Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

•This ESMO Clinical Practice Guideline provides key recommendations for managing gastric cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, treatment and follow-up.•Treatment and management algorithms for localised and advanced/metastatic disease are provided.•The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.•Recommendations are based on available scientific evidence and the authors' collective expert opinion. More than 1 million (1 089 103) new cases of gastric cancer were estimated globally in 2020, resulting in 768 793 deaths.1Ferlay J. Ervik M. Colombet M. et al.Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer.https://gco.iarc.fr/todayGoogle Scholar These burden estimates will continue to increase due to the ageing population and growth of high-risk groups. Of these global numbers, an estimated 136 038 cases and 96 997 deaths occurred in Europe.1Ferlay J. Ervik M. Colombet M. et al.Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer.https://gco.iarc.fr/todayGoogle Scholar Gastric cancer displays substantial global variation in incidence; the highest rates are observed in Eastern Asia, Central and Eastern Europe and South America.1Ferlay J. Ervik M. Colombet M. et al.Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer.https://gco.iarc.fr/todayGoogle Scholar A gradual decline in the incidence of gastric cancer has been observed in Western Europe and North America over the past 60 years, and more recent declines in high-risk countries have also become apparent.2GBD 2017 Stomach CollaboratorsThe global, regional, and national burden of stomach cancer in 195 countries, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.Lancet Gastroenterol Hepatol. 2020; 5: 42-54Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar This is epidemiologically distinct from the relative increase in oesophageal adenocarcinoma, including tumours of the oesophagogastric junction (OGJ), which are discussed in a separate guideline document. Incidence in men is twice as high as in women. Risk factors vary by anatomical subsite of disease; non-cardia gastric cancer, which is more common in East Asia and Latin America, represents ∼80% of gastric tumours globally and has been associated with Helicobacter pylori (H. pylori) infection, alcohol use, high salt intake and low consumption of fruit and vegetables. Proximal (cardia) gastric cancer is associated with obesity and gastro-oesophageal reflux and is more common in North America and Western Europe.3Colquhoun A. Arnold M. Ferlay J. et al.Global patterns of cardia and non-cardia gastric cancer incidence in 2012.Gut. 2015; 64: 1881-1888Crossref PubMed Scopus (248) Google Scholar Epstein-Barr virus (EBV)-positive gastric cancer is more prevalent in the fundus or body (62%) and its prevalence seems to be similar in Asia, Europe and the Americas.4Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (3703) Google Scholar Recent studies report an increase in non-cardia gastric cancer among young individuals (<50 years), especially in low-incidence countries such as the UK and US – populations with a low prevalence of H. pylori infection. Dysbiosis of the gastric microbiome associated with modern lifestyles and an increase in autoimmune disorders in this age group have been postulated as potential explanations.5Arnold M. Ferlay J. van Berge Henegouwen M.I. et al.Global burden of oesophageal and gastric cancer by histology and subsite in 2018.Gut. 2020; 69: 1564-1571Crossref PubMed Scopus (113) Google Scholar Gastric cancer demonstrates familial aggregation in ∼10% of cases, and an inherited genetic predisposition is identified in up to 3% of cases.6Rustgi S.D. Ching C.K. Kastrinos F. Inherited predisposition to gastric cancer.Gastrointest Endosc Clin N Am. 2021; 31: 467-487Abstract Full Text Full Text PDF PubMed Google Scholar Genetic tumour risk syndromes are characterised by an increased risk of early-onset cancers in a familial context. High cancer risk is mostly driven by loss-of-function variants in a single cancer-associated gene. CDH1 and CTNNA1 germline variants predispose to hereditary diffuse gastric cancer (HDGC), while APC promoter 1B single nucleotide variants predispose to gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Familial intestinal gastric cancer (FIGC), recognised as a gastric cancer-predisposing disease, remains understudied and genetically unsolved.7Garcia-Pelaez J. Barbosa-Matos R. São José C. et al.Gastric cancer genetic predisposition and clinical presentations: established heritable causes and potential candidate genes.Eur J Med Genet. 2022; 65104401Crossref Scopus (1) Google Scholar Gastric cancer can also occur within the spectrum of other genetic tumour risk syndromes, such as Lynch syndrome, familial adenomatous polyposis (FAP), Li–Fraumeni and Peutz–Jeghers syndromes (Table 1).6Rustgi S.D. Ching C.K. Kastrinos F. Inherited predisposition to gastric cancer.Gastrointest Endosc Clin N Am. 2021; 31: 467-487Abstract Full Text Full Text PDF PubMed Google Scholar HDGC is the most studied hereditary gastric cancer risk syndrome and is estimated to have a population incidence rate of ∼5-10/100 000 births.8Blair V.R. McLeod M. Carneiro F. et al.Hereditary diffuse gastric cancer: updated clinical practice guidelines.Lancet Oncol. 2020; 21: e386-e397Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar The incidence rates for other gastric cancer risk syndromes are less well defined. HDGC is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. HDGC is caused by CDH1/E-cadherin germline single nucleotide variants and copy number variants, classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology CDH1 variant curation guidelines.9Lee K. Krempely K. Roberts M.E. et al.Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants.Hum Mutat. 2018; 39: 1553-1568Crossref PubMed Scopus (79) Google Scholar Pathogenic variants in CTNNA1 occur in a minority of families with HDGC. The International Gastric Cancer Linkage Consortium provides updated practice guidelines for HDGC, recognising the emerging evidence of variability in gastric cancer risk between families, the growing capability of endoscopic and histological surveillance in HDGC and greater experience managing long-term sequelae following total gastrectomy in young patients.8Blair V.R. McLeod M. Carneiro F. et al.Hereditary diffuse gastric cancer: updated clinical practice guidelines.Lancet Oncol. 2020; 21: e386-e397Abstract Full Text Full Text PDF PubMed Scopus (104) Google ScholarTable 1Gene mutations associated with inherited predisposition to gastric cancer6Rustgi S.D. Ching C.K. Kastrinos F. Inherited predisposition to gastric cancer.Gastrointest Endosc Clin N Am. 2021; 31: 467-487Abstract Full Text Full Text PDF PubMed Google ScholarGene mutationAssociated syndromeAPCFAPAPC promoter 1BGAPPSCDH1, CTNNA1HDGCMLH1, MSH2, MSH6, PMS2Lynch syndromeSMAD4, BMPR1AJuvenile polyposis syndromeSTK11Peutz–Jeghers syndromeTP53Li–Fraumeni syndromeFAP, familial adenomatous polyposis; GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; HDGC, hereditary diffuse gastric cancer.Adapted with permission.6Rustgi S.D. Ching C.K. Kastrinos F. Inherited predisposition to gastric cancer.Gastrointest Endosc Clin N Am. 2021; 31: 467-487Abstract Full Text Full Text PDF PubMed Google Scholar Open table in a new tab FAP, familial adenomatous polyposis; GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; HDGC, hereditary diffuse gastric cancer. Adapted with permission.6Rustgi S.D. Ching C.K. Kastrinos F. Inherited predisposition to gastric cancer.Gastrointest Endosc Clin N Am. 2021; 31: 467-487Abstract Full Text Full Text PDF PubMed Google Scholar There is consistent evidence that eradication of H. pylori substantially reduces the incidence of gastric cancer in healthy individuals, patients with gastric atrophy and people with a family history of gastric cancer.10Choi I.J. Kim C.G. Lee J.Y. et al.Family history of gastric cancer and Helicobacter pylori treatment.N Engl J Med. 2020; 382: 427-436Crossref PubMed Scopus (136) Google Scholar,11Ford A.C. Yuan Y. Forman D. et al.Helicobacter pylori eradication for the prevention of gastric neoplasia.Cochrane Database Syst Rev. 2020; 7: CD005583PubMed Google Scholar Non-cardia intestinal-type cancer—the most common histological subtype of gastric cancer—follows a pattern of stepwise progression (known as the Correa Cascade) from normal mucosa to non-atrophic gastritis, atrophic gastritis with or without intestinal metaplasia (IM), dysplasia and finally cancer.12Correa P. Gastric cancer: overview.Gastroenterol Clin North Am. 2013; 42: 211-217Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In high-risk East Asian countries (China, Japan and South Korea), population- and endoscopy-based screening programmes have been implemented.13Choi K.S. Jun J.K. Suh M. et al.Effect of endoscopy screening on stage at gastric cancer diagnosis: results of the National Cancer Screening Programme in Korea.Br J Cancer. 2015; 112: 608-612Crossref PubMed Scopus (92) Google Scholar, 14Fan X. Qin X. Zhang Y. et al.Screening for gastric cancer in China: advances, challenges and visions.Chin J Cancer Res. 2021; 33: 168-180Crossref PubMed Google Scholar, 15Mabe K. Inoue K. Kamada T. et al.Endoscopic screening for gastric cancer in Japan: Current status and future perspectives.Dig Endosc. 2022; 34: 412-419Crossref PubMed Scopus (1) Google Scholar These programmes have resulted in higher detection rates of early-stage gastric cancer, with substantially reduced mortality. In contrast, population-based endoscopic screening of asymptomatic individuals is not recommended in low incidence countries.16Banks M. Graham D. Jansen M. et al.British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma.Gut. 2019; 68: 1545-1575Crossref PubMed Scopus (174) Google Scholar,17Cubiella J. Pérez Aisa Á. Cuatrecasas M. et al.Gastric cancer screening in low incidence populations: position statement of AEG, SEED and SEAP.Gastroenterol Hepatol. 2021; 44: 67-86Crossref PubMed Scopus (4) Google Scholar Since individuals with IM have an increased risk of gastric cancer, multidisciplinary European and UK endoscopy guidelines recommend that patients with IM as well as a family history of gastric cancer, incomplete-type IM or persistent H. pylori-associated gastritis should undergo endoscopic surveillance with guided biopsies every 3 years. •If a familial cancer syndrome is suspected, referral to a geneticist for assessment is recommended [V, A].•Population-based endoscopic screening of asymptomatic individuals is only recommended in regions with a very high incidence of gastric cancer [V, B]. Gastric cancer is often asymptomatic in the early stages. In advanced disease, common signs and symptoms include dysphagia, asthenia, indigestion, vomiting, weight loss, early satiety and/or iron deficiency anaemia. In many cases, however, these non-specific symptoms do not lead to urgent investigations. Overall, ∼60% of people with gastric cancer are not eligible for curative treatment owing to late presentation or comorbidities.18Allum W. Lordick F. Alsina M. et al.ECCO essential requirements for quality cancer care: oesophageal and gastric cancer.Crit Rev Oncol Hematol. 2018; 122: 179-193Crossref PubMed Scopus (29) Google Scholar Endoscopic examination and forceps biopsies are the gold standard method for diagnosing gastric cancer. Multiple (5-8) biopsies should be carried out to provide adequately sized material for histological and molecular interpretation, especially in the setting of ulcerated lesions.19Gullo I. Grillo F. Molinaro L. et al.Minimum biopsy set for HER2 evaluation in gastric and gastro-esophageal junction cancer.Endosc Int Open. 2015; 3: E165-E170Crossref PubMed Google Scholar,20Tominaga N. Gotoda T. Hara M. et al.Five biopsy specimens from the proximal part of the tumor reliably determine HER2 protein expression status in gastric cancer.Gastric Cancer. 2016; 19: 553-560Crossref PubMed Scopus (36) Google Scholar Details of the mucosal surface can be evaluated by narrow-band imaging or chromoendoscopy in combination with magnifying endoscopy. Endoscopic ultrasonography (EUS) is also a helpful tool to identify infiltrated regions of the gastric wall.21Hamada K. Itoh T. Kawaura K. et al.Examination of endoscopic ultrasonographic diagnosis for the depth of early gastric cancer.J Clin Med Res. 2021; 13: 222-229Crossref PubMed Scopus (2) Google Scholar Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) may also be used for diagnosis. Both procedures can deliver reliable staging information and can also be used to treat superficial lesions such as dysplasia or intramucosal carcinoma.22Ono H. Yao K. Fujishiro M. et al.Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer (second edition).Dig Endosc. 2021; 33: 4-20Crossref PubMed Scopus (84) Google Scholar Approximately 90% of gastric cancers are adenocarcinomas (ACs). This Clinical Practice Guideline (CPG) does not apply to rarer gastric malignancies such as gastrointestinal stromal tumours, lymphomas and neuroendocrine tumours. Based on macroscopic features, early gastric carcinomas are sub-classified into three main types according to the Endoscopic Classification Review Group (Paris classification): 0-I (protruded); 0-II (superficial); and 0-III (excavated).23Endoscopic Classification Review GroupUpdate on the Paris classification of superficial neoplastic lesions in the digestive tract.Endoscopy. 2005; 37: 570-578Crossref PubMed Scopus (582) Google Scholar Locally advanced gastric carcinomas are macroscopically sub-classified according to the Borrmann classification as polypoid/fungating without ulceration (type I), ulcerated with elevated borders and sharp margins (type II), ulcerated with diffuse infiltration at the base (type III) and diffusely infiltrative with thickening of the wall (type IV).24Borrmann R. Geschwulste des Magens und Duodenum.in: Henke F. Lubarch O. Handbuch der Spezielen Pathologischen Anatomie und Histology. Springer Verlag, Berlin, Germany1926Google Scholar There are several gastric cancer histopathological classification schemes. The most commonly used are the World Health Organization (WHO)25Carneiro F. Fukayama M. Grabsch H.I. et al.Gastric adenocarcinoma.in: WHO Classification of Tumours Editorial Board, ed. Digestive System Tumours. 5th ed. International Agency for Research on Cancer, Lyon, France2019: 85-95Google Scholar and Japanese Gastric Cancer Association26Japanese Gastric Cancer AssociationJapanese classification of gastric carcinoma.15th ed. Kanehara Shuppan, Tokyo, Japan2017Google Scholar classifications, which are very similar, as well as those proposed by Nakamura and colleagues27Nakamura K. Sugano H. Takagi K. Carcinoma of the stomach in incipient phase: its histogenesis and histological appearances.Gan. 1968; 59: 251-258PubMed Google Scholar and Laurén, the latter of which recognises three main subtypes: intestinal, diffuse and mixed.28Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification.Acta Pathol Microbiol Scand. 1965; 64: 31-49Crossref PubMed Google Scholar The WHO classification is widely used in Western countries and recognises five main histological subtypes: tubular, papillary, poorly cohesive (including signet ring cell and other subtypes), mucinous and mixed ACs. The recently identified molecular profiles of gastric cancer are important for better understanding gastric cancer subtypes and may also be useful for identifying clinically relevant biomarkers and new therapeutic targets. Intratumoural and intertumoural heterogeneity is a feature of gastric carcinoma which leads to diagnostic and therapeutic challenges. The Cancer Genome Atlas (TCGA) research network identified four molecularly distinct gastric cancer subtypes: EBV positive, microsatellite instability-high (MSI-H), genomically stable (GS) and tumours with chromosomal instability (CIN).4Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (3703) Google Scholar Each subtype is enriched for selected molecular abnormalities, with some overlap. The CIN subtype is enriched for copy number changes in key receptor tyrosine kinase oncogenes such as human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 2 (FGFR2) and MET. Other genomic classifications, such as the Asian Cancer Research Group subtyping, show some overlap with TCGA classification.29Cristescu R. Lee J. Nebozhyn M. et al.Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.Nat Med. 2015; 21: 449-456Crossref PubMed Scopus (1107) Google Scholar Based on positive phase III trial data, HER2 status and programmed death-ligand 1 (PD-L1) combined positive score (CPS) should be evaluated in patients with metastatic gastric cancer to tailor first-line treatment in combination with chemotherapy (ChT) [see the table of ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) scores for further details, Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2022.07.004].30Bang Y.J. Van Cutsem E. Feyereislova A. et al.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.Lancet. 2010; 376: 687-697Abstract Full Text Full Text PDF PubMed Scopus (5008) Google Scholar,31Janjigian Y.Y. Shitara K. Moehler M. et al.First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.Lancet. 2021; 398: 27-40Abstract Full Text Full Text PDF PubMed Google Scholar Patients with HER2-overexpressing gastric cancer [HER2 immunohistochemistry (IHC) score 3+ or HER2 IHC 2+ and FISH positive] benefit from treatment with the anti-HER2 antibody trastuzumab in addition to standard platinum–fluoropyrimidine ChT.30Bang Y.J. Van Cutsem E. Feyereislova A. et al.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.Lancet. 2010; 376: 687-697Abstract Full Text Full Text PDF PubMed Scopus (5008) Google Scholar,32Smyth E.C. Nilsson M. Grabsch H.I. et al.Gastric cancer.Lancet. 2020; 396: 635-648Abstract Full Text Full Text PDF PubMed Google Scholar The prevalence of HER2 overexpression is 10%-20%, with higher prevalence in proximal/OGJ cancers and in the intestinal subtype according to Laurén.30Bang Y.J. Van Cutsem E. Feyereislova A. et al.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.Lancet. 2010; 376: 687-697Abstract Full Text Full Text PDF PubMed Scopus (5008) Google Scholar,32Smyth E.C. Nilsson M. Grabsch H.I. et al.Gastric cancer.Lancet. 2020; 396: 635-648Abstract Full Text Full Text PDF PubMed Google Scholar,33Haffner I. Schierle K. Raimúndez E. et al.HER2 expression, test deviations, and their impact on survival in metastatic gastric cancer: results from the prospective multicenter VARIANZ study.J Clin Oncol. 2021; 39: 1468-1478Crossref PubMed Scopus (15) Google Scholar Efficacy of HER2-targeted treatment is hampered by the intratumoural heterogeneity of HER2 expression. Therefore, quantitative reporting of the proportion of tumour cells staining positive for HER2 by IHC and the gene amplification ratio (if in situ hybridisation was carried out, especially in IHC 2+ patients) have been suggested.33Haffner I. Schierle K. Raimúndez E. et al.HER2 expression, test deviations, and their impact on survival in metastatic gastric cancer: results from the prospective multicenter VARIANZ study.J Clin Oncol. 2021; 39: 1468-1478Crossref PubMed Scopus (15) Google Scholar Emerging data from clinical trials suggest that immunotherapies such as programmed cell death protein 1 (PD-1) inhibitors demonstrate efficacy in gastric cancer. Evaluation of PD-L1 expression in patients with gastric cancer using CPS has been proposed, where a cut-off ≥1 would indicate positive PD-L1 expression; the prevalence of PD-L1 CPS ≥1 tumours is between 50% and 60%.34Kulangara K. Zhang N. Corigliano E. et al.Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer.Arch Pathol Lab Med. 2019; 143: 330-337Crossref PubMed Scopus (270) Google Scholar,35Wainberg Z.A. Fuchs C.S. Tabernero J. et al.Efficacy of pembrolizumab monotherapy for advanced gastric/gastroesophageal junction cancer with programmed death ligand 1 combined positive score ≥10.Clin Cancer Res. 2021; 27: 1923-1931Crossref PubMed Scopus (21) Google Scholar A CPS cut-off ≥5 represents a validated threshold for overall survival (OS) benefit of nivolumab given in addition to standard platinum–fluoropyrimidine first-line ChT.31Janjigian Y.Y. Shitara K. Moehler M. et al.First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.Lancet. 2021; 398: 27-40Abstract Full Text Full Text PDF PubMed Google Scholar Different antibodies for staining of PD-L1 in gastric cancer are used. In a recent study, PD-L1 22C3 and 28-8 pharmDx assays, both tested on the same platform (hardware), were highly comparable at CPS cut-offs of 1, 10 and 50, providing evidence for the potential interchangeability of the two PD-L1 assays in gastric cancer.36Ahn S. Kim K.M. PD-L1 expression in gastric cancer: interchangeability of 22C3 and 28-8 pharmDx assays for responses to immunotherapy.Mod Pathol. 2021; 34: 1719-1727Crossref PubMed Scopus (11) Google Scholar These results, however, were not confirmed in another study, which suggested that scoring PD-L1 CPS with the 28-8 assay may result in higher PD-L1 scores and a higher proportion of PD-L1 positivity compared with the 22C3 and other assays. Until stronger evidence of inter-assay concordance is found, caution should be taken when treating the assays as equivalent.37Yeong J. Lum H.Y.J. Teo C.B. et al.Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy.Gastric Cancer. 2022; 25: 741-750Crossref PubMed Scopus (5) Google Scholar MSI-H/mismatch repair deficiency (dMMR) are associated with better prognosis in localised stages of gastric cancer.38Pietrantonio F. Miceli R. Raimondi A. et al.Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer.J Clin Oncol. 2019; 37: 3392-3400Crossref PubMed Scopus (150) Google Scholar There is an ongoing debate on whether microsatellite instability (MSI)/mismatch repair (MMR) status should be used in order to tailor peri-operative ChT.39Lordick F. Chemotherapy for resectable microsatellite instability-high gastric cancer?.Lancet Oncol. 2020; 21: 203Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,40Smyth E.C. Chemotherapy for resectable microsatellite instability-high gastric cancer?.Lancet Oncol. 2020; 21: 204Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar As MSI-H/dMMR are associated with a high response rate and improved benefit from immunotherapy compared with ChT in stage IV gastric cancer,41Chao J. Fuchs C.S. Shitara K. et al.Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials.JAMA Oncol. 2021; 7: 895-902Crossref PubMed Scopus (39) Google Scholar MSI/MMR status should be assessed for patients with locally advanced and unresectable or metastatic gastric cancer to tailor treatment accordingly.32Smyth E.C. Nilsson M. Grabsch H.I. et al.Gastric cancer.Lancet. 2020; 396: 635-648Abstract Full Text Full Text PDF PubMed Google Scholar Other molecular markers, such as FGFR2 amplification/overexpression, MET amplification, claudin-18.2 overexpression and EBV,32Smyth E.C. Nilsson M. Grabsch H.I. et al.Gastric cancer.Lancet. 2020; 396: 635-648Abstract Full Text Full Text PDF PubMed Google Scholar are being investigated and their validation as predictive biomarkers in randomised controlled trials (RCTs) is awaited. •Diagnosis should be made from multiple (5-8) endoscopic biopsies to guarantee an adequate representation of the tumour [IV, B].•The histological diagnosis should be reported according to WHO criteria [V, B].•HER2 expression by IHC and/or amplification by in situ hybridisation [I, A; ESCAT score: I-A], PD-L1 by IHC according to CPS [I, A] and MSI-H/dMMR [II, A; ESCAT score: I-B] are validated predictive biomarkers for drug therapy. Careful tumour staging is essential to ensure patients are appropriately selected for treatment interventions. The recommended initial staging investigations are detailed in Table 2.Table 2Diagnostic and staging investigations in gastric cancer.ProcedurePurposeFBCAssess for iron deficiency anaemiaRenal and liver functionAssess renal and liver function to determine appropriate therapeutic optionsEndoscopy and biopsyObtain tissue for diagnosis, histological classification and molecular biomarkers, e.g. HER2 statusCT of thorax + abdomen ± pelvisStaging of tumour – to detect local/distant lymphadenopathy and metastatic disease or ascitesEUSAccurate assessment of T and N stage in potentially operable tumoursDetermine the proximal and distal extent of tumourLaparoscopy + washingsExclude occult metastatic disease involving peritoneum/diaphragmPET, if availableMay improve detection of occult metastatic disease in some cases. Often negative in diffuse-type gastric cancerAssessment of nutritional statusMay detect relevant dietary and nutritional deficiencies in both localised and advanced disease settingsCT, computed tomography; EUS, endoscopic ultrasound; FBC, full blood count; HER2, human epidermal growth factor receptor 2; N, node; PET, positron emission tomography; T, tumour. Open table in a new tab CT, computed tomography; EUS, endoscopic ultrasound; FBC, full blood count; HER2, human epidermal growth factor receptor 2; N, node; PET, positron emission tomography; T, tumour. The following characteristics are frequently demonstrated in malignant lymph nodes detected on computed tomography (CT)42Kwee R.M. Kwee T.C. Imaging in local staging of gastric cancer: a systematic review.J Clin Oncol. 2007; 25: 2107-2116Crossref PubMed Scopus (256) Google Scholar:•Short axis diameter 6-8 mm in perigastric lymph nodes•Round shape•Central necrosis•Loss of the fatty hilum•Heterogeneous or high enhancement Nevertheless, the sensitivity of CT for lymph node staging is variable (62.5%-91.9% on systematic review42Kwee R.M. Kwee T.C. Imaging in local staging of gastric cancer: a systematic review.J Clin Oncol. 2007; 25: 2107-2116Crossref PubMed Scopus (256) Google Scholar) and global consensus is lacking on specific diagnostic criteria. EUS is more sensitive for N staging compared with CT (91% versus 77%, respectively). Additionally, for T1 staging, the sensitivity for EUS (82%) is higher than that for multidetector CT (41%); however, both EUS and CT show limited specificity (49% and 63%, respectively).43Nie R.C. Yuan S.Q. Chen X.J. et al.Endoscopic ultrasonography compared with multidetector computed tomography for the preoperative staging of gastric cancer: a meta-analysis.World J Surg Oncol. 2017; 15: 113Crossref PubMed Scopus (23) Google Scholar [18F]2-Fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)–CT imaging may improve staging by detecting involved lymph nodes or metastatic disease; however, FDG–PET may not be informative in patients with mucinous or diffuse tumours due to lower tracer uptake.44Gertsen E.C. Brenkman H.J.F. van Hillegersberg R. et al.18F-fludeoxyglucose-positron emission tomography/computed tomography and laparoscopy for staging of locally advanced gastric cancer: a multicenter prospective Dutch cohort study (PLASTIC).JAMA Surg. 2021; 156e215340Crossref PubMed Scopus (8) Google Scholar Therefore, FDG–PET–CT is not routinely recommended for staging of gastric cancer. Laparoscopy and peritoneal washings for malignant cells are recommended in all stage IB-III gastric cancers which are considered potentially resectable, to exclude radiologically and macroscopically occult peritoneal metastatic disease. The benefit is greater for patients with T3/T4 disease and poorly cohesive tumours.44Gertsen E.C. Brenkman H.J.F.