OLGA staging for gastritis: A tutorial

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Digestive and Liver Disease 40 (2008) 650–658

Mini-Symposium

OLGA staging for gastritis: A tutorial M. Rugge a,b,∗ , P. Correa c , F. Di Mario d , E. El-Omar e , R. Fiocca f , K. Geboes g , R.M. Genta h , D.Y. Graham i , T. Hattori j , P. Malfertheiner k , S. Nakajima l , P. Sipponen m , J. Sung n , W. Weinstein o , M. Vieth p a

Department of Medical Diagnostic Sciences & Special Therapies (Pathology Section), University of Padova, Italy b Veneto Institute of Oncology (IOV-IRCSS), Padova, Italy c Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA d Department of Clinical Sciences, Section of Gastroenterology, University of Parma, Italy e Department of Medicine & Therapeutics Institute of Medical Sciences, Aberdeen University, UK f Department of Surgical, Morphological & Integrated Disciplines (Anatomic Pathology Section), University of Genova, Italy g Department of Pathology, Catholic University of Leuven, Belgium h Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA i Michael E. Debakey VA Medical Center & Baylor College of Medicine, Houston, TX, USA j Department of Pathology Shiga University Medical Sciences, Shiga, Japan k Department of Gastroenterology Hepatology And Infectious Diseases, Otto-Von-Guericke-University, Magdeburg, Germany l Department of Medicine, Gastroenterology and Healthcare Social Insurance Shiga Hospital, Shiga, Japan m Division of Pathology, HUSLAB, Helsinki University Hospital, Helsinki, Finland n Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, China o Department of Medicine Division of Digestive Diseases, UCLA Center for Health Sciences, USA p Institute of Pathology Klinikum Bayreuth, Bayreuth, Germany Received 1 February 2008; accepted 18 February 2008 Available online 17 April 2008

Abstract Atrophic gastritis (resulting mainly from long-standing Helicobacter pylori infection) is a major risk factor for (intestinal-type) gastric cancer development and the extent/topography of the atrophic changes significantly correlates with the degree of cancer risk. The current format for histology reporting in cases of gastritis fails to establish an immediate link between gastritis phenotype and risk of malignancy. The histology report consequently does not give clinical practitioners and gastroenterologists an explicit message of use in orienting an individual patient’s clinical management. Building on current knowledge of the biology of gastritis and incorporating experience gained worldwide by applying the Sydney System for more than 15 years, an international group of pathologists (Operative Link for Gastritis Assessment) has proposed a system for reporting gastritis in terms of stage (the OLGA staging system). Gastritis staging arranges the histological phenotypes of gastritis along a scale of progressively increasing gastric cancer risk, from the lowest (stage 0) to the highest (stage IV). This tutorial aims to provide unequivocal information on how to consistently apply the OLGA staging system in routine diagnostic histology practice. © 2008 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. Keywords: Atrophic gastritis; Gastritis staging; OLGA staging

1. Introduction ∗

Corresponding author at: Chair, Anatomic Pathology, Universit`a degli Studi di Padova, Istituto Oncologico del Veneto IOV-IRCCS, Via Aristide Gabelli 61, 35121 Padova, Italy. E-mail address: [email protected] (M. Rugge).

Chronic (Helicobacter-associated) gastritis is a crucial step in the natural history of gastric oncogenesis and its epidemiological link with gastric carcinoma is well established [1,2].

1590-8658/$30 © 2008 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. doi:10.1016/j.dld.2008.02.030

M. Rugge et al. / Digestive and Liver Disease 40 (2008) 650–658

Upper gastrointestinal endoscopy with biopsy sampling is the definitive diagnostic procedure whenever a gastric malignancy is suspected. Its use for the secondary prevention of gastric cancer (GC) is generally limited because of its invasiveness and cost, but for selected high-risk patients it remains the only available strategy [3,4]. While many aspects of the biology of gastritis remain to be elucidated, a large body of information indicates that gastric atrophy is the single most powerful predictor of the onset of intestinal-type GC [5–9]. Intestinal metaplasia is generally considered as the “field cancerisation” in the gastric mucosa and, at cell level, intestinalised glands provide the cellular substrate on which gastric non-invasive neoplasia (NiN) develops [10,11]. There is some evidence to show that intestinal metaplasia can be reversed (by clearing H. pylori infection or applying chemoprevention strategies), but the chances of aborting the progression of NiN to cancer are considerably lower, and that high-grade NiN will evolve into invasive adenocarcinoma is a virtual certainty [9]. In spite of the greater consistency brought about by the Sydney System and its updated 1996 Houston version, the commonly-used nomenclature for gastritis remains inconsistent and individual, non-standard styles of histology reporting for gastritis are still widely used to the consternation of clinicians [12–15]. Many practitioners are unable to perceive the different cancer risk associated with “multifocal atrophic gastritis”, “corpus predominant gastritis”, or “antrum-predominant H. pylori chronic active gastritis”, and even well-informed specialists are often frustrated by a terminology that makes it difficult to identify candidates for endoscopic surveillance [1,7,13,15–18]. Building on current knowledge of the natural history of gastritis and the associated cancer risk, an international group of gastroenterologists and pathologists (the Operative Link for Gastritis Assessment [OLGA]) has proposed a system for reporting gastritis in terms of stage (the OLGA staging system), which arranges the histological phenotypes of gastritis along a scale of progressively increasing GC risk, from the lowest (OLGA stage 0) to the highest (OLGA stage IV) [19,20]. The staging framework is borrowed from the oncology vocabulary and applies the histology reporting format successfully employed for chronic hepatitis to the gastritis setting too [21,22]. Just as fibrosis is the main lesion used to weigh the risk of liver cirrhosis, gastric mucosal atrophy is considered the marker of cancer risk. Additionally, just as a given number of portal tracts are required for the accurate staging of hepatitis, a well-defined biopsy sampling protocol (as recommended by the Sydney System) is considered a “minimum requirement” for the reliable staging of gastritis [13,23–25]. The stage of gastritis results from the combination of the extent of atrophy (scored histologically) with its topographical location (resulting from the mapping protocol) [26]. In line with the Sydney recommendations, the OLGA staging system also includes information on the likely aetiology of

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the gastric inflammatory disease (e.g. H. pylori, autoimmune, etc.). This tutorial aims to expand on the available information with a view to a consistent application of the OLGA staging system. The provided clues are founded basically on the current definition of gastric atrophy and on the worldwide experience accumulated by practicing the Houston-updated Sydney System.

2. Definition of atrophy in the gastric mucosa Normal gastric biopsy samples (from adolescents and adults) feature different populations of glands (mucosecreting or oxyntic), appropriate for the functional compartment (antrum or corpus) from which the specimen has been obtained (i.e. “appropriate glands”) [27,28] (Fig. 1). Occasionally, minuscule foci metaplastic (goblet) cells may be encountered, particularly in the foveolar epithelium, but the overall density of appropriate glands is not affected. In the gastric mucosa, atrophy is defined as the “loss of appropriate glands”. Different phenotypes of atrophic transformation may be encountered, i.e. (a) vanishing, or evident shrinkage of glandular units associated with (fibrotic) expansion of the surrounding lamina propria. Such a situation results in a reduced glandular mass, but does not imply any modification of the original epithelium phenotype (Fig. 1); (b) metaplastic replacement of the native glands by glands featuring a new cellular commitment (= intestinal and/or pseudopyloric metaplasia). The number of glands is not necessarily lower, but the metaplastic replacement of the original glandular units results in a smaller population of the native glands (which are “appropriate” for the compartment considered). Such a condition is also consistent with the general definition of “loss of appropriate glands” (Fig. 1). Sometimes (particularly in H. pylori-associated gastritis), severe inflammation makes it impossible to determine whether glands that “appear to be lost” are merely obscured by the inflammatory infiltrate or whether they have genuinely vanished. In such cases, a temporary diagnosis of “indefinite for atrophy” can be made, deferring the final judgment until the inflammation has resolved (e.g. after eradication of the H. pylori infection). This “indefinite” category, borrowed from the classification of intra-epithelial neoplasia (dysplasia) in the gastrointestinal tract, is not intended to represent a biological entity [28]. In tune with the above-mentioned criteria, an International Group of Gastrointestinal Pathologists (Atrophy club) arranged the histological spectrum of atrophic changes into a formal classification (Table 1). After testing in real cases, the interobserver consistency in recognizing/scoring the atrophic lesions was considered more than adequate [28].

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Fig. 1. Normal and atrophic glandular units in the stomach. 1: Normal mucosecreting gland. The glandular structure consists of mucosecreting cells (yellow line). In this, as in all the other glandular structures, both the superficial layer and proliferative zone are represented as a pink line. 2: Non-metaplastic atrophy in a mucosecreting gland: the number of glandular coils is decreased and the gland’s profile has become simpler (shrunk) and does not reach the bottom of the mucosal layer. 3: Metaplastic atrophy (intestinal metaplasia): the glandular profile is simplified, looking like an intestinal crypt (intestinalized epithelia are represented as bright blue line). 4: Normal oxyntic gland (green profile). 5: Non-metaplastic atrophy in an oxyntic gland: the gland’s profile is shorter (shrunk) and the tubular structure does not reach the bottom of the mucosal layer. 6: Pseudopyloric metaplasia in oxyntic gland: the parietal and chief cells (green line) are replaced by mucosecreting epithelia (yellow line, as in the antral glands). The intestinalization of a native oxyntic gland is similar to that shown for mucosecreting glands (see 3).

3. Gastritis staging: the OLGA system Gastritis can be interpreted on two different levels: (a) a basic level represented by the elementary lesions; and (b) a hierarchically higher level (as a “stomach disease” proper) depending on the extent and topographic distribution of the different elementary lesions. In 1955 Basil Morson said that, “the incidence and the extent of intestinal metaplasia are greatest in stomachs containing carcinomas and least in those with duodenal ulcer, with cases of gastric ulcer taking an intermediate position”. Correa later demonstrated that patchy areas of atrophic–metaplastic changes in the antral and oxyntic

mucosa (i.e. multifocal atrophic gastritis) frequently coexist with gastric ulcer, creating the most frequent setting for gastric carcinoma [16,29,30]. Based on the assumption that a different extent and topographical distribution of atrophy expresses a different clinico-biological situation (associated with a different cancer risk), the Houston-updated Sydney System established that multiple biopsy samples should be obtained to explore the different mucosa compartments [13]. Different biopsy locations have been suggested in the international literature to map the mucosa, all of them consistent with the general assumption that both the oxyntic and the antral mucosa have to be “explored”, and also considering the incisura

Table 1 Atrophy in the gastric mucosa: histological classification and grading Atrophy 0 Absent (= score 0) 1 Indefinite (no score is applicable) Histological type 2 Present

2.1 Non-metaplastic

2.2 Metaplastic

Location and key lesions Antrum Glands: shirking/vanishing Lamina propria: fibrosis Intestinal metaplasia

Grading Corpus Glands: shirking/vanishing Lamina propria: fibrosis Intestinal metaplasia Pseudopyloric metaplasia

2.1.1 Mild = G1 (1–30%) 2.1.2 Moderate = G2 (31–60%) 2.1.3 Severe = G3 (>60%) 2.2.1 Mild = G1 (1–30%) 2.2.2 Moderate = G2 (31–60%) 2.2.3 Severe = G3 (>60%)

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advances from the reversible inflammatory lesions (mostly limited to the antrum) at one end to the atrophic changes extensively involving both functional compartments (antrum and corpus) and associated with a high risk of GC at the other [23].

4. How to apply the OLGA staging system for gastritis The OLGA staging system integrates the above experiences in an internationally-agreed staging proposal. The System uses gastric atrophy as the lesion marking disease progression. The stage of gastritis is obtained by combining the extent of atrophy scored histologically with the topography of atrophy identified by the multiple biopsies (Fig. 3). The OLGA histology report also includes the etiological information obtainable from the tissue samples available (i.e. H. pylori infection; autoimmune disease, etc.). The following paragraphs are intended as a brief OLGA staging system “user’s manual”. Visual Analogue Scales (VAS) are used to give an example of how the histology changes featured at single biopsy level can be pieced together to stage a given patient (Figs. 4–9).

Fig. 2. Gastric biopsy sampling protocol.

angularis “highly informative” for the purpose of establishing the earliest onset of atrophic–metaplastic transformation [24]. The OLGA proposal (basically consistent with the Houston-updated biopsy protocol [13]) consists in recommending (at least) five biopsy samples from: (1) the greater and lesser curvatures of the distal antrum (A1–A2 = mucussecreting mucosa); (2) the lesser curvature at the incisura angularis (A3), where the earliest atrophic–metaplastic changes mostly occur; and (3) the anterior and posterior walls of the proximal corpus (C1–C2 = oxyntic mucosa) (Fig. 2). The information obtained enables to place patients at approximate points along the path where chronic gastritis

4.1. Atrophy score 4.1.1. Scoring atrophy (loss of appropriate glands) at single biopsy level In each single biopsy, atrophy is scored as a percentage of atrophic glands. Ideally, the atrophy is assessed on perpendicular (full thickness) mucosal sections. Nonmetaplastic and metaplastic subtypes are considered together. For each biopsy sample (whatever the area it comes from), atrophy is scored on a four-tiered scale (no atrophy = 0%, score = 0; mild atrophy = 1–30%, score = 1; moderate atrophy = 31–60%, score = 2; severe atrophy = > 60%, score = 3) (Figs. 4–9).

Fig. 3. The OLGA staging frame.

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Fig. 4. All 5 biopsy samples (3 from the mucosecreting compartment and 2 from the oxyntic compartment) consist of normal glands. This figure shows a normal gastric mucosa at both antral and corpus levels. Each strip (=1 biopsy sample) is labeled according to its site of origin (antral/angular = A, corpus = C) and includes 10 glandular units. Any inflammation (lymphocytes, monocytes, plasmacytes, granulocytes) is disregarded. The percentages given on the left refer to the percentage of atrophic glands at single biopsy level (in this VAS, the percentage of atrophy is 0 in all the available biopsies). The total (“compartmental”) prevalence of atrophy is given on the right, distinguishing between antral and corpus compartments; the final “compartment atrophy score” is also shown. The OLGA staging frame is provided in the bottom right-hand corner, where the OLGA-stage is reported (OLGA-stage 0).

4.1.2. Assessing atrophy in each compartment (mucosecreting and oxyntic) According to the Sydney protocol, three biopsy samples should be taken from the mucosecreting area (two antral samples + one from the incisura angularis), and two from the oxyntic mucosa. It is important to note that the atrophic transformation in samples of incisura angularis mucosa

is only assessed in terms of glandular shrinkage/vanishing (with fibrosis of the lamina propria) or intestinal metaplasia (replacing original mucosecreting and/or oxyntic glands). In each of the two mucosal compartments (mucosecreting and oxyntic), an overall atrophy score expresses the percentage of compartmental atrophic changes (con-

Fig. 5. Scoring atrophy at each single antral/angular biopsy level (atrophic glands are identified by a red marker): A1 = 20%, A2 = 20% and A3 = 40%. Assessing atrophy at compartment level (antrum): dividing 80 (=20 + 20 + 40) by 3 (the number of antral biopsies considered), the final prevalence of antral atrophy is 27% (<30%), which means a score of 1. Scoring atrophy at each single corpus biopsy level (atrophic glands are identified by a red marker): C1 = 20%; C2 = 30%. Assessing atrophy at compartment level (corpus): dividing 50 (=20 + 30) by 2 (the number of corpus biopsies considered), the final prevalence of corpus atrophy is 25% (<30%), which means a score of 1. Combining the atrophy scores for the antrum (Antral atrophy score [Aas] = 1) and corpus (Corpus atrophy score [Cas] = 1) gives us the OLGA stage, as shown in the reference chart (bottom right-hand corner: OLGA-stage I). H. pylori-status (as histologically assessed by special stain) has to be reported.

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Fig. 6. Scoring atrophy at each single antral/angular biopsy level (atrophic glands are identified by a red marker): A1 = 20%; A2 = 30%; A3 = 70%. Assessing atrophy at compartment level (antrum): dividing 120 (=20 + 30 + 70) by 3 (the number of biopsies considered), the final prevalence of antral atrophy is 40% (>30% < 60%), which means a score of 2. Scoring atrophy at each single corpus biopsy level (atrophic glands are identified by a red marker): C1 = 30%; C2 = 20%. Assessing atrophy at compartment level (corpus): dividing 50 (=30 + 20) by 2 (the number of biopsies considered), the final prevalence of corpus atrophy is 25%(<30%), which means a score of 1. Combining the atrophy scores for the antrum (Aas = 2) and corpus (Cas = 1) gives us the OLGA stage, as shown in the reference chart (bottom right-hand corner: OLGA-stage II). H. pylori-status (as histologically assessed by special stain) has to be reported.

sidering all together the biopsies obtained from the same functional compartment). The same cut-offs are used at this hierarchically higher assessment level as for the single biopsies (no atrophy = 0%, score = 0; mild atrophy = 1–30%, score = 1; moderate atrophy = 31–60%, score = 2; severe atrophy = > 60%, score = 3). Using this strategy, an overall

atrophy score is obtained that separately summarizes the scores for the antrum ([Aas] Aas0, Aas1, Aas2, Aas3) and the corpus mucosa ([Cas] Cas0, Cas1, Cas2, Cas3) (Figs. 4–9). The OLGA stage results from the combination of the overall “antrum score” with the overall “corpus score” (Fig. 3).

Fig. 7. Scoring atrophy at each single antral/angular biopsy level (atrophic glands are identified by a red marker): A1 = 40%; A2 = 40%; A3 = 40%. Assessing atrophy at compartment level (antrum): dividing 120 (=40 + 40 + 40) by 3 (the number of biopsies considered), the final prevalence of antral atrophy is 40% (>30% < 60%), which means a score of 2. Scoring atrophy at each single corpus biopsy level (atrophic glands are identified by a red marker): C1 = 30%; C2 = 60%. Assessing atrophy at compartment level (corpus): dividing 90 (=30 + 60) by 2 (the number of biopsies considered), the final prevalence of corpus atrophy is 45% (>30% < 60%), which means a score of 2. Combining the atrophy scores for the antrum (Aas = 2) and corpus (Cas = 2) gives us the OLGA stage, as shown in the reference chart (bottom right-hand corner: OLGA-stage III). H. pylori-status (as histologically assessed by special stain) has to be reported.

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Fig. 8. Scoring atrophy at each single antral/angular biopsy level (atrophic glands are always identified by a red marker): A1 = 0%; A2 = 0%; A3 = 40%. Assessing atrophy at compartment level (antrum): dividing 40 (=0 + 0 + 40) by 3 (the number of biopsies considered), the final prevalence of antral atrophy is 13% (<30%), which means a score of 1. Scoring atrophy at each single corpus biopsy level (atrophic glands are identified by a red marker): C1 = 90%; C2 = 90%. Assessing atrophy at compartment level (corpus): dividing 180 (=90 + 90) by 2 (the number of biopsies considered), the final prevalence of corpus atrophy is 90% (>60%), which means a score of 3. Combining the atrophy scores for the antrum (Aas = 1) and corpus (Cas = 3) gives us the OLGA stage, as shown in the reference chart (bottom right-hand corner: OLGA-stage III). H. pylori-status (as histologically assessed by special stain) has to be reported. In this case, the pattern of atrophic gastritis (corpus predominant atrophy) should suggest an autoimmune etiology.

5. From atrophy score to OLGA stage 5.1. Stage 0 gastritis (i.e. non-atrophic mucosa) (Fig. 4) When the overall score for atrophy is 0 in both the mucosecreting and the oxyntic compartments (which means that none of the five standard biopsy samples show signs of

atrophy), the OLGA stage is obviously 0. The score for inflammatory lesions is independent of said stage, except in cases considered “indefinite for atrophy” because a florid inflammatory infiltrate may prevent the proper assessment of appropriate gland loss. To avoid confounding the issue, all the VAS provided have been cleansed of any inflammatory component and no mention is made of any grading of the

Fig. 9. Scoring atrophy at each single antral/angular biopsy level (atrophic glands are identified by a red marker): A1 = 70%; A2 = 90%; A3 = 70%. Assessing atrophy at compartment level (antrum): dividing 230 (=70 + 90 + 70) by 3 (the number of biopsies considered), the final prevalence of antral atrophy is 77% (>60%), which means a score of 3. Scoring atrophy at each single corpus biopsy level (atrophic glands are identified by a red marker): C1 = 40%; C2 = 70%. Assessing atrophy at compartment level (corpus): dividing 110 (=40 + 70) by 2 (the number of biopsies considered), the final prevalence of corpus atrophy is 55% (>30% < 60%), which means a score of 2. Combining the atrophy scores for the antrum (Aas = 3) and corpus (Cas = 2) gives us the OLGA stage, as shown in the reference chart (bottom right-hand corner: OLGA-stage IV). H. pylori-status (as histologically assessed by special stain) has to be reported.

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inflammatory lesions. The VAS refer to non-atrophic (normal) mucosa and are given as a standard reference to enable comparisons to be drawn with the “pathological” VAS.

and GC, so endoscopic surveillance programmes should focus on stage III–IV-patients.

5.2. Stage I gastritis (Fig. 5)

6. Conclusions

Stage I gastritis is the lowest “atrophic” stage. In most cases (and especially in H. pylori-infected patients), atrophic lesions are only detected in some of the biopsy samples. H. pylori status (positive versus negative) must be reported explicitly and is an essential part of the OLGA format. H. pylori may be difficult (or even impossible) to identify histologically at either antral or corpus level (particularly in patients on proton pomp inhibitors [PPI]), in which case coexisting inflammatory lesions (polymorphs and lymphoid infiltrate) may suggest the bacterium’s presence even if it is not confirmed histologically. A comment on the suspected aetiology (“suspicious for H. pylori infection”) should be added in such cases (whatever their stage).

Recent experience suggests that gastritis staging may afford a reliable indication of the cancer risk of individual patients. If this is confirmed, we may be able to add to the pathologist’s diagnosis a brief but clinically relevant message to help the physician develop a clinical, serological or endoscopic management plan tailored to each patient’s disease.

5.3. Stage II gastritis (Fig. 6) This may result from a combination of different scores and locations of atrophic transformation. Atrophy can affect mucosecreting and/or oxyntic mucosa, but in most cases the atrophic lesions are detected in the biopsy samples obtained from the mucosecreting area. H. pylori status (positive versus negative) has to be reported (see above). From preliminary experience of OLGA staging, stage II is the most represented in the low GC risk epidemiological setting [31]. 5.4. Stage III gastritis (Figs. 7 and 8) Stage III gastritis results from at least moderate atrophy at mucosecreting or oxyntic level. Atrophy is most frequently identified in the incisura angularis sample and the most prevalent histological subtype of atrophic transformation is the metaplastic variant. Any presence of H. pylori needs to be reported (see above). When stage III is found in patients with no atrophy (score 0) in the biopsy samples of mucosecreting mucosa, the aetiological hypothesis of autoimmune (corpus restricted) atrophic gastritis should be considered. In most populations at low risk of GC, stage III is only rarely encountered and may coexist with NiN or even more advanced (invasive) neoplastic disease [32].

Practice points • The histological assessment of atrophic changes within gastric mucosa needs welldefined criteria. VAS may help in the consistent assessment of the different phenotypes of atrophic transformation. • VAS are illustrated to provide an operative support in the histological staging of gastritis (OLGA staging).

Research agenda • To validate the OLGA staging system for gastritis in different epidemiological contexts. • To correlate the different OLGA stages of gastritis with serological markers of gastric atrophy. • To validate preliminary information which associates the OLGA stages III and IV to a high risk of gastric epithelial malignancy.

Conflict of interest statement None declared.

5.5. Stage IV gastritis (Fig. 9) References This means atrophy involving both antral and oxyntic mucosa, a situation basically corresponding to the panatrophic gastritis phenotype. In patients with H. pylori infection, extensive metaplastic transformation can interfere with the histological detection of the bacterium. This stage is rarely seen in areas with a low incidence of GC. Preliminary data show a strong association between OLGA stages III–IV

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