: The histological report should include the topography and extent of atrophic changes as well as the OLGA/OLGIM stage, which correlates well with gastric cancer risk and may affect surveillance strategies.116–120 If the pathologist can access the OGD report, a comment with harmonised data from both endoscopy and histopathological examination is strongly recommended. When discrepancies occur between endoscopic and histological staging, surveillance should be tailored according to the higher patient-associated risk of gastric cancer.42

Non-invasive ancillary testing: When the cause of atrophy is not immediately evident, the report should suggest ancillary tests that may help unravel its aetiological determinants (for H. pylori: UBT, SAT, H. pylori serology, for autoimmunity: anti-parietal cell and anti-intrinsic factor antibodies (AIFA)).60 Other tests may elucidate the functional status of the gastric mucosa (PgI and II, PgI/II ratio, gastrin-17 levels) (see section 2.2.2).52 In managing individual patients, serological tests may contribute to the follow-up strategies, particularly when functional serology is available from the time of the initial endoscopy. A systematic review and meta-analysis assessing the diagnostic performance of serological testing in atrophic gastritis (PgI ≤70 ng/mL and PgI/II ratio ≤3) showed a sensitivity of 59% (95% CI: 38% to 78%).121 Recently, a small-sized nested case–control study in the USA showed that subjects with PgI ≤70 ng/mL and PgI/II ratio ≤3 had an increased risk of developing non-cardia gastric cancer (OR 11.1, 95% CI: 4.3 to 28.8).122 Aetiological speculations that cannot be verified by additional testing should not be included in either endoscopy or histological reports.

2.3.3 High-quality OGD with gastric biopsies is required and highly recommended for the accurate diagnosis of gastritis and its severity, extension, type and aetiology.

Comment

A high-quality endoscopy requires: (a) appropriate indications, including patients’ clinical history and their informed consent, (b) efficient equipment, (c) appropriate technical procedures (mucosal cleaning, adequacy of the inspection time as required by a full upper gastrointestinal assessment, extensive reporting with photo documentation) and (d) safety.108 123 124 The patients’ clinical history and their symptoms/signs are crucial to determine the aetiology. High-resolution and virtual chromoendoscopy will be helpful to determine the presence, topography and extension of atrophy, particularly IM.7 42 98 110

The presence of some features detected by high-resolution endoscopy (eg, RAC venules in the distal gastric body) is considered evidence of a healthy stomach (figure 1).16 However, to confirm that the mucosa is within normal limits, biopsy samples are needed, particularly at the first gastroscopy (see section 2.3.1). In endoscopically abnormal stomachs, biopsies are always required to characterise the features of gastritis (see section 2.3.2).18 19 75

2.3.4 Both non-metaplastic atrophy and IM are endoscopically recognisable and an estimate of the percentage of affected gastric mucosa should be included in the report. Currently, systems such as EGGIM, Kyoto and Kimura-Takemoto have some limitations (eg, in AIG), but correlate well with histological assessment and gastric cancer risk.

Comment

Endoscopy should be performed according to best practice guidelines, which is crucial to merge reliable endoscopic with histological information (see section 2.3.3).36 125

Given its consistent association with cancer risk, the endoscopy profile of atrophy is of paramount importance.8 42 98 126 The report on atrophic lesions, irrespective of their aetiology, should include: (1) topography (eg, compartmental distribution; ‘closed’ (ie, C pattern) vs ‘open’ (ie, O pattern)); (2) extent of the mucosal involvement; and (3) the phenotype, as seen on magnified endoscopy (eg, non-metaplastic or metaplastic) (figures 6 and 7).

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Figure 6

Gastroscopy showing prominent atrophic non-metaplastic mucosa. White-light gastroscopy: atrophic non-metaplastic mucosa in antrum (A) and corpus (B). Narrow-band imaging: focal loss of pit pattern in atrophic antral mucosa (C) and severe corpus atrophy (D).

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Figure 7

Gastroscopy in atrophic gastritis due to Helicobacter pylori infection. White-light gastroscopy: H. pylori atrophic gastritis in antral (A) and corpus mucosa (B). Atrophic gastritis in antrum (C) and corpus mucosa (D) in narrow-band imaging gastroscopy; in the square, atrophic intestinalised mucosa and yellow star next to light-blue crest. IM, intestinal metaplasia.

Endoscopists should recognise the atrophic mucosal changes such a pale appearance of mucosa and increased visibility of vasculature due to thinning, and loss of gastric folds (figure 6). The Kimura-Takemoto classification distinguishes six patterns of atrophy (from C1 to O3), which correlate with gastric cancer risk (see sections 2.3.4 and 2.5.5; figure 5).100 113 Endoscopic detection of IM is also possible with high-definition endoscopes with virtual chromoendoscopy and is identified by a light-blue crest white opaque areas and a ridge/tubulovillous pattern (figure 7)127 128; NBI has proven highly accurate in diagnosing gastric precancerous lesions.129–131 An EGGIM has been proposed and validated.63 110 129 In this classification, the stomach mucosa is divided in five areas (lesser and greater curvature of the antrum and corpus and incisura), and 0–2 points are assigned according to the extension of IM in the corresponding area (scale 0–10). In two multicentre studies, EGGIM ≥5 has been shown to identify extensive IM (OLGIM III/IV) with 96–98% accuracy,63 131 and also to correlate with gastric cancer risk (OR 21.2).110 Another multicentre study reported that OLGIM stage III/IV, high EGGIM score and open-type atrophy to be significantly associated with gastric cancer risk.98

Since many endoscopists are not yet trained in these technologies, initial confirmation of the mucosal changes by biopsy is strongly recommended, because it allows the determination of the H. pylori status and the severity of gastritis. Biopsy specimens from the antrum and corpus (and from any focal lesions) should be submitted in separate vials, properly documenting the topographical location.7

2.3.5 There is evidence that the extension of IM correlates with the proportion of incomplete IM. Therefore, IM subtyping can thus be used to integrate the evaluation of cancer risk as assessed by the OLGA/OLGIM staging.

Comment

Multifocal IM is part of the histological spectrum of gastric mucosa atrophy, thus representing a key component of the gastric cancerisation field.7 105 106 Intestinalisation of the gastric mucosa is biologically and phenotypically heterogeneous; a simplified histological classification distinguishes complete versus incomplete IM.132–137 Immunohistochemical and immunocytochemical studies support the higher gastric cancer risk associated with incomplete-type intestinalisation.138

Available evidence indicates that the extension of IM correlates with the proportion of incomplete IM.67 139 In a cohort study from Italy, when OLGA staging is applied, the proportion of incomplete IM was found to strongly correlate with high-risk stages (OR=4.8; 95% CI: 3.0 to 7.9; p<0.001)67 and similar results were obtained in a Colombian cohort of patients in whom incomplete IM increased significantly (p<0.001) by OLGA/OLGIM stages.104 Current evidence from the literature has shown that assessing the percentage of the atrophic lesions in each gastric compartment correlates with cancer risk.

In clinical practice, when the number of collected biopsies is insufficient for OLGA/OLGIM staging, IM subtyping and reporting the incomplete versus complete IM ratio may be considered a useful surrogate for extensive IM. The recent American Gastroenterological Association (AGA) ‘technical review’ acknowledges the higher risk of gastric cancer linked to incomplete IM,136 but also recognises the low quality of the evidence.140 Both the AGA and the Management of Epithelial Precancerous Conditions and Lesions in the Stomach (MAPS II) guidelines agree that both IM subtyping and extension can help decide whether to pursue surveillance.42 140 However, it must be noted that subtyping IM on a limited biopsy sampling may be clinically misleading, and results of such evaluations should be interpreted cautiously. IM subtyping may expand the current information on the gastric cancerogenic pathway in research settings.

2.3.6 OLGA and OLGIM staging systems are useful for the risk prediction of both intestinal-type and diffuse-type gastric cancer.

Comment

Gastric cancers, classified by Laurén as intestinal type (I-GC) and diffuse type (D-GC), have distinct clinical, histopathological and epidemiological characteristics.141 Both subtypes are strongly associated with H. pylori infection.142

Gastric mucosa atrophy with extensive IM is the main precursor of I-GC.67 Conversely, D-GC is assumed to be most commonly linked to genetic abnormalities and is characterised by ‘disperse/incohesive’ cancer cells diffusely infiltrating the gastric wall.143 The two histotypes frequently coexist (cancer heterogeneity), and the diffuse (non-cohesive) variant may also represent a dedifferentiation of the intestinal subtype.144 145 The risk of I-GC largely depends on the extent and severity of atrophic gastritis and IM and should be stratified using scoring systems such as OLGA and OLGIM.65 119 However, the role of atrophic gastritis and IM as potential precursors for D-GC is not fully understood.

A recent meta-analysis including 14 studies from both eastern and western countries found an association of both atrophic gastritis and IM with D-GC (pooled OR=1.9, 95% CI: 1.5 to 2.4, and OR=2.3, 95% CI: 1.9 to 2.9, respectively).146 On subgroup analysis, high-risk OLGA stages (III or IV) conferred an increased risk of D-GC compared with low-risk stages (I or II) (OR=1.7, 95% CI: 1.2 to 2.3). Similarly, high-risk OLGIM stages were associated with increased D-GC risk (OR=1.9, 95% CI: 1.3 to 2.7) as compared with low-risk stages. Another meta-analysis of six Asian prospective studies demonstrated a significant association of OLGA/OLGIM stages III or IV with both I-GC (OR=4.6, 95% CI: 1.0 to 21.1) and mixed gastric cancer (OR=2.4, 95% CI: 1.4 to 3.9).147

Molecular and genetic studies have shown that the differentiation between Laurén’s histological types can sometimes be elusive.146 148 It has been proposed that at least a subgroup of sporadic D-GC may develop from an ‘alternative’ carcinogenetic pathway involving H. pylori infection, atrophic gastritis and IM, in association with CDH1 mutations (see section 2.6.5).146 148–150

Related to serologically diagnosed atrophy, a large long-term prospective cohort study of healthy asymptomatic males showed an increased risk of both I-GC and D-GC among patients with extensive atrophic gastritis, as assessed by serum PgI/II levels (HR=3.1, 95% CI: 1.9 to 5.3; HR=2.7, 95% CI: 1.3 to 5.7, respectively). Notably, among 87 observed gastric cancer cases, 28 (32%) were D-GC and equally distributed among individuals with and without serum extensive gastric atrophy.151 In summary, high-risk OLGA and OLGIM stages can predict increased risk of both I-GC and D-GC.

2.3.7 To evaluate the risk of gastric cancer, endoscopy with full mucosal inspection and histological analysis of topographical biopsies according to OLGA and/or OLGIM is recommended.

Comment

Individuals at risk of gastric cancer can be evaluated by serology, histology and image-enhanced endoscopy. Image-enhanced endoscopy with histological staging according to OLGA or OLGIM staging systems is considered the best approach.36 37 119 A meta-analysis showed that subjects with stages III–IV of OLGA or OLGIM were at increased risk of gastric cancer compared with those with stages 0–II. In countries of intermediate-high gastric cancer incidence, the OR was 2.64 (95% CI: 1.84 to 3.79) for OLGA stages III–IV and 3.99 (95% CI: 3.0 to 5.21) for OLGIM stages III–IV.147

Topographically designated biopsies compliant with either OLGA or OLGIM staging are time-consuming and subject to sampling error.89 New endoscopic technologies have been developed to reliably evaluate disease severity and extent.41 A systematic review and meta-analysis revealed that subjects with severe and open-type endoscopic atrophy (according to the Kimura-Takemoto classification) had an increased risk of gastric cancer; the pooled risk ratios (RRs) were 3.89 (95% CI: 2.92 to 5.17) and 8.02 (95% CI: 2.39 to 26.88), respectively.113 In a multicentre validation study involving 250 consecutive patients, EGGIM by using NBI correlated with OLGIM stages III–IV, with area under the receiver operating characteristic curve of 0.96 (95% CI: 0.93 to 0.98).63

Comment

The combination of PMN (active) and mononuclear cell (chronic) inflammation may result in damage and eventual loss of the native gastric glands (atrophy), which may be replaced by multifocal islands of intestinalised glandular units.35 37 In the antral compartment, native mucosecreting epithelia can be replaced by intestinal-type cells (goblet cells and absorptive cells). The oxyntic mucosa may initially undergo pseudopyloric transformation, potentially progressing to intestinal-type changes.24 37 153 154 The atrophic mucosa is considered the cancerisation field where neoplasia develops.37 155–157 Neoplastic changes, initially restricted to the glandular epithelia (IEN, synonym: dysplasia), may eventually progress into invasive cancer.158 159 Symptoms are not a reliable indicator of cancer risk.

2.4.2 Non-atrophic gastritis is a potentially reversible inflammatory condition with minimal gastric cancer risk. The diagnosis should include the plausible or suspected aetiology, which may determine management and strategies for the prevention of atrophy.

Comment

The diagnosis of non-atrophic gastritis relies on both endoscopic and histology to exclude atrophy (metaplastic and non-metaplastic subtypes), dysplasia and neoplasia, and to evaluate the nature, severity and aetiology of the inflammatory changes.2 160

Non-atrophic phenotypes consist of potentially reversible inflammatory lesions not included in the precancerous spectrum because of their negligible cancer risk. The report should mention a plausible or suspected aetiology, which will help guide management strategies (figure 4).38 160

In the past, non-atrophic gastritis was referred to as ‘superficial’ (see section 2.4.1). This definition is discouraged due to its potentially misleading because inflammation, particularly in the antrum, often involves the full thickness of the mucosa.

There may be discrepancies between the endoscopic and histological assessments in the evaluation of atrophy. The histological categorisation of non-atrophic lesions is based only on the mucosal sites from which biopsy samples have been obtained; therefore, when atrophic (particularly metaplastic) foci are documented endoscopically but not confirmed histologically, the endoscopic phenotype per se prevails, and the patient should be categorised as having atrophic gastritis, with the resulting surveillance strategy. Conversely, histologically documented atrophic pseudopyloric foci may not be apparent endoscopically; in such cases, the histological assessment will prevail and determine the management.112

The progression of atrophy is incompletely understood as it involves both environmental (eg, bacterial virulence) and host-related factors. Among the environmental causes, H. pylori infection is the leading trigger of atrophy, which initially develops in the distal stomach, further spreading to the oxyntic compartment.160 161 Other environmental agents (transmissible and non-transmissible) may be involved in the aetiology of non-atrophic gastritis and affect both the (distal) mucosecreting and the (proximal) oxyntic mucosa (see section 2.7). Examples include self-limited acute gastritis (see section 2.1.2) and other infectious gastritides (table 2).

The impairment of acid secretion resulting from severe non-atrophic oxyntic inflammation additionally contributes to the further extension of atrophy.161 In the presence of H. pylori, PPIs lead to increased inflammation of the oxyntic mucosa and may promote the progression of atrophy in H. pylori gastritis, hence the recommendation to eradicate H. pylori infection in candidates for long-term PPI therapy.162–164 Non-atrophic corpus-restricted gastritis may also be an expression of an early phase of AIG (see section 2.5.3).52 165

The balance of these factors modulates the severity of the atrophic mucosal transformation and the timing of progression from non-atrophic to atrophic phenotypes. Understanding the complex mechanisms involved in the development of atrophic gastritis is a research priority, as limiting the development and progression of atrophy may be one of the most important steps in the primary prevention of gastric cancer.166

2.4.3 There is serological, endoscopic and histological evidence that regression of atrophic lesions can occur in response to the removal of the aetiological agent. Studies are needed to determine the most reliable method to assess and possibly quantify the presence and extent of the regression.

Comment

Regression of atrophic lesions may occur, but the unequivocal demonstration of atrophy reversion is difficult to obtain.167 168 Existing information rests on serological, endoscopic and histological data obtained from different populations using a vast array of different testing methods.169

Epidemiological studies support the reliability of assessment of serum PgI and PgI/II ratio as indicators of the functional status of gastric mucosa.116 170 On this basis, Pg serology has been employed as a functional indicator of post-eradication regression of atrophy. In Korean patients, successful eradication resulted in a significant increase in serum PgI/II ratio (from 3.07 to 4.98, p<0.001). Failure to recover was associated with severe gastric atrophy and age ≥60 years.171 Similar results were obtained by Daugule et al who found a significant increase of PgI/PgII ratio (from 5.59 to 11.64) in H. pylori-eradicated subjects.172 In a recent Japanese study, the post-eradication PgI/II ratio steadily rose to reach values similar to those of uninfected subjects.169 173 However, Pg levels are increased by inflammation and may also be altered following therapy.

Similar trends supporting regression have been obtained in studies combining endoscopy with histology.174 In the Shandong intervention trial, successful H. pylori treatment was associated with a higher likelihood of IM regression compared with placebo (RR: 1.55; 95% CI: 1.03 to 2.33).136 173 In two studies by Hwang et al, H. pylori eradication resulted in a significant regression of IM: any difference between H. pylori-eradicated and naïve-negative patients disappeared from the proximal stomach after 3 years of follow-up and from the distal stomach after 5 years.175 176 In a population-based study conducted in a low prevalence area, H. pylori eradication was associated with a significant reduction of endoscopic and histological IM (60.4% vs 39.4%, p=0.035). Contrasting results were obtained by Zhou et al, who failed to detect any significant atrophy regression in a 5-year follow-up after H. pylori eradication.177

From a biological viewpoint, the regression of atrophy is potentially achievable by removing its putative aetiological agent(s) (see section 2.4.4). Complete regression of atrophy and IM has been documented anecdotally in H. pylori-associated AIG, following the eradication of H. pylori.178 Even after H. pylori eradication, however, several host-related (eg, extensive atrophy resulting in loss of acid secretion, changes in microbiota) and environmental agents (eg, diet, tobacco smoking) may continue to act as promotor of atrophy. These multifaceted and still poorly understood aetiologies hamper the unequivocal demonstration that atrophy regresses after H. pylori eradication.136 154 179 Obtaining evidence of atrophy reversibility is further limited by the need for prospective long-term follow-up studies and by the great variability of endoscopic and histological criteria applied in the assessment of regression. Moreover, documenting a significant change in the extension of IM is hampered by its patchiness combined with the technical difficulty of obtaining repeated biopsies from the same areas.36 89 180

2.4.4 Eradication of H. pylori halts the progression of mucosal injury and promotes the improvement of gastric structure and function.

Comment

H. pylori eradication is highly effective in arresting and reversing inflammation and histological damage, particularly in active H. pylori gastritis with or without atrophy (figure 8).56 Randomised controlled trials and cohort studies have indicated a risk reduction for gastric cancer of about 50%.181–183

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Figure 8

Metaplastic atrophy following Helicobacter pylori eradication (biopsy samples obtained from incisural mucosa 2 months after successful H. pylori eradication). The native mucosa is partially replaced by intestinalised glands of complete and incomplete subtypes; metaplastic atrophy covers about 40–45% of the biopsy specimen. After bacterial eradication, a vaguely nodular, low-grade lymphocytic infiltrate remains (interalveolar area in the left corner). In a serial section of the same specimen, Alcian-PAS histochemistry shows native mucosa coexisting with atrophic–metaplastic glands ((A) H&E; (B) Alcian-PAS; original magnifications 10×). PAS, periodic acid–Schiff.

Modification of lifestyles and social behaviours, including reducing the consumption of salted and processed food,184–186 refraining from smoking,187 avoiding excessive alcohol intake,188 and increasing the dietary amount of fresh vegetables and fruits,186 may also play an important role, when combined with successful H. pylori eradication.189

2.4.5 Factors associated with an accelerated progression of gastritis include the strain of H. pylori causing the infection, certain host genetic susceptibilities, having first-degree relatives with a history of gastric cancer, and unhealthy lifestyles and social habits.

Comment

The potential stepwise progression of H. pylori gastritis starts from non-atrophic chronic active gastritis and may proceed to atrophic metaplastic gastritis, dysplasia and eventually to gastric cancer.190 A Japanese long-term prospective follow-up study after H. pylori eradication showed a 5-year cumulative cancer risks of 0.7%, 1.9% and 10% in patients with none/mild, moderate and severe atrophic gastritis, at baseline.191 In a nationwide cohort study from the Netherlands, the annual incidence rate of gastric cancer was 0.1%, 0.25%, 0.6% and 6%, respectively, for patients with atrophic gastritis, IM, mild-to-moderate dysplasia and severe dysplasia at baseline.192 Similarly, in an observational cohort study from Sweden, the incidence rates were 0.1%, 0.13% and 0.26% for atrophic gastritis, IM and dysplasia, respectively; collectively, the rate of progression to cancer increased along with the stages of gastritis.193 Conversely, studies on the global burden of cancers attributable to infections estimated that if all H. pylori infections were eradicated, approximately 89% of non-cardia gastric cancers, 29% of cardia gastric cancers and 74% of gastric non-Hodgkin’s lymphomas would be prevented.194 195

Host susceptibility to H. pylori infection, with certain single-nucleotide polymorphisms, may promote the disease progression.196 197 Moreover, an increasing risk of gastric cancer has been associated with an interaction between H. pylori-positive status and pathogenic variants in homologous-recombination genes.198 A first-degree family history of gastric cancer is associated with accelerated gastritis progression.199 Smoking, high salt intake and heavy alcohol consumption have been associated with a 1.7-fold, 2.9-fold and 1.1-fold increase of risk, respectively.185 187 188

People who inherit a genetic mutation for the hereditary cancer syndrome are at high risk of developing stomach cancer at a young age, which may occur without following the inflammation–atrophy pathway.200 Elucidating the aetiology and natural course of gastric cancer may provide preventive implications for the patients and their relatives.

2.4.6 It is suggested that subjects with high-risk endoscopic findings or stages III–IV of OLGA/OLGIM and/or extensive incomplete IM undergo endoscopic/histological surveillance at a 3-year interval or according to local recommendations.

Comment

H. pylori eradication decreases the risk of gastric cancer.181 However, patients who have already developed atrophic gastritis likely retain a risk level similar to that present at the time of H. pylori eradication.

A systematic review and meta-analysis reported that the incidence rates of gastric cancer in atrophic gastritis and IM were 2.25 (95% CI: 1.67 to 2.90) and 7.58 (95% CI: 4.10 to 11.91) per 1000 person-years in Asia and 0.74 (95% CI: 0.13 to 1.71) and 1.72 (95% CI: 0.36 to 3.70) per 1000 person-years in Europe.201 The role of surveillance endoscopy is to detect preneoplastic lesions and gastric carcinoma at an early stage so as to prevent or reduce cancer deaths.

The balance between efficacy and costs should be considered when designing a surveillance programme. A cost-effectiveness analysis in Singapore suggested that the optimal interval was annual surveillance for subjects with OR 5.46–21.5 of gastric cancer, and 2-year intervals for surveillance for those with OR 2.4–5.46.202 Thus, a 2-year endoscopic surveillance interval for patients with OLGA/OGLIM stages III–IV may be optimal. However, in East Asia, gastric cancer may be more likely develop from early stages of atrophy or IM, such as OLGIM stage II.203 204 Therefore, the need for and the optimal interval for endoscopic surveillance in OLGIM II patients may need to be adjusted for regional differences in risk.

In countries of low-intermediate gastric cancer incidence, a systematic review of decision model analyses showed that endoscopic surveillance of extensive atrophy or IM every 3 years was cost-effective.205 In a European long-term follow-up study, no subject with OLGIM stages 0–II developed gastric cancer during a 51-month follow-up.120 Thus, endoscopic surveillance every 3 years for patients with OLGA or OLGIM stages II or IV would appear adequate in low to intermediate cancer incidence regions.7 36

Patients with low/high-grade dysplasia or early gastric cancer after endoscopic mucosal resection or endoscopic submucosal dissection remain at risk of the development of synchronous or metachronous gastric cancer, with reported incidence rates of between 7.7 and 33.9 per 1000 person-years.206–208 The interval of endoscopic surveillance after endoscopic mucosal resection at 1 year, 5 years or 10 years proved cost-effective for Asian patients, and at 5 years or 10 years was also cost-effective for subjects of Hispanic ancestry in the USA.205

Comment

AIG is a host-related, non-self-limiting gastritis. AIG results from a ‘primary autoimmune reaction’ targeting the gastric parietal cells (see tables 1 and 2). The topography of the target autoantigen restricts the inflammatory lesions to the oxyntic mucosa; less frequently, due to the variable distal extension of native oxyntic glands, the inflammation also extends distally to the incisura angularis (see sections 2.3.1 and 2.3.4).21 216 217

The aetiology and the pathogenesis of ‘primary AIG’ are still unclear.52 The major target autoantigen is represented by the gastric proton pump H+/K+ATPase and its α and β subunits,218 which are targeted by both anti-parietal cell autoantibodies (PCA)219 and autoreactive T cells.220 In vivo, it is likely that the major pathogenetic role in AIG can be attributed to autoreactive T helper52 and cytotoxic cells, upregulating proinflammatory cytokines, as suggested by previous ex vivo experiments.220 221 However, the exact trigger for the expansion of these autoreactive clones is unknown.

The marker of the disease is its histologically documented restriction to the oxyntic mucosa (figure 9). Current or previous H. pylori infection affecting the antral mucosecreting compartment may mask the oxyntic restriction of the disease, resulting in atrophic mucosa involving both gastric compartments. The natural history of AIG includes non-atrophic and atrophic histological patterns.222 In most of the cases, however, the clinicopathological diagnosis is made only in advanced disease, when atrophic oxyntic changes are already established and a functional impact has become evident.

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Figure 9

Autoimmune gastritis: atrophic phase. (A) Antral mucosa in autoimmune gastritis: the native mucosecreting mucosa is easily recognisable. In this case, the absence of any inflammatory involvement coexists with elongated foveolae and smooth muscle hyperplasia (spindle cells interposed to the glandular units). Both features are characteristic of reactive gastropathy, which often coexists with oxyntic autoimmune disease (H&E; original magnification 20×). (B) Atrophic oxyntic mucosa with mononuclear inflammatory infiltrate. The lamina propria is expanded by fibrosis and inflammatory cells. Intestinalised and pseudopyloric metaplastic glandular units replace the tubular native glands. Intestinalised cells mostly feature complete-type intestinal metaplasia (H&E; original magnification 20×). (C) Oxyntic mucosa biopsy specimen stained with anti-chromogranin A antibodies for enterochromaffin-like cells, showing nodular hyperplasia (immunostain for chromogranin A; original magnification 10×).

The diagnosis of AIG is achieved by serology (autoantibodies against PCA and AIFA, Pgs as markers of advanced atrophy and gastrin-17), gastroscopy and the characteristic histological findings (see sections 2.5.3 and 2.5.4).223 Gastric hypoacidity results in loss of intrinsic factor, with iron and vitamin B₁₂ malabsorption and eventually pernicious megaloblastic anaemia (see section 2.5.5).52 Micronutrient malabsorption favours the occurrence of life-threatening and irreversible complications.

2.5.2 The prevalence of AIG is variable and likely increasing, particularly in western populations. This trend needs to be confirmed by further, well-designed population-based studies excluding current or previous H. pylori comorbidity. The burden of AIG is difficult to assess properly due to methodological issues.

Comment

AIG is part of the spectrum of autoimmune diseases and its prevalence is much higher in patients with autoimmune comorbidities, particularly thyroiditis and type I diabetes mellitus; among these patients, the AIG prevalence is reported to range from 10% to 40%.224–227

Histopathological changes (corpus-restricted atrophy and IM, nodular or linear ECL hyperplasia) remain the foundation for the diagnosis of AIG.52 The need to perform endoscopic biopsies to confirm the diagnosis precludes large population-based studies. Consequently, different surrogate diagnostic markers have been used to estimate the burden of the disease.52 228 229 These include serum PCA (potentially declining in the advanced stage of oxyntic atrophy) and intrinsic factor (AIFA), serum Pgs and gastrin levels. Studies based on the prevalence of cobalamin levels and pernicious anaemia (both late manifestations) suffer from low sensitivity.

Estimates of the AIG burden are rather uncertain.213 230 Despite these methodological inconsistencies, some studies have estimated that the prevalence of AIG ranges from 0.1% to 2% in the general population,231 and may be higher in individuals over 60 years of age and in women.222 232 233 The data on the prevalence of AIG obtained in different studies and the diagnostic criteria used are summarised in table 4. Although no unequivocal conclusions can be drawn regarding the trends in the AIG prevalence, some data suggest an increasing incidence, parallel to the observed rise in the incidence of other primary autoimmune diseases.234 235 One study showed an increase from 22 to 64 per 1000 individuals in the prevalence of corpus atrophic gastritis (likely related to AIG) in a Northern Swedish population between 1990 and 2009.236 AIG is not believed to be associated with gastric carcinoma, except in the presence of a cancer risk ‘expansion’ due to concurrent or previous H. pylori infection.237 There is, however, a distinct risk for gastric NET related to the sustained increase in serum gastrin.

2.5.3 Autoimmune atrophic gastritis can be diagnosed with a high degree of confidence based on endoscopic, histopathological and serological data.

Comment

AIG includes non-atrophic and atrophic stages.52 213 230 238 239 Due to the paucity of clinical signs and symptoms, the non-atrophic AIG stage is rarely recognised.240–242 The progression from non-atrophic to atrophic stage increases the clinical manifestations, including comorbidities,52 226 as serological, endoscopic and histopathological abnormalities develop. Histological changes are the most specific and can be reliably used for the diagnosis. Serological and haematological data are useful to support the diagnosis (see section 2.5.5).

Hypochlorhydria prevents iron absorption, resulting in iron-deficiency anaemia; intrinsic factor-dependent cobalamin (vitamin B₁₂) deficiency is at the root of both megaloblastic anaemia and degeneration of the dorsal and lateral columns of the spinal cord due to demyelination, a late development associated with severe neurological manifestations.241

The most sensitive serum test for AIG is the detection of antibodies against PCA. However, their absence, more common in the elderly, does not exclude AIG.223 The detection of AIFA, low Pg or high gastrinemia assists in the diagnosis, but both their sensitivity and specificity are low and need to be integrated with endoscopic and histopathological findings (see section 2.5.5).7 52 In a recent prospective multicentre cohort study, low Pg levels resulted to be more sensitive than the autoantibodies for the detection of AIG.243

In a cross-sectional study of 210 patients with AIG undergoing surveillance gastroscopy with NBI, EGGIM staging detects oxyntic IM with high sensitivity (91.5%, 95% CI: 86.1% to 95.3%) but low specificity (21.7%, 95% CI: 10.9% to 36.4%). This finding has been interpreted as being related to the NBI overassessment of IM when only pseudopyloric metaplasia is already established.25 112

The histological findings of AIG consist of loss of native oxyntic glands accompanied by mononuclear infiltrate and replacement by micro-scars of inflamed fibrous tissue (ie, non-metaplastic atrophy). The disappearance of oxyntic glands coexists with two types of metaplastic transformation: (1) pseudopyloric metaplasia as phenotypical change covering the molecular profiles belonging to pyloric metaplasia, ulcer-associated cell lineage and spasmolytic polypeptide-expressing metaplasia; (2) IM, in all its phenotypical and molecular subtypes.52 153 244 In the oxyntic compartment, the IM mainly exibits complete phenotype (see section 2.4.6).245 Atrophic AIG (also referred as ‘florid phase’) commonly features hyperplastic polypoid lesions (rarely associated with pyloric gland adenomas) and either linear or nodular hyperplasia of the ECL cells (figure 9).238 246

2.5.4 In a subset of patients, it is postulated that H. pylori may trigger the autoimmune process leading to the atrophy of the oxyntic mucosa.

Comment

Solid evidence confirms that primary AIG (ie, unrelated to H. pylori) is a real nosological entity. Many case series report a higher frequency of primary AIG, especially in countries with a low prevalence of H. pylori infection.52 213 222 Additionally, AIG is far more prevalent in patients with autoimmune thyroid disease, Addison’s disease, vitiligo, coeliac disease and other autoimmune disorders,52 and in those displaying the HLA-DRB1*03 and HLA-DRB1*04 haplotypes, commonly associated with autoimmunity.247

The role of H. pylori in the pathogenesis of AIG is still debated, but there is some evidence that in a subset of patients, H. pylori may trigger the autoimmune process leading to atrophy of the oxyntic mucosa (ie, ‘secondary’ AIG). This may be due to the cross-reactivity between H. pylori-induced antibodies and proton pump antigens in the parietal cells of oxyntic mucosa (ie, antigenic mimicry).248 According to this theory, at least in a subset of cases, H. pylori may act as a trigger of the inflammatory process by shifting towards the non-self-limiting autoimmune destruction of the oxyntic mucosa.52 249

2.5.5 The diagnosis of AIG is achieved by gastroscopy, with separately collected biopsies of the antrum and corpus showing typical histological findings. The most sensitive serum test for AIG is the detection of antibodies against parietal cells (PCA).

Comment

The histological diagnosis of AIG requires biopsies from the antrum and corpus to be collected separately and submitted in topographically identified vials.

In the earliest phase of non-atrophic AIG, all mucosal compartments may appear endoscopically normal.239 In the subsequent atrophic phase, endoscopy shows oxyntic (ie, fundic and corpus) atrophy, loss of gastric folds, pale and thin mucosa rendering submucosal capillary vessels visible.7 52 When using the Kimura-Takemoto classification, East Asian endoscopists include atrophic AIG in the O3 category.240 The O3 category, however, implies antral atrophic involvement, which is absent in primary AIG (figures 3 and 5).

In the absence of previous or current H. pylori comorbidity, the antral mucosecreting compartment may be endoscopically normal or erythematous when reactive gastropathy is present (tables 1 and 5). It has been suggested that image-enhanced endoscopy allows the identification of some characteristics that distinguish atrophic gastritis in AIG from H. pylori-induced atrophic gastritis250; these criteria, however, have not yet been validated for application in clinical practice (see section 2.5.3).

Oxyntic inflammation and atrophy are associated with a spectrum of ECL cell hyperplastic changes, ranging from linear and nodular hyperplasia to a neoplastic progression to type 1 NET (see section 2.5.3). In patients with AIG, the role of OLGA/OLGIM in the prediction of epithelial gastric neoplastic lesions should be further evaluated. Because primary AIG spares the antrum, the OLGA stage in these patients is never higher than stage II. Stages III–IV strongly suggest prior H. pylori infection that has resulted in antral atrophic lesions (see section 2.5.7). In these patients with AIG with high OLGA stages (related to the effects of H. pylori), the risk of gastric neoplasia has been estimated to range between 6.3% and 25%.251 252

Due to the absence or paucity of symptoms in the early stages of AIG, a substantial diagnostic delay may result in the development of life-threatening and irreversible complications.222 Micronutrient malabsorption in AIG is responsible for the wide spectrum of clinical manifestations in advanced disease (see section 2.5.3).

2.5.6 Measurements of PgI and PgI/II ratio and serum gastrin-17 levels are the most accurate serological tests when screening for advanced atrophic stages of AIG.

Comment

The British Society of Gastroenterology advised against the use of biomarkers as screening tools in areas of low incidence of gastric adenocarcinoma, such as the UK.36 The biomarkers serum PgI and II levels, the PgI/II ratio, serum gastrin-17 and H. pylori serology have long been measured and explored, alone or in combination, to detect advanced or late-stage atrophic gastritis.253–255 Low serum PgI and a low PgI/II ratio can provide a non-invasive diagnosis of advanced stage atrophic gastritis, and, importantly when H. pylori serology is also negative, endoscopy is recommended by the MAPS II Guideline Update 2019.42

An observational study evaluating screening tests in 28 Japanese patients with confirmed histological AIG reported a 78.6% positive predictive value with a serum gastrin >172 pg/mL, or with cut-off values of PgI and PgI/II ratio 14.5 ng/dL and 2.1, respectively.256 Prospective studies of surveillance for patients with AIG using such non-invasive biomarkers as above are urgently needed to define the optimal long-term management of patients with AIG.

2.5.7 Endoscopic surveillance should be considered in patients with AIG. Based on limited data, an interval of 3–5 years is suggested.

Comment

Prior studies examining the AIG-associated gastric cancer risk have included pernicious anaemia among the preneoplastic gastric conditions (see section 2.1.4).44 46 Most of these studies are based on large retrospective cohorts of patients who had possibly also been exposed to H. pylori infection.237 251 257 258 By modifying the topographical extension of the gastric cancerisation field, any previous or current H. pylori infection promotes pangastritis atrophy, acts as a cancer-promoting cofactor and ultimately limits the punctual estimate of the AIG-linked cancer risk (figure 3).237

Addressing the gastric cancer risk associated with AIG unaccompanied by an H. pylori infection, more recent studies have required a normal mucosecreting antrum, which plausibly excludes previous or current H. pylori co-responsibility in establishing a cancer-prone gastric microenvironment.36 37 105 213 259 A normal antral mucosa, or one showing only reactive gastropathy, is probably the best marker for excluding prior H. pylori infection (see table 2 and section 2.6.3).36

The risk of neuroendocrine neoplasia in AIG is related to the increase of serum gastrin (as a proxy for oxyntic atrophy) promoting ECL proliferation and potentially resulting in type I NETs (also referred to as gastric carcinoids).260–262 The optimal interval for AIG endoscopic surveillance has not been agreed upon. One small prospective study concluded that four yearly intervals were safe and sufficient to detect early neoplastic mucosal lesions.263 The MAPS II European guidelines state that intervals for endoscopic surveillance should be based on the presence of epithelial precancerous conditions and lesions, with an emphasis on the presence of endoscopically or histologically detectable lesions.42

Based on the available data on the negligible risk of gastric malignancies associated with primary AIG, an interval of 3–5 years endoscopy and biopsy follow-up is suggested, more tailored for the early detection of NETs rather than for gastric cancer secondary prevention.213 251 260 261

Comment

In a proportion of patients with chronic active gastritis (ie, mononuclear infiltrate with a variable neutrophil component), current or previous H. pylori infection cannot be detected either by special histological stains, immunohistochemistry, PCR or a positive serology.72 264 268 269

Several possible aetiologies for chronic active gastritis without detectable Helicobacter organisms have been suspected (eg, medications, chemical injuries, other infections, AIG), but no specific causes have been confirmed.265 270

Rarely, other infections (eg, EBV, cytomegalovirus, Mycobacterium avium intracellulare, herpes simplex virus) or immune-mediated disorders (eg, lymphocytic gastritis, Crohn’s disease and ulcerative colitis) may show low-grade or focal chronic active inflammation in the gastric mucosa. When sufficient sampling is available, the correct diagnosis can often be established (see section 2.1.2).271 272 Currently, it is believed that the most likely cause of Helicobacter-negative chronic gastritis may be an ‘altered gastric microbiome’ (see section 2.7).273 The contribution of H. pylori-negative gastritis to the overall burden of gastritis is low (<1% of all chronic active gastritis).271 274 None of these other types of gastritis have been associated with the development of epithelial neoplastic lesions, but occasional reports have noted the possible occurrence of primary gastric mucosa-assisted lymphoid tissue (MALT) lymphomas.265 270 Studies on the aetiological role of non-H. pylori Helicobacter spp (NHPH) transmitted to humans from pigs, canines and felines have shown that the prevalence of NHPH infections ranges between 0.2% and 6%, depending on the diagnostic methods and the addressed population. Human zoonosis due to NHPH infection has been associated with chronic gastritis, peptic ulcer disease, low-grade MALT lymphoma and gastric cancer.275–277

2.6.2 Chronic (long-standing) gastritis of specific aetiology is rare and usually represents the phenotypical expression of a condition involving other parts of the gastrointestinal tract. The aetiology can be due to communicable or non-communicable agents and is distinct from gastritis associated with systemic disease.

Comment

Rare forms of gastritis, often asymptomatic or associated with dyspeptic symptoms, may be detected incidentally during gastroduodenoscopy performed as part of the investigation of gastrointestinal symptoms, systemic diseases or in the context of preventive medicine.278 With some notable exceptions, our knowledge of these forms of gastritis is derived from case reports and relatively small series, and causal links with clinical symptoms have yet to be established.28 279–281

The different types of low-prevalence gastritis are summarised in table 2 (section 2.1.2). Most of them have no specific endoscopic findings and, with some notable exceptions (eg, Crohn’s disease), even histology may fail to identify a specific aetiology.282–287 In the aetiological assessment, it is crucial to critically ponder on various factors, including the patient’s anamnesis, the clinical presentation and course of the disease, whether chronic gastritis is limited to the stomach or extragastric pathology, and whether it responds to treatment. It is worth noting that none of these forms of gastritis are linked to an increased risk of gastric cancer.

2.6.3 Drugs may induce either acute self-limiting or long-lasting lesions. The identification of the aetiological agents rests primarily on the temporal relationship with drug intake and, in some cases, supported by the histological findings.

Comment

The clinical presentation of drug-induced gastritis (DIG) manifestations is highly variable, ranging from an asymptomatic condition to mild dyspepsia and even alarming symptoms (acute and chronic gastrointestinal bleeding, anaemia). Essential determinants of the manifestations are the dose, duration and type of drugs used. Gastric lesions may be focal (erosion, ulcer) and not necessarily parallel the severity of the clinical manifestation. Drugs may also cause non-inflammatory mucosal lesions (ie, gastropathy; see table 5 and section 2.1). These lesions, which are not part of the gastritis spectrum, are mentioned here because of their frequent occurrence. They include, among others, oxyntic gland polyps associated with long-term PPI use and lanthanum deposition, resulting from lanthanum carbonate used in the treatment of hyperphosphataemia in patients with chronic renal failure.288 289

The key to establishing a diagnosis of DIG is the chronological link between drug assumption and the occurrence of clinical, endoscopic and histological changes, as well as the disappearance or a pronounced decrease of those manifestations after drug withdrawal.290

Endoscopic findings are non-specific and include erythema, petechiae and mucosal lesions (erosions and ulcers), most often seen in the context of NSAID, aspirin, and oral iron or potassium tablets. Immune checkpoint inhibitors may induce diffuse, oedematous, granular mucosal lesions with erosions or ulcers. In the absence of coagulopathy, gastric biopsies are recommended according to the standard updated Sydney System protocol. Histological assessment may provide findings that allow ascribing specific types of drugs to clinical manifestations and gastric mucosal damage (table 5).30 291–298

The management of DIG rests on the withdrawal of the drug and the use of acid inhibitors (H₂ blockers or PPI). If present, H. pylori eradication is indicated, especially in NSAID or aspirin treatment.299 Gastritis associated with immune checkpoint inhibitors may require additional steroid therapy and infliximab.300 301

Drug-induced gastritis does not progress if the responsible drug is withdrawn. Neither gastric atrophy nor the development of preneoplastic or neoplastic changes has been described in association with DIG. Interestingly, a decrease in the risk of gastrointestinal neoplasia has been reported in association with using low-dose aspirin and certain NSAIDs.302

2.6.4 Some systemic disorders, including immune-mediated diseases, may be associated with damage to the gastric mucosa.

Comment

Several immune-mediated systemic (non-communicable; see tables 1 and 2; section 2.1.2) diseases, including lupus erythematous, scleroderma, Sjögren syndrome and IgG₄-related disease, have been associated with gastric involvement and atrophic gastritis. Patients are often asymptomatic and chronic gastritis is detected incidentally during OGD performed for other indications.303–306 When dyspeptic symptoms are present, their expression depends on the nature of the associated condition.

In patients with uraemia, dyspeptic symptoms are more frequent than in other systemic diseases and the gastric damage consists of a haemorrhagic gastropathy.307 308 Although sarcoidosis rarely affects the gastrointestinal tract, when it does, the stomach is commonly involved. Non-necrotising granulomas may be found, usually without much accompanying inflammation, and patients may present with weight loss and hypoalbuminaemia.309–312 Gastric mastocytosis, usually associated with mastocytic infiltration of the intestine, commonly presents with abdominal pain and diarrhoea.313

The diagnosis is based on clinical course, serology (particularly in immune-mediated systemic diseases), endoscopy and histology. Autoantibodies may be present in up to 55% of patients with systemic disorders and H. pylori-negative gastritis; the antinuclear antibody is commonly detected. Endoscopic features include erythema, oedema, focal petechial haemorrhages, erosions and ulcers. The most common histological features are summarised in table 6. Isolated reports of multifocal low-grade dysplasia in patients with atrophic gastritis associated with autoimmune systemic disease—if confirmed—suggest that this condition may have neoplastic potential.314 315

2.6.5 Most lymphoepithelioma-like gastric carcinomas are causally associated with EBV infection, while a small group of adenocarcinomas features clonal growth of EBV-infected epithelial cells. There is lack of robust evidence of EBV presence in gastric premalignant lesions.

Comment

The aetiological role of EBV in gastric carcinogenesis is not fully understood. Previous studies suggest a causal association between the viral infection and a rare type of gastric carcinoma (lymphoepithelioma-like (LEL)).316 317 The global prevalence of EBV positivity among LEL cases is 90%.318 Between 7.5% and 10% of gastric adenocarcinomas harbour monoclonal EBV episomes, with no major variation across populations.3 4

EBV-positive gastric cancer is the most common EBV malignancy globally, with ~80 000 cases annually.195 EBV-positive gastric cancers have demographic, clinicopathological and molecular differences from EBV-negative tumours.319 320 The Cancer Genome Atlas associates with EBV-positive gastric cancer a distinctive molecular pattern (ie, DNA hypermethylation, PIK3CA mutations, and JAK2, programmed cell death protein ligand 1 (PD-L1) and PD-L2 amplifications), which molecular profile differs from that of the variants associated with microsatellite instability (with high mutational rates), chromosomal instability mostly showing aneuploidy, p53 mutations and RTK-RAS activation, or with genomically stable cancers mostly involving the RHO-family GTPase-activating proteins.319 320

EBV-positive cancer prevails in males, is associated with smoking habit and history of gastric surgery, and most frequently displays proximal gastric location.318 321 322 EBV expression in cancer tissue specimens is a favourable prognostic factor.323 324 A similar humoral response to H. pylori-specific proteins in both EBV-positive and EBV-negative adenocarcinomas reflects the essential aetiological role of H. pylori in EBV-positive gastric cancer.325

EBV-positive gastric cancer features diffuse histological phenotype coexisting with prominent inflammatory infiltrate,326 327 and expressing PD-L1.328 Alterations in specific chemokines and PD-L1 characterise the systemic response to EBV-positive tumours.329 Thus, patients with EBV-positive gastric cancer may benefit from immunomodulatory therapies.330 Oxidative stress may play a critical role mediating EBV reactivation from latency.331 Unlike other EBV-associated malignancies, the EBV-positive gastric cancer-specific humoral response is exclusively directed against lytic cycle immediate-early and early antigens.332 EBV integration into the host genome is rare.319 333 The mechanism for EBV epithelial cell entry remains elusive, and it is still unknown the exact stage during carcinogenesis when EBV enters gastric epithelial cells.267 Recent evidence demonstrates that EBV uses ephrin A2 receptor to enter epithelial cells.334 By promoting exposure of ephrin A2 receptor, H. pylori ultimately promotes the infection of gastric epithelia.335

It is proposed that H. pylori-driven gastritis attracts EBV-positive B lymphocytes. The cell-to-cell contact between lymphocytes and gastric epithelia initiates the EBV lytic cycle in B cells, promoting viral transmission.336 337 Expression of EBV by in situ hybridisation is variable in gastric dysplastic lesions.338 339 Studies of atrophic gastritis documenting EBV DNA by PCR-based techniques lack information on the localisation of the viral gene products in the gastric tissues and do not provide conclusive results.340 Further research is required to advance the EBV-positive gastric cancer field.

Comment

Compared with non-infected gastric mucosa, H. pylori-positive gastric mucosal specimens feature reduced microbial diversity, an altered microbiota community and decreased interactions among gastric microbes.344 345

Non-Helicobacter gastric microbiota reach the stomach with the swallowed saliva and appear to be transient, having no apparent ability to permanently colonise the gastric mucosa.344 346 However, the relevance of gastric bacteria and their potential in modulation of the inflammatory response in H. pylori gastritis, enhancement of the gastric mucosa barrier function and biocine/defensin production needs to be explored.

The biodiversity of gastric bacteria with potential beneficial effects in the regulation of inflammation is high, and it is possible that some of them may become viable candidates for future probiotic management of H. pylori.347 348

2.7.2 Gastric microbiota may play a pathogenetic role in gastritis, particularly once gastric atrophy and achlorhydria develop.

Comment

The role of bacterial species other than H. pylori had been considered minimal or null in the aetiology of gastritis. Recent evidence, however, has changed this assumption and non-H. pylori microbiota have been ascribed a causal role in gastric inflammatory diseases, also suggesting their plausible involvement in the morphogenesis of mucosal atrophy.342 Moreover, the richness of potential pathogenetic bacteria has been shown to increase from the normal mucosa to precancerous conditions.349 350

Several studies have reported that, with advancing gastric atrophy and impaired acid secretion, the gastric microbiota become dominated by components of the oral and/or intestinal microbiome. In a hypochlorhydric gastric microenvironment, the expected discrepancy between the microbial profile adherent to the mucosa (as detected by testing mucosal biopsies) and that detected in juice aspirates disappears (see section 2.7.1). These findings support the hypothesis that the oral component of gastric bacteria, usually believed to pass through, may settle in an atrophic mucosa and act as co-players in the oncogenetic cascade.350–355

2.7.3 Gastric microbiota may impact on different stages of gastric carcinogenesis initiated by H. pylori infection. Further studies to identify microbiota-driven carcinogenic pathways are needed.

Comment

Experimental and small clinical studies support the potential role of microorganisms other than H. pylori in the different steps of the gastric oncogenetic cascade.356–358

The gastric microbiota population is ‘dynamic’, and it is modulated by acid production, mucosal inflammation, atrophic–metaplastic lesions and gastric cancer.359 Dysbiotic microbial profiles that develop along with the progression of gastritis (ie, non-atrophic to atrophic) may carry a genotoxic potential, acting as co-promoters of oncogenesis.341 Dysbiotic microbiota are also detected in H. pylori-positive mucosa associated with early and advanced gastric precancerous conditions and lesions (ie, high-stage atrophic gastritis and dysplasia) and can still be reversed by eradication (see section 2.1.4).349 Microbial communities found in advanced atrophic gastritis differ in different populations and are influenced by lifestyle, nutritional habits and the severity of organic lesions (ie, gastritis stages OLGA/OLGIM III–IV).360

In advanced atrophic gastritis, H. pylori may no longer be detectable, and the bacterial community consists mainly of Fusobacterium, Neisseria, Prevotella, Veillonella and Rothia. 349 A meta-analysis confirmed the increased abundance of Fusobacterium, but indicated that, in addition, other bacteria, Leptotrichia, Bifidobacterium, Lactobacillus and Streptococcus anginosus, are enriched in patients with gastric cancer compared with patients with gastritis across studies.361 Another meta-analysis confirmed that in gastric cancer, the opportunistic pathobionts Fusobacterium, Parvimonas, Veillonella, Prevotella and Peptostreptococcus are enriched.361 362

Among the bacteria found to be most abundant in preneoplastic conditions, F. nucleatum may contribute to neoplastic progression by causing a strong inhibition of the host immune responses and antioxidative systems. The mechanisms of gastric microbes following the initial events driven by H. pylori in gastric carcinogenesis remain to be elucidated in future studies.

Comment

In 2020, there were 1.1 million new cases of gastric cancer worldwide, which accounted for 770 000 cancer deaths, making it the fifth most common cancer and the fourth most common cause of cancer death.363 It ranks among the top three most common cancers in 19 countries and the three most common causes of cancer death in 42 countries.364 Based on the GLOBOCAN 2020 database, the majority of gastric cancer cases occurred in Asia (n=819 944, 75%); China accounted for 44% of all gastric cancer cases in the world, followed by Europe (12.5%), South America and the Caribbean (6.2%), Africa (3%), North America (2.7%) and Oceania (0.3%). Similarly, 75% of all gastric cancer deaths were observed in Asia (n=575 206), of which 49% occurred in China alone.363

There is a significant geographical variation in the incidence and mortality of gastric cancer, with age-standardised incidence rates (ASIRs) (per 100 000, both sexes combined) ranging from 5 in most African regions, to 5–10 in America, Oceania, Western European and Asian regions (except for East Asia) to 17 in Central-Eastern Europe and 33 in East Asia. Gastric cancer occurs predominantly in men compared with women. Countries with the highest incidence rates in men included Japan (ASIR, 48.1), Mongolia (47.2) and the Republic of Korea (39.7), while the highest incidence in females was observed in Mongolia (20.7) and Tajikistan (18.8). The patterns of gastric cancer incidence and mortality are closely aligned in most countries, with the highest mortality rates being observed in Mongolia (36.5) and Kyrgyzstan (26.2) in males.363

When the gastric cancer burden was estimated by anatomical subsite, non-cardia gastric cancer was globally dominant, accounting for >80% of all gastric cancer cases, with a high case burden in Asia, but also in South and Central America. The global distribution of cardia gastric cancers had a different pattern, with the highest incidence rates being observed in East Asia, parts of Oceania, Western Europe and Western Asia.365

The most important prognostic factor for gastric cancer survival is its stage at diagnosis, with 5-year net survival of >60% for early gastric cancer in contrast to ~5% for advanced disease.366 Given its often late detection, the 5-year survival proportions remain poor, in the range of 20–30% in most countries worldwide,367–369 except in Japan and Korea, where endoscopic screening is widely practised.366 In Korea, for example, implementation of national screening programmes has led to an increasing number of cases diagnosed at an early, curable stage and high 5-year survival proportions of over 76% between 2013 and 2017.370

2.8.2 Despite the worldwide decline in incidence, the gastric cancer burden is predicted to grow and will remain a major challenge to public health on a global scale. Notably, the incidence of gastric cancer is increasing in some young populations, particularly in the west.

Comment

Gastric cancer incidence rates have been declining in many parts of the world. A recent study using the longitudinal high-quality cancer registry data from 92 cancer registries in 34 countries found that the overall incidence rates will continue to fall until 2035 in most countries, regardless of their background incidence rates.371 Nonetheless, the absolute number of new cases is predicted to further increase in many countries due to growing populations and ageing. If current rates remain stable, 1.8 million cases and 1.3 million deaths are expected to occur in 2040, which is 66% and 71% higher than estimated in 2020.372 Even with an assumed 2% annual decrease in rates, there would be an increased burden with 1.18 million new cases and 0.85 million deaths predicted by 2040.372

It is noteworthy that the observed stable or declining trends were more evident in older age groups, while this was not always the case in the younger age groups.371 373 Increases in incidence in individuals aged <50 years are predicted in 15 out of 34 countries of both low and high incidence, including Belarus, Chile, the Netherlands, Canada and the UK.371 A US population-based registry study reported increasing incidence of non-cardia gastric cancer in non-Hispanic white patients aged <50 years (estimated annual percentage change for 1995–2013, 1.3%).374 The increase was more pronounced in females (2.6%). Notably, the largest increases were observed for proximal malignancies. These observations, however, require a critical interpretation, given the large proportion (50% on average globally) of cancers with unspecified anatomical location.365

Gastric cancer disproportionately affects populations in Eastern Asia and Eastern Europe, and specific subgroups, such as people with lower socioeconomic status, and various ethnic populations.375–377 According to a comprehensive review, immigrants from regions with high to low gastric cancer incidence maintain their original higher risk of developing cancer and related mortality.378 Foreign birth, daily consumption of ethnic food, slower acculturation and low socioeconomic status were important predictors of gastric cancer cases in US multiethnic populations.379 Gastric cancer may therefore need to be recognised as an important disease for prevention even in lower-risk countries.

2.8.3 The prevalence of preneoplastic gastric conditions and lesions varies across populations, and usually correlates with gastric cancer incidence, prevalence of H. pylori infection, family history of gastric cancer, environmental (eg, smoking and diet) and host-related risk factors.

Comment

Due to the heterogeneity of study populations and diagnostic methods, the reported prevalence of gastric preneoplastic lesions, including atrophic gastritis and IM, shows wide variations. Among asymptomatic patients, a meta-analysis including endoscopic and serological studies showed a prevalence of atrophic gastritis and IM of 33% and 25%, respectively.380 The prevalence of IM was significantly higher in East Asia (21%) and South America (23.9%) than in Northern Europe (3.4%), Western Europe (3.2%) and North America (4.8%).381 382 A more recent meta-analysis of 14 studies (years 2010–2020) reported that 25% of study population had atrophic gastritis.383 The risk of atrophic gastritis was about 2.4-fold higher in H. pylori-positive versus negative subjects.

Overall, the local prevalence of atrophic gastritis and IM correlated well with the prevalence of H. pylori infection57 and the incidence of gastric cancer.54 Moreover, the prevalence of atrophic gastritis and IM is usually higher in males, in individuals aged 40 years or above380 and with a family history of gastric cancer.384 Individuals who consume a diet high in salt,185 and with smoking or drinking habits385 are also at higher risk. One of the reasons for the variable prevalence of atrophic gastritis is the use of different diagnostic methods, including serological, endoscopic and histological techniques. The latter two are further subject to high interobserver variations. The prevalence of atrophic gastritis is generally higher in biopsy-based compared with serology-based diagnoses, in countries with a high incidence of gastric cancer (41.7% vs 22.8%) and in selected rather than general populations.380 383

In high-income countries, the incidence of atrophic gastritis and IM is declining, as demonstrated by both period and cohort phenomenon.386 In Asia, a similar trend was also observed for the prevalence of atrophic gastritis in Japan, which decreased from 82% in 1970s to 19% in 2010s387; in contrast, the prevalence of corpus atrophy and IM in Korea was reduced in females only.388 Further long-term studies are necessary to clarify the trends of atrophic gastritis and IM in different regions.

2.8.4 The prevalence of H. pylori is declining in many parts of the world, particularly in young populations. The contribution of other factors to the epidemiology of chronic gastritis in the absence of H. pylori or after its eradication remains to be determined.

Comment

Systematic reviews and meta-analyses estimated that up to 4 billion people worldwide were infected with H. pylori,57 but the prevalence of H. pylori infection is declining in many developed countries, particularly in the younger populations.3 68 With the gradual decline in the prevalence of H. pylori infection due to both successful eradication and reduced new infection, there might be a shift in the relative proportion and importance of other agents contributing to gastritis, whose characterisation will require more epidemiological studies to characterise.72 Currently, the role of other microorganisms within the gastric microbiota in the pathogenesis of gastritis and preneoplastic lesions remains uncertain (see section 2.7.3).69

2.8.5 The risk of progression of premalignant gastric lesions differs depending on the presence of active H. pylori infection, the topographical extent and severity of the lesions, the type of IM, and various host and environmental factors.

Comment

Dysplasia (synonym: IEN; non-invasive neoplasia) is the most advanced neoplastic non-invasive lesion.45 389 390 In a meta-analysis,391 the annual progression rate to gastric cancer was 40.4 (95% CI: 27.1 to 55.7) per 1000 person-years, while for high-grade dysplasia and low-grade dysplasia was 186.4 (95% CI: 106.6 to 285.6) and 11.3 (95% CI: 3.9 to 21.2), respectively. For atrophic gastritis, the pooled incidence rate of progression to gastric cancer was 1.24 (95% CI: 0.80 to 1.76) per 1000 person-years, and to IM and dysplasia, it was estimated as 41.4 (95% CI: 3.1 to 64.5) and 6.2 (95% CI: 2.34 to 11.5) per 1000 person-years.201 For IM, a cardinal lesion belonging to the spectrum of gastric atrophy, the incidence of gastric cancer was 3.38 (95% CI: 2.13 to 4.85) per 1000 person-years, while the progression rate to dysplasia was 12.51 (95% CI: 5.45 to 22.03) per 1000 person-years.201

IM can be subtyped into complete and incomplete.392 Incomplete IM has been found to be associated with a 3.3-fold (RR 3.33, 95% CI: 1.96 to 5.64) higher risk of gastric cancer compared with complete IM during follow-up ranging from 3 to 12.8 years.136 Of note, however, the histological criteria to be applied to include any single case into the complete or incomplete risk group are less clearly defined. Incomplete IM has been significantly associated with extensive gastric intestinalisation, which assimilates widespread incomplete IM to high-risk OLGA/OLGIM gastritis stages (see section 2.3.5).67 393

Family history of gastric cancer, dietary habits and smoking also contribute to the risk of progression.394 395 However, the progression rate of premalignant gastric lesions appears to be similar between countries with low and high background gastric cancer incidences.104 192 193 396 In a meta-analysis of nine randomised controlled trials, H. pylori eradication alone has been shown to improve both atrophic gastritis (OR 2.61, 95% CI: 1.41 to 4.81) and IM (OR 2.61, 95% CI: 1.66 to 4.11) when compared with placebo (see section 2.4.3).397 Although gastric cancer of the intestinal type is considered to be associated with premalignant gastric lesions, a recent meta-analysis suggested a similar association with diffuse-type gastric cancer.146 Furthermore, high-risk patients with OLGA/OLGIM stages III and IV are at higher risk of metachronous gastric cancer following curative endoscopic submucosal dissection for early gastric cancer.398