Gastritis staging as a clinical priority

’Review article Gastritis staging as a clinical priority Claudia Mescolia, Aly Gallo Lopezc, Luis Taxa Rojasd, Walker Jove Oblitase, Matteo Fassana and Massimo Ruggea,b The elective background for gastric adenocarcinoma is the atrophic transformation of the gastric mucosa. The extent of mucosal atrophy basically parallels the risk of developing gastric cancer. This means that either noninvasive (serology) or invasive (endoscopy/histology) methods enabling the atrophic transformation to be quantified can be used theoretically to assess a given patient’s gastric cancer risk. This review aims to focus on the reliability of histology gastritis Operative Link for Gastritis Assessment -staging system for assessing the ‘personalized’ cancer risk in individuals with (atrophic) gastritis. Eur J Gastroenterol Hepatol 00:000–000 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Introduction Before the year is out, more than one million new cases of gastric cancer (GC) will have been diagnosed worldwide, and the patients’ overall 5-year survival rate will not exceed 30%, mainly because of the advanced stage of their disease [1–3]. GC, one of the most typical inflammation-associated epithelial malignancies, is usually the result of a multistep accumulation of genotypic and phenotypic changes triggered by a longstanding gastritis. Longstanding (not self-limiting) gastritis is epidemiologically, clinically, and biologically linked to Helicobacter pylori, which has been qualified as a class I carcinogen. The oncogenic role of other inflammatory gastric diseases is more elusive, although autoimmune gastritis has been considered a precancerous condition since the latter half of the last century. Assessment of gastritis-related cancer risk in individual patients is far from easy as it depends on the confounding shared responsibilities of several etiologic factors, both environmental and host related. Once we have excluded the (rare) cases of syndromic GC because of hereditary mechanisms [4], the elective background for gastric adenocarcinoma is the atrophic transformation of the gastric mucosa (the so-called ‘cancerization field’ for GC). The extent of mucosal atrophy basically parallels the risk of developing GC. This means that either noninvasive (serology) or invasive (endoscopy/histology) European Journal of Gastroenterology & Hepatology 2017, 00:000–000 Keywords: atrophic gastritis, gastric oncogenesis, intestinal metaplasia, Operative Link for Gastritis Assessment staging a Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padova, bVeneto Tumor Registry (RTV), Veneto Regional Authority, Padova, Italy, cProyecta Diagnostico Scientific Research Center-CONCYTEC Instituto de Investigación de la Facultad de Medicina Humana de la Universidad de San Martín de Porres, dDepartment of Pathology, Instituto Nacional de Enfermedades Neoplásicas INEN, Lima and eGastroenterology Division, Honorio Delgado Hospital, Arequipa, Peru Correspondence to Massimo Rugge, Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padova, Via A. Gabelli, 61, 35121 Padova, Italy Tel: + 39 049 821 8990; fax: + 39 049 827 2277; e-mail: [email protected] Received 26 August 2017 Accepted 5 September 2017 methods enabling the atrophic transformation to be quantified can be used theoretically to assess a given patient’s GC risk [5,6]. This review aims to focus on the reliability of histology for assessing the ‘personalized’ cancer risk in individuals with gastritis. The natural history of gastric mucosal atrophy In most cases, gastric mucosal atrophy is the outcome of longstanding inflammatory conditions. Among the etiologies of atrophy, H. pylori infection is the most prevalent worldwide. Because of the antral location of the earliest H. pylori-associated inflammatory lesions, the gastric antrum (including its cranial ‘atrophic’ border) is the gastric compartment that is exposed the soonest to the risk of atrophy [7]. In the natural history of H. pylori-related gastritis, the progressive distal-to-cranial spread of the inflammatory lesions may involve the oxyntic mucosa, eventually resulting in a patchily atrophic gastritis. This phenotype, originally described by Correa [8] as ‘multifocal atrophic gastritis’, is the elective substrate in which more severe (neoplastic) lesions may develop, first as intraepithelial neoplasia, and ultimately as invasive cancer (Fig. 1). Less commonly, gastric atrophy may result from a primary autoimmune disease, targeting the (oxyntic) parietal cells [9–11]. This ‘autoimmune atrophy-variant’ is also a non-selflimiting inflammatory disease, which may result in two basic glandular changes, that is, a numerical loss of glandular units and/or a ‘phenotypic remodulation’ of the oxyntic glands, which lose their native acid-secreting commitment and acquire the metaplastic morphology of pyloric glands (pseudopyloric metaplasia). Both these conditions are consistent with the current definition of mucosal atrophy (see below). A third route to mucosal atrophy involves the pathogenic combination of a H. pylori infection with a ‘secondary’, H. pylori-triggered autoimmunity. The assumption of this ‘secondary autoimmunity’ is based on the assumption of a molecular mimicry between H. pylori antigens and structural proteins of the gastric parietal cells. This hypothesis has been supported by evidence of longstanding H. pylori infection 0954-691X Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000001015 Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1 2 European Journal of Gastroenterology & Hepatology Month 2017 • Volume 00 • Number 00 triggering the emergence of gastric CD4 + T-cells that cross-react with epitopes shared by gastric H/K ATPase and H. pylori proteins [12]. It is not known whether this H. pylori-induced gastric autoimmunity is influenced by a given host’s immunological profile or by a peculiar biological trait of the H. pylori strain involved, or both. It is also unclear whether eradicating the H. pylori can also extinguish the subordinate autoimmune disease and/or its putative associated cancer risk. Including a score of 0 (i.e. no atrophy), a four-tiered scale has been proposed, where a score of 1 = global atrophy affecting 1–30% of the biopsy sample; 2 = global atrophy affecting 31–60% of the biopsy sample; and 3 = global atrophy affecting more than 60% of the biopsy sample. This global score of all the (frequently coexisting) histological variants of mucosal atrophy enables a consistent assessment of the level of atrophy in a biopsy set obtained from both the antral mucosa (including the incisura angularis) and the oxyntic mucosa (Fig. 3). Atrophy: definition and histological phenotypes Gastric atrophy is defined as ‘loss of appropriate glands’ [13]. This definition includes two phenotypes of atrophic transformation (Table 1): (i) the disappearance of glandular units, replaced by fibrotic lamina propria (i.e. a reduced glandular mass, but no change in the native glandular phenotype), or (ii) the replacement of the native glands by metaplastic glands featuring a new commitment (this is called ‘metaplastic atrophy’) involving intestinal metaplasia (IM) and/or pseudopyloric metaplasia (also known as spasmolytic polypeptideexpressing metaplasia). The spasmolytic polypeptide-expressing metaplasia variant (only affecting the oxyntic mucosa) can be (more) easily assessed by exploiting its positive immunostaining with TFF2 antibodies (Fig. 2) [14–19]. Unlike nonmetaplastic atrophy, the metaplastic variant does not necessarily feature a reduction in the number of glandular units. It is simply that the metaplastic replacement of the original glands ultimately results in a decreasing number of ‘native’ glandular structures being ‘appropriate’ for the compartment concerned. In each biopsy sample, atrophic transformation can be graded as a percentage of the atrophic transformation. Endoscopy and biopsy sampling for the histological assessment of gastric mucosal atrophy The biological rationale behind any endoscopy protocol for obtaining biopsies is based on the following wellestablished conviction: ‘the greater the extent of atrophy, the higher the risk of GC’. Generally, a gastrointestinal endoscopy procedure can never be considered ‘complete’ unless some biopsy samples are obtained (with the obvious exception of cases of bleeding). Different biopsy sampling protocols have been proposed, which rightly differ depending on the clinical setting and the main purpose of the endoscopy procedure (clinical practice vs. clinical research). Both the oxyntic and the antral mucosa should be explored histologically because of the potentially different diseases affecting the two compartments. Apart from the procedures requiring extensive mucosal mapping (to seek endoscopically silent focal lesions) and those performed for clinical research purposes, the biopsy sampling protocol suggested by the Sydney System should consistently satisfy most clinical diagnostic needs. Inflammation Inflammation ATROPHY H. pylori infection “Primary” Autoimmune Gastritis Fig. 1. Nonself-limiting gastritis: etiology and topography. The H. pylori infection initially results into nonatrophic antral inflammation, followed by mucosal atrophy. At the same time, corpus-inflammation also develops, which progresses to atrophy (multifocal atrophic gastritis, according to Correa). Primary autoimmune gastritis initially results in corpus-restricted (nonatrophic) inflammation, which ultimately progresses to corpus-restricted atrophic gastritis. Dark grey color = inflammation; medium grey = Atrophy. Table 1. Nosology, histology phenotypes, and score method for gastric mucosa atrophy Site/type of lesions Atrophy Absent Indefinite Present Histological type Antral mucosa including the incisura angularis Nonmetaplastic (decline in the number of native glands) High-grade inflammation Glands vanishing/shrinking Fibrosis/inflammation of the lamina propria Metaplastic (metaplasia of native glands) Intestinal metaplasia Oxyntic mucosa High-grade inflammation Glands vanishing/shrinking Fibrosis/inflammation of the lamina propria Pseudopyloric metaplasia (SPEM) Intestinal metaplasia Histology score Score 0 Not assessable Score 1 = 1–30% Score 2 = 31–60% Score 3 = > 60% SPEM, spasmolytic polypeptide-expressing metaplasia. Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. OLGA staging for gastritis Mescoli et al. www.eurojgh.com According to the Sydney System recommendations, two biopsy samples should be obtained from the antral mucosa, one from the so-called atrophic border (and specifically from the angularis incisura), and two from the oxyntic mucosa (the corpus/fundus area) [20]. The biopsy samples should be submitted to the Pathology Department in two separate vials: one containing the antral and angularis samples, and the other containing the oxyntic biopsies. The angularis incisura has been considered a ‘sentinel’ site where atrophic modifications are assessable soonest. Sampling the angularis mucosa is time-consuming, however, and many gastroenterologists would prefer to skip this sampling step. Additional samples should be obtained from any focal lesions, including ulcers (especially in the proximal stomach). Fig. 2. Tff2 immunostaining significantly increases the specificity in the histology detection of pseudopyloric metaplasia [SPEM; Tff2 polyclonal antibody; Proteintech (Chicago, Illinois, USA); working dilution 1 : 180]. Biopsy sample obtained from the oxyntic mucosa: pseudopylorized glands show intense cytoplasmic immunoreaction. 3 From a descriptive diagnostic approach to the stagingframe of histology reporting Our current understanding of the natural history of gastritis and the established criteria for the histological examination of atrophy together lay the foundations for a new framework for reporting gastritis histology. This new approach replaces the traditional, descriptive ‘Sydney model’ with a histological report in terms of the stage and the grade of gastritis [20]. Grading is used to determine the cumulative intensity of the inflammation, whereas staging provides information on the topographical extent of the atrophic-metaplastic changes identified and their extent is considered the main determinant of the gastritis-associated cancer risk. This grading and staging approach was proposed formally in March 2005 by an international group of gastric pathologists and other experts [the Operative Link for Gastritis Assessment (OLGA)] [21,22]. Briefly, the OLGA system includes two ‘compartmental’ scores for atrophy: one based on the antral/angularis biopsy samples and the other on the oxyntic samples (each scored as: 0/1/2/3). Combining the antral with the oxyntic scores results in an OLGA gastritis stage theoretically associated with different levels of GC risk (Table 2). Preliminary studies carried out in different epidemiological contexts consistently associated only stages III and IV with a risk of progression to GC. In other words, the OLGA stage indicates the individual likelihood of a patient developing a malignancy and can be adopted as a ‘personalized’ rationale for guiding the endoscopic follow-up of patients at a higher risk of cancer. The stage of the organic lesions correlates significantly with ‘functional’ gastric mucosa parameters and with serum pepsinogen levels, thus providing support for the clinical feasibility of reserving endoscopy and biopsy procedures for a limited subgroup of patients whose serological profile is consistent with gastric mucosal atrophy. Because IM scoring was judged more consistent than atrophy scoring, an alternative staging system (OLGIM) was subsequently proposed, which only considers the IM score [23]. More studies are needed to compare the two ATROPHY PREVALENCE AT EACH SINGLE BIOPSY SAMPLE LEVEL MEAN ATROPHY AT EACH COMPARTMENT LEVEL OLGA STAGE B1 A1 A2 A3 B1 B2 ANTRUM BODY CASE 1 20% 20% 25% 10% 0% 21%= score 1 5%= score 1 I CASE 2 35% 40% 50% 0% 10% 42%= score 1 5%= score 1 II CASE 3 50% 60% 90% 20% 50% 67%= score 3 5%= score 1 III B2 A3 A2 A1 VIAL 1: Samples A1-A2-A3 VIAL 2: Samples B1-B2 1 2 3 4 Fig. 3. Simulations of the gastritis staging process: (1) atrophy score (%) at each single biopsy sample level as obtained by the antral (a) mucosa: percentages; (2) atrophy score (%) at each single biopsy sample level as obtained by the body (b) mucosa: percentages; (3) mean of the atrophy score as obtained from the antral and body’s biopsy samples; and (4) by combining the score values as obtained from the antrum and the body, Table 1 allows to finalize the gastritis staging. Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 4 European Journal of Gastroenterology & Hepatology Month 2017 • Volume 00 • Number 00 Table 2. Operative Link for Gastritis Assessment staging frame Mean percentage of atrophy as assessed in two specimens obtained from the oxyntic mucosa Atrophy (any subtype) at the single biopsy level: Score 1 = 1–30% Score 2 = 31–60% Score 3 = > 60% Mean percentage of atrophy as assessed in three specimens obtained from the antral mucosa (including the incisura angularis) Score 0 Score 1 Score 2 Score 3 Score 0 0 I II II Score 1 Score 2 Score 3 I II III II II III II III IV III IV IV staging proposals, but both are consistent with the aim to identify unequivocally as to which gastritis patients should be placed under surveillance. ‘Gastric serology’ in gastric cancer secondary prevention strategies The invasiveness and cost of endoscopy and biopsy procedures limit their extensive use as part of GC secondary prevention strategies. Serological tests have therefore been proposed as a first-line (noninvasive) method for identifying the patients with atrophic gastritis who warrant endoscopic investigation. The serological assessment of gastric atrophy is based largely on two main proenzymes produced by the gastric mucosa, pepsinogen I (PgI) and pepsinogen II (PgII), and on their ratio (PgI/PgII). Although PgII is produced by the antral and corpus mucosa, PgI is produced almost exclusively by the oxyntic chief cells. This means that any atrophy-induced loss of oxyntic glands results in lower PgI levels and a lower PgI/PgII ratio [24]. In the setting of H. pylori-related gastritis, a normal PgI/ PgII ratio virtually rules out any presence of gastric mucosal atrophy (with a high negative predictive value), enabling a patient to be confidently excluded from any further invasive (endoscopic) diagnostic procedures. Patients with H. pylori infection and a low PgI/PgII ratio should be considered at a higher risk of GC and a secondlevel diagnostic procedure(endoscopy and histological examination) could be warranted. The cut-off for distinguishing patients ‘at risk’ on serology may differ depending on the population-related cancer risk. management of gastritis patients, simply reported: ‘The gastritis OLGA staging conveys useful information on the potential clinicopathological outcome (including cancer progression). The adoption of this system is therefore useful for patient management. According to OLGA staging and H. pylori status, patients with gastritis can be confidently stratified and managed according to their cancer risk’ [28]. In February 2014, the Kyoto Global Consensus Conference unanimously recognized that the risk of developing GC parallels the extent and location of atrophy and IM, as assessed by gastritis staging. To be precise, according to statement no. 4 (consensus level: 100%): ‘new staging systems for the characterization of gastritis have been introduced to assess the GC risk. They are used in clinical practice and are either based on the severity of atrophy in various gastric subsites (OLGA) or on IM (OLGIM)’ [29]. The same document (statement no. 14) qualifies the histological staging of gastritis as ‘useful for risk stratification (grade of recommendation: strong; evidence level: low; consensus level: 97.3%)’. The adoption of gastritis staging for orienting patient management was addressed more recently both in the ‘Guidelines for the management of H. pylori infection in Italy: the III Working Group Consensus Report 2015’ and in the subsequent ‘Maastricht V/Florence Consensus Report’. The Italian document includes OLGA staging among the criteria to consider when scheduling the follow-up of patients with atrophic gastritis (i.e. no follow-up for patients with stage 0–I–II gastritis; endoscopy/biopsy follow-up for those with stage III–IV gastritis) [30]. As for the ‘Maastricht V/Florence Consensus Report’, statement no. 14 reads: ‘the selection of patients for follow-up should be based on histological classification criteria (OLGA/OLGIM) [31]’. Gastritis staging in international guidelines In 2002, an expert consensus statement suggested that H. pylori eradication therapy can prevent GC [25]. A few years later, the Asia-Pacific consensus guidelines recommended an eradication strategy in countries with a high incidence of GC [26]. In 2012, an international consensus document on the ‘Management of precancerous conditions and lesions in the stomach (MAPS)’ stated that: ‘Systems for histopathological staging… may be useful for identifying subgroups of patients with different risks of progression to gastric cancer (recommendation grade C), namely those with extensive lesions (i.e., atrophy and/or intestinal metaplasia in both antrum and corpus)’. Gastritis staging was not mentioned, however, among the crucial variables for distinguishing atrophic gastritis by different levels of cancer risk [27]. In the same year, the ‘Maastricht IV/Florence Consensus Report’, addressing the use of gastritis staging in the routine Conclusion Less than 30% of GC patients survive more than 3 years after the disease has been diagnosed clinically. This unacceptable mortality rate is because of the neoplastic dissemination that has already occurred by the time the cancer becomes clinically apparent. More than 40 years ago, Pelayo Correa described the natural history of gastric epithelial malignancies, also providing the biological rationale for secondary prevention strategies. The subsequently emerging evidence of H. pylori being responsible for triggering the GC inflammatory–neoplastic cascade also made a new primary cancer prevention scenario theoretically possible. Leaving aside the imperative of cleansing the world of H. pylori infection (by improving lifestyles, and providing anti-H. pylori vaccination, and anti-H. pylori therapies), Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. OLGA staging for gastritis Mescoli et al. this review focused on the secondary prevention of GC. The strategy basically requires a task force comprising a trio of specialists (gastroenterologist, endoscopist, pathologist). The endoscopists and pathologists are responsible for assessing precancerous diseases, and play a fundamental role in improving the present state of affairs. Sophisticated digital endoscopy can now capture minute mucosal lesions that were invisible 15 years ago. Pathologists are now asked to deliver diagnostic messages (i.e. to stage cases of gastritis) that can be used consistently to rank a given patient’s cancer risk. Gastroenterologists are in charge of providing appropriate anti-H. pylori therapies (where necessary) and establishing patient-tailored follow-up protocols [32,33]. By combining these complementary competences optimally, GC will become (it already is!) a preventable disease. Acknowledgements This work was partly supported by grants from the Italian Association for Cancer Research (AIRC regional grant no. 6421 to MR). Conflicts of interest There are no conflicts of interest. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Siegel R, Ma J, Zou Z, Jemal A. 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