2025 ACG临床指南：胃癌前病变的诊断和管理

指南肿瘤内科· 消化道肿瘤 · 2025

INTRODUCTION

Gastric cancer (GC) is the leading infection-associated cancer and the fourth leading cause of cancer-related mortality globally, with more than 1 million new cases diagnosed and more than 768,000- related deaths in 2020 (1,2). There is marked variation in GC incidence globally, with the highest incidence rates reported in Eastern Asia, Eastern Europe, and Latin America (2). The overall United States is considered a low-incidence country with an age standardized incidence rate (ASIR) of 6.5 per 100,000 person

years with an estimated 26,890 new cases and 10,088-related deaths in 2023 (3). However, speci ﬁ c US populations, such as immigrants from high-GC incidence countries and certain nonWhite populations, have substantially higher GC incidence rates, with rates exceeding those for esophageal cancer and in some cases approaching those for colorectal cancer (4,5,230). Several studies and meta-analyses indicate that GC risk and mortality are maintained among immigrants from high-incidence to lowincidence countries (6), with incidence rates ranging from 2- to

13-fold higher in speci ﬁ c non-White populations compared with non-Hispanic White individuals (7,8). GC ranks among the top 8 leading causes of cancer death in US Hispanic and Asian American populations, compared with ranking 15th in the overall US population (9). Based on 2020 data from the Pew Research Center, more than 40 million people living in the United States were born in another country, with over $70\%$ immigrating from high-incidence GC countries (6). By 2065, it is estimated that Asian and Hispanic individuals, the immigrant groups with the highest GC risk, will comprise nearly $70\%$ of the US population.

Although GC represents a major cancer disparity in the United States, this cancer has long been underrecognized as a public health concern. There is a growing bodyof evidencedemonstrating that the burden of GC in high-risk populations is su ﬃ ciently high tojustifypreventionandearlydetectioninterventions.Thereis also evidence from US populations that Helicobacter pylori treatment is associated with reduced GC incidence (10,11). A combination of primary prevention strategies with the H. pylori “ screen and eradicate ” approach for reducing GC incidence, and secondary prevention strategies predominantly focused on early detection of GPMC/GC through endoscopic screening and surveillance of precancerous conditions, seems to be the optimal approach to reducing GC mortality as has been clearly demonstrated in Asian countries. However, the potential impact of implementation of precision strategies on GC incidence and mortality in US populations is unknown given the lack of national data.

Gastric adenocarcinoma, in most cases, is preceded by a typically asymptomatic precancerous cascade of discrete histopathological stages and is therefore amenable to surveillance — analogous to the practice of endoscopic and colonoscopic surveillance of esophageal and colorectal precancerous conditions, respectively. These histopathologic stages, referred to as the “ Correa cascade, ” progress from normal mucosa and chronic gastritis to atrophic gastritis (AG), multifocal AG (MAG), gastric intestinal metaplasia (GIM), low-grade or high-grade dysplasia (LGD/HGD), and ﬁ - nally, adenocarcinoma. H. pylori is the dominant risk factor for noncardia gastric adenocarcinoma, the most common form of GC, with an attributable risk of $75\%{-}89\%$ (12). AG, GIM, and dysplasia constitute gastric premalignant conditions (GPMC). Early gastric cancer (EGC) is de ﬁ ned as adenocarcinoma that has not invaded pastthe submucosal layer,irrespectiveoflymph nodeinvolvement, and resection is typically curative $\scriptstyle\left.<=95\%$ 5-year overall survival) (13). This multifactorial process is driven by H. pylori virulence factors, thecumulative duration of H. pylori infection,hostgenetics and responses to H. pylori infection, and dietary and environmental factors, such as tobacco exposure. Although the multifactorial stages of the Correa cascade best align with intestinal GC, the principles herein apply to di ﬀ use GC, albeit with an alternate balance of host genetic, microbial, and environmental factors. Highrisk populations for GPMC parallel high-risk populations for GC. The risk factors for prevalent GPMC, GPMC progression to GC, and GC overlap and yet have di ﬀ erences, which are areas of active investigation.

The focus of this clinical guideline is the diagnosis and management of GPMC, with noncardia gastric adenocarcinoma being the primary outcome of interest unless otherwise stated. The diagnosis of GPMC in the US necessitates upper endoscopy, and thus, guidance regarding which asymptomatic individuals warrant upper endoscopy for GPMC and GC diagnosis and risk strati ﬁ cation is relevant. In this ﬁ rst iteration of the American College of Gastroenterology (ACG) clinical guideline on GPMC,

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we ﬁ rst discuss methodology, followed by a review of GC screening, diagnosis of GPMC, endoscopic and nonendoscopic management of GPMC, and then conclude with 2 special topic sections on the diagnosis and management of autoimmune gastritis (AIG) and gastric epithelial polyps (GEP) because respective subsets of these patients have an increased risk of GC. Extensive high-quality data from US populations regarding GPMC management are lacking but continue to accumulate; the quality of evidence for the recommendations presented herein should be interpreted with this dynamic context in mind.

METHODS

This document presents o ﬃ cial recommendations from the ACG on the diagnosis, management, and surveillance of GPMC in adults. These guidelines are established to support clinical practice and suggest preferable approaches to a typical patient with a particular medical problem based on the currently available published literature. When exercising clinical judgment, particularly when treatments pose signi ﬁ cant risks, healthcare providers should incorporate this guideline in addition to patient-speci ﬁ c medical comorbidities, health status, and preferences to arrive at apatient-centeredcareapproach thatmaximizesbene ﬁ t to patients and minimizes harm.

The guideline is structured in the format of statements that were considered to be clinically important by the content authors and were approved by the Governing Board. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process was used to assess the quality of evidence for each statement (Table 1)(14). The quality of evidence is expressed as high (we are con ﬁ dent in the e ﬀ ect estimate to support a particular recommendation), moderate, low, or very low (we have very little con ﬁ dence in the e ﬀ ect estimate to support a particular recommendation) based on the risk of bias of the studies, evidence of publication bias, heterogeneity among studies, directness of the evidence, and precision of the estimate of e ﬀ ect (15). A strength of recommendation is given as either strong (recommendations) or conditional (suggestions) based on the quality of evidence, risks vs bene ﬁ ts, feasibility, and costs taking into account perceived patient-based and population-based factors (16). Furthermore, a narrative evidence summary for each section provides important de ﬁ nitions and further details for the data supporting the statements.

The ACG Practice Parameters Committee and ACG leadership identi ﬁ ed and approved a group of experts in the area of GC and GPMC for the writing group. The writing group formulated PICO questions to guidethe subsequent literature search,development of recommendation statements and key concepts, GRADE assessments, and the preparation of the full-guideline document. The PICO questions and subsequent recommendations were reviewed and approved by 2 GRADE methodologists. The authors, in consultation with a certi ﬁ ed medical librarian, conducted an electronic search using MEDLINE, EMBASE, and the Cochrane Library through October 2023, with literature update through August 2024. The search was limited to English language and fully published articles. For each PICO question developed, the authors reviewed the existing literature, with a focus on studies of the highest quality of evidence (e.g., when available, systematic reviews and meta-analyses, followed by randomized controlled trials [RCTs], and followed by observational studies). In addition to the GRADE recommendations, the content authors generated key concept statements, which are not amenable to GRADE

Strength of recommendation

Criteria

Factors influencing the strength of the recommendation include the quality of the evidence, clinical-reported and patient

Strong

reported outcomes, risk of harm, and costs

Strong recommendations are offered when the desirable effects of an intervention clearly outweigh the undesirable effects

Implications from a patient and clinician

perspective:

• Patients: Most people in this situation would want the recommended course of action, and only a small proportion would not • Clinicians: Most patients should receive the

Conditional

recommended course of action

Conditional recommendations are offered when trade-offs are less certain — either because of low-quality evidence or because evidence suggests that desirable and undesirable effects are closely balanced

Implications from a patient and clinician

perspective:

• Patients: Some individuals would want the suggested course of action, whereas others may not. Appropriate discussion regarding pros/cons/alternatives is appropriate to come to a patient-specific decision • Clinicians: A shared decision-making model through a discussion regarding the evidence and alternatives is appropriate, taking into consideration patients ’ values and

preferences

Table 1. Grading of Recommendations, Assessment, Development, and Evaluation: strength of recommendations, quality of evidence, and implications for the patients and clinicians (14 – 16)

|Qualityofevidence|Criteria| |---|---| |High| We are very confident that the true effect lies close to that of the estimate of the effect | |Moderate|We are moderately confident in the effect| |Moderate| estimate: The true effect is likely to be close to the estimate of the effect, but there is | |Moderate| a possibility that it is substantially different| |Moderate|LOW| ||The true effect may be substantially different| ||from the estimate of the effect| |Verylow| We have very little confidence in the effect estimate: The true effect is likely to be | |Verylow| estimate: The true effect is likely to be substantially different from the estimate of | |Verylow||

details hereditary GC risk factors. The following topics are beyond the scope of this guideline: management of hereditary GC syndromes, GIM of the cardia, nonadenocarcinoma GC, gastric mucosa-associated lymphoid tissue lymphoma, therapeutic management of GC including endoscopic resection, and postdiagnostic management of GC other than H. pylori eradication.

This is the ﬁ rst iteration of this ACG guideline, and it is expected that the quality of evidence informing the respective recommendations will signi ﬁ cantly increase. We anticipate and hope that robust data from the US will continue to accumulate and inform future iterations of this topic guideline, especially data related to opportunistic screening, risk strati ﬁ cation, and outcomes of endoscopic surveillance.

SCREENING OF GC AND GPMC

Recommendations: GC screening

1. We suggest against routine screening with upper endoscopy for GC and GPMC in the general population in the United States (Very low quality of evidence, conditional recommendation).

2. We cannot make a recommendation on opportunistic screening for GC and GPMC with upper endoscopy in individuals considered high-risk for GC based on immigration status, race and ethnicity, and certain environmental factors due to insufficient direct evidence from US populations (Insufficient evidence, no recommendation).

Risks factors for GC in US populations

The United States is considered a low-intermediate GC incidence country overall, with an ASIR of 6.5 per 100,000 person-years. However, in certain US populations, the incidence rates of GC are 2 – 13 times higher vs White individuals (230). Multiple factors are associated with an increased risk of GC, including precancerous gastric mucosal changes (e.g., MAG, GIM, and dysplasia), nonWhite race or Hispanic ethnicity, early-generation immigrant from a high-GC incidence region, family history of GC, speci ﬁ c inherited cancer syndromes, persistent H. pylori infection, tobacco smoking, and possibly AIG (6,8,17,18). Other than H. pylori infection, the attributable risk of these factors for GC alone and in combination, as well as the interaction with other environmental factors such as smoking and diet, is not known.

assessment. We prioritized evidence from US populations, and where US data were limited or lacking, we relied on high-quality datafromnon-USpopulations,whichis acknowledged in the main text where relevant. Tables 2 and 3 summarize the recommendations and key concept statements, respectively. Table 4

Race, ethnicity, and immigration history

GC varies substantially by race and ethnicity. GC ranks among the top 8 leading causes of cancer death in US Hispanic and Asian American populations, compared with ranking 15th in the overall US population (9). Compared with non-Hispanic White individuals, East Asian and Paci ﬁ c Islander, Black, Hispanic, and American Indian and Alaska Native (AIAN) individuals have signi ﬁ cantly higher incidence of noncardia gastric adenocarcinoma (NCGA) (7,9). A population-based study using California Cancer Registry data reported that age-standardized and sexstandardized incidence of NCGA among individuals of 50 years or older (i.e., a screening-age population) was 1.8- to 13.3-fold higher in the most populous non-White groups compared with non-Hispanic White individuals (5). In fact, the incidence rates of NCGA in certain groups, such as Japanese Americans (33.6 [27.0 – 41.4] per 100,000 person-years) and Korean Americans (70.0 [60.5 – 80.5] per 100,000 person-years) were similar or considerably higher than the incidence rates of colorectal cancer among the general US population (230).

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Table 2. Recommendations for the management of GPMC

GC screening

1. We suggest against routine screening with upper endoscopy for GC and GPMC in the general population in the United States (Very low quality of evidence, conditional recommendation)

2. Wecannot make arecommendationonopportunisticscreeningforGCandGPMCwithupperendoscopyinindividualsconsideredhigh-riskforGCbasedonimmigration status, race, and ethnicity, and certain environmental factors due to insufficient direct evidence from US populations (Insufficient evidence, no recommendation)

GPMC noninvasive diagnosis

3. Wesuggest against the use of noninvasive biomarkers for the purpose of GPMC or GC screening or surveillance in the United States (Very low quality of evidence, conditional recommendation)

GPMC endoscopic diagnosis

4. In patients undergoing upper endoscopy, we recommend a high-quality endoscopic evaluation of the stomach to identify GPMC (or GC). This includes achieving adequate mucosal visualization with cleansing and insufflation, visual station mapping, photodocumentation of anatomic landmarks and any abnormalities, and adequate gastric evaluation time (Low quality of evidence, strong recommendation)

5. In patients undergoing upper endoscopy for evaluation of GPMC, we suggest the use of HDWLE and IEE for gastric examination (Low quality of evidence, conditional recommendation)

GPMC histologic diagnosis

7. In individuals with GIM, we suggest that thehistological subtype of GIM (incomplete, complete, and mixed) be reported for the purpose of GPMC risk stratification and informing surveillance (Low quality of evidence, conditional recommendation)

8. In individuals with GIM, we suggest that the anatomic extent and severity of GIM be reported for the purpose of risk stratification and informing GPMC surveillance. Anatomically limited GIM is confined to the antrum and incisura, whereas anatomically extensive GIM also involves the corpus. The severity refers to the proportion of atrophy or GIM in individual biopsies from each compartment (antrum, incisura, and corpus) (Very low quality of evidence, conditional recommendation)

GPMC surveillance

9. In individuals with GIM who are considered high risk for GC, we suggest endoscopic surveillance at 3-year intervals. High-risk groups include individuals with

(i) High-risk GIM histology:

• Incomplete GIM histological subtype vs complete subtype • Corpus-extension, defined as corpus involvement also with antrum or incisura involvement

(ii) Any GIM histology with one of the following risk factors for GC:

• Family history of GC in a first-degree relative • Foreign-born, with emigration from a high-incidence nation • High-risk race or ethnicity, including East Asian, Latino/a, Black, and AIAN individuals

(Very low quality of evidence, conditional recommendation)

10. In individuals with severe GIM or AG in biopsies of the antrum or corpus, we suggest endoscopic surveillance at 3-year intervals (Very low quality of evidence, conditional recommendation)

11. In individuals with low-risk GIM or atrophy, we suggest against endoscopic surveillance. Low-risk groups include (i) Complete type GIM, without evidence of incomplete GIM (ii) Complete GIM of focal anatomic extent that is confined to the antrum (iii) None of the “ high-risk ” clinical criteria listed in Recommendation 9 above (iv) AG which is mild in severity (Very low quality of evidence, conditional recommendation)

Endoscopic management of dysplastic GPMC

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|Table 2. (continued)| |---| | 15. In patients with confirmed complete resection of dysplasia, we suggest endoscopic surveillance. We recommend surveillance examinations be performed by an experienced endoscopist and using HDWLE and IEE, with biopsies according to the systematic biopsy protocol in addition to targeted biopsies (Low quality of evidence, strong recommendation) | |GPMC nonendoscopic management| | 16. We recommend testing for Helicobacter pylori (and eradication treatment if positive) in patients with GPMC and resected early GC to reduce the risk of progression to GC and metachronous early GC, respectively (Moderate quality of evidence, strong recommendation) | | 17. We do not suggest the use of aspirin, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, or antioxidants for individuals with GPMC for the purpose of GC chemoprevention (Very low quality of evidence, conditional recommendation) | |Autoimmunegastritis| | 18. Among individuals diagnosed with AIG, we recommend assessment for H. pylorinfection with a nonserological test, eradication treatment if positive, and posttreatment testing to confirm eradication (Low quality of evidence, strong recommendation) | | 19. There is insufficient evidence to make a formal recommendation on endoscopic surveillance in individuals with AlG. Given the increased risk of type 1 neuroendocrine tumors and the possible increased risk of GC, individualized surveillance may be considered (Low quality of evidence, conditional recommendation) | |Gastric epithelial polyps| | 20. We recommend endoscopic resection of all gastric adenomas,regardless of size, to exclude and prevent dysplasia and early GC. Foradenomas that are not amenable to endoscopic resection, we recommend referral for surgical resection, if clinically appropriate (Low quality of evidence, conditional recommendation) | | 21. We could not make a recommendation on the endoscopic resection of all hyperplastic polyps greater than 10 mm in size based on the current evidence (Insufficient evidence, no recommendation) | | 22. In individuals with GEP, with the exception offundic gland polyps, we recommend systematic gastric biopsies(e.g., updated Sydney protocol) be obtained from the surrounding flat mucosa given the high prevalence of GPMC, H. pylori infection, and AlG in these patients (Very low quality of evidence, conditional recommendation) | | AIAN, American Indian and Alaska Native; AIG, autoimmune gastritis; GC, gastric cancer; GEP, gastric epithelial polyps; GIM, gastric intestinal metaplasia; GPMC, gastric premalignant condition; HDWLE, high-definition white lightendoscopy; HGD, high-grade dysplasia; IEE, image-enhanced endoscopy;IND, low-grade dysplasia; LGD, low- grade dysplasia. |

Immigrant populations contribute in part to the race and ethnicity disparity of GC incidence in the United States. GC incidence varies widely across di ﬀ erent nations and geographic regions, with the highest incidence regions being East Asia, Eastern Europe, and Central and Andean South America (2). A systematic review and meta-analysis reported signi ﬁ cantly higher incidence and mortality of GC among ﬁ rst-generation immigrants from high-incidence to low-incidence geographic areas, with the pooled relative risk (RR) for all types of GC (measured as standardized incidence ratio) 1.66 ( $\mathbf{\zeta}_{95\%}$ con ﬁ dence interval [CI] 1.52 – 1.80) for men and 1.83 ( $95\%$ CI 1.69 – 1.98) for women, and for NCGA speci ﬁ cally, 1.80 (1.65 – 1.95) for men and 1.62 (1.47 – 1.76) for women (6) (see Supplement 1, Supplementary Digital Content 1, http://links.lww. com/AJG/D556 for additional discussion).

Family history

Individuals with a family history of GC have 2- to 10-fold higher risk of GC compared with individuals without a family history, based on observational studies (19). Multiple factors may contribute to the familial aggregation of GC, such as shared genetic predisposition, shared H. pylori infection and strains, shared environmental factors (lifestyle, diet, and cultural factors), and combinations thereof (19). Overall, approximately $10\%$ of patients with GC have a positive family history, while only about $1\%–3\%$ are related to inherited cancer syndromes; although, the proportion may be greater with the recent identi ﬁ cation of the importance of pathogenic germline variants such as the hereditary homologous recombination de ﬁ ciency (e.g., breast

cancer gene [BRCA]) (20,21). Based on one study, patients with GIM and a ﬁ rst-degree family history of GC had 4.5-fold higher odds (odds ratio [OR] 4.53, $95\%$ CI 1.33 – 15.46) of GC compared to patients with GIM but without a family history of GC (22). In a recent prospective single-center pilot screening study from California, among individuals with a family history of GC in a ﬁ rst-degree relative $\mathbf{\dot{n}}=61\mathbf{\Omega}$ ; mean age 59 years old), 27 (44%) had GIM and 4 $(7\%)$ had dysplasia on screening endoscopy (23). Although it is challenging to parse out shared genetic vs shared nongenetic contributors, the increased risk of GPMC and GC among individuals with a ﬁ rst-degree family history of GC provides rationale for considering this population for endoscopic screening on an individual basis.

Inherited cancer syndromes with increased risk of GC

Individuals who carry pathogenic variants of GC susceptibility genes are at a substantially higher lifetime risk of GC. There are 2 groups of hereditary cancer syndromes with increased GC risk: (i) Hereditary GC syndromes: hereditary di ﬀ use GC, familial intestinal GC, and gastric adenocarcinoma with proximal polyposis of the stomach and (ii) Hereditary syndromes with an increased GC risk: Lynch syndrome, hereditary gastrointestinal (GI) polyposis syndromes (familial adenomatous polyposis [FAP], PeutzJeghers syndrome, juvenile polyposis, and MUTYH -associated polyposis), hereditary breast and ovarian cancer syndrome, and Li-Fraumeni syndrome, and hereditary homologous recombination de ﬁ ciency ( BRCA1, BRCA2, PALB2 , and ATM ) particularly in the setting of H. pylori infection (Table 4). Patients

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Table 3. Key concepts for the management of GPMC

|Table 3.Key concepts for the management of GPMc| |---| |GC epidemiology and screening| | ·The epidemiologic and biologic rsk factors overlap, and yet are distinct, for the 3outcomes of GPMC prevalence, GC incidence, and GPMCto GC progression. Mechanistic studis | ·There are no randomized clinical trals from the United States norother populations evaluating the efficacy of GC screening. The large observational studies from East Asia and meta- | · Endoscopic screening should be considered in persons with a family history of GC (first-degree relative) on an individualized basis. Endoscopy would startat age 45-60 or 10 years | ·Firstgeerationmmigrant populationscontribute totheraceandethnicitydisparityofGCincidence intheU.ndoscoic screeningshouldbeonsiderednanindividualiedbasis, withshared | GPMC endoscopic and histologic diagnosis| | ·A high-quality endoscopy examination of the gastric compartment has 5 main components:(i use of HDWLE;(i adequate gastric distension using insuffation (CO2 preferably, or | ·HDWLEand IEE eg, narowband maging, blue lasemaging, etc)are aropriate forinividual withat increased GC risk, thosewth susected GPMCorGCdurin endso, | ·Thecoordinationbetweenthegastroenterologistand pathologistfor pathology reporing iscriticalfordelineationofthe patientGPMCsurveilance plan.Thiscoordinationisneededat | ·The diagnostic challenges for GPMC and dysplasia include sampling error during biopsies (e.g., AG and GIM patchy multifocality), the interobserver variabilityamong pathologists, |GPMC endoscopic surveillance| | ·Delineation of GPMC surveillance intervals requiresfurtherstudy in the US. Patients with multiple risk factors forGC may be considered forshorterthan 3-yr intervals. Forexample, an | · We suggest against performing routine repeat endoscopy within 12 months in individuals with nondysplastic GPMC for the purpose of risk stratification unless there are concerns | ·Weacknowdge that somestudissuggest that White race,ethnicity, and countryoforiginre important riskfactorsforprevalentGPMCandGC; yet, thesefactorsarenot proven | ·In patients with INDor GD without visible lesions, the rates of progressonare modest yet measurable. he surveillance interals are proposed but have nt been evaluated in | ·Patients with HGDwithoutvisiblemucosalabnormalitieshaveahigh probabityofeitheralreadyhavinga prevalentGCorprogressingtoGCwithinashortimeframe.Arepeatendoscopic | ·In patients with endoscopically resected dysplastic lesions, the optimal postresection surveillance interval has not been investigated in prospective studies. Shorer intervals maybe |Autoimmune gastritis| | ·AGisniedgastricplatiiaei,e arhrtssiatdwicreerif differentiated neuroendocrine tumors of enterochromafi-like cells(also termed type I gastricarcinoid | ·The overlap of H. pylriassociated GPMC and AIG is common, and thus, the same risk stratification parametersapply, as does testing foractive H. pylorinfection and eradication | Gastric epithelial polyps| | ·The malignant potentialof GEP is based on histology, polyp size, and the presence of specific polyposis syndromes. All patients withhyperplastic oradenomatous GEP should have | ·There is insuffcient evidence to recommend endoscopic resection of hyperplastic polyps >10 mm at the index endoscopy. An individualied approach is warranted, with | AG, atrophic gastritis; AIG, autoimmune gastritis; GC, gastric cancer; GEP, gastric epithelial polyps; GIM, gastric intestinal metaplasia; GPMC, gastric premalignant and novel biomarkers are needed to improve our understanding and surveillance paradigms for GPMC to GC progression | analyses of these studies demonstrate that endoscopyforGC screening is associated with asubstantialreduction in GC mortality, and a 5-yrsurvivalof nearly 70%This is primarly driven by the increased detection of early-stage GC (eligible for endoscopic resection), rather than a decrease in incident GC. | before the diagnosis of GC in the youngest affected family member. These individuals should be screened for H. pyloriand eradicated if positive. | decisionainnthgest-risdiviulsCincidencearwidcrsnatisandggrahc rn,wththhighst nidencerensnEast AsiaEastrein western Russia), and Central/South America. The South America high-incidence area encompasses the Andean region from Colombia to Chile. Immigrant generation and level of acculturation affect risk. These individuals should be screened for H. pylori and eradicated if positive. | air) to flaten the gastric folds and expose the gastric mucosa adequately; (i) mucosal cleansing to clearalldebris, mucous and bubbles; (iv) standard photodocumentation; and (v) adequate gastric inspection time.Gastric examination time and photodocumentationare surrogate quality metricsforthe gastric evaluation. The 2-3 min upperendoscopy, especialy for patients with GPMC, flls short of the standard of care. | and those undergoing GPMC suveilance. Near focus and optical zoom are helpful but not mandatory for GPMC detection. | the locallevel (“localadvocates"), as wellas the national society evel Pathology reort details should include information specific to stomach lcation(eg, antrum, incisura and corpus), AG and GIM severity(biopsy-specific), AG and GIM extent (e.g., antrum and corpus), the subtype ofGIM (e.g., complete, incomplete, mixed), severityof dysplasia(IND, LGD, HGD), and presence/absence of H. pylori organisms, at a minimum. | particularly for IND and LGD, and the variable training among gastroenterologists for the detection of GPMC and early GC. | individual with extensive GIM and with a family history of GC may be considered for a 1-2-yr surveillance interval. Patient-physician decision-making for GPMC surveillance is appropriate in these cases | regarding the quality of the endoscopy oradherence to the Sydney biopsy protocol | be independent predictors of progression, although US and global studies are limited in this domain. However, endoscopic surveillance of individuals with GPMC who identify as a high-risk race or ethnicity or who emigrated from a high-incidence region, should be recommended for 3-yr endoscopic surveilance given the substantial increased risk of GC in these groups | prospective studies. We suggest a repeat endoscopic exam in 12 months if advanced neoplasia was confidently ruled out. Referralto an endoscopist with expertise in diagnosing and ideally resecting gastric neoplasia is reasonable. | exam within 3 months with an endoscopist with expertise in diagnosing and ideally endoscopically resecting gastric neoplasia is suggested. | warranted in patients with additional risk factors for synchronous or metachronous GC | tumor and possibly gastric adenocarcinoma. | treatment if positive. Individuals with AIG are also established to be at risk for type I carcinoids. In patients with AIG, surveillance with HD-WLE and IEE should be considered. The interval is determined based on GPMC risk stratification parameters (e.g., family history of GC), which should be individualied | standard Sydney protocol biopsies and testing for active H. pylorinfection, given the increased prevalence of GPMC in this setting | consideration of resection or biopsies, and 12 month surveilance, as clinically appropriate. | condition; HDWLE, high-definition white light endoscopy; HGD, high-grade dysplasia; IEE, image-enhanced endoscopy; IND, low-grade dysplasia; LGD,low-grade dysplasia. |

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|Table 4. Hereditary and genetic gastric cancer syndromes|CD| |---|---| |Familial gastric cancer syndromes|CD| |· Hereditary diffuse gastric cancer|CD| |· CDH1 germline mutations (E-Cadherin)|CD| |· Familial intestinal gastric cancer|CD| |· Gastric cancer and proximal polyposis of the stomach|CD| |Hereditary syndromes with increased gastric cancer risk|CD| |· Gastrointestinal polyposis syndromes with increased gastric cancer risk|CD| |· Familial adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis, MUTYH-associated polyposis|CD| |· Cancer syndromes with increased gastric cancer risk|CD| |· Lynch syndrome, hereditary breast and ovarian cancer syndrome, and Li-Fraumeni syndrome|CD| |· Hereditary homologous recombination deficiency (e.g. BRCA1, BRCA2)|CD| | Common germline gene variant syndromes are important regarding the biology; however, to date, they are not clinically actionable. Common gene variants with gastric cancer risk are often identified in genome-wide association studies, which are limited in number (e.g., Asia, Europe, and Latin America). In addition, there are gene variants which influence the H. pylori-environmental interactions, and specifically the inflammatory response (e.g., proinflammatory cytokine genotypes). |CD|

with a family history suggestive of hereditary cancer should be referred to Genetic Counseling, and potential endoscopic screening should be individualized based on the syndromespeci ﬁ c guidelines and patient preferences (24 – 27).

Screening for GPMC and GC in high-risk US populations: US evidence, a work in progress

Routine screening with upper endoscopy for GC and GPMC in the low-risk general US population is not indicated given the overall low-to-moderate incidence, the lack of cost-e ﬀ ectiveness, and the absence of evidence. Although focused screening of highrisk populations in the United States may address the GC cancer disparity, there is a lack of evidence in the United States to make a recommendation. In addition to the epidemiologic data identifying high-risk US populations, the current evidence base in the US for screening is mostly limited to cost-e ﬀ ectiveness studies and indirect evidence from regions with screening programs, primarily in East Asia.

The epidemiological evidence suggests that high-risk groups who may bene ﬁ t from screening include those with a family history of GC, speci ﬁ c hereditary syndromes, foreign-born immigrants from high-incidence regions, and US populations with a high incidence of GC, including East Asian individuals, Latino/a groups, Black individuals, and AIAN individuals. Cancer screening and surveillance speci ﬁ cto high-risk race and ethnic populations is proposed to be both ethical and e ﬃ cacious, particularly with respect to GC (28), at least until accurate biological biomarkers are available. The age of 45 – 60 would be reasonable given that the prevalence of GPMC is signi ﬁ cant by age 45 in high-risk populations, and also since this aligns with the colorectal screening recommendations. Persons with multiple risk factors may also be appropriate to consider, for example, male sex, smoker, and with H. pylori infection (29). Examples of nascent screening studies in high risk groups include combined H. pylori- fecal immunochemical testing and opportunistic endoscopy with screening colonoscopy.

There is consistent evidence in the form of large observational epidemiological studies identifying populations in the United States who are at increased risk for GPMC and GC, and among whom the rates of GC mirror rates in populations were GC

screening studies have been conducted (5,30,31). However, there are no large US-based observational studies or RCTs directly evaluating the impact of screening for GC vs no screening in these populations. There are also no relevant studies of GC screening vs no screening from other global regions with heterogeneous populations as in the United States, although notably, some Western countries do advocate for opportunistic endoscopic screening (29,32 – 34,231). The most robust, albeit indirect, evidence comes from studies conducted in East Asia, where GC screening has been consistently associated with substnatially reduced GC-related mortality and increased 5-year survival (see below).

Only 1 clinical trial from the United States has evaluated the impact of GC screening in a high-risk population, and this was a small prospective pilot screening program conducted between 2017 and 2020 within the Kaiser integrated health system (23). Of 61 individuals with a ﬁ rst-degree family history of GC, $44\%$ had GIM and $7\%$ hadLGD,consistentwiththeclassi ﬁ cationasanat-riskgroup.

The majority of evidence demonstrating the impact of endoscopic GC screening on early GC detection is from Asia. Multiple observational studies from East Asia have unequivocally demonstrated mortality bene ﬁ ts associated with endoscopic GC screening (35 – 40). In the study analyzing data from the Korean National Cancer Screening Program, which included more than 39 million adults of older than 40 years who underwent screening endoscopy between 2007 and 2016, the sensitivity of endoscopy for GC ranged from $66\%$ to $69\%$ (vs $17\%{-24\%}$ for radiographic screening) and with speci ﬁ city consistently exceeding $99\%$ (41). The mortality data from this South Korea program revealed that organized GC screening among individuals aged ${\geq}40$ years was associated with $47\%$ (OR 0.53, $95\%$ CI 0.51 – 0.56) lower GC mortality compared with no screening (35).

In the meta-analysis by Zhang et al (42), which included 342,013 individuals from Asian countries, endoscopic screening was associated with an overall $40\%$ RR reduction in GC mortality (RR 0.60, 95% CI 0.49 – 0.73); however, endoscopic screening was not associated with lower GC incidence, indicating that early detection of gastric neoplasia is the primary driver of the observed mortality and survival bene ﬁ ts. As further support, data from the Korean National Cancer Screening Program demonstrated that screening endoscopy was associated with 2-fold higher odds (OR

2.10, $95\%$ CI 1.90 – 2.33) of diagnosing localized GC compared with individuals who were never screened (43). With implementation of GC screening in Japan and South Korea, now at least $50\%$ of GC are early-stage and only $12\%–16\%$ are metastatic at the time of diagnosis, which is in stark contrast to ${<}30\%$ being diagnosed as early-stage before implementation of screening in these countries (4). This has translated to current 5-year overall survival rates for GC in South Korea and Japan ${>}60\%{-}70\%$ , whereas the 5-year overall survival was about $30\%$ before implementation of these programs (44 – 46). In the United States, nearly $40\%$ of GC are metastatic at the time of diagnosis, and only $15\%$ diagnosed in the curative early-stage GC (47). The current 5- year GC survival rate in the United States is $36\%$ , comparable with the prescreening implementation rates in South Korea and Japan.

These non-US data provide evidence thatsystematic screening among individuals from high-risk populations is associated with markedly improved GC mortality and survival, related to higher proportion of cancer diagnosed in an early, curative stage. However, the data regarding endoscopic screening for GPMC and GC in US populations are essentially nonexistent, which precludes a speci ﬁ c recommendation for GC screening in US high-risk populations.

Cost-effectiveness of risk-based screening for GPMC and GC in the United States

Cost-e ﬀ ectiveness studies provide additional indirect evidence for endoscopic screening among at-risk populations in the United States. This complements a large body of evidence demonstrating the cost-e ﬀ ectiveness of endoscopic GC screening in East Asian countries and Portugal (48 – 52). Saumoy et al. assessed the cost-e ﬀ ectiveness of screening for GC using upper endoscopy bundled with screening colonoscopy, in the US screening-age population, strati ﬁ ed by race and ethnicity (53). The study found that endoscopy starting at age 45 – 50 years with continued surveillance when GIM or more advanced pathology is diagnosed was cost-e ﬀ ective for East Asian (\$71,451/quality adjusted life years [QALYs]), Hispanic (\$76,070/QALY), and non-Hispanic Black (\$80,278/QALY) individuals, but not for non-Hispanic White individuals (\$122,428/QALY). By contrast, biennial esophagogastroduodenoscopy for screening irrespective of histologic ﬁ ndings was not cost-e ﬀ ective. Using the same screening strategies (vs no screening), Shah et al demonstrated the coste ﬀ ectiveness of endoscopic GC screening among the most populous East Asian American populations in the United States disaggregated by country of birth (54). One-time endoscopy at the time of screening colonoscopy, with continued surveillance if GIM or more advanced pathology was diagnosed, demonstrated the lowest incremental cost-e ﬀ ectiveness ratios among Chinese, Japanese, and Korean Americans (all , \$75,000/QALY). The above studies examined bundled endoscopy with screening colonoscopy; thus, the ﬁ ndings cannot necessarily be extrapolated to those who undergo noninvasive colorectal cancer screening or those who opt out of colorectal cancer screening.

In summary, direct, high-quality US-based data in the form of randomized trials or large observational studies evaluating the impact of screening on patient-important outcomes in US populations are nonexistent. We acknowledge the extensive evidence from speci ﬁ c Asian countries demonstrating the bene ﬁ ts of endoscopic screening in increasing the detection of early-stage GC and reducing GC-related mortality in populations with high GC burden. The panel cannot at this time make a recommendation

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on screening for GPMC and GC with upper endoscopy in high-risk US populations given the lack of robust US evidence, the invasiveness and risks of upper endoscopy, and projected costs (including ill-de ﬁ ned insurance coverage). Endoscopic screening should be considered in individuals with certain hereditary genetic syndromes or a ﬁ rst-degree family history of GC on an individualized basis (e.g., starting at the age 10 years before the youngest ﬁ rst-degree family member with GC). The de ﬁ ciency of US-based studies in this area delineates a critical knowledge gap with important public health implicationsgiventhecurrentandgrowingproportionofUSadultsat increased risk for GC, which de ﬁ ne this cancer disparity.

DIAGNOSIS OF GPMC

Noninvasive evaluation of GPMC Recommendations: GPMC noninvasive diagnosis

3. We suggest against the use of noninvasive biomarkers for the purpose of GPMC or GC screening or surveillance in the United States (Very low quality of evidence, conditional recommendation).

Noninvasive biomarkers are a desirable and potentially coste ﬀ ective approach for identifying individuals who would bene ﬁ t from upper endoscopy to detect GPMC/GC and resect, if appropriate. Candidate noninvasive tests that have been evaluated include H. pylori IgG, H. pylori CagA or VacA (strain-speci ﬁ c virulence factors), pepsinogen I, pepsinogen II, gastrin, gastrin17, C-reactive protein, migration inhibitory factor 1, trefoil factor family 3, reprimo, or a combination of these (55,56). Blood multiomic technologies are under study and may o ﬀ er an appealing approach. Overall, and particularly in the United States, de ﬁ nitive studies are lacking regarding e ﬃ cacy of noninvasive biomarkers for the purpose of screening or surveillance for GPMC and GC. Based on a review of the evidence, which is summarized in Supplement 1 (see Supplementary Digital Content 1, http://links.lww.com/AJG/D556), currently there are no noninvasive biomarkers that would (i) replace upper endoscopy or (ii) serve as a method to discriminate subjects at low vs high risk of GPMC, GPMC progression, or GC and warrant referral for upper endoscopy.

Endoscopic evaluation of GPMC Recommendations: GPMC endoscopic diagnosis

4. In patients undergoing upper endoscopy, we recommend a highquality endoscopic evaluation of the stomach to identify GPMC. This includes achieving adequate mucosal visualization with cleansing and insufflation, visual station mapping, photodocumentation of anatomic landmarks and any abnormalities, and adequate gastric evaluation time (Low quality of evidence, strong recommendation). 5. In patients undergoing upper endoscopy for evaluation of GPMC, we suggest the use of high-definition white light endoscopy and image-enhanced endoscopy for gastric examination (Low quality of evidence, conditional recommendation).

Quality endoscopy considerations

The endoscopic and histopathologic evaluations are the core of GPMC diagnosis and risk strati ﬁ cation. The primary goal of upper endoscopy is the early detection of gastric dysplasia and

cancer, ideally at a stage for which endoscopic resection is curative. The secondary goal is the diagnosis and assessment of the severity andextent of AG and GIM to identify the individuals who would bene ﬁ t from ongoing surveillance for early dysplasia/ cancer detection purposes. This section is focused on the endoscopic and histological assessment and diagnosis of GPMC, while the same core principles of the high-quality endoscopic examination apply to endoscopy in general (57,58).

Individuals who warrant endoscopy with high-de ﬁ nition white light endoscopy (HDWLE) and image-enhanced endoscopy (IEE), as well as systematic biopsy sampling, are (i) individuals with known GPMC or prior GC with indications for surveillance, (ii) individuals at increased risk for GPMC or GC (e.g., family history and early-generation immigrant from highincidence region), and (iii) individuals with an endoscopic appearance concerning for GPMC.

A high-quality evaluation of the entire gastric mucosa is the foundation for identifying GPMC and GC, noting that $4.7\%-$ $11.3\%$ of neoplastic lesions are missed on upper endoscopy completed within 3 years of GC diagnosis (59 – 61). Neoplastic lesions are often subtle and endoscopic miss rates even approach $25\%$ , particularly in less-experienced endoscopists. Complete mucosal evaluation is best achieved by using insu ﬄ ation to adequately distend the gastric folds, mucosal cleansing, and spending su ﬃ cient time evaluating all gastric areas ( “ stations ” ) (Figure 1). Although adequate mucosal cleansing can often be achieved with water irrigation alone, the use of mucolytic and defoaming agents (i.e., simethicone and N-acetylcysteine) signi ﬁ cantly improves mucosal visibility scores and reduces total procedure time (62 – 64). Standardized cleansing scores are available (65,66). The quality of visualization of the gastric mucosa should be routinely documented in the endoscopic report, analogous to reporting bowel preparation quality in colonoscopy reports.

Training endoscopists to perform a detailed gastric evaluation and recognize and classify lesions signi ﬁ cantly increases the detection of GPMC and reduces the time to referral for endoscopic resection (67,68). Surrogate measures for a quality endoscopic evaluation include endoscopic visualization time and photodocumentation, which are analogous to documentation of withdrawal time and photodocumentation of landmarks during colonoscopy. Retrospective data from high-incidence regions demonstrate that GPMC detection rates increase after detailed gastric evaluation (e.g., 6 – 7 minutes) conducted after mucosal cleansing is completed, independent of the endoscopist training level (29,69 – 72).

Photodocumentation of each of the gastric stations and any abnormal ﬁ ndings is important to structure the endoscopic examination. Additional reasons include correlation with histological ﬁ ndings and monitoring the ﬁ ndings over time for surveillance or referral for endoscopic treatment. Photodocumentation protocols in East Asia and Latin America generally recommend photodocumentation of at least 20 stations (73). Observational studies suggest that such protocols alone signi ﬁ cantly increase the detection of GPMC in high-risk patients, although the data are mixed (67,74). When extrapolating this evidence to the overall low-incidence US population and considering time feasibility, we advocate for, at minimum, photodocumentation of 6 anatomic stations: 3 antegrade images of the corpus-greater curvature, corpus-lesser curvature, and antrum-pylorus, and 3 retrograde images of the incisura, corpusgreater curvature, and fundus-cardia (57,58,73). Mucosal abnormalities warrant dedicated images.

High-definition endoscopy and image-enhanced endoscopy

High-de ﬁ nition (HD) is de ﬁ ned as an image with more than 650 to 720 lines of resolution and requires all components of the system (endoscope chip, processor, transition cables, and

![Antegrade Retrograde Antegrade Retrograde ](https://venus-llm-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-03-15/98164939-a73b-49b7-995b-298762f2ce64/98164939-a73b-49b7-995b-298762f2ce64.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1742023869%3B1742027469&q-key-time=1742023869%3B1742027469&q-header-list=host&q-url-param-list=&q-signature=6be17e448c922301e3736e8fe3dcc7e632f81553) Figure 1. Systematic stomach endoscopic evaluation with cleansing, insufflation, and photodocumentation. Inadequate ( a ) and high quality ( b ) visualization.

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monitor) to be HD compatible. All major endoscopy manufacturers now o ﬀ er HD gastroscope systems in the United States (Olympus 190 series; Pentax 2990i and 2790i; Fujinon 590 series) (75). HDWLE systems o ﬀ er electronic magni ﬁ cation of $\times1.5$ or $\times2$ .

Chromoendoscopy is achieved with topical dyes or “ virtually ” with modi ﬁ cations of light wavelength or computer image processing herein, labeled as IEE. Topical dye chromoendoscopy evaluates the mucosa after spraying Lugol iodine or indigo carmine. Virtual chromoendoscopy is the most practical for use in the United States. The optical image processing uses 1 of 3 commercially available modalities: narrow band imaging (NBI) from Olympus, Fujinon Intelligent Color Enhancement from Fujinon (including blue laser imaging (BLI) and linked color imaging (LCI), and iScan from Pentax. Emerging endoscopic technologies and the potential environmental impact of a GPMC surveillance program are reviewed in Supplement 1 (see Supplementary Digital Content 1, http://links.lww.com/AJG/D556).

Recognition and categorization of GPMC

Endoscopy can identify GPMC as visible nonpolypoid or polypoid mucosal changes, or as “ nonvisible ” mucosal changes that are identi ﬁ ed incidentally on biopsies collected for other purposes (e.g., evaluation of dyspepsia). Three mucosal changes should be identi ﬁ ed endoscopically: (i) AG, (ii) GIM, and (iii) dysplasia. Endoscopy alone cannot reliably di ﬀ erentiate between dysplasia (i.e., inde ﬁ nite for dysplasia [IND], LGD, HGD) and early carcinoma, and histologic con ﬁ rmation is needed (76). Gastric polyps and polypoid lesions are discussed separately.

We suggest using HDWLE and virtual IEE to evaluate the gastric mucosa to optimize the identi ﬁ cation and characterization

of GPMC. Herein, we use the term “ HDWLE with IEE ” to refer to the common US setting with the use of HDWLE with NBI or BLI, with or without optical zoom (77). We note that NBI/BLI in the stomach has inadequate illumination for a wide- ﬁ eld view, as compared with the narrow-lumen esophagus (78). NBI is therefore less e ﬃ cacious for detecting, as opposed to characterizing gastric lesions. This is true for many optical biopsy technologies (e.g., Raman and confocal endomicroscopy), and contrasts with IEE with LCI, that uses short wavelengths to produce bright images even for distant views (78).

The ﬁ rst step in recognizing GPMC is becoming familiar with the appearance of normal gastric folds, pit patterns, and the regular arrangement of collecting venules (Figure 2). Gastric folds are typically 5 – 10 mm thick in the fundus and body and traverse in parallel, with ﬂ attening toward the antrum (79). Healthy gastric mucosa has round pit patterns in the corpus and elongated pit patterns in the gastric antrum on HDWLE, which are more apparent with IEE. Healthy gastric mucosa with regular arrangement of collecting venules appears as red spidery vessels in the corpus (80).

Gastric atrophy is the loss of glandular mass with variable lamina propria ﬁ brosis, with or without replacement by metaplastic tissue (GIM). There are 4 hallmark endoscopic ﬁ ndings that characterize gastric atrophy: (i) pallor, (ii) loss of gastric folds, (iii) prominence of the visible submucosal vessels (submucosal venules), and (iv) a border between atrophic and normal mucosa in patients with H. pylori -related AG (HpAG) (81). Among these changes, the loss of gastric folds is the most sensitive change followed by increased visibility of the submucosal venules (sensitivity $67\%$ /speci ﬁ city $85\%$ and sensitivity $48\%$ /speci ﬁ city $87\%$ , respectively) (82). Separating antral and corpus biopsies into distinct specimen jars and correctly orienting the specimens

![Normal Atrophicgastritis Intestinalmetaplasia Dysplasia Earlyadenocarcinoma Roundpitpatternsinthe Pallor,lossof folds,prominence Tubulovillousmucosalpattern, corpusandelongatedpit ofsubmucosalvenulesand elevationwithwhitishpatches Irregularvesselpatternswithlossofarchitecture patternsintheantrum atrophicborder(AB,whiteline) andlightbluecrest Antrum Fundus Complete Incomplete Low gradeHigh grade ](https://venus-trag-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-03-15/81667464-00b3-469c-8575-af43e9f16e03/81667464-00b3-469c-8575-af43e9f16e03.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1742023869%3B1742027469&q-key-time=1742023869%3B1742027469&q-header-list=host&q-url-param-list=&q-signature=4a62196a3c3c5ee531126861af00ebd7dab64796) The Correa cascade: endoscopy (HDWLE, NBI) and histology correlation. HDWLE, high definition white light endoscopy; NBI, narrow band imaging.

Figure 2.

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during para ﬃ n-embedding may assist pathologists with reporting AG, which is often underdiagnosed and subject to interobserver variability. Most examples of gastric atrophy can be divided into 2 patterns, HpAG and AIG. HpAG develops in the gastric antrum and incisura and may extend proximally. In some individuals, especially if there is persistent infection, there is the replacement of the normal glandular tissue by multifocal metaplastic tissue. The border of the atrophic mucosa can be identi ﬁ ed endoscopically and is used by the Kimura Takemoto system to estimate atrophy severity and the risk of progression through the Correa cascade (83). AIG, also termed autoimmune metaplastic AG, is detected in the gastric corpus and fundus with characteristic sparing of the antrum unless there is concomitant HpAG (84). Diagnosing gastric atrophy based on endoscopy alone may be inaccurate and should be con ﬁ rmed and its extent evaluated using a standardized biopsy protocol (see below).

On HDWLE, GIM appears as irregular, patchy, white mucosa with a tubulovillous pattern (Figure 3). The tubulovillous pattern is associated with a sensitivity of $89\%$ and a speci ﬁ city of $90\%$ and is better appreciated using NBI (85). Other features of GIM on HDWLE and NBI (or BLI) are the light blue crest sign (sensitivity of $48\%–89\%$ and speci ﬁ city of $93\%{-}96\%$ ) (85 – 87), marginal turbid band (sensitivity $100\%$ and speci ﬁ city $66\%$ ) (86), and the “ white opaque substance ” sign, which appears as nodular patches of white raised mucosa and histologically represents accumulation of lipid droplets (88). The light blue crests are ﬁ ne, light blue-white lines on the crests of the epithelial surface. One limitation is the moderate interobserver reliability of these endoscopic ﬁ ndings; improved agreement comes with experience (85,89,90).

The mucosal changes of dysplasia and EGC are nonspeci ﬁ c and subtle. Dysplasia manifests either erythema or pallor, slight

![Near Focus ](https://venus-llm-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-03-15/eccf8d86-1deb-4a6d-bda1-62edd24877f7/eccf8d86-1deb-4a6d-bda1-62edd24877f7.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1742023869%3B1742027469&q-key-time=1742023869%3B1742027469&q-header-list=host&q-url-param-list=&q-signature=f6922007f9ec58f14c07bf8884f94b9a023e9343) Figure 3. Gastric intestinal metaplasia on HDWLE with or without NBI and near-focus: ( a ) HDWLE, ( b ) NBI, ( c ) HDWLE with near-focus, and ( d ) NBI with near-focus. The patchy aspect of GIM is demonstrated in ( c ). In the left area, normal glandular structures are arranged in a regular honeycomb pattern. In the central area, the tubulovillous white glandular structures of intestinal metaplasia are observed. The LBCs are thin white or blue lines located at the borders of the tubulovillous glands ( c and d ). LBCs often appear in whitish color on NBI and are specific for GIM. The NBI examination with near-focus facilitates targeted biopsies within the framework of the Sydney system biopsy protocol. GIM, gastric intestinal metaplasia; HDWLE, high-definition white light endoscopy; LBC, light blue crest; NBI, narrow band imaging.

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elevation or depression, thickening, abnormal convergence or ﬂ attening of gastric folds, or irregular mucosal vessels with loss of mucosal architecture (91,92). Ulcerated lesions often re ﬂ ect invasive adenocarcinoma, with higher likelihood of submucosal invasion (at least stage T1b) and lymph node metastases that generally preclude patients from endoscopic treatment. In patients with HpAG, mucosal changes may persist even after successful H. pylori eradication therapy. In such patients, reddish depressed lesions may represent precursors to carcinomas that should undergo detailed evaluation, biopsies or endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD) when feasible (93).

Histologic diagnosis of GPMC Recommendations: GPMC histologic diagnosis

6. In individuals at increased risk for or with suspected GPMC or GC, we suggest systematic gastric sampling according to the updated Sydney biopsy protocol. At minimum, 2 separate containers should be used for the antrum and incisura, and for the corpus. Targeted biopsies of any other mucosal abnormalities should be placed in additional separate containers (Low quality of evidence, conditional recommendation). 7. In individuals with GIM, we suggest that the histological subtype of GIM (incomplete, complete, and mixed) be reported for the purpose of GPMC risk stratification and informing surveillance (Low quality of evidence, conditional recommendation). 8. In individuals with GIM, we suggest that the anatomic extent and severity of GIM be reported for the purpose of risk stratification and informing GPMC surveillance. Limited GIM is confined to the antrum and incisura, whereas anatomically extensive GIM also involves the corpus. The severity refers to the proportion of atrophy or GIM in individual biopsies from each compartment (antrum, incisura, and corpus) (Very low quality of evidence, conditional recommendation).

Gastric pathology reporting

The pathology reporting of GPMC requires coordination between the endoscopist and pathologist at the local level in accordance with national standards. Explicit details include information speci ﬁ c to stomach location (e.g., antrum and corpus), severity and extent of GPMC (AG, GIM, dysplasia), subtype of GIM, and presence/absence of H. pylori organisms. The Sydney system for evaluation of gastritis was developed in the 1990s and consists of systematic biopsies of 5 sites, the greater and lesser curvatures of the antrum and corpus, and the incisura angularis (94 – 96) (Figure 2). Typically, 1 – 2 biopsies are obtained at each of the 5 sites and placed in 2 separate jars (antrum/incisura and corpus). Biopsies may be “ directed ” within each of the 5 Sydney zones if the endoscopic appearance suggests GPMC. “ Targeted ” biopsies refer to biopsies obtained for mucosal abnormalities and lesions, which are placed in a separate jar. The incisura, as an epithelial transition zone, is often the ﬁ rst zone to display AG or GIM in the setting of H. pylori gastritis and increase the likelihood of detecting GPMC.

GIM subtyping separates GIM into complete and incomplete types. This determination is readily made on hematoxylin and eosin (H&E)-stained sections without the need for additional special stains if the specimens are adequately cut and processed. Felipe described further subtyping based on mucin histochemical stains (e.g., high iron diamine staining): type I (complete) and types II and III (both considered incomplete), but this level of discrimination is typically reserved for research purposes and is not needed clinically (97,98). There are limited data on patient-related outcomes associated with GIM subtyping in the United States (17). However, in high-risk populations, there are strong, consistent data that support GIM subtyping as complete vs incomplete (or mixed if both are present) to delineate the risk for progression to neoplasia (97,99 – 101).

The severity of AG and GIM refers to the proportion of atrophy or GIM in individual biopsies in each compartment (antrum, incisura, and corpus). Increased severity of AG/GIM is consistently associated with higher risk of neoplastic progression, independent of anatomic extent (22). Mild atrophy can be di ﬃ cult to appreciate; however, extensive loss is readily apparent. Intestinal metaplasia in up to one-third and twothirds of glands can be regarded as mild and moderate, respectively, whereas greater than two-thirds is considered severe (94,95). The Operative Link for Gastritis Assessment and Gastric Intestinal Metaplasia (OLGA/OLGIM) is a validated histologic scoring system that considers both the extent and severity of AG/GIM and is strongly associated with risk of progression based on robust non-US data. OLGA/OLGIM is not routinely used in the United States, and therefore, US-speci ﬁ c data are limited (Figure 4, Box 1).

All samples concerning for dysplasia, including IND, LGD, and HGD, should be reviewed by a pathologist with expertise in GI pathology. Many cases of IND and LGD are “ downgraded ” to negative for dysplasia after expert review (102). The IND category is often applied in the presence of obscuring in ﬂ ammation, but attention to histomorphologic details on review by an expert pathologist can most often clarify the presence vs absence of dysplasia (102). It is important to ensure that causes of in ﬂ ammation, such as H. pylori infection and/or nonsteroidal anti-in ﬂ ammatory drug use, are addressed and removed because superimposed in ﬂ ammation can make the diagnosis of dysplasia challenging (see below). In general, the histologic features of LGD are similar to those of colorectal tubular adenomas, with enlarged hyperchromatic nuclei that are aligned perpendicular to the cell basement membranes of the a ﬀ ected glands. HGD shows loss of this nuclear polarity with an erratic arrangement of enlarged hyperchromatic nuclei. Some examples of gastric dysplasia show gastric rather than intestinal type di ﬀ erentiation, instead showing pyloric gland or foveolar cell di ﬀ erentiation (103). Describing di ﬀ erences in classi ﬁ cation systems across di ﬀ erent countries is beyond the scope of this document. However, it is worth recognizing that some areas of the world may classify HGD and early GC di ﬀ erently (e.g., carcinoma in situ may be classi ﬁ ed as cancer, but in the United States, this would be classi ﬁ ed as HGD).

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MANAGEMENT OF GPMC

Recommendations: nondysplastic GPMC surveillance

9. In individuals with GIM who are considered high risk for GC, we suggest endoscopic surveillance at 3-year intervals. High-risk groups include individuals with GIM and at least one of the following criteria: (i) High-risk GIM histology: · Incomplete GIM histological subtype, vs complete · subtype Corpus-extension, defined as corpus involvement also with antrum or incisura involvement (ii) Any GIM histology with one of the following risk factors for GC: · · Family history of GC in a first-degree relative Foreign-born, with emigration from a high-incidence · nation High risk race or ethnicity, including East Asian, Latino/a, Black, and AIAN individuals (Very low quality of evidence, conditional recommendation). 10. In individuals with severe GIM or AG in biopsies of the antrum or corpus, we suggest endoscopic surveillance at 3-year intervals (Very low quality of evidence, conditional recommendation). 11. In individuals with low-risk GIM or atrophy, we suggest against endoscopic surveillance. Low-risk groups include (i) Complete type GIM, without evidence of incomplete GIM (ii) GIM of focal anatomic extent that is confined to the antrum (iii) None of the high-risk clinical criteria listed in Recommendation 9 above (iv) AG that is mild in severity (Very low quality of evidence, conditional recommendation).

The epidemiology of GPMC

High-risk populations for GPMC parallel high-risk populations for GC. AG is the most common GPMC with an estimated prevalence of $15\%$ in the United States overall, although these estimates should be considered in the context that AG is often underdiagnosed and subject to interobserver variability (104). Based on data from Western populations, GIM is observed in approximately $5\%{-}15\%$ of patients undergoing upper endoscopy with gastric biopsies (17,105,106). The prevalence of both AG and GIM is signi ﬁ cantly higher in certain populations such as nonWhite groups and ﬁ rst-generation immigrants from highincidence nations where the GPMC prevalence may approach $40\%$ in 40 – 60-year-olds (107).

Based on limited data from Western populations, the prevalence of dysplasia ranges from $0.5\%$ to $3.75\%$ , but some cohorts report higher prevalence depending on the population (e.g., populations with GIM, high racial and ethnic diversity, and family history in a ﬁ rst-degree relative) (108 – 112). Variability in the reported prevalence of dysplasia across studies may also stem from variability based on histologic interpretation. For example, IND or even LGD may arguably represent an in ﬂ ammatory or regenerative process as opposed to true neoplastic transformation. Indeed, even in studies with expert GI pathologists, low interobserver agreement for LGD has been demonstrated (kappa 0.2), although the agreement is higher for HGD (113). Further compromising our understanding of the true burden of the spectrum of GPMC from an epidemiological standpoint is

that these conditions are generally asymptomatic and require a high-quality endoscopy with appropriate biopsies to diagnose.

Chronic H. pylori infection is the leading risk factor for GPMC, although less common etiologies, such as AIG, are recognized. GPMC are more common in non-White individuals and immigrants from high GC incidence regions. Additional risk factors include male sex, having a ﬁ rst-degree relative with GC, smoking and dietary factors. Each of these factors may confer an independent risk of prevalent GPMC ranging from approximately 1.5- to 3.5-fold (17,114 – 119). We emphasize that the risk factors for the development of GPMC and GC and the progression from GPMC to GC overlap, yet the dominant risk factors likely vary for the 3 domains, and will vary in di ﬀ erent populations. For the transition from GPMC to GC, the principal drivers and their respective biomarkers are critical need areas for research.

Nondysplastic GPMC and the risk of progression

Individuals with con ﬁ rmed GPMC have a higher risk of intestinal-type gastric adenocarcinoma. One population-based study from Sweden, a low GC incidence nation, reported that AG and GIM were associated with minimally adjusted hazard ratios ( $(95\%$ CI), of 5.0 (3.8 – 6.7) and 6.5 (4.8 – 8.9), respectively, for noncardia GC, compared with normal gastric mucosa (120). This study excluded the ﬁ rst 2 years of follow-up and did not provide details regarding H. pylori status, surveillance history, anatomic extent, or other relevant histological features (e.g., GIM subtype). Based on other studies, including 1 comprehensive meta-analysis, the overall baseline risk of progression of AG and GIM is low and parallels the rate of progression of other preneoplastic changes (e.g., Barrett ’ s esophagus and low-risk colorectal adenomas) (22,121,122). Based on meta-analysis, the 10-year cumulative risk of progression to GC among patients with histologically conﬁ rmed GIM is $1.6\%$ ( $95\%$ CI 1.5% – 1.7%) (22). The baseline risk of GC among individuals with GPMC varies signi ﬁ cantly depending on histological features, anatomic extent, microbial (e.g., persistent H. pylori infection), family history and hereditary factors, and other factors with less de ﬁ ned risk estimates (e.g., tobacco and diet) (123,124); this is why appropriate risk strati ﬁ cation is the main branch point informing the management of patients with GPMC.

Individuals with GIM and additional risk factors for progression have anywhere from 2.0- to 20-fold higher risk of progression to GC (22,123). These risk factors include corpusextended AG/GIM, incomplete-type GIM, moderate-severe AG or GIM (i.e., OLGA/OLGIM III-IV, see INSERT and Supplement 2, Supplementary Digital Content 2, http://links.lww.com/ AJG/D557), and family history of GC in a ﬁ rst-degree relative. By contrast, some individuals with mild GPMC (e.g., mild unifocal AG or GIM) may show regression, particularly after con ﬁ rmed H. pylori eradication and improvement in the severity of background gastritis (22,120,122,123,125,126). Some studies suggest that although race, ethnicity, and country of origin are signi ﬁ cant risk factors for GPMC and GC, these factors are not proven to be independent predictors of progression, also noting that US studies are limited (22,127). That said, endoscopic surveillance of individuals with GPMC who identify as a high-risk race or ethnicity, or who emigrated from a high-incidence region, should be considered for endoscopic surveillance given the substantial increased risk of GC in these groups.

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![Corpus OR OLGA Staging Mild Moderate Severe No Atrophy Atrophy Atrophy Atrophy 3 (score0) (score1) (score2) (score3) S No Atrophy(score O) STAGEO STAGEI STAGEII STAGEII (including incisura angularis) Mild Atrophy(score1) STAGEI STAGE STAGEI STAGEI (including incisura angularis) Moderate Atrophy(score2) STAGEII STAGEII STAGEIII STAGEIV (including incisura angularis) Severe Atrophy(score3) STAGEII STAGEI! STAGEIV STAGEIV #2 (including incisuraangularis) ANTRUM& CORPUS INCISURAANGULARIS OR corpus OLGIM Staging NO1M MildIM Moderate SevereIM (score0) (score 1) IM(score2) (score3) No IM (score 0) STAGEO STAGEI STAGEII STAGEII (including incisura angularis) Mild IM(score 1) STAGEI STAGEI STAGEII STAGEIII (including incisuraangularis) Moderate IM(score 2) STAGEII STAGEII STAGEIII STAGEIV (including incisuraangularis) (including incisuraangularis) Severe IM (score 3) STAGEIII STAGEIII STAGEIV STAGEIV Biopsy Report STAGEO STAGEI STAGEII STAGEIII STAGEIV ](https://venus-trag-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-03-15/06bbdc82-cdba-412c-b24e-7f6714a5c15e/06bbdc82-cdba-412c-b24e-7f6714a5c15e.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1742023869%3B1742027469&q-key-time=1742023869%3B1742027469&q-header-list=host&q-url-param-list=&q-signature=d3784eac3e139f597c8d45a38ef1158acc9f15e3) Figure 4. The OLGA/OLGIM histology staging system (see Box 1). OLGA, Operative Link on Gastritis Assessment; OLGIM, Operative Link on Gastric Intestinal Metaplasia Assessment.

Histologic determinants of nondysplastic GPMC progression

Appropriate sampling of the gastric mucosa using the Sydney protocol allows determination of anatomic extent, GIM subtype, histopathological stage/severity, and the presence of H. pylori infection or AIG (95,113,128). Obtaining robust estimates of the risk of GC associated with each of these factors is challenging, particularly in the United States, because GIM is often diagnosed incidentallyonupperendoscopyperformedforotherindicationsand without adequate sampling (129). In 1 US population-based study, $66\%$ of patients with GIM had the anatomic location categorized as “ not otherwise speci ﬁ ed ” (129). In the United States, the GIM histological subtypes are rarely reported on pathology reports.

Anatomic extent. In retrospective cohort studies conducted in US populations, corpus-extended GIM has a higher risk of progression to GC compared with GIM limited to the antrum and incisura (22,108,129). The ﬁ ndings are generally similar in high-risk populations outside the United States. For example, a retrospective analysis of a large cohort of high-risk Colombian patients undergoing surveillance endoscopy with 20 years of follow-up reported that individuals with corpus-extended GIM had a statistically nonsigni ﬁ cant higher risk of GC compared with individuals with antrum-limited GIM (OR 2.1, $95\%$ CI 0.7 – 6.6) (101). A metaanalysis by Shao et al reported that compared with patients without GIMasthereferencegroup,patientswithGIMlimitedtotheantrum had a 4-fold (OR 4.06, $95\%$ CI 2.79 – 5.91; $\mathrm{I}^{2}=27.4\%$ ) higher risk of GC, while those with corpus extension had a 7.4-fold (OR 7.39, $95\%$

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CI 4.94 – 11.06; $\mathrm{I}^{2}=37.8\%$ ) higher risk of GC; no US studies were included in this meta-analysis (130). GPMC focality is also relevant but similarly depends on obtaining a su ﬃ cient number of gastric biopsies. Unifocal AG or GIM, de ﬁ ned as 1 biopsy specimen containing AG/GIM, is associated with lower risk than multifocal AG/ GIM, which is de ﬁ ned as at least 2 biopsies containing AG/GIM. Moderate to severe AG/GIM, as noted below, even if anatomically limited to the antrum, is still considered high-risk and such individuals should be considered for surveillance.

Histologic severity. Moderate to severe AG/GIM is associated with substantially higher risk of GC compared with mild AG/GIM and is a strong predictor of progression. However, reporting of histologic severity of AG/GIM in routine US clinical practice is not always performed. As previously noted, OLGA/OLGIM is a histopathologic staging system that considers both the anatomic location and the histologic severity of AG/GIM that is regularly used in other Western countries (e.g., Europe and Latin America) but not the United States. Basedonrobustdata,includingameta-analysisof2prospectivecohort studies from Italy and the Netherlands, moderate-severe AG/GIM (stage III/IV) was associated with a 27.7-fold $95\%$ CI 3.75 – 204.87) higher RR of GC compared with mild-intermediate AG/GIM (stage 0/ I/II) (113,131,132). The use of OLGA/OLGIM staging is limited in the United States, and therefore, data are minimal in US populations. As with GIM subtype, gastroenterologists should work with their local pathologiststooptimizeprotocolsfortheroutinereportingofhistologic severity given its value as a risk strati ﬁ cation parameter.

Copyright $\copyright$ 2025 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.

Box 1. OLGA and OLGIM (see Figure 4)

Background . The Operative Link for Gastritis Assessment (OLGA) and Operative Link for Gastric Intestinal Metaplasia Assessment (OLGIM) are validated histopathological staging systems that consider both the anatomic location and histological severity of AG and GIM. They were developed primarily for staging $H.$ pylori associated atrophy with or without metaplasia. These systems necessitate adequate quality biopsies obtained separately from the antrum/incisura and corpus. (See Supplement 2, Supplementary Digital Content 2,http://links.lww.com/AJG/D557for additional background). The OLGA/OLGIM system is in widespread use in Europe and some centers in Asia and Latin America. A limited number of U.S. centers use OLGA/OLGIM. OLGA/ OLGIM stages range from 0 (normal pathology) to IV (moderate/severe AG $+/-$ GIM of the antrum and corpus). There is lower interobserver variability for OLGIM than for OLGA. OLGA/OLGIM staging is a strong predictor of progression to GC in high-risk populations. Higher stages of OLGA/OLGIM (III-IV) in patients with H. pylori -associated gastritis are consistently associated with a substantially higher risk of progression to gastric cancer compared to lower stages (0-I). OLGA/OLGIM II is considered an intermediate-risk category and individual risk assessment is helpful. In the Singapore GCEP cohort, the largest cohort of patients with GPMC published to date, the incidence of early gastric neoplasia was 543.8 per 10000 person-years in individuals with OLGIM III/IV (versus 21.5 in OLGIM I). OLGA/OLGIM staging should not be applied to patients with autoimmune gastritis (AIG) in the absence of H. pylori infection, since AG and GIM only occur in the corpus in patients with H. pylori - negative AIG. Implementation in Practice . In centers where OLGA/OLGIM staging is routinely used, we suggest that individuals with OLGA/OLGIM III/IV (without dysplasia) undergo surveillance endoscopy every 3 years based upon the global literature, with consideration of a 2-year interval if they have any additional demographic or clinical risk factors (e.g., family history). For patients who are intermediate-risk (OLGA/ OLGIM II), endoscopic surveillance in 3 years may be considered if multiple additional high-risk factors are present. US studies are needed regarding the value versus the burden of routine OLGA/OLGIM staging and the impact on gastric cancer prevention and early detection.

a higher prevalence (123). The evidence is consistent across lower incidence regions such as Western Europe but is still indirect because no studies were identi ﬁ ed from US populations.

Active H. pylori infection. Active H. pylori infection is strongly associated with GPMC progression, whereas successful H. pylori eradication may be associated with stable histology or even regression in some individuals. H. pylori eradication is considered an adjunct intervention to GPMC surveillance (see below). Although uncommon, patients may have refractory H. pylori infection after failure of several lines of appropriate H. pylori therapy — these patients are particularly high risk and should be o ﬀ ered surveillance endoscopy at a 3-year interval, which is primarily based on expert opinion (a shorter interval should be considered if additional GC risk factors).

Additional determinants of nondysplastic GPMC progression

A family history of GC, particularly in a ﬁ rst-degree relative, is a strong risk factor for incident GC among patients with nondysplastic GPMC, although there are mixed data (17). Based on a meta-analysis of 4 studies, including 1 from the United States, among patients with GIM, having a ﬁ rst-degree relative with GC was associated with 4.5-fold higher odds of GC (OR 4.53, $95\%$ CI 1.33 – 15.46), but with very low certainty of evidence, because only the US study showed an association (17). Family history showed a null association in the Singapore “ GCEP ” study with multiethnic Asian populations (94). Hereditary and germline genetic factors are increasingly recognized; however, their role as a determinant of GPMC prognosis remains to be de ﬁ ned (21).

Active tobacco smoking is a modi ﬁ able risk factor associated with a higher prevalence of GPMC, and possibly progression, although the data are mixed and population-based data are limited (22). One US population-based study reported a null association between smoking history and GIM progression (22). By contrast, in the GCEP cohort, patients with OLGIM II-IV and a smoking history ${>}20$ pack-years had a 3.7-fold ( $\cdot95\%$ CI 1.03 – 13.2) higher risk of early gastric neoplasia compared with nonsmokers, whereas those with ${<}20$ pack-years did not (HR 2.06, $95\%$ CI 0.41 – 10.3) (123). Smoking cessation should be recommended regardless due to the broad positive health impacts; however, there are insu ﬃ cient data to inform whether smoking per se warrants consideration of GPMC surveillance independent of the risk factors described above.

GIM subtype. Several studies and meta-analyses consistently report a several-fold higher risk of progression in patients with incomplete-type GIM compared with complete-type GIM histology (133 – 135). One meta-analysis published in 2021 of 12 cohort studies comprising nearly 6,500 individuals reported a pooled RR of dysplasia and GC of 3.72 ( $95\%$ CI 1.42 – 9.72) and 5.16 ( $\textbar{\textmd{95\%}} $ CI 3.28 – 8.12), respectively, in patients with incomplete-type vs complete-type GIM (99). A second 2021 meta-analysis, with subgroup analysis according to geography, reported that incomplete GIM was associated with a signi ﬁ cantly higher risk of GC (pooled RR for GC 4.05, $95\%$ CI 1.65 – 9.93) or dysplasia/GC (pooled RR for dysplasia/GC 4.65, $95\%$ CI 2.30 – 9.92) in Western European populations (136). In addition, based on meta-analysis, the presence of only completetype GIM does not seem to confer a higher risk of GC compared with patients without GIM (pooled OR 1.55, $95\%$ CI 0.91 – 2.65) (130). It should be noted that among patients with con ﬁ rmed GIM, the incomplete type is common, with an estimated pooled prevalence of $42\%$ ( $95\%$ CI 34 – 49), although some studies report

Other putative markers of GPMC progression risk include microbial dysbiosis, changes in the non- H. pylori gastric microbiome, and tissue-level molecular changes (137,138). Tissue-level factors certainly hold promise for developing a personalized approach to GPMC surveillance; however, there is currently insu ﬃ cient evidence to inform clinical practice, and most studies have been performed in East Asian populations. Similarly, there are mixed data in non-US populations regarding the predictive value of serum biomarkers (e.g., pepsinogens), about progression of GPMC to GC (123,125). Novel, ideally noninvasive, biomarkers represent a critical unmet need to better delineate individuals at highest risk for GPMC progression.

Dysplastic GPMC and risk of progression

The diagnosis of dysplasia (or “ intraepithelial neoplasia ” ) is subject to interobserver variability, especially for IND and LGD, and less so for HGD, even among expert pathologists (125). In one study, among 47 patients initially diagnosed with IND, a rereview by expert GI pathologists resulted in the same diagnosis in

25 $(53.2\%)$ ), and reclassi ﬁ cation as negative for dysplasia $(23.4\%)$ , LGD $(21.3\%)$ , and even HGD $\left(2.1\%\right)$ , in the remaining individuals (139). This diagnostic uncertainty informs the interpretation of risk estimates for dysplasia progression reported in the current literature. In addition, many studies analyze dysplasia as a composite outcome agnostic of dysplasia grade. One populationbased study from Sweden reported a 7.1-fold $\cdot95\%$ CI 5.1 – 9.8) higher standardized incidence ratio (SIR) for dysplasia progression to noncardia GC (reference: normal mucosa), compared with SIRs of 3.0 ( $95\%$ CI 2.5 – 3.7) and 3.7 ( $95\%$ CI 2.9 – 4.6) for AG and GIM, respectively, but did not provide SIRs according to dysplasia grade (120).

It is undeniable that HGD is associated with a synchronous carcinoma or a high rate of progression to invasive carcinoma. The rate of progression of HGD has been estimated to be $47\%-$ $100\%$ over 4 – 48 months (139 – 149). One nationwide cohort study from a low-incidence region demonstrated that approximately one-quarter of patients with HGD were diagnosed with invasive cancer within 12 months (125,150). In one retrospective study in Australia, of 160 patients with dysplasia, $26.9\%$ , $57.5\%$ , and $15.6\%$ were classi ﬁ ed as HGD, LGD, and IND, respectively, the majority of which were classi ﬁ ed as nonpolypoid $(70.6\%)$ (139). In this cohort, among patients with HGD undergoing surveillance only (mean follow-up $1.0\,\pm\,1.4$ [SD] years), $42.9\%$ had cancer identi ﬁ ed on their index examination, and $4.8\%$ developed an interval cancer (de ﬁ ned as ${>}12$ months after index). The literature has also demonstrated similar rates of HGD “ regression, ” ranging from $0\%$ to $33\%$ which underscores the challenges of sampling error in research and in patient care (139 – 148,151 – 153).

IND and LGD have a lower rate of progression to more advanced neoplasia and may even show regression. Based on more recent longitudinal cohort data from both low-intermediate and high-GC incidence regions, a measurable percentage of IND/ LGD do in fact regress or remain stable on long-term follow-up (123,125,126,148). Notwithstanding, IND/LGD demonstrate a signi ﬁ cant rate of progression, especially considering that diagnostic upstaging to more severe lesions occurs in a minority, up to $30\%$ based on most cohort studies (120,139,148). Endoscopic resection is recommended for IND or LGD as a diagnostic and therapeutic intervention when associated with a visible lesion, as detailed below. One retrospective study of 119 patients with biopsy-con ﬁ rmed IND found that on resection, 26 $(21.8\%)$ had early GC; lesion, and diameter ${\geq}10~\mathrm{mm}$ and surface erythema were both independently associated with GC (154). In the Australian cohort cited above, among patients with LGD undergoing surveillance only (mean follow-up $2.3\pm2.1$ [SD] years), $7.9\%$ had cancer identi ﬁ ed at the index examination, $5.3\%$ developed interval cancer, $28.9\%$ had unchanged pathology, whereas $57.9\%$ demonstrated no dysplasia on follow-up examinations. These LGD estimates are similar in other cohorts (1,139,141,149). As in the case of nondysplastic GPMC progression, US data and novel biomarkers are needed.

GPMC “ regression ”

Longitudinal data from large prospective non-US cohorts (e.g., Singapore, northern Europe, Colombia, and Chile) support the observation that GPMC may improve or “ regress, ” particularly after H. pylori eradication in patients with less severe baseline histology (22,101,120,123,125,126). This observation nuances the notion that GIM represents a “ point of no return. ” Robust observational cohort data also suggest that even LGD may show

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improvement, particularly in the setting of H. pylori eradication. That said, in general, robust data regarding risk factor modi ﬁ - cation are not consistently ascertained in these observational studies. A principal challenge in studies is the inherent multifocal ( “ patchy ” ) nature of GPMC, wherein sampling error and misclassi ﬁ cation are signi ﬁ cant. In addition, gastric histopathology scoring systems (e.g., OLGA/OLGIM and Correa Score) provide an ordinal system to detect change, yet the global diagnosis (e.g., AG and GIM) may not change. Finally, there is important interobserver variability among pathologists, particularly with mild AG and IND/LGD.

Endoscopic surveillance and intervals for nondysplastic GPMC The sojourn time of nondysplastic GPMC (AG/GIM) to GC is relatively long, which allows the opportunity for endoscopic surveillance for early gastric neoplasia detection and resection. Resection of early gastric neoplasia before submucosal invasion is potentially curative and is in marked contrast to the poor prognosis associated with advanced-stage GC. The primary purpose of the high-quality endoscopic surveillance examination is to identify neoplasia, while the secondary purpose is to appropriately risk-stratify patients with GPMC. The individual surveillance endoscopy recommendation should be based on patient-physician decision-making, patient comorbidities, and overall prognosis (Figure 5).

Surveillance vs no surveillance based on risk. There are no prospective RCTs in the US or globally that have evaluated the impact of endoscopic surveillance vs no surveillance, nor surveillance intervals, on important outcomes, especially the impact on GC-related mortality. There is, however, a sizeable body of non-US observational data from low-intermediate and highincidence regions supporting that endoscopic surveillance vs no surveillance is associated with an earlier stage of GC among patients with high-risk GPMC de ﬁ ned based on the clinical and histopathological factors detailed above (42). Patients with GPMC who are at low risk for neoplastic progression (e.g., complete-type GIM limited to the antrum with no additional risk factors) are unlikely to bene ﬁ t from routine interval endoscopic surveillance. Indeed, a substantial proportion of patients with nondysplastic GPMC may be considered low-risk. In a crosssectional study of 415 US Veterans who underwent Sydney protocol biopsies, $73\%$ had focal GIM, while the remainder were classi ﬁ ed as extensive GIM (118). In the GCEP study, less than $15\%$ were categorized as high-risk, which is similar to other cohort studies (113,123). Some caution is merited in classifying individuals as low-risk based on a single endoscopic examination because studies have demonstrated that up to $30\%$ of patients originally classi ﬁ ed as low-risk based on an index endoscopy without systematic biopsies are upstaged to high-risk histological classi ﬁ cation on repeat short-interval endoscopic examination $(\sim\!1\!-\!2$ years) with Sydney protocol biopsies (155). However, there are currently no US data to support performing a repeat endoscopy with Sydney protocol biopsies within 12 months among patients who are initially classi ﬁ ed as low-risk. An individualized approach is recommended.

Surveillance intervals. The optimal surveillance interval for individuals with GPMC is not de ﬁ ned and should be determined based on individual risk assessment until more precise data are available. Data from microsimulation and cost-e ﬀ ectiveness analyses conducted with a US population in mind are illustrative and provide guidance regarding an individualized approach

NondysplasticGPMCManagement

![Gastric intestinal Nonmetaplasticatrophic metaplasia gastritis Low-risk High-risk Low-risk High-risk Surveillancein3 Repeatexam in Nofurther Nofurther Surveillance in 3 years;consider 3yearsto surveillance surveillance years shorterinterval reassessrisk\* ifmultiplerisk RECOMMENDATIONS factors 1.In individualswith GIM who are considered highriskforprogression orgastric cancer,we suggestendoscopic surveillance at3-yearintervals.High-riskgroups Persistentlow-risk include individualswithnon-neoplastic GIMandatleastone of the following: ·High-risk GIM histology. ·IncompleteGIMhistologicalsubtypeversuscompletesubtye Nofurther ·Corpus-extension,defined ascorpusinvolvement alsowith antrumorincisurainvolvement surveillance ·AnyGlMhistologywithoneofthefollowinghigh-riskfactors: ·Familyhistoryofgastriccancerinafirst-degreerelative ·Foreign-born,with emigrationfroma high-incidence nation. ·Highriskraceorethnicity(EastAsian,Latino/a,Black&AlAN) 2.In individualswithsevere GIM orsevere atrophicgastritis in biopsiesofthe antrum and/or corpus,we suggest endoscopic surveillance at 3-yearintervals. 3.Severeisdefinedas≥2/3rdofglandinvolvement ](https://venus-trag-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-03-15/4a579d1d-7f95-4586-b9b7-cf467ef58c0c/4a579d1d-7f95-4586-b9b7-cf467ef58c0c.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1742023869%3B1742027469&q-key-time=1742023869%3B1742027469&q-header-list=host&q-url-param-list=&q-signature=77ec6b42810b6cfeef281b38cf37bf0a4458cc58) Figure 5. Nondysplastic GPMC management algorithm. All patients should be tested for H. pylori using nonserologic methods, treated if positive, and confirmed to be eradicated, irrespective of GPMC histology, severity, grade, or associated visible vs nonvisible lesion. Ideally, H. pylori eradication should confirmed at least 1-2 months before the endoscopic surveillance examination because active H. pylori infection can affect endoscopic and histologic appearanceofGPMC.ThesurveillanceexaminationcomprisesHDWLEwithIEEformucosalinspectionandsystematicprotocolbiopsies.Thealgorithmspresented assume that patients are medically appropriate for endoscopic surveillance. \*Some studies in non-US populations have demonstrated that approximately $30\%$ of patients originally classified as low-risk, based on the initial examination diagnosing GPMC, are upstaged to high-risk histological classification on repeat shortinterval endoscopic examination ( ; 1 – 2 years) with Sydney protocol biopsies. There are no US data to inform such practice. If there is concern regarding the quality of the initial examination, or patient preference and patient-physician shared decision-making, repeat surveillance in 3 years can be considered among individuals withGIMdeemedlow-riskbasedontheinitialexamination.IndividualswithGIMandmultipleriskfactorsforGCshouldbeconsideredforsurveillanceatshorterthan 3-year intervals. GIM, gastric intestinal metaplasia; GPMC, gastric premalignant condition; HDWLE, high-definition white light endoscopy.

to endoscopic surveillance vs no surveillance in patients with GPMC (156,157). One study found that the cost-e ﬀ ectiveness of endoscopic surveillance of GIM was highly sensitive to the rate of progression to GC, again underscoring the importance of risk strati ﬁ cation (53). Another microsimulation analysis demonstrated that surveillance of incidentally detected GIM every 5 years in all patients is associated with reduced GC incidence and mortality and is cost-e ﬀ ective (\$40,706/QALY) from a US healthcare perspective; however, in high-risk individuals, namely those with a family history of GC, anatomically extensive or incomplete-type GIM, a 3-year surveillance was the favored strategy and was cost-e ﬀ ective (157). Based on the microsimulation analysis by Thiruvengadam, endoscopic surveillance of incidentally diagnosed GIM results in 87 – 190 life-years gained (LYG)/1,000 in all-comers, 351 – 851 LYG/1,000 in individuals with a ﬁ rst-degree family history of GC, 157 – 335 LYG/1,000 in individuals with anatomically extensive or incomplete-type GIM, and only 43 – 97 LYG/1,000 in individuals with antrum-limited, complete-type GIM (157). For context, colorectal cancer screening in the average-risk population compared with no screening results in 286-335 LYG/1,000.

Based on availabledata, including indirect datafrom modeling studies cited above, we recommend that patients with GPMC and any of the following high-risk features be considered for

endoscopic surveillance at every 3-year intervals: GIM histology (corpus-extension and incomplete-type), family history of GC in a ﬁ rst-degree relative, and demography (immigration from a high-incidence nation, race, and ethnicity considerations). Severe GIM or atrophy histology in the antrum/incisura or corpus also warrants surveillance. The principal race and ethnic groups at-risk include East Asians, Latino/a, Black, and AIAN individuals (28). In centers where OLGA/OLGIM staging is used, we suggest that individuals with OLGA/OLGIM III/IV (without dysplasia) undergo surveillance endoscopy at least every 3 years based on the global literature, with a low threshold to consider a shorterinterval (e.g., 2-year). This isbased on observational data from the GCEP cohort (one of the largest GIM surveillance cohorts to date) demonstrating that individuals with OLGIM III/ IV had a 20-fold higher independent risk of neoplasia (adjusted HR 20.8; $95\%$ CI, 5.04-85.6), with over $50\%$ of early gastric neoplasia being diagnosed within 2 years of the index exam (range: 12.7-44.8 months) (123).

In summary, the plan for endoscopic surveillance for a patient with AG/GIM should be individualized based on risk strati ﬁ cation and should also consider shared patient-physician decisionmaking. The patient with complete GIM limited to the antrum would not warrant surveillance, yet if the GIM were graded as severe in the antrum/incisura biopsies, surveillance is

reasonable. Patients with multiple risk factors do warrant surveillance (130).

Endoscopic management of dysplastic GPMC Recommendations: endoscopic management ofdysplastic GPMC

12. In patients with dysplasia (IND, LGD, and HGD) and visible margins, we suggest endoscopic resection in clinically appropriate patients (Low quality of evidence, conditional recommendation). 13. In patients with dysplasia (IND, LGD, and HGD) without visible margins, we suggest a repeat endoscopic evaluation with HDWLE and IEE by an experienced endoscopist (Low quality of evidence, conditional recommendation). 14. In patients appropriate for endoscopic resection of dysplasia, particularly endoscopic submucosal dissection, we recommend referral to a high-volume center with appropriate expertise in the diagnosis and therapeutic resection of gastric neoplasia (Low quality of evidence, strong recommendation). 15. In patients with confirmed complete resection of dysplasia, we suggest endoscopic surveillance. We recommend surveillance examinations be performed by an experienced endoscopist and using HDWLE and IEE, with biopsies according to the systematic biopsy protocol in addition to targeted biopsies (Low quality of evidence, strong recommendation).

Endoscopic management of dysplastic GPMC

In patients diagnosed with dysplastic GPMC, management depends on the grade of dysplasia, presence and characteristics of a visible lesion, status of the surrounding mucosa (e.g., severe GIM), active H. pylori infection, and individual patient considerations. We acknowledge that in other regions of the world, particularly East Asia, the diagnosis of dysplasia or invasive carcinoma may be made based on endoscopic appearance using IEE typically in conjunction with magni ﬁ cation endoscopy, with ﬁ nal con ﬁ rmation and staging based on the en bloc resected lesion. In the United States, the reality is that the diagnosis of dysplasia generally hinges on con ﬁ rmation from biopsy sampling. Poor quality of samples (e.g., preparation artifacts), absent targeted biopsies, or signi ﬁ cant mucosal in ﬂ ammation (e.g., H. pylori infection) may compromise the accuracy of dysplasia diagnosis. We recommend that any biopsies concerning for dysplasia be reviewed by an expert GI pathologist. In all patients diagnosed with active H. pylori infection, it is recommended that eradication treatment be immediately provided with con ﬁ rmation of eradication because (i) concomitant H. pylori infection may a ﬀ ect the diagnostic certainty of dysplasia; (ii) H. pylori eradication is associated with reduced risk of progression, particularly for IND and LGD; and (iii) active H. pylori infection may compromise delineation of the resection margin for visible lesions (158). However, awaiting eradication con ﬁ rmation should not delay endoscopic management, especially for patients with HGD, given the high rates of synchronous cancer and short-interval progression (Figure 6).

If the index examination diagnosing dysplastic GPMC was performed by a provider with limited volume or experience in managing GPMC, or if there is concern about the quality of the initial examination, referral to a high-volume center with expertise is preferred. This examination serves several purposes that are relevant for clinical decision-making, speci ﬁ cally allowing (i) repeat visualization to characterize the area in question;

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(ii) systematic protocol biopsies of the surrounding ﬂ at mucosa to inform surveillance intervals; and (iii) repeat evaluation for other neoplasia missed on the index exam, given that several studies have demonstrated rates of missed synchronous cancers around $10\%$ , even in expert hands (159).

Visible dysplasia. Dysplasia can be visible and delineated by areas of nodularity, erythema, pallor, or depression. Dysplasia can also be found incidentally on macroscopically normal appearing mucosa. For visible lesions found on endoscopy, endoscopic resection serves both diagnostic and therapeutic purposes. One of 4 lesions with biopsies showing LGD is upstaged after complete endoscopic resection ( $17\%$ upstaged to HGD and $7\%$ to carcinoma) (160).

All patients with dysplastic GPMC associated with a visible lesion amenable to endoscopic resection should be referred for endoscopic resection if medically appropriate. If the visible lesions and involvement are too extensive or if the lesion characteristics are not favorable for a compete resection, then surgical consultation is indicated. This discussion should be reserved for patients with biopsy-con ﬁ rmed HGD or who have multifocal LGD with multiple additional risk factors for progression. Ongoing surveillance after dysplasia resection is indicated given the high risk of metachronous lesions (161,162). The duration of surveillance after resection is not clear. Borrowing from the literature of metachronous GC occurrence after endoscopic resection of EGC, surveillance should continue for at least 10 years postresection, and perhaps longer, if medically appropriate (163,164).

Endoscopic resection of LGD is safe (perforation and bleeding rates are ${<}1\%$ and ${<}7\%$ , respectively) and is associated with reduced rates of progression to HGD or carcinoma (165,166). Lesions greater than 10 mm, with HGD, or depressed lesions are more likely to harbor carcinoma and should be resected with ESD (160,167). Compared with EMR, ESD has signi ﬁ cantly higher rates of “ en bloc ” resection, higher rates of complete resection (negative histologic margins), and lower recurrence rates but requires longer procedure times and results in signi ﬁ cantly higher perforation rates $(<\!1\%\!-\!5\%$ ; OR 3.5 and 4.7 in separate metaanalyses) (167 – 169). No signi ﬁ cant di ﬀ erences in postprocedure bleedinghave been reportedbetween EMRandESD. Thelearning curve for ESD is higher than for other endoscopic procedures. Expert pro ﬁ ciency requires at least 150 cases in a Western training environment, which underlies the recommendation to refer patients to high-volume centers (170). Hybrid ESD allows safe en bloc resection of gastric lesions ${<}20~\mathrm{mm}$ with shorter times than conventional ESD (171). Ideally, patients with highrisk lesions who are candidates for endoscopic resection should also be discussed in a multidisciplinary setting including pathologists, therapeutic endoscopists, and surgeons. Patients should be counseled regarding the rate of recurrence, the risk of metachronous lesions, and thus, the need for ongoing endoscopic surveillance of the remnant mucosa. The surveillance recommendation should be based on the ﬁ nal histopathologic diagnosis and whether complete resection was achieved. Patients should also be counseled that if the ﬁ nal histology demonstrates cancer, additional treatment including surgery may be indicated depending on the cancer stage, grade, and patient-level factors. Nonvisible dysplasia. In patients with dysplasia without visible lesions, so-called “ nonvisible dysplasia, ” the rates of progression are also signi ﬁ cant (125,150). In such cases, a short-interval endoscopy with detailed evaluation using HDWLE and IEE is

![DysplasticGPMCManagement LGD HGD Confirmedby2expertGlpathologists Confirmedby2expertGlpathologists Referral toan endoscopistwith skill assessing and endoscopicallyresecting GPMCand neoplasiaforrepeatendoscopicexamusingHD-WLE+IEEandsystematicbiopsies Visible Nonvisible Visible Nonvisible Endoscopic Surveillance by an Endoscopic Surveillancebyan resectionen expertq6-12months resectionenbloc expertq3months bloc w/systematicbiopsies (ESD)orsurgical w/systematic resection biopsies Complete Incomplete Complete Incomplete Resection,RO Resection Resection,RO Resection Surveillance q1year Repeat endoscopy<6 months; Surveillanceq3-6 Repeatendoscopy<3months;if then continueq3 if still incompleteresection, monthsx1-2yearsthen stillincompleteresection,consider yearsifAG/GIM in surveillancevssurgical q3yearsifAG/GIM in surgicalresection remainingmucosa resection remainingmucosa ](https://venus-llm-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-03-15/476554af-0f4e-48f2-b4c9-9ce983436458/476554af-0f4e-48f2-b4c9-9ce983436458.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1742023869%3B1742027469&q-key-time=1742023869%3B1742027469&q-header-list=host&q-url-param-list=&q-signature=d064726951b85fa28c4558c9bca2495fbcfeeaf5) Figure 6. Dysplastic GPMC management algorithm. All patients should be tested for H. pylori using nonserologic methods, treated if positive, and confirmed to be eradicated, irrespective of GPMC histology, severity, grade, or visible vs nonvisible lesion. Ideally, H. pylori eradication should confirmed at least several weeks before the endoscopic surveillance examination because active H. pylori infection can affect endoscopic and histologic appearance of GPMC. The surveillance examination comprises HDWLE with IEE for mucosal inspection and systematic protocol biopsies. The algorithms presented assume that patients are medically appropriate for endoscopic treatment and surveillance. Patients with IND have elevated risk of gastric neoplasia and warrant followup. The diagnosis of IND should be confirmed by a second pathologist with gastrointestinal expertise. If this is confirmed, patients should undergo repeat high-quality endoscopy with HDWLE 1 IEE with biopsies obtained according to the systematic biopsy protocol, in addition to any biopsies targeted toward visibly abnormal areas, in 6 – 12 months (assuming the baseline examination diagnosing IND was of sufficient quality). The subsequent management algorithm is dictated by the presence vs absence of an associated visible lesion, and management should parallel that for visible vs nonvisible LGD. In patients without confirmed IND on the repeat examination, surveillance should be according to the results of the systematic biopsies. GIM, gastric intestinal metaplasia; GPMC, gastric premalignant condition; HDWLE, high-definition white light endoscopy; HGD, high-grade dysplasia; IEE, image-enhanced endoscopy; IND, indefinite dysplasia; LGD, low-grade dysplasia.

recommended, along with targeted biopsies of any mucosal abnormalities and nontargeted biopsies according to the Sydney biopsy protocol. This so-called second-look endoscopy should be performed by an experienced endoscopist in a high-volume center with EMR/ESD expertise. The second-look endoscopy has been shown to detect focal neoplastic lesions in $90\%$ of patients (172). In patients with initial nonvisible HGD, with pathology con ﬁ rmed by an expert GI pathologist, the second-look examination is also helpful given the risk of a synchronous cancer. In patients with IND/LGD and con ﬁ rmation by an expert GI pathologist, the time frame for the second-look should be within 6 – 12 months and, ideally, after measures to reduce in ﬂ ammation ( H. pylori eradication and nonsteroidal anti-in ﬂ ammatory drug cessation). In patients with active H. pylori infection and IND/ LGD, the second-look endoscopy should be performed at least 1 month after con ﬁ rming eradication, which allows time for the background in ﬂ ammation to improve. This principle has been useful in the evaluation of esophageal intestinal metaplasia (Barrett ’ s esophagus) and nonvisible IND/LGD where there is concomitant erosive esophagitis; initiation or optimization of gastric acid suppressing medications (e.g., PPI) in this analogous scenario improves in ﬂ ammation and improves the accuracy of the dysplasia diagnosis.

If high-quality upper endoscopic examination using HDWLE with IEE by an experienced endoscopist con ﬁ rms nonvisible dysplasia, patients who are medically appropriate should enter regular endoscopic surveillance. Patients with nonvisible HGD should undergo endoscopic surveillance in 3 – 6 months, while for those with nonvisible IND or LGD, every 6 – 12 months is reasonable. Additional risk factors such as a prior history of GC, multifocal GPMC, family history of GC in a ﬁ rst-degree relative, or persistent H. pylori maybeconsideredfor shorterintervalsurveillance.Ifdysplasiaisnot demonstrated on consecutive subsequent high-quality examinations over a 2-year period with IEE and targeted/Sydney biopsies, then returning to non-dysplastic GPMC surveillance intervals is reasonable. Endoscopic surveillance is subject to variability related to endoscopist technique, training, experience, and equipment; therefore,weadditionallyrecommendthatexaminationsbeperformedby an experienced endoscopist in high-volume centers.

Although there is a role of endoscopic ultrasound in staging early GC, data do not support the routine use of endoscopic ultrasound in the evaluation of GPMC. In addition, Japanese pathologists recognize the concept of intraepithelial carcinoma, but this concept is not recognized by most Western pathologists (109). Early GC is de ﬁ ned as adenocarcinoma limited to the mucosa, including the muscularis mucosae (T1a) and submucosa

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(T1b). The management of early GC is outside of the scope of these guidelines.

Nonendoscopic management of GPMC Recommendations: GPMC nonendoscopic management

16. We recommend H. pylori eradication in patients with GPMC (AG, GIM, and dysplasia) and resected EGC to reduce the risk of progression to GC and metachronous EGC, respectively (Moderate quality of evidence, strong recommendation).

17. We do not suggest the use of aspirin, nonsteroidal antiinflammatory drugs, COX-2 inhibitors, or antioxidants for individuals with GPMC for the purpose of GC chemoprevention (Very low quality of evidence, conditional recommendation).

H. pylori eradication

H. pylori is the dominant global risk factor for GC and has been classi ﬁ ed by the World Health Organization ’ s International Agency forResearchonCancerasagroup1orde ﬁ nitecarcinogen(173).The attributable risk is $75\%{-}89\%$ for noncardia gastric adenocarcinoma, which initiates and perpetuates the carcinogenesis cascade (12). H. pylori eradication is consistently associated with a signi ﬁ cant reduction of GC incidence and mortality (174). In patients with high-risk GPMC, H. pylori eradication serves as an adjunct measure because it is not su ﬃ cient alone to prevent progression, again underscoring the role of endoscopic surveillance in individuals with high-risk GPMC (174,175).

The literature supporting H. pylori eradication in patients with GPMC comprises a range of studies, from population eradication to eradication in patients with resected early GC. In multiple RCTs (and meta-analyses of these RCTs), as well as observational studies successful eradication of H. pylori was associated with a substantial reduction in GC incidence and mortality (176 – 178). In the meta-analysis of 22 studies (8 RCTs, 16 cohort) by Ford et al (176), H. pylori eradication was associated with $46\%$ and $39\%$ risk reductions of GC incidence and mortality, respectively, in studies with follow-up ranging from 4 to 22 years. The risk reduction is signi ﬁ cantly greater in individuals without GPMC at baseline (234). In the meta-analysis by Kahn et al, of 9 RCTs (6,967 patients) of H. pylori eradication in patients with EGC after endoscopic resection, there was a $53\%$ reduction in GC incidence, in studies ranging from 3 to 6 years of follow-up. Also in this study, patients with GPMC treated for H. pylori infection demonstrated an improvement in histology, but with a nonsigni ﬁ cant trend (OR 0.47, $95\%$ CI 0.42 – 1.07) toward GC incidence reduction(179)(see Supplement 1, Supplementary Digital Content 1, http://links.lww.com/AJG/D556). As an aside, the gastric mucosa-associated lymphoid tissue lymphoma is typically a lowgrade B-cell neoplasia strongly associated with H. pylori -driven gastritis. A recent meta-analysis demonstrated a pooled complete remission of $75\%$ with H. pylori eradication, with the e ﬀ ect modi ﬁ er of t(11;18) status (180).

Until recently, the bene ﬁ t of H. pylori eradication on GC incidence and mortality had not been directly demonstrated in US populations. However, 2 independent observational studies from 2020 to 2023 from US cohorts (a nationwide Veterans Health Administration and a Kaiser Northern California Health System cohort) demonstrated that H. pylori eradication resulted in a substantial and signi ﬁ cant risk reduction, albeit delayed (e.g., 8 years post-eradication) (10,181).

The American Journal of GASTROENTEROLOGY

Chemoprevention for GPMC

Apart from H. pylori eradication treatment, chemoprevention of GC for patients with GPMC is not currently recommended given the lack of potential agents and supporting data. Antiin ﬂ ammatory agents and antioxidants may reduce the risk of progression by inhibiting cytokines, prostaglandins, and angiogenesis (182). In secondary analyses, cardiovascular medications have also been studied, including statins, metformin, and aspirin. Quality prospective trials with GC incidence and mortality as the primary endpoints are lacking. The existing literature is compromised by heterogeneity, medication usage precision (dosage, regularity, and duration), concurrent medications, data completeness, and the population studied. These data are further discussed in Supplement 1 (see Supplementary Digital Content 1, http://links.lww.com/AJG/ D556).

General prevention measures

In patients with GPMC, general behavioral recommendations are warranted related to tobacco and alcohol use, salt intake, and fresh fruit and vegetable consumption given that all of these factors are modi ﬁ able and may a ﬀ ect GC risk. Maintaining a healthy weight is also important, although the association between obesity and noncardia gastric adenocarcinoma is not as robustly established as the association with cardia and esophageal adenocarcinoma.

The quality of evidence related to the association between diet and behavioral factors and GC risk, speci ﬁ cally among individuals with GPMC, is low and the data are challenging to extrapolate due to heterogeneity in study design, population, exposure assessment, confounder adjustment, and recall bias. Few studies provide data speci ﬁ c to individuals with GPMC, and many studies also do not provide GC outcome data according to anatomic subsite. There are no data in US populations concerning diet and behavioral factors and the risk of GPMC progression. The uncertain bene ﬁ t of positive diet and behavioral changes about GC risk speci ﬁ cally is balanced by other known health bene ﬁ ts. Tobacco use may have the strongest association with GC among the behavioral factors, and patients with GPMC should receive smoking cessation counseling. In Supplement 1 (see Supplementary Digital Content 1, http://links.lww.com/ AJG/D556), we describe relevant data regarding the association between diet and behavioral factors and GC risk, emphasizing those studies that evaluated patients with GPMC or suspected GPMC.

Chronic acid suppression on the risk of GC and GPMC

PPIs irreversibly inhibit the $\mathrm{H}+/\mathrm{K}+$ ATPase (proton pump) leading to potent gastric acid suppression (183). Although PPIs are now among the most widely prescribed medications worldwide (e.g., gastroesophageal re ﬂ ux disease and dyspepsia), the long-term carcinogenic risk related to chronic PPI use is unclear. Speci ﬁ cally, it is uncertain whether chronic hypochlorhydria due to PPI use and the resultant hypergastrinemia and potential gastric pancolonization of the antrum and corpus by H. pylori and other microbes (and their byproducts) increases the risk of gastric malignancy particularly in patients with GPMC. Potassiumcompetitive acid blockers, the newer class of potent gastric acidsuppressors that also inhibit the proton pump, have been less studied about their association with gastric neoplastic risk (184)

(see Supplement 1, Supplementary Digital Content 1, http://links. lww.com/AJG/D556, for further discussion).

SPECIAL TOPICS: AIG AND GASTRIC POLYPS Autoimmune Gastritis Recommendations: AIG

18. Among individuals diagnosed with AIG, we recommend assessment for H. pylori infection with a nonserological test, eradication treatment if positive, and posttreatment testing to confirm eradication (Low quality of evidence, strong recommendation).

19. There is insufficient evidence to make a formal recommendation on endoscopic surveillance in individuals with AIG. Given the increased risk of type 1 neuroendocrine tumors (NETs) and the possible increased risk of GC, individualized surveillance may be considered (Low quality of evidence, conditional recommendation).

AIG is an immune-mediated condition whereby autoantibodies target and destroy parietal cells, resulting in progressive in ﬂ ammation and eventual replacement of the native oxyntic mucosa with connective tissue (nonmetaplastic atrophy) or nonnative epithelium (metaplastic atrophy), in a background of chronic in ﬂ ammation. Antral-sparing is the sine qua non of AIG in the absence of prior or concurrent H. pylori infection, based on systematic biopsies. The diagnosis is supported by positive autoantibodies to parietal cells and intrinsic factor. Autoantibodies alone have inadequate positive and negative predictive value for the diagnosis. Pernicious anemia is a rare, late-stage complication of AIG characterized by vitamin B12 de ﬁ ciency, megaloblastic anemia, and usually with autoantibodies to intrinsic factor (see Supplementary Figure 1, Supplementary Digital Content 4, http://links.lww.com/AJG/ D559). AIG is a progressive condition without cure or evidence of regression over time (185). There is a female:male predominance of approximately 3:1, and associations with older age and autoimmune disorders (see further discussion in Supplement 1, Supplementary Digital Content 1, http://links. lww.com/AJG/D556).

AIG is a preneoplastic condition, and endoscopic surveillance is indicated to allow for early detection and management of neoplasia. The ongoing in ﬂ ammation in AIG leads to progressive oxyntic gland loss and the replacement of native glands with pyloric, intestinal, and pancreatic metaplasia and variable ﬁ brous tissue. The parietal cell loss and resulting hypochlorhydria or achlorhydria lead to persistent stimulation of gastrin production from the antrum. Gastrin is trophic for both parietal and enterochroma ﬃ n-like cells. AIG is associated with well-di ﬀ erentiated NETs of enterochroma ﬃ n-like cells (also termed type I gastric carcinoid tumors). However, the independent association between AIG and gastric adenocarcinoma in the absence of concomitant H. pylori infection has been called into question (186 – 188).

Based on recent data, in the absence of H. pylori infection, the risk of gastric adenocarcinoma in patients with AIG seems to be similar to that of the baseline general population (186). In another Italian study ofpatients with corpus-restricted atrophy, at median follow-up of 5 (1 – 17) years, the annual incidence rate person-year of HGD/GC was $0.5\%$ (187). However, caution is warranted given the relatively short follow-up time of the recent studies from the

vantage point of cancer progression. Prior literature reporting an increased association did not appropriately control for current H. pylori infection, thus precluding assessment of an independent association between AIG and gastric adenocarcinoma speci ﬁ cally (179,186,189 – 195). Indeed, most of these studies were performed in an era before the formal discovery of H. pylori or when H. pylori prevalence was substantially higher than in the modern era. These ﬁ ndings underscore the importance of testing for H. pylori in any patient with metaplastic or nonmetaplastic AG.

There are no RCTs of surveillance vs no surveillance for the purpose of early neoplasia detection in patients with histologically con ﬁ rmed AIG. However, given the increased risk of gastric NET and possibly gastric adenocarcinoma, endoscopic surveillance is suggested in the context of shared decision-making. In patients with pernicious anemia, there is evidence to suggest that the risk of GC is highest within the ﬁ rst year of diagnosis, and thus, endoscopy should be considered in patients with a new diagnosis of pernicious anemia, with particular consideration of women 50 years or older (196,197) (see Supplementary Algorithm 1, Supplementary Digital Content 3, http://links.lww.com/ AJG/D558). Otherwise, there are limited data regarding risk strati ﬁ cation parameters in individuals with AIG; accordingly, we suggest that the endoscopic surveillance interval should be determined based on the same risk strati ﬁ cation factors as described above for GPMC in general (e.g., family history of GC, anatomic extent, and severity of GPMC). Patients with AIG are also at increased risk for nonneoplastic complications including other autoimmune disorders, particularly autoimmune thyroid disease and type I diabetes mellitus, nutritional de ﬁ ciencies (due to achlorhydria/hypochlorhydria), and dermatologic manifestations (198).

Gastric epithelial polyps Recommendations: GEP

20. We recommend endoscopic resection of all gastric adenomas, regardless of size, to exclude and prevent dysplasia and EGC. For adenomas that are not amenable to endoscopic resection, we recommend referral for surgical resection, if clinically appropriate (Low quality of evidence, conditional recommendation). 21. We could not make a recommendation on the endoscopic resection of all hyperplastic polyps greater than 10 mm in size based on the current evidence. 22. In individuals with GEP, with the exception of fundic gland polyps, we recommend systematic gastric biopsies be obtained from the surrounding mucosa given the high prevalence of GPMC, H. pylori infection, and AIG in these patients (Very low quality of evidence, conditional recommendation).

Diagnosis of GEP

GEPs are found in approximately $3\%{-}10\%$ of esophagogastroduodenoscopies performed in the United States, and most are incidental fundic gland polyps (FGPs, $40\%–77\%$ ), followed by hyperplastic polyps $(14\%–40\%)$ ) and gastric adenomas $(3\%–25\%)$ (199). However, there is regional variation, which may re ﬂ ect chronic PPI use (FGP association) and H. pylori prevalence (association with hyperplastic and adenomatous polyps) (106,200,201). Most GEPs arise in the setting of in ﬂ ammatory conditions (e.g., H. pylori gastritis and AIG), and a limited

number occurs in polyposis syndromes. Repeated episodes of mucosal injury and repair ultimately may lead to genetic mutations that induce neoplasia. Most polypoid gastric dysplastic lesions arise in a background of gastritis and metaplasia. Therefore, biopsy of the ﬂ at mucosa surrounding the gastric polyp and Sydney protocol biopsies are indicated, unless the polyp is clearly an FGP.

Sporadic FGPs are typically small, hyperemic, sessile and have a smooth surface contour (Figure 7). They occur exclusively in the gastric fundus and corpus. Occasionally sporadic FGPs harbor surface dysplasia; however, the risk of progression for these patients is essentially nil (202,203). FGPs may develop after longterm PPI use and are not associated with an increased risk of gastric adenocarcinoma. Multiple FGPs $(>\!50)$ in young patients, especially those not taking PPIs, should raise suspicion for FAP and other polyposis syndromes (i.e., attenuated FAP, gastric adenocarcinoma, proximal polyposis of the stomach [GAPPS], and MUTYH-associated polyposis). These patients should be referred for genetic evaluation and colonoscopy, and their management is reviewed in detail in prior literature (204). Approximately onethird of FGPs in patients with FAP have surface dysplasia, but most do not progress except in patients with GAPPS (205).

Gastric hyperplastic polyps (particularly large ones) and adenomas are considered premalignant conditions (GPMC). Gastric hyperplastic polyps have a smooth, red buttered appearance with white exudates. While usually small and dome shaped, they can become lobulated or pedunculated with super ﬁ cial erosions. Hyperplastic polyps are associated with gastric atrophy with or without intestinal metaplasia (206 – 208). Thus, it is important to biopsy the surrounding mucosa with a systematic gastric sampling protocol. Hyperplastic polyps may harbor dysplasia in $1.9\%{-}19\%$ of cases and undergo malignant transformation in up

to $2\%$ ofcases (209,210). Neoplastic transformation is seen mostly in hyperplastic polyps ${>}10\,\mathrm{\mm}$ . Hyperplasia of the foveolar epithelium is a separate entity, with white ﬂ at lesions and a foveolar pit pattern. Limited evidence suggests that foveolar hyperplasia is a benign entity associated with chronic PPI use.

Sporadic gastric adenomas are rare. Polypoid gastritisassociated dysplastic lesions have been traditionally classi ﬁ ed as adenomas, including by the World Health Organization (211). Because gastritis-associated dysplastic polyps have been termed “ adenomas ” (212 – 214) rather than “ endoscopically de ﬁ ned dysplastic lesions, ” recent guidelines may create misunderstanding (215,216). Adenomas or adenomatous polyps are usually single lesions, pedunculated or sessile, in the antrum or incisura. They have a velvety pink lobulated appearance. They most often occur in the setting of H. pylori -associated gastric atrophy with or without metaplasia, arguing for systematic biopsies of the surrounding mucosa. Approximately $40\%$ of adenomatous polyps harbor dysplastic foci, particularly those ${\geq}20$ mm. Adenomatous gastric polyps are also strongly associated with synchronous GC, which re ﬂ ects the “ ﬁ eld e ﬀ ect ” of the surrounding mucosa harboring other stages along the Correa cascade (210,217,218). Gastric adenomas arising in the setting of normal gastric mucosa rarely occur, and this is usually in the setting of FAP (205,212,219).

Gastric NETs are typically hyperemic and multifocal but can have diverse endoscopic presentations di ﬃ cult to di ﬀ erentiate from other GPMC. The diagnosis and management of NETs are beyond the scope of this guideline and are reviewed elsewhere (220).

Endoscopic management of GEP

The endoscopic approach to GEP is based on histologic subtype, polyp size, and morphologic features. However, during the index

![Fundicgland polyp Hyperplasticpolyp Adenomatouspolyp Neuroendocrinetumor Typicallysmall,hyperemic,sessile, Smooth，redbuttered,withwhite Variable presentation(red or Velvety,pink,lobulatedappearance withasmoothsurfacecontour exudates yellowish),hyperemic,multifocal ](https://venus-llm-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-03-15/4a5e1cc6-4c0b-4544-bbb1-127aa45b0924/4a5e1cc6-4c0b-4544-bbb1-127aa45b0924.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1742023869%3B1742027469&q-key-time=1742023869%3B1742027469&q-header-list=host&q-url-param-list=&q-signature=2d6d1ac5ff001a3eb8ac7b0e6441abc8fa48ea15) Gastric epithelial polyps: endoscopy (HDWLE, NBI) and histology correlation. HDWLE, high definition white light endoscopy; NBI, narrow band imaging.

Figure 7.

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|Table 5. Knowledge gaps and future research directions for GPMC and gastric cancer| |---| |Gastric cancer screening in the United States | |·Randomized clinical rials are needed to evaluate the utity of GC/GPMC screening on GC incidence and mortality, and potential harms of screening| | · Risk prediction models for GC/GPMC are needed to identify the optimal screening population. Initial US studies may incorporate “convenience endoscopy” paired with screening colonoscopy for patients at increased risk for GC. The optimal threshold for GC/GPMC screening using endoscopy alone without bundling with colonoscopy needs to be evaluated thereafter | | ·Theefectivenessof existing noninvasive biomarkers (eg, pepsinogens), aloneorin combination, edstobeealuated fortheirefectiveness for screening high-rsk GC/ GPMC populations. Novel noninvasive screening modalities (e.g., blood-based testing) are needed for GC/GPMC screening | |· Barriers and adherence to GC/GPMC screening of eligible groups warrant investigation, particularly among marginalized high-risk groups| | Diagnosis of GPMC| |Endoscopic evaluation| | ·Implementation and validation of upper endoscopy quality metrics specificallytargeting the gastric compartment (e.g., mucosal cleansing scores, gastric photodocumentation, and GIM detection rate) | |·Developmentof training interventions for US endoscopists for the diagnosis and management of GPMC/GC| |· The role of novel imaging (e.g., LCl) and synergistic technologies (machine learning, Al) in clinical algorithms warrant evaluation, along with cost-efectiveness studies | |Histopathologic evaluation| |· Develop standardized gastric pathology reporting systems, with consideration of GPMC| |·Advance methods to improve adherence to systematic biopsy protocols among gastroenterologists and related gastric pathology reporing among pathologists| |· Evaluate the outcomes for the current histology markers of GIM high-risk subtypes (e.g., incomplete and extensive GIM)| |· Implement methods to improve the interobserver variability for reporting dysplasia, with a focus on IND and LGD| |· Develop protocols for the use of the OLGA/OLGIM system in the gastroenterology and pathology disciplines, and investigate patient outcomes| | GPMC endoscopic surveillance and dysplasia treatment| |· Develop registries for the evaluation of the clinical impact of GPMC surveilance programs (e.g., proportion of GC diagnosed as early GC, GC incidence, and GC 5-yr survival)| |·Investigate the optimal interval forendoscopic surveillance in patients diagnosed with GPMC according toa risk-stratified approach, which includes when to stop surveillance| |· Develop robust risk prediction models that accurately predict AG/GIM progression in US populations and are prospectively validated| |· Identify noninvasive (e.g., serum-based) and tissue-based markers of progression that are prospectively validated in US populations| |· Prospective studies to evaluate the natural history of indeterminate and low-grade dysplasia| |· Prospective studies to evaluate the optimal timeframe and approach to repeat endoscopic evaluation of nonvisible gastric dysplasia (i.e., "second-look endoscopy")| | ·Health-system research on optimization of referals to high-volume ESD centers/providers in the United States. Peform microsimulation analyses with US data to evaluate the impact of ESD access and clinical outcomes for patients with dysplasia | |· Develop and implement a standardized ESD curriculum in advanced endoscopy training programs | |Nonendoscopic management of GPMC| |· Enhanced efforts to identify chemoprevention agents for GPMC progression | |· Develop robust interventional trials to understand the impact of diet and behavioral changes (e.g., smoking) on GPMC prevalence and GPMC progression| |· Develop robust clinical trials to better understand the impact of chronic gastric acid suppression (e.g., PI and PCAB) on GPMC and GPMC progression| | Autoimmune gastritis| |· Clarify the risk of adenocarcinoma in patients with autoimmune gastritis, with and without H. pylorinfection| |· Improve detection of autoimmune gastritis with attention to appropriate biopsy protocols | |Gastric epithelial polyps| | · Design studies to understand the natural history of hyperplastic polyps and adenomas, and the modulatory effects of background mucosal disorders (e.g., H. pylorinfection and GPMC) | |· Larger studies describing the risk of dysplasia and carcinoma in gastric polyps (5-20 mm)| |· Prospective studies describing the adequate time interval for surveillance after resection of hyperplastic polyps and adenomatous polyps| |Education initiatives| | ·Training initiatives, following the example of East Asia programs, are imperative to improve outcomes related to the diagnosis of GPMC and (early) GC,incorporation of novel imaging technologies, pathology protocols, and endoscopy therapeutics | | AG, atrophic gastritis; Al, arificial inteligence; AIG, autoimmune gastritis; EGC, early gastric cancer; ESD, endoscopic submucosal dissection; GC, gastric cancer; GIM, gastric intestinal metaplasia; GPMC, gastric premalignant condition; LCI inked color imaging; OLGA, Operative Link on Gastritis Assessment; OLGIM, Operative Link on Gastric Intestinal Metaplasia Assessment; PCAB, potassium-competitive acid blocker; PPl, proton pump inhibitor. | ||

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endoscopy, the de ﬁ nitive histologic subtype may not be clear. Therefore, obtaining biopsies from any GEP that is not an obvious FGP is recommended for histopathological assessment. One meta-analysis showed that forceps biopsy of hyperplastic and adenomatous polyps can miss foci of HGD or carcinoma. Speci ﬁ cally, $25\%$ of these polyps were upgraded after complete excision, with gastric HGD in $16.7\%$ and adenocarcinoma in $6.9\%$ . Upstaging is more frequent in lesions ${\geq}20\;\mathrm{mm}$ , and lesions with depressed or nodular features (160). If there are no contraindications, small GEP should be completely excised for both diagnosis and therapy, considering that complete excision ismore likely to reveal dysplasia neoplasia (221). Data extrapolated from colon polypectomies suggest that diminutive polyps $({\leq}3~\mathrm{mm})$ may be removed completely with forceps, but snare polypectomy is suggested for polyps . 3 mm (222,223). In patients with larger polyps, concerns for bleeding, or incomplete resection, a “ biopsythen-resect ” approach is advised allowing time to discuss with the patient the risks and bene ﬁ ts of endoscopic resection or referral.

The resection and surveillance plan should be tailored to the polyp subtype if previous histology results are available. FGPs (in the absence of FAP) seldom harbor dysplasia or adenocarcinoma (202,203). Excision of FGPs is only suggested if the polyp is ${>}10~\mathrm{mm}$ or ulcerated. Hyperplastic polyps may harbor dysplasia or carcinoma. Despite heterogeneity in the literature, with most reports being ${>}30$ years old or from high-incidence countries, carcinoma foci were frequently reported in polyps ${>}10\,\mathrm{mm}$ (224,225). Therefore, several guidelines recommend resection of all hyperplastic polyps . 10 mm or ${>}5\,\mathrm{mm}$ (29,226). However, in weighing the uncertain bene ﬁ t due to quality of the data and indirectness with the potential risk of complications due to resection (e.g., bleeding), we could not make a recommendation regarding the resection of all hyperplastic polyps ${\tt>}5~\mathrm{mm}$ , although it seems prudent to resect hyperplastic polyps ${>}10~\mathrm{mm}$ . Adenomas are more likely to harbor microscopic carcinoma foci $(5\%{-10\%}$ in small case series and up to $50\%$ in polyps ${>}20\;\mathrm{mm}$ ) (218). Most consortia recommend resection of all adenomas regardless of size (29,216,227). Similar to ﬂ at lesions with dysplasia, hyperplastic polyps or adenomas ${\leq}10\ \mathrm{mm}$ can be removed with EMR, but ESD should be considered for lesions ${>}10{-}20\ \mathrm{mm}$ (160,167).

Most international GI societies recommend surveillance endoscopy after resection of hyperplastic polyps or adenomas, but high-quality data informing optimal surveillance intervals are lacking (29,216). Current evidence demonstrates no clear bene ﬁ t from performing surveillance endoscopy after complete excision of high-risk sporadic FGP (228). Considering that gastric adenomas are strongly associated with synchronous neoplasia (up to $30\%$ ), follow-up endoscopy is recommended within 12 months regardless of background mucosa (e.g., GIM). In patients with resected hyperplastic polyps ${>}10\ \mathrm{mm}$ , surveillance endoscopy can be considered in 12 months (207,229). Subsequent surveillance endoscopies for adenomas and hyperplastic polyps are dictated by the background mucosa, per GPMC surveillance recommendations herein.

CONCLUSIONS

The GPMC research agenda to support the implementation, evolution, and optimization of clinical practice related to the diagnosis and management of GPMC in the United States is extensive (Table 5). Critical areas include the study of health

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outcomes related to GPMC surveillance, screening for GC, barriers to prevention in marginalized populations, novel diagnostic and prognostic biomarkers, advancement of endoscopic technologies (e.g., IEE, AI, and therapeutics) and gastroenterology training, novel H. pylori treatment and adjuvant measures, and chemoprevention, speci ﬁ cally as these relate to the impact on GC incidence and mortality. Coordination with pathology colleagues at the local and national levels is imperative. Research in AIG and GEP is needed, each area with substantial knowledge gaps. In parallel, training initiatives, following the example of East Asia programs, are critical, particularly in the areas of endoscopic diagnosis and therapeutics.

These ACG Guidelines for the management of GPMC are a paradigm shift in US clinical practice. Implementation and change in clinical practice will require concrete targets and include training and quality initiatives. It is anticipated that this will begin to address the marked US GC disparity, and the burden on minority and marginalized populations. The overarching goals are to reduce GC incidence in the United States, increase the detection of early stage disease (early GC), and to signi ﬁ cantly increase the 5-year survival rates in the near term.

ACKNOWLEDGEMENTS

This guideline was produced in collaboration with the Practice Parameters Committee of the American College of Gastroenterology. The Committee gives special thanks to Brijen Shah, MD, who served as the guideline monitor for this document; Jennifer Westrick who performed the systematic review of literature; and Jose Ignacio Vargas, MD (Department of Gastroenterology, Faculty of Medicine, Ponti ﬁ cia Universidad Cat´olica de Chile, Santiago, Chile), for providing endoscopic photographs.

CONFLICTS OF INTEREST

Guarantor of the article: Douglas R. Morgan, MD, MPH, FACG. Speci ﬁ c author contributions: All authors contributed in the analysis and interpretation of evidence, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Financial support: NCI P01CA028842, R01CA190612, K07CA125588, and P30CA068485 (D.R.M.); VA ICX002027A and NIH P30 DK120515 (S.C.S.); FONIS SA19/0188, European Union ’ s Horizon 2020 research and innovation program grant agreement no. 825832 FONDECYT 1230504, and FONDAP 152220002 (A.R.). Potential competing interests: D.R.M.: research support: Panbela Therapeutics, Thorne Research, American Molecular Labs. J.E.C., D.L. and E.A.M.: None. S.C.S.: ad hoc consultant and advisor to Phathom Pharmaceuticals and RedHill Biopharma. A.R.: research support: American Molecular Labs.

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表 1
Qualityofevidence	Criteria
High	We are very confident that the true effect lies close to that of the estimate of the effect
Moderate	We are moderately confident in the effect
Moderate	estimate: The true effect is likely to be close to the estimate of the effect, but there is
Moderate	a possibility that it is substantially different
Moderate	LOW
	The true effect may be substantially different
	from the estimate of the effect
Verylow	We have very little confidence in the effect estimate: The true effect is likely to be
Verylow	estimate: The true effect is likely to be substantially different from the estimate of
Verylow

表 2
Table 2. (continued)
15. In patients with confirmed complete resection of dysplasia, we suggest endoscopic surveillance. We recommend surveillance examinations be performed by an experienced endoscopist and using HDWLE and IEE, with biopsies according to the systematic biopsy protocol in addition to targeted biopsies (Low quality of evidence, strong recommendation)
GPMC nonendoscopic management
16. We recommend testing for Helicobacter pylori (and eradication treatment if positive) in patients with GPMC and resected early GC to reduce the risk of progression to GC and metachronous early GC, respectively (Moderate quality of evidence, strong recommendation)
17. We do not suggest the use of aspirin, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, or antioxidants for individuals with GPMC for the purpose of GC chemoprevention (Very low quality of evidence, conditional recommendation)
Autoimmunegastritis
18. Among individuals diagnosed with AIG, we recommend assessment for H. pylorinfection with a nonserological test, eradication treatment if positive, and posttreatment testing to confirm eradication (Low quality of evidence, strong recommendation)
19. There is insufficient evidence to make a formal recommendation on endoscopic surveillance in individuals with AlG. Given the increased risk of type 1 neuroendocrine tumors and the possible increased risk of GC, individualized surveillance may be considered (Low quality of evidence, conditional recommendation)
Gastric epithelial polyps
20. We recommend endoscopic resection of all gastric adenomas,regardless of size, to exclude and prevent dysplasia and early GC. Foradenomas that are not amenable to endoscopic resection, we recommend referral for surgical resection, if clinically appropriate (Low quality of evidence, conditional recommendation)
21. We could not make a recommendation on the endoscopic resection of all hyperplastic polyps greater than 10 mm in size based on the current evidence (Insufficient evidence, no recommendation)
22. In individuals with GEP, with the exception offundic gland polyps, we recommend systematic gastric biopsies(e.g., updated Sydney protocol) be obtained from the surrounding flat mucosa given the high prevalence of GPMC, H. pylori infection, and AlG in these patients (Very low quality of evidence, conditional recommendation)
AIAN, American Indian and Alaska Native; AIG, autoimmune gastritis; GC, gastric cancer; GEP, gastric epithelial polyps; GIM, gastric intestinal metaplasia; GPMC, gastric premalignant condition; HDWLE, high-definition white lightendoscopy; HGD, high-grade dysplasia; IEE, image-enhanced endoscopy;IND, low-grade dysplasia; LGD, low- grade dysplasia.

表 3
Table 3.Key concepts for the management of GPMc
GC epidemiology and screening
·The epidemiologic and biologic rsk factors overlap, and yet are distinct, for the 3outcomes of GPMC prevalence, GC incidence, and GPMCto GC progression. Mechanistic studis and novel biomarkers are needed to improve our understanding and surveillance paradigms for GPMC to GC progression
·There are no randomized clinical trals from the United States norother populations evaluating the efficacy of GC screening. The large observational studies from East Asia and meta- analyses of these studies demonstrate that endoscopyforGC screening is associated with asubstantialreduction in GC mortality, and a 5-yrsurvivalof nearly 70%This is primarly driven by the increased detection of early-stage GC (eligible for endoscopic resection), rather than a decrease in incident GC.
· Endoscopic screening should be considered in persons with a family history of GC (first-degree relative) on an individualized basis. Endoscopy would startat age 45-60 or 10 years before the diagnosis of GC in the youngest affected family member. These individuals should be screened for H. pyloriand eradicated if positive.
·Firstgeerationmmigrant populationscontribute totheraceandethnicitydisparityofGCincidence intheU.ndoscoic screeningshouldbeonsiderednanindividualiedbasis, withshared decisionainnthgest-risdiviulsCincidencearwidcrsnatisandggrahc rn,wththhighst nidencerensnEast AsiaEastrein western Russia), and Central/South America. The South America high-incidence area encompasses the Andean region from Colombia to Chile. Immigrant generation and level of acculturation affect risk. These individuals should be screened for H. pylori and eradicated if positive.
GPMC endoscopic and histologic diagnosis
·A high-quality endoscopy examination of the gastric compartment has 5 main components:(i use of HDWLE;(i adequate gastric distension using insuffation (CO2 preferably, or air) to flaten the gastric folds and expose the gastric mucosa adequately; (i) mucosal cleansing to clearalldebris, mucous and bubbles; (iv) standard photodocumentation; and (v) adequate gastric inspection time.Gastric examination time and photodocumentationare surrogate quality metricsforthe gastric evaluation. The 2-3 min upperendoscopy, especialy for patients with GPMC, flls short of the standard of care.
·HDWLEand IEE eg, narowband maging, blue lasemaging, etc)are aropriate forinividual withat increased GC risk, thosewth susected GPMCorGCdurin endso, and those undergoing GPMC suveilance. Near focus and optical zoom are helpful but not mandatory for GPMC detection.
·Thecoordinationbetweenthegastroenterologistand pathologistfor pathology reporing iscriticalfordelineationofthe patientGPMCsurveilance plan.Thiscoordinationisneededat the locallevel (“localadvocates"), as wellas the national society evel Pathology reort details should include information specific to stomach lcation(eg, antrum, incisura and corpus), AG and GIM severity(biopsy-specific), AG and GIM extent (e.g., antrum and corpus), the subtype ofGIM (e.g., complete, incomplete, mixed), severityof dysplasia(IND, LGD, HGD), and presence/absence of H. pylori organisms, at a minimum.
·The diagnostic challenges for GPMC and dysplasia include sampling error during biopsies (e.g., AG and GIM patchy multifocality), the interobserver variabilityamong pathologists, particularly for IND and LGD, and the variable training among gastroenterologists for the detection of GPMC and early GC.
GPMC endoscopic surveillance
·Delineation of GPMC surveillance intervals requiresfurtherstudy in the US. Patients with multiple risk factors forGC may be considered forshorterthan 3-yr intervals. Forexample, an individual with extensive GIM and with a family history of GC may be considered for a 1-2-yr surveillance interval. Patient-physician decision-making for GPMC surveillance is appropriate in these cases
· We suggest against performing routine repeat endoscopy within 12 months in individuals with nondysplastic GPMC for the purpose of risk stratification unless there are concerns regarding the quality of the endoscopy oradherence to the Sydney biopsy protocol
·Weacknowdge that somestudissuggest that White race,ethnicity, and countryoforiginre important riskfactorsforprevalentGPMCandGC; yet, thesefactorsarenot proven be independent predictors of progression, although US and global studies are limited in this domain. However, endoscopic surveillance of individuals with GPMC who identify as a high-risk race or ethnicity or who emigrated from a high-incidence region, should be recommended for 3-yr endoscopic surveilance given the substantial increased risk of GC in these groups
·In patients with INDor GD without visible lesions, the rates of progressonare modest yet measurable. he surveillance interals are proposed but have nt been evaluated in prospective studies. We suggest a repeat endoscopic exam in 12 months if advanced neoplasia was confidently ruled out. Referralto an endoscopist with expertise in diagnosing and ideally resecting gastric neoplasia is reasonable.
·Patients with HGDwithoutvisiblemucosalabnormalitieshaveahigh probabityofeitheralreadyhavinga prevalentGCorprogressingtoGCwithinashortimeframe.Arepeatendoscopic exam within 3 months with an endoscopist with expertise in diagnosing and ideally endoscopically resecting gastric neoplasia is suggested.
·In patients with endoscopically resected dysplastic lesions, the optimal postresection surveillance interval has not been investigated in prospective studies. Shorer intervals maybe warranted in patients with additional risk factors for synchronous or metachronous GC
Autoimmune gastritis
·AGisniedgastricplatiiaei,e arhrtssiatdwicreerif differentiated neuroendocrine tumors of enterochromafi-like cells(also termed type I gastricarcinoid tumor and possibly gastric adenocarcinoma.
·The overlap of H. pylriassociated GPMC and AIG is common, and thus, the same risk stratification parametersapply, as does testing foractive H. pylorinfection and eradication treatment if positive. Individuals with AIG are also established to be at risk for type I carcinoids. In patients with AIG, surveillance with HD-WLE and IEE should be considered. The interval is determined based on GPMC risk stratification parameters (e.g., family history of GC), which should be individualied
Gastric epithelial polyps
·The malignant potentialof GEP is based on histology, polyp size, and the presence of specific polyposis syndromes. All patients withhyperplastic oradenomatous GEP should have standard Sydney protocol biopsies and testing for active H. pylorinfection, given the increased prevalence of GPMC in this setting
·There is insuffcient evidence to recommend endoscopic resection of hyperplastic polyps >10 mm at the index endoscopy. An individualied approach is warranted, with consideration of resection or biopsies, and 12 month surveilance, as clinically appropriate.
AG, atrophic gastritis; AIG, autoimmune gastritis; GC, gastric cancer; GEP, gastric epithelial polyps; GIM, gastric intestinal metaplasia; GPMC, gastric premalignant condition; HDWLE, high-definition white light endoscopy; HGD, high-grade dysplasia; IEE, image-enhanced endoscopy; IND, low-grade dysplasia; LGD,low-grade dysplasia.

表 4
Table 4. Hereditary and genetic gastric cancer syndromes	CD
Familial gastric cancer syndromes	CD
· Hereditary diffuse gastric cancer	CD
· CDH1 germline mutations (E-Cadherin)	CD
· Familial intestinal gastric cancer	CD
· Gastric cancer and proximal polyposis of the stomach	CD
Hereditary syndromes with increased gastric cancer risk	CD
· Gastrointestinal polyposis syndromes with increased gastric cancer risk	CD
· Familial adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis, MUTYH-associated polyposis	CD
· Cancer syndromes with increased gastric cancer risk	CD
· Lynch syndrome, hereditary breast and ovarian cancer syndrome, and Li-Fraumeni syndrome	CD
· Hereditary homologous recombination deficiency (e.g. BRCA1, BRCA2)	CD
Common germline gene variant syndromes are important regarding the biology; however, to date, they are not clinically actionable. Common gene variants with gastric cancer risk are often identified in genome-wide association studies, which are limited in number (e.g., Asia, Europe, and Latin America). In addition, there are gene variants which influence the H. pylori-environmental interactions, and specifically the inflammatory response (e.g., proinflammatory cytokine genotypes).	CD

表 5
Table 5. Knowledge gaps and future research directions for GPMC and gastric cancer
Gastric cancer screening in the United States
·Randomized clinical rials are needed to evaluate the utity of GC/GPMC screening on GC incidence and mortality, and potential harms of screening
· Risk prediction models for GC/GPMC are needed to identify the optimal screening population. Initial US studies may incorporate “convenience endoscopy” paired with screening colonoscopy for patients at increased risk for GC. The optimal threshold for GC/GPMC screening using endoscopy alone without bundling with colonoscopy needs to be evaluated thereafter
·Theefectivenessof existing noninvasive biomarkers (eg, pepsinogens), aloneorin combination, edstobeealuated fortheirefectiveness for screening high-rsk GC/ GPMC populations. Novel noninvasive screening modalities (e.g., blood-based testing) are needed for GC/GPMC screening
· Barriers and adherence to GC/GPMC screening of eligible groups warrant investigation, particularly among marginalized high-risk groups
Diagnosis of GPMC
Endoscopic evaluation
·Implementation and validation of upper endoscopy quality metrics specificallytargeting the gastric compartment (e.g., mucosal cleansing scores, gastric photodocumentation, and GIM detection rate)
·Developmentof training interventions for US endoscopists for the diagnosis and management of GPMC/GC
· The role of novel imaging (e.g., LCl) and synergistic technologies (machine learning, Al) in clinical algorithms warrant evaluation, along with cost-efectiveness studies
Histopathologic evaluation
· Develop standardized gastric pathology reporting systems, with consideration of GPMC
·Advance methods to improve adherence to systematic biopsy protocols among gastroenterologists and related gastric pathology reporing among pathologists
· Evaluate the outcomes for the current histology markers of GIM high-risk subtypes (e.g., incomplete and extensive GIM)
· Implement methods to improve the interobserver variability for reporting dysplasia, with a focus on IND and LGD
· Develop protocols for the use of the OLGA/OLGIM system in the gastroenterology and pathology disciplines, and investigate patient outcomes
GPMC endoscopic surveillance and dysplasia treatment
· Develop registries for the evaluation of the clinical impact of GPMC surveilance programs (e.g., proportion of GC diagnosed as early GC, GC incidence, and GC 5-yr survival)
·Investigate the optimal interval forendoscopic surveillance in patients diagnosed with GPMC according toa risk-stratified approach, which includes when to stop surveillance
· Develop robust risk prediction models that accurately predict AG/GIM progression in US populations and are prospectively validated
· Identify noninvasive (e.g., serum-based) and tissue-based markers of progression that are prospectively validated in US populations
· Prospective studies to evaluate the natural history of indeterminate and low-grade dysplasia
· Prospective studies to evaluate the optimal timeframe and approach to repeat endoscopic evaluation of nonvisible gastric dysplasia (i.e., "second-look endoscopy")
·Health-system research on optimization of referals to high-volume ESD centers/providers in the United States. Peform microsimulation analyses with US data to evaluate the impact of ESD access and clinical outcomes for patients with dysplasia
· Develop and implement a standardized ESD curriculum in advanced endoscopy training programs
Nonendoscopic management of GPMC
· Enhanced efforts to identify chemoprevention agents for GPMC progression
· Develop robust interventional trials to understand the impact of diet and behavioral changes (e.g., smoking) on GPMC prevalence and GPMC progression
· Develop robust clinical trials to better understand the impact of chronic gastric acid suppression (e.g., PI and PCAB) on GPMC and GPMC progression
Autoimmune gastritis
· Clarify the risk of adenocarcinoma in patients with autoimmune gastritis, with and without H. pylorinfection
· Improve detection of autoimmune gastritis with attention to appropriate biopsy protocols
Gastric epithelial polyps
· Design studies to understand the natural history of hyperplastic polyps and adenomas, and the modulatory effects of background mucosal disorders (e.g., H. pylorinfection and GPMC)
· Larger studies describing the risk of dysplasia and carcinoma in gastric polyps (5-20 mm)
· Prospective studies describing the adequate time interval for surveillance after resection of hyperplastic polyps and adenomatous polyps
Education initiatives
·Training initiatives, following the example of East Asia programs, are imperative to improve outcomes related to the diagnosis of GPMC and (early) GC,incorporation of novel imaging technologies, pathology protocols, and endoscopy therapeutics
AG, atrophic gastritis; Al, arificial inteligence; AIG, autoimmune gastritis; EGC, early gastric cancer; ESD, endoscopic submucosal dissection; GC, gastric cancer; GIM, gastric intestinal metaplasia; GPMC, gastric premalignant condition; LCI inked color imaging; OLGA, Operative Link on Gastritis Assessment; OLGIM, Operative Link on Gastric Intestinal Metaplasia Assessment; PCAB, potassium-competitive acid blocker; PPl, proton pump inhibitor.

图示：Antegrade Retrograde Antegrade Retrograde

图示：Normal Atrophicgastritis Intestinalmetaplasia Dysplasia Earlyadenocarcinoma Roundpitpatternsinthe Pallor,lossof folds,prominence Tubulovillousmucosalpattern, corpusandelongatedpit ofsubmucosalvenulesand elevationwithwhitishpatches Irregularvesselpatternswithlossofarchitecture patternsintheantrum atrophicborder(AB,whiteline) andlightbluecrest Antrum Fundus Complete Incomplete Low gradeHigh grade

图示：Near Focus

图示：Corpus OR OLGA Staging Mild Moderate Severe No Atrophy Atrophy Atrophy Atrophy 3 (score0) (score1) (score2) (score3) S No Atrophy(score O) STAGEO STAGEI STAGEII STAGEII (including incisura angularis) Mild Atrophy(score1) STAGEI STAGE STAGEI STAGEI (including incisura angularis) Moderate Atrophy(score2) STAGEII STAGEII STAGEIII STAGEIV (including incisura angularis) Severe Atrophy(score3) STAGEII STAGEI! STAGEIV STAGEIV #2 (including incisuraangularis) ANTRUM& CORPUS INCISURAANGULARIS OR corpus OLGIM Staging NO1M MildIM Moderate SevereIM (score0) (score 1) IM(score2) (score3) No IM (score 0) STAGEO STAGEI STAGEII STAGEII (including incisura angularis) Mild IM(score 1) STAGEI STAGEI STAGEII STAGEIII (including incisuraangularis) Moderate IM(score 2) STAGEII STAGEII STAGEIII STAGEIV (including incisuraangularis) (including incisuraangularis) Severe IM (score 3) STAGEIII STAGEIII STAGEIV STAGEIV Biopsy Report STAGEO STAGEI STAGEII STAGEIII STAGEIV

图示：Gastric intestinal Nonmetaplasticatrophic metaplasia gastritis Low-risk High-risk Low-risk High-risk Surveillancein3 Repeatexam in Nofurther Nofurther Surveillance in 3 years;consider 3yearsto surveillance surveillance years shorterinterval reassessrisk\* ifmultiplerisk RECOMMENDATIONS factors 1.In individualswith GIM who are considered highriskforprogression orgastric cancer,we suggestendoscopic surveillance at3-yearintervals.High-riskgroups Persistentlow-risk include individualswithnon-neoplastic GIMandatleastone of the following: ·High-risk GIM histology. ·IncompleteGIMhistologicalsubtypeversuscompletesubtye Nofurther ·Corpus-extension,defined ascorpusinvolvement alsowith antrumorincisurainvolvement surveillance ·AnyGlMhistologywithoneofthefollowinghigh-riskfactors: ·Familyhistoryofgastriccancerinafirst-degreerelative ·Foreign-born,with emigrationfroma high-incidence nation. ·Highriskraceorethnicity(EastAsian,Latino/a,Black&AlAN) 2.In individualswithsevere GIM orsevere atrophicgastritis in biopsiesofthe antrum and/or corpus,we suggest endoscopic surveillance at 3-yearintervals. 3.Severeisdefinedas≥2/3rdofglandinvolvement

图示：DysplasticGPMCManagement LGD HGD Confirmedby2expertGlpathologists Confirmedby2expertGlpathologists Referral toan endoscopistwith skill assessing and endoscopicallyresecting GPMCand neoplasiaforrepeatendoscopicexamusingHD-WLE+IEEandsystematicbiopsies Visible Nonvisible Visible Nonvisible Endoscopic Surveillance by an Endoscopic Surveillancebyan resectionen expertq6-12months resectionenbloc expertq3months bloc w/systematicbiopsies (ESD)orsurgical w/systematic resection biopsies Complete Incomplete Complete Incomplete Resection,RO Resection Resection,RO Resection Surveillance q1year Repeat endoscopy<6 months; Surveillanceq3-6 Repeatendoscopy<3months;if then continueq3 if still incompleteresection, monthsx1-2yearsthen stillincompleteresection,consider yearsifAG/GIM in surveillancevssurgical q3yearsifAG/GIM in surgicalresection remainingmucosa resection remainingmucosa

图示：Fundicgland polyp Hyperplasticpolyp Adenomatouspolyp Neuroendocrinetumor Typicallysmall,hyperemic,sessile, Smooth，redbuttered,withwhite Variable presentation(red or Velvety,pink,lobulatedappearance withasmoothsurfacecontour exudates yellowish),hyperemic,multifocal

引用 / 出处

2025 ACG临床指南：胃癌前病变的诊断和管理. 2025.