Big Data on Gastric Dysplasia Support Gastric Cancer Prevention

Abstract

As in other cancer settings, strategies for preventing gastric cancer (GC) demand a multimodal approach. A recent thorough study by Xiao et al1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar addresses the heterogeneous spectrum of epidemiologic, biologic, clinical, and operative variables involved in advanced gastric precancerous lesions. Because of the peculiar clinicopathologic setting of “cardia” precancerous lesions (<1% in the Xiao et al1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar study), this editorial focuses, in particular, on the important contribution of the Chinese study on the “proper gastric” advanced precancerous lesions.Multimodal primary and secondary GC prevention relies on 4 main pillars: (1) eradication of Helicobacter pylori infection,2Malfertheiner P. Megraud F. O'Morain C.A. et al.for the European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection: the Maastricht V/Florence Consensus Report.Gut. 2017; 66: 6-30Crossref PubMed Scopus (1644) Google Scholar,3Pimentel-Nunes P. Libânio D. Marcos-Pinto R. et al.Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019.Endoscopy. 2019; 51: 365-388PubMed Google Scholar (2) the “digitalized eyes” of well-trained endoscopists,2Malfertheiner P. Megraud F. O'Morain C.A. et al.for the European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection: the Maastricht V/Florence Consensus Report.Gut. 2017; 66: 6-30Crossref PubMed Scopus (1644) Google Scholar, 3Pimentel-Nunes P. Libânio D. Marcos-Pinto R. et al.Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019.Endoscopy. 2019; 51: 365-388PubMed Google Scholar, 4Delgado-Guillena P.G. Morales-Alvarado V.J. Elosua-González A. et al.Gastroenterologists' attitudes on the detection and management of gastric premalignant conditions: results of a nationwide survey in Spain.Eur J Cancer Prev. 2021; 30: 431-436Crossref PubMed Scopus (2) Google Scholar (3) the diagnostic reliability of (skilled) pathologists, and (4) structured health care systems and specialists familiar with the clinical management of patients at risk.5Hamashima C. for the Systematic Review Group and Guideline Development Group for Gastric Cancer Screening Guidelines. Update version of the Japanese Guidelines for Gastric Cancer Screening.Jpn J Clin Oncol. 2018; 48: 673-683Crossref PubMed Scopus (133) Google ScholarEtiology of Dysplasia: Helicobacter Pylori Infection and OthersH pylori is, by far, the main driver of any (nonsyndromic) biologic pathway toward gastric dysplasia (GDy). Whether dysplasia derives primarily from bacterial genotoxicity or from molecular damage triggered by inflammation remains to be clarified.6Yamaoka Y. Graham D.Y. Helicobacter pylori virulence and cancer pathogenesis.Future Oncol. 2014; 10: 1487-1500Crossref PubMed Scopus (98) Google Scholar,7Navashenaq J.G. Shabgah A.G. Banach M. et al.The interaction of Helicobacter pylori with cancer immunomodulatory stromal cells: new insight into gastric cancer pathogenesis.Semin Cancer Biol. 2021; (S1044-579X(21)00248-0)Crossref PubMed Scopus (11) Google Scholar Anti–H pylori therapy is mandatory in infected patients, and low-grade lesions may no longer be detectable after the bacterium’s successful eradication.2Malfertheiner P. Megraud F. O'Morain C.A. et al.for the European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection: the Maastricht V/Florence Consensus Report.Gut. 2017; 66: 6-30Crossref PubMed Scopus (1644) Google Scholar,3Pimentel-Nunes P. Libânio D. Marcos-Pinto R. et al.Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019.Endoscopy. 2019; 51: 365-388PubMed Google Scholar The chances of finding GDy in individuals never infected with H pylori are minimal (if any).8Nordenstedt H. Graham D.Y. Kramer J.R. et al.Helicobacter pylori-negative gastritis: prevalence and risk factors.Am J Gastroenterol. 2013; 108: 65-71Crossref PubMed Scopus (54) Google Scholar Eradicating H pylori does not abolish the risk of GDy, however, which may be also promoted by atrophy-induced modifications in the microbiota.1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar,9Chen H.N. Wang Z. Li X. et al.Helicobacter pylori eradication cannot reduce the risk of gastric cancer in patients with intestinal metaplasia and dysplasia: evidence from a meta-analysis.Gastric Cancer. 2016; 19: 166-175Crossref PubMed Scopus (127) Google Scholar GDy is associated far more rarely with primary autoimmune gastritis,10Rugge M. Savarino E. Sbaraglia M. et al.Gastritis: the clinico-pathological spectrum.Dig Liver Dis. 2021; 53: 1237-1246Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar which is in keeping with the results obtained by Xiao et al,1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar who documented mild or moderate GDy in about 2% of their metaplastic or nonmetaplastic corpus-restricted (ie, autoimmune) atrophic gastritis.Gastric Dysplasia: Natural HistoryDysplasia: Not a Minor By-product of Cancer, but a Major Product of AtrophyUntil the mid-20th century, GDy was considered a minor lesion accompanying invasive cancers.11Ming S.C. Goldman H. Gastric polyps: a histogenetic classification and its relation to carcinoma.Cancer. 1965; 18: 721-726Crossref PubMed Scopus (161) Google Scholar Over the last 30 years, however, clinical and histologic evidence unequivocally identified dysplasia as genetically modified neoplastic cell clones lacking in invasive capability. Dysplasia was consequently renamed “intraepithelial neoplasia,” but the term dysplasia is still often used.12Rugge M. Correa P. Dixon M.F. et al.Gastric dysplasia: the Padova international classification.Am J Surg Pathol. 2000; 24: 167-176Crossref PubMed Scopus (347) Google Scholar,13Kushima R, Lauwers GY, Rugge M. Gastric dysplasia. In: WHO Classification of Tumors Editorial Board, ed. Digestive system tumors. 5th ed. Geneva: WHO Press, 2019:71–75.Google ScholarA crucial change came with the realization that dysplastic foci almost never occur in healthy stomachs. Dysplasia develops mainly in stomachs featuring severe morphofunctional changes and a markedly reduced population of native glands.14Rugge M. Genta R.M. Graham D.Y. et al.Chronicles of a cancer foretold: 35 years of gastric cancer risk assessment.Gut. 2016; 65: 721-725Crossref PubMed Scopus (48) Google Scholar,15Rugge M. Genta R.M. Fassan M. et al.OLGA gastritis staging for the prediction of gastric cancer risk: a long-term follow-up study of 7436 patients.Am J Gastroenterol. 2018; 113: 1621-1628Crossref PubMed Scopus (68) Google Scholar Such anatomic alterations lead to the failure of the distinctive phylogenetic gastric function: acid production (hypochlorhydria or achlorhydria).16Hunt R.H. Camilleri M. Crowe S.E. et al.The stomach in health and disease.Gut. 2015; 64: 1650-1668Crossref PubMed Scopus (195) Google Scholar On these grounds Correa founded his visionary “cascade,” with dysplasia as the earliest-appearing neoplastic phenotype in a stepwise series of morphofunctional changes.17Correa P. Haenszel W. Cuello C. et al.A model for gastric cancer epidemiology.Lancet. 1975; 2: 58-60Abstract PubMed Scopus (875) Google Scholar This radically changed how dysplasia is interpreted: from a lesion developing with cancer to a neoplastic process developing from an atrophic stomach. Mucosal atrophy is now universally recognized as the cancerization field in which (nonsyndromic) GC develops.18McDonald S.A. Greaves L.C. Gutierrez-Gonzalez L. et al.Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells.Gastroenterology. 2008; 134: 500-510Abstract Full Text Full Text PDF PubMed Scopus (198) Google ScholarHistologic Phenotypes of DysplasiaThe World Health Organization defines dysplasia as “unequivocal epithelial neoplastic changes, with no evidence of stromal invasion,”13Kushima R, Lauwers GY, Rugge M. Gastric dysplasia. In: WHO Classification of Tumors Editorial Board, ed. Digestive system tumors. 5th ed. Geneva: WHO Press, 2019:71–75.Google Scholar but “unequivocal” is an “equivocal” descriptor. Particularly in the earliest stages of invasive cancer, histologic evidence of invasion may be controversial, possibly necessitating a second opinion when dysplasia is diagnosed, particularly if major invasive therapies are envisaged.3Pimentel-Nunes P. Libânio D. Marcos-Pinto R. et al.Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019.Endoscopy. 2019; 51: 365-388PubMed Google ScholarBased on hematoxylin-eosin staining and/or immune profiling, the 2 most prevalent dysplasia phenotypes are labelled as “intestinal” and “foveolar.”12Rugge M. Correa P. Dixon M.F. et al.Gastric dysplasia: the Padova international classification.Am J Surg Pathol. 2000; 24: 167-176Crossref PubMed Scopus (347) Google Scholar,13Kushima R, Lauwers GY, Rugge M. Gastric dysplasia. In: WHO Classification of Tumors Editorial Board, ed. Digestive system tumors. 5th ed. Geneva: WHO Press, 2019:71–75.Google Scholar The former arises in or from intestinalized glands mimicking large bowel adenomas and coexpressing CDX2, MUC2, and CD10, and its β-catenin nuclear expression is significantly greater than in foveolar dysplasia. The latter recalls the phenotype of foveolar/pyloric-type glands, mostly exhibiting MUC5A and/or MUC6 immunostaining.13Kushima R, Lauwers GY, Rugge M. Gastric dysplasia. In: WHO Classification of Tumors Editorial Board, ed. Digestive system tumors. 5th ed. Geneva: WHO Press, 2019:71–75.Google Scholar,19Sugai T. Uesugi N. Habano W. et al.The clinicopathological and molecular features of sporadic gastric foveolar type neoplasia.Virchows Arch. 2020; 477: 835-844Crossref PubMed Scopus (4) Google Scholar Mixed or “null” variants have also been described. “Unconventional,” less prevalent dysplasia variants include: crypt, pit, serrated, oxyntic, and the newly proposed Epstein-Barr virus–associated subtype.20Pereira D. Kővári B. Brown I. et al.Non-conventional dysplasias of the tubular gut: a review and illustration of their histomorphological spectrum.Histopathology. 2021; 78: 658-675Crossref PubMed Scopus (10) Google Scholar All GDy variants are recognized at risk of progression, and this risk is judged mainly on the strength of GDy grading, and the staging of coexisting atrophic lesions.21Shah S.C. Piazuelo M.B. Kuipers E.J. et al.AGA Clinical Practice Update on the Diagnosis and Management of Atrophic Gastritis: expert review.Gastroenterology. 2021; 161: 1325-1332Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 22Rugge M. Capelle L.G. Cappellesso R. et al.Precancerous lesions in the stomach: from biology to clinical patient management.Best Pract Res Clin Gastroenterol. 2013; 27: 205-223Crossref PubMed Scopus (81) Google Scholar, 23Rugge M. Genta R.M. Di Mario F. et al.Gastric cancer as preventable disease.Clin Gastroenterol Hepatol. 2017; 15: 1833-1843Abstract Full Text Full Text PDF PubMed Scopus (129) Google ScholarGiven its major impact on patient management, histologic grading is far more important than subtyping. Since the late 20th century, the traditional 3-tiered grading system has been collapsed into 2 tiers: low-grade dysplasia (LGD), and high-grade dysplasia (HGD).11Ming S.C. Goldman H. Gastric polyps: a histogenetic classification and its relation to carcinoma.Cancer. 1965; 18: 721-726Crossref PubMed Scopus (161) Google Scholar, 12Rugge M. Correa P. Dixon M.F. et al.Gastric dysplasia: the Padova international classification.Am J Surg Pathol. 2000; 24: 167-176Crossref PubMed Scopus (347) Google Scholar, 13Kushima R, Lauwers GY, Rugge M. Gastric dysplasia. In: WHO Classification of Tumors Editorial Board, ed. Digestive system tumors. 5th ed. Geneva: WHO Press, 2019:71–75.Google Scholar This has improved interobserver agreement on histologic findings, and simplified treatment decisions. Observational long-term follow-up studies have associated HGD with a higher risk of progression, the reported prevalence of which varies enormously, from 10% to 100% in HGD as opposed to 0% to 32% in LGD.1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar,24Park S.Y. Jeon S.W. Jung M.K. et al.Long-term follow-up study of gastric intraepithelial neoplasias: progression from low-grade dysplasia to invasive carcinoma.Eur J Gastroenterol Hepatol. 2008; 20: 966-970Crossref PubMed Scopus (57) Google Scholar,25Rugge M. Cassaro M. Di Mario F. et al.for the Interdisciplinary Group on Gastric Epithelial Dysplasia (IGGED). The long term outcome of gastric non-invasive neoplasia.Gut. 2003; 52: 1111-1116Crossref PubMed Scopus (155) Google Scholar This significant variability may be caused by patients’ ethnicity, H pylori status or comorbidities, or by diagnostic criteria, and study design. Unfortunately, because of the retrospective design of their study, Xiao et al1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar necessarily collapsed mild with moderate GDy grades, which has limited any critical appraisal on the clinical advantages offered by the 2-tiered histologic assessment.The Molecular Profiling ControversyMolecular profiling of dysplastic lesions was expected to replace the clinical impact of traditional histologic grading, potentially leading to targeted therapies. GDy has revealed a large array of molecular profiles, however, making it difficult to obtain consistent discriminating information to support clinical practice.26Businello G. Angerilli V. Parente P. et al.Molecular landscapes of gastric pre-neoplastic and pre-invasive lesions.Int J Mol Sci. 2021; 22: 9950Crossref PubMed Scopus (6) Google Scholar Without excluding a biologic heterogeneity, even because of the possible occurrence of multiple (coexisting, or metachronous) lesions (22% in the Xiao et al1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar study), inconsistencies in GDy molecular profile may be affected by several covariables, including ethnicity, differences in histologic assessment, the use of biopsy versus resection specimens, or fresh versus formalin-fixed, paraffin-embedded tissues samples, and technical issues. Whatever the molecular qualities of the alterations documented, the prevalence of abnormalities/dysregulations basically increases from LGD to HGD, to early invasive cancer.13Kushima R, Lauwers GY, Rugge M. Gastric dysplasia. In: WHO Classification of Tumors Editorial Board, ed. Digestive system tumors. 5th ed. Geneva: WHO Press, 2019:71–75.Google Scholar,26Businello G. Angerilli V. Parente P. et al.Molecular landscapes of gastric pre-neoplastic and pre-invasive lesions.Int J Mol Sci. 2021; 22: 9950Crossref PubMed Scopus (6) Google Scholar Intriguingly, some changes documented in nondysplastic lesions may no longer be detectable in LGD, then feature again in HGD. These on-and-off findings support the nonlinear progression of Correa’s model, and deserve careful clinical attention.Dysplasia-associated mutations involve oncogenes and tumor suppressors, such as APC, Tp53, MUC6, ARID2, KRAS, and BRAF, to mention but a few.27Rokutan H. Abe H. Nakamura H. et al.Initial and crucial genetic events in intestinal-type gastric intramucosal neoplasia.J Pathol. 2019; 247: 494-504Crossref PubMed Scopus (18) Google Scholar Posttranscriptional micro-RNA dysregulations (downregulated miR-26a, miR-375; upregulated miR 106a, miR-107, miR-300), functionally acting as either oncogenes or tumor suppressors, have also been documented.27Rokutan H. Abe H. Nakamura H. et al.Initial and crucial genetic events in intestinal-type gastric intramucosal neoplasia.J Pathol. 2019; 247: 494-504Crossref PubMed Scopus (18) Google Scholar,28Hwang J. Min B.H. Jang J. et al.MicroRNA expression profiles in gastric carcinogenesis.Sci Rep. 2018; 8: 14393Crossref PubMed Scopus (50) Google ScholarEndoscopy in the Assessment and Treatment of DysplasiaEndoscopy can identify and treat dysplastic lesions. White light endoscopy, chromoendoscopy, narrow band imaging (NBI), magnifying endoscopy with NBI, and blue laser imaging have all been tested for their reliability in identifying potentially dysplastic foci. The sensitivity of white light endoscopy in detecting GDy is 51%–74%. NBI and magnifying endoscopy with NBI can further improve the sensitivity of endoscopy to 92%.29Young E. Philpott H. Singh R. Endoscopic diagnosis and treatment of gastric dysplasia and early cancer: current evidence and what the future may hold.World J Gastroenterol. 2021; 27: 5126-5151Crossref PubMed Scopus (8) Google ScholarCombined with visual inspection, biopsy sampling enables the microscopic profiling of GDy foci and surrounding mucosa, the latter providing important information on the risk of synchronous/metachronous neoplasia associated with high-stage (OLGA stages III-IV) gastritis.1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar,14Rugge M. Genta R.M. Graham D.Y. et al.Chronicles of a cancer foretold: 35 years of gastric cancer risk assessment.Gut. 2016; 65: 721-725Crossref PubMed Scopus (48) Google Scholar,15Rugge M. Genta R.M. Fassan M. et al.OLGA gastritis staging for the prediction of gastric cancer risk: a long-term follow-up study of 7436 patients.Am J Gastroenterol. 2018; 113: 1621-1628Crossref PubMed Scopus (68) Google Scholar,22Rugge M. Capelle L.G. Cappellesso R. et al.Precancerous lesions in the stomach: from biology to clinical patient management.Best Pract Res Clin Gastroenterol. 2013; 27: 205-223Crossref PubMed Scopus (81) Google Scholar,23Rugge M. Genta R.M. Di Mario F. et al.Gastric cancer as preventable disease.Clin Gastroenterol Hepatol. 2017; 15: 1833-1843Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar,30Cassaro M. Rugge M. Gutierrez O. et al.Topographic patterns of intestinal metaplasia and gastric cancer.Am J Gastroenterol. 2000; 95: 1431-1438Crossref PubMed Google ScholarEndomucosal or submucosal resection is always recommended for HGD. A less aggressive approach suffices for LGD, but the Xiao et al1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar trial provides evidence that does not mean doing nothing, particularly in at-risk subjects harboring cancer-prone atrophic microenvironment.1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar,14Rugge M. Genta R.M. Graham D.Y. et al.Chronicles of a cancer foretold: 35 years of gastric cancer risk assessment.Gut. 2016; 65: 721-725Crossref PubMed Scopus (48) Google Scholar,15Rugge M. Genta R.M. Fassan M. et al.OLGA gastritis staging for the prediction of gastric cancer risk: a long-term follow-up study of 7436 patients.Am J Gastroenterol. 2018; 113: 1621-1628Crossref PubMed Scopus (68) Google Scholar,23Rugge M. Genta R.M. Di Mario F. et al.Gastric cancer as preventable disease.Clin Gastroenterol Hepatol. 2017; 15: 1833-1843Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar,31Rugge M. Meggio A. Pravadelli C. et al.Gastritis staging in the endoscopic follow-up for the secondary prevention of gastric cancer: a 5-year prospective study of 1755 patients.Gut. 2019; 68: 11-17Crossref PubMed Scopus (88) Google Scholar LGD patients should be managed clinically at tertiary centers well versed in the diagnostic-therapeutic procedures required (from high-resolution endoscopy to therapeutic resection), and in managing the mandatory postablation follow-up.3Pimentel-Nunes P. Libânio D. Marcos-Pinto R. et al.Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019.Endoscopy. 2019; 51: 365-388PubMed Google ScholarDysplasia Guidelines and Real-World Clinical PracticeA major challenge in GC prevention is to exploit the rapidly growing biologic knowledge in real-world clinical practice. Well-designed trials on the long-term outcome of GDy have clarified its risk of invasive cancer progression.1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar,31Rugge M. Meggio A. Pravadelli C. et al.Gastritis staging in the endoscopic follow-up for the secondary prevention of gastric cancer: a 5-year prospective study of 1755 patients.Gut. 2019; 68: 11-17Crossref PubMed Scopus (88) Google Scholar,32Piazuelo M.B. Bravo L.E. Mera R.M. et al.The Colombian Chemoprevention Trial: 20-year follow-up of a cohort of patients with gastric precancerous lesions.Gastroenterology. 2021; 160: 1106-1117Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar With a few minor inconsistencies, guidelines currently provide reliable recommendations on how to deal with patients with GDy. Numerous patient-related and operational variables interact with theoretical benchmarks, however, demanding a compromise between ideal strategies and the multifaceted reality of clinical practice.33Spellberg B. Wright W.F. Shaneyfelt T. et al.The future of medical guidelines: standardizing clinical care with the humility of uncertainty.Ann Intern Med. 2021; (Epub ahead of print. PMID: 34781711)Crossref Scopus (5) Google Scholar It has consequently become a priority to monitor how clinical guidelines are implemented. Real-world GDy is influenced by patients’ demographics, socioeconomic status, and comorbidities, and by the abilities of clinicians and other medical staff, the availability of latest-generation drugs/devices, and the efficiency of local health care systems. Monitoring all, or at least most of these variables involves digitally recording large volumes of data.34Parikh R.B. Gdowski A. Patt D.A. et al.Using big data and predictive analytics to determine patient risk in oncology.Am Soc Clin Oncol Educ Book. 2019; 39: e53-e58Crossref PubMed Google Scholar Critically reviewing such big data will enable stepwise adjustments to diagnostic and therapeutic capabilities. As in other cancer settings, strategies for preventing gastric cancer (GC) demand a multimodal approach. A recent thorough study by Xiao et al1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar addresses the heterogeneous spectrum of epidemiologic, biologic, clinical, and operative variables involved in advanced gastric precancerous lesions. Because of the peculiar clinicopathologic setting of “cardia” precancerous lesions (<1% in the Xiao et al1Xiao S. Lu H. Xue Y. et al.Long-term outcome of gastric mild-moderate dysplasia: a real-world clinical experience.Clin Gastroenterol Hepatol. 2022; 20: 1259-1268Abstract Full Text Full Text PDF Scopus (1) Google Scholar study), this editorial focuses, in particular, on the important contribution of the Chinese study on the “proper gastric” advanced precancerous lesions. Multimodal primary and secondary GC prevention relies on 4 main pillars: (1) eradication of Helicobacter pylori infection,2Malfertheiner P. Megraud F. O'Morain C.A. et al.for the European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection: the Maastricht V/Florence Consensus Report.Gut. 2017; 66: 6-30Crossref PubMed Scopus (1644) Google Scholar,3Pimentel-Nunes P. Libânio D. Marcos-Pinto R. et al.Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019.Endoscopy. 2019; 51: 365-388PubMed Google Scholar (2) the “digitalized eyes” of well-trained endoscopists,2Malfertheiner P. Megraud F. O'Morain C.A. et al.for the European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection: the Maastricht V/Florence Consensus Report.Gut. 2017; 66: 6-30Crossref PubMed Scopus (1644) Google Scholar, 3Pimentel-Nunes P. Libânio D. Marcos-Pinto R. et al.Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019.Endoscopy. 2019; 51: 365-388PubMed Google Scholar, 4Delgado-Guillena P.G. Morales-Alvarado V.J. Elosua-González A. et al.Gastroenterologists' attitudes on the detection and management of gastric premalignant conditions: results of a nationwide survey in Spain.Eur J Cancer Prev. 2021; 30: 431-436Crossref PubMed Scopus (2) Google Scholar (3) the diagnostic reliability of (skilled) pathologists, and (4) structured health care systems and specialists familiar with the clinical management of patients at risk.5Hamashima C. for the Systematic Review Group and Guideline Development Group for Gastric Cancer Screening Guidelines. Update version of the Japanese Guidelines for Gastric Cancer Screening.Jpn J Clin Oncol. 2018; 48: 673-683Crossref PubMed Scopus (133) Google Scholar Etiology of Dysplasia: Helicobacter Pylori Infection and OthersH pylori is, by far, the main driver of any (nonsyndromic) biologic pathway toward gastric dysplasia (GDy). Whether dysplasia derives primarily from bacterial genotoxicity or from molecular damage triggered by inflammation remains to be clarified.6Yamaoka Y. Graham D.Y. Helicobacter pylori virulence and cancer pathogenesis.Future Oncol. 2014; 10: 1487-1500Crossref PubMed Scopus (98) Google Scholar,7Navashenaq J.G. Shabgah A.G. Banach M. et al.The interaction of Helicobacter pylori with cancer immunomodulatory stromal cells: new insight into gastric cancer pathogenesis.Semin Cancer Biol. 2021; (S1044-579X(21)00248-0)Crossref PubMed Scopus (11) Google Scholar Anti–H pylori therapy is mandatory in infected patients, and low-grade lesions may no longer be detectable after the bacterium’s successful eradication.2Malfertheiner P. Megraud F. O'Morain C.A. et al.for the European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection: the Maastricht V/Florence Consensus Report.Gut. 2017; 66: 6-30Crossref PubMed Scopus (1644) Google Scholar,3Pimentel-Nunes P. Libânio D. Marcos-Pinto R. et al.Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019.Endoscopy. 2019; 51: 365-388PubMed Google Scholar The chances of finding GDy in individuals never infected with H pylori are minimal (if any).8Nordenstedt H. Graham D.Y. Kramer J.R. et al.Helicobacter pylori-negative gastritis: prevalence and risk factors.Am J Gastroenterol. 2013; 108: 65-71Crossref PubMed Scopus (54) Google Schol