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The new 6th edition of the World Health Organization Classification of Tumours for the Digestive System updates evidence and guidance on aetiology, pathogenesis, diagnosis, classification, grading, staging, and prognosis. Nonetheless, significant knowledge gaps remain, especially concerning precursor lesions and rare cancers. This review prioritizes research needs across oesophageal, gastric, ampulla-duodenum, jejunoileum, anal canal, colorectal serrated polyposis, and inflammatory bowel disease–associated dysplasia, and further highlights gaps in multiple rare tumour entities. It proposes research questions and frameworks to address persistent challenges, noting that collective registries and collaboration are required.",{"@graph":69,"@context":121},[70,84,104],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/knowledge-gaps-in-tubular-gut-tumours-a-critical-appraisal-of-the-6th-edition-of-the-world-health-organization-classification-of-tumours/345968/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":98,"encodingFormat":97,"isAccessibleForFree":99,"interactionStatistic":100},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/knowledge-gaps-in-tubular-gut-tumours-a-critical-appraisal-of-the-6th-edition-of-the-world-health-organization-classification-of-tumours/345968.png","ImageObject",300,407,{"name":92,"@type":93},"Seraphina","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-22",true,{"@type":101,"interactionType":102,"userInteractionCount":4},"InteractionCounter",{"@type":103},"ViewAction",{"@type":105,"mainEntity":106},"FAQPage",[107,113,117],{"name":108,"@type":109,"acceptedAnswer":110},"What is the main purpose of this review?","Question",{"text":111,"@type":112},"To critically assess the 6th edition of the WHO classification for tubular gut tumours and outline significant remaining knowledge gaps. It also proposes research questions and frameworks to guide future evidence generation.","Answer",{"name":114,"@type":109,"acceptedAnswer":115},"Which tumour areas and precursor lesions receive emphasis?",{"text":116,"@type":112},"The review focuses on precursor lesions and rare cancers where evidence needs are urgent, including oesophagus, stomach, ampulla-duodenum, jejunoileum, anal canal, and entities related to colorectal serrated polyposis and inflammatory bowel disease–associated dysplasia.",{"name":118,"@type":109,"acceptedAnswer":119},"How does the review suggest addressing the remaining knowledge gaps?",{"text":120,"@type":112},"By identifying priority research questions and persistent challenges for specific tumour entities, and by proposing research frameworks that rely on coordinated efforts, including collective registries and collaborative research.","https://schema.org",{"og:url":83,"og:type":123,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":125,"canonical":83},"index,follow",{"doc_id":127,"site_id":62},345968,1790059566,{"code":4,"msg":5,"data":130},{"doc_id":127,"user_id":131,"nickname":92,"user_avatar":132,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":4,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":138,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":139,"faqs":140,"seo_title":141,"seo_description":67,"update_tm":128,"read_time":142},962075114101,"https://ap-avatar.wpscdn.com/avatar/e000253a75eb197efd?x-image-process=image/resize,m_fixed,w_180,h_180&k=1780044092746381165","Journal of Pathology  \nJ Pathol September 2026; 270: 4–22  \nPublished online 7 July 2026 in Wiley Online Library (wi[leyonlinelibrary.com](leyonlinelibrary.com) DOI: 10.1002/path.70089)[)](leyonlinelibrary.com) DOI: 10.1002/path.70089)[ DOI:](leyonlinelibrary.com) DOI: 10.1002/path.70089)[ 10.1002/path.70089](leyonlinelibrary.com) DOI: 10.1002/path.70089)  \nINVITED REVIEW  \nKnowledge gaps in tubular gut tumours: a critical appraisal of the 6th edition of the World Health Organization classification of tumours  \nIris D Nagtegaal 1 , Elizabeth A Montgomery2, Alexandros D Polydorides3, Anthony J Gill4,5, Motohiro Kojima6 and Mark J Arends7*  \n1 Department of Pathology, Radboudumc, Nijmegen, The Netherlands  \n2 Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, USA  \n3 Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA  \n4 NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia  \n5 Sydney Medical School, University of Sydney, Sydney, NSW, Australia  \n6 Department of Surgical Pathology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan  \n7 Edinburgh Pathology, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK  \n*Correspondence to: MJ Arends, Edinburgh Pathology, The University of Edinburgh, Cancer Research UK Scotland Centre, Institute of Genetics and  \nCancer, Western General Hospital Campus, Crewe Road South, Edinburgh, EH4 2XR, [UK. E-mail:](UK. E-mail: m.arends@ed.ac.uk)[ m.arends@ed.ac.uk](UK. E-mail: m.arends@ed.ac.uk)  \nAbstract  \nGastrointestinal cancer is a global health problem. In the new 6th edition of the World Health Organization Classification of Tumours (WCT) of the Digestive System, updated evidence and guidance is provided for the aetiology, pathogenesis, diagnosis, classification, grading, staging and prognosis of these tumours. However, significant knowledge gaps remain, some of which are addressed in this review. To provide for a research framework to fill these knowledge gaps, we focused on precursor lesions and rare cancers, where the need for new evidence is most urgent. Areas with a need for further research are discussed for neoplastic precursorsofthe oesophagus(squamous epithelium), stomach (gastric dysplasia and adenomas), ampulla-duodenum, jejunoileum, anal canal, as well as for colorectal serrated polyposis and inflammatory bowel disease associated dysplasia(conventional and non-conventional). Knowledge gaps are also presented as they exist in rare cancers of the oesophagus (mixed type), appendix (mucinous neoplasms and mucinous adenomas), colorectum (three new subtypes) and anus, as well as for neuroendocrine tumours (grading, necrosis and two new gastric subtypes) and undifferentiated carcinomas (deficiencies of the SWI/SNF chromatin remodelling complex and mesenchymal differentiation). We identify and present research questions and persistent challenges for these entities and thus propose research frameworks that focus on specific priority areas. Progress in these core research topics for both neoplastic precursors and rare cancers will hopefully be reflected in future editions of the WCT, but many of these knowledge gaps will only be resolved with collective registries and collaborative research efforts.  \n© 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.  \nKeywords: gastrointestinal; tumours; cancers; precursors; knowledge gaps; research questions  \nReceived 27 February 2026; Revised 27 April 2026; Accepted 25 May 2026  \nConflict of interest statement: IDN declares no conflicts of interest. EAM declares a consultancy forJohnson and Johnson Pharmaceuticals and reviewing slides from clinical trials patients who have taken CAR-T therapy, both concerning unrelated to the scope of the current work. ","cbCaijep5CP2Hiuh","https://ap.wps.com/l/cbCaijep5CP2Hiuh","pdf",39598683,"English","# Abstract\n# Introduction\n# Knowledge gaps and research frameworks","[{\"question\":\"What is the main purpose of this review?\",\"answer\":\"To critically assess the 6th edition of the WHO classification for tubular gut tumours and outline significant remaining knowledge gaps. It also proposes research questions and frameworks to guide future evidence generation.\"},{\"question\":\"Which tumour areas and precursor lesions receive emphasis?\",\"answer\":\"The review focuses on precursor lesions and rare cancers where evidence needs are urgent, including oesophagus, stomach, ampulla-duodenum, jejunoileum, anal canal, and entities related to colorectal serrated polyposis and inflammatory bowel disease–associated dysplasia.\"},{\"question\":\"How does the review suggest addressing the remaining knowledge gaps?\",\"answer\":\"By identifying priority research questions and persistent challenges for specific tumour entities, and by proposing research frameworks that rely on coordinated efforts, including collective registries and collaborative research.\"}]","Knowledge gaps in tubular gut tumours - a critical appraisal of the 6th edition of the World Health Organization classification of tumours | PDF",48]