The Journal of Pathology最新文献

{"title":"Fibroblast heterogeneity in Peutz-Jeghers syndrome: identifying the polyp-driving subset^†.","authors":"Takashi Nishina","doi":"10.1002/path.70112","DOIUrl":"10.1002/path.70112","url":null,"abstract":"<p><p>Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder caused by germline mutations in STK11, and is characterized by gastrointestinal hamartomatous polyps, the recurrent development of which significantly impacts patients' quality of life. While stromal cells have been implicated in PJS polyp formation, their specific characteristics remain unclear. Domènech-Moreno et al identify polyp-enriched crypt top fibroblasts (pCTFs) as the pathogenic fibroblast population and demonstrate that interleukin (IL)-11, a major secretory factor produced by these cells, serves as a critical mediator linking STK11 deficiency to epithelial proliferation. The study reveals that Stk11 loss triggers IL-11 expression, which in turn reinforces the pathogenic pCTF phenotype through autocrine signaling, forming a feedforward loop. Importantly, IL-11 neutralization significantly reduces polyp formation in a faithful mouse model, providing strong preclinical evidence for therapeutic translation. This work represents a significant advance in our understanding of PJS pathogenesis and establishes IL-11 as a promising therapeutic target. Future investigations into the effects of IL-11 neutralization on established polyps will further refine the translational potential of these findings for preventive intervention strategies. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SRF fusion genes in myoid soft tissue tumors.","authors":"Ariane Sablon, Constance Pirson, Cristina R Antonescu, Jean-Baptiste Demoulin","doi":"10.1002/path.70114","DOIUrl":"https://doi.org/10.1002/path.70114","url":null,"abstract":"<p><p>Serum response factor (SRF) is a ubiquitously expressed transcription factor that regulates immediate early genes, cytoskeletal organization, and muscle differentiation. Although SRF plays critical roles in development and cell growth, genomic alterations of SRF have long appeared absent in human neoplasms. Recently, however, recurrent SRF gene rearrangements have been identified in a spectrum of soft tissue tumors with myogenic features, including rhabdomyosarcomas, perivascular tumors, inflammatory myofibroblastic tumors, myoepitheliomas and peripheral nerve sheath tumors. This review summarizes current knowledge on SRF fusion genes and their biological and clinical implications. SRF fusions retain the N-terminal DNA-binding domain while replacing the native transactivation domain with that of a partner protein, frequently a transcription factor or co-activator. This structural configuration leads to constitutive activation of SRF and dysregulation of transcriptional programs related to myogenesis, cytoskeleton organization, and, in some cases, inflammatory signaling. SRF-rearranged tumors predominantly affect children, usually display low-grade behavior, and are often cured by complete surgical resection, although rare recurrences and metastases have been reported. Within perivascular myoid neoplasms, SRF-rearranged tumors show consistent phenotypic and clinical features, supporting their recognition as a distinct tumor entity, whereas SRF fusions identified in rhabdomyosarcomas and rare isolated cases likely represent separate biological contexts. Understanding SRF fusion-driven transcriptional dysregulation provides insights into tumorigenesis and may inform future diagnostic and therapeutic strategies in myoid soft tissue neoplasms. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreatic polypeptide interacts with neuropeptide Y4 receptor to promote hepatocellular carcinoma progression.","authors":"Laura Wormser, Sabrina Kojic, Valerie Fritz, Matthias Benkert, Miriam Düll, Maximilian Waldner, Jürgen Siebler, Jonel Trebicka, Claus Hellerbrand, Markus F Neurath, Anja K Bosserhoff, Peter Dietrich","doi":"10.1002/path.70115","DOIUrl":"https://doi.org/10.1002/path.70115","url":null,"abstract":"<p><p>Pancreatic polypeptide (PP) and neuropeptide Y4 receptor (Y4R) are part of a conserved system that is involved in appetite regulation, gastrointestinal functions, and energy homeostasis. Experimental evidence suggests that PP-Y4R signaling might play a role in various extrahepatic cancer types, but the exact mechanisms remain unclear. Moreover, the potential role of PP-Y4R crosstalk in hepatocellular carcinoma (HCC) was unknown and has been addressed in this study. We found that the ligand (PP) and the receptor (Y4R) were markedly overexpressed in HCC cells and in patient-derived tissues, which was correlated with a poor prognosis. Mechanistically, we found that PP promoted migration of HCC cells mediated via activation of extracellular signal-regulated kinase (ERK) signaling. Knockdown of Y4R or pharmacological inhibition of Y4R decreased migration, clonogenicity, and proliferation of HCC cells and induced a G1-cell cycle arrest and cellular senescence. Conversely, activation of the PP-Y4R axis was sufficient to overcome both spontaneous and sorafenib-induced senescence, which was mediated by ERK signaling. Our study provides novel insights into the pro-tumorigenic roles of PP and Y4R in HCC, indicating that PP-Y4R crosstalk might represent a potential novel therapeutic target. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lymph node stromal topology as a hidden regulator of breast cancer outcome: commentary on reticular network analysis†","authors":"Andrea Vethencourt,&nbsp;Roberto Salgado,&nbsp;Eva Gonzalez-Suarez","doi":"10.1002/path.70085","DOIUrl":"10.1002/path.70085","url":null,"abstract":"<p>The axillary lymph node remains a cornerstone of breast cancer staging and therapeutic decision-making, yet it is still largely interpreted through a static anatomical framework. Emerging evidence challenges this paradigm, positioning tumor-draining lymph nodes as dynamic immunological ecosystems that actively regulate tumor progression and host response. In this context, Llewellyn <i>et al</i> introduce a quantitative framework to characterize fibroblastic reticular cell network topology and link nodal architecture to clinical outcomes. By quantifying features such as lacunarity, branching, and alignment in a breast cancer cohort, the authors show that fibroblastic reticular cell network organization is associated with prognosis in a context-dependent manner. While this approach represents a significant conceptual and methodological advance, its biological interpretation remains limited by the absence of functional validation and integrated immune profiling. Accumulating evidence indicates that lymph node microenvironments undergo profound immune reprogramming, highlighting the close interdependence between stromal topology and immune composition. These findings suggest that structural features alone may reflect distinct underlying biological states. Integrating spatial metrics with immune characterization may refine current staging systems, improve risk stratification, and ultimately inform future evolution of staging classifications by incorporating functional and spatial dimensions of nodal involvement. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 1","pages":"1-3"},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant alternative splicing of purinergic receptor P2RX4 prevents sensitivity towards combinatorial treatment in colorectal and pancreatic cancer","authors":"Christoph Steup,&nbsp;Julian Dosch,&nbsp;Christopher Dietz-Fricke,&nbsp;Sara Khosraviseftejani,&nbsp;Esther Engel,&nbsp;Adalbert F de Valk,&nbsp;Dominic Menger,&nbsp;Patrick Welker,&nbsp;Peter J Wild,&nbsp;Kilian B Kennel,&nbsp;Maja Kantlehner,&nbsp;Paul K Ziegler,&nbsp;Florian R Greten","doi":"10.1002/path.70082","DOIUrl":"10.1002/path.70082","url":null,"abstract":"<p>Recently, we suggested the combination of chemotherapy and P2RX4 inhibition as a promising novel therapeutic approach for P2RX4-expressing epithelial tumors to prevent paracrine resistance. Here, we aimed to assess whether determining <i>P2RX4</i> expression status in colorectal and pancreatic cancer patients would allow stratification of potentially responsive patients. Therefore, <i>P2RX4</i> expression levels were determined by RNA sequencing and immunohistochemistry. Subcellular localization of P2RX4 isoforms was analyzed in HeLa cells and patient-derived tumor organoids. In contrast to its RNA expression profile, P2RX4 protein levels exhibited differential regulation in human colorectal and pancreatic cancer epithelia due to alternative splicing. Interpatient heterogeneity was greater in colorectal cancer than in pancreatic cancer. Notably, these variations in expression did not correlate with overall patient survival. Alternative <i>P2RX4</i> transcripts gave rise to functionally distinct protein isoforms that differed in subcellular localization and total protein abundance. Only the correctly spliced, canonical P2RX4 isoform was localized to the plasma membrane and was capable of mediating downstream signaling. Accordingly, P2RX4 inhibition in combination with chemotherapy was effective exclusively in patient-derived tumor organoids expressing the canonical <i>P2RX4</i> transcript. In summary, immunohistochemical, but not transcriptomic, assessment of P2RX4 expression enabled the prediction of sensitivity to combinatorial treatment and facilitated the identification of patients who may benefit from P2RX4 inhibition during chemotherapy. Given the lower degree of heterogeneity observed in pancreatic cancer, this tumor entity may represent a promising candidate for early-phase clinical evaluation of chemotherapy combined with P2RX4 inhibition. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 1","pages":"55-68"},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148147755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histiocytosis development and clinical variation through the lens of genomics","authors":"Paul G Kemps,&nbsp;Astrid GS van Halteren,&nbsp;Tom van Wezel,&nbsp;Pancras CW Hogendoorn","doi":"10.1002/path.70081","DOIUrl":"10.1002/path.70081","url":null,"abstract":"<p>Histiocytic neoplasms are rare haematologic diseases characterised by clonal expansions of cells with a monocyte, macrophage or dendritic cell phenotype. Their clinical manifestations are diverse, ranging from indolent lesions to aggressive systemic disease. Over recent decades, advances in genomic profiling have transformed the biological understanding of these conditions. The discovery of recurrent oncogenic mutations has reframed histiocytoses from primary inflammatory disorders to myeloid neoplasms, with a notable dependence on aberrant mitogen-activated protein kinase (MAPK) signalling. Novel genetic drivers continue to be uncovered, with many alterations correlating with distinct clinical and pathological phenotypes. Parallel studies have refined the understanding of disease ontogeny, demonstrating that diverse histiocytoses originate from haematopoietic stem/progenitor cells. In Langerhans cell histiocytosis, the differentiation stage of the mutated precursor cell is considered an important — but not the sole — determinant of disease extent and severity. Additional evidence suggests that specific clinical manifestations, such as neurodegenerative disease, may result from somatic mosaicism affecting tissue-resident macrophages derived from yolk sac progenitors. Collectively, these findings refine histiocytosis diagnosis, risk stratification, disease monitoring and treatment, with robust activity of kinase inhibitors in patients with severe or refractory disease. In this review, we synthesise recent genomic insights into histiocytosis development and variation, while addressing remaining questions and future directions. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 1","pages":"23-39"},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optical mapping reveals a higher level of large-scale structural variants in a family with paternally transmitted myotonic dystrophy and independent Parkinson's disease","authors":"Md Mehedi Hasan,&nbsp;Jenna Craddock,&nbsp;Tingting Gong,&nbsp;Ruth J Lyons,&nbsp;Igor Stevanovski,&nbsp;Sanjog R Chintalaphani,&nbsp;Ira W Deveson,&nbsp;Weerachai Jaratlerdsiri,&nbsp;Kishore R Kumar,&nbsp;Vanessa M Hayes","doi":"10.1002/path.70084","DOIUrl":"10.1002/path.70084","url":null,"abstract":"<p>Myotonic dystrophy type 1 (DM1) is a clinically challenging multisystem neuromuscular hereditary disorder, with generational increase in severity and earlier age at onset. It is caused by an unstable cytosine-thymine-guanine repeat expansion at the <i>DMPK</i> locus, accompanied by associated genetic and epigenetic modifications. While somatic mosaicism and meiotic instability are well established, to the best of our knowledge, no study has performed a genome-wide interrogation for global inherited instability. Performing whole-genome optical mapping, with sequence base-resolved structural variant verification, we examine global inherited genomic instability in an atypical paternally transmitted DM1 family presenting with a range of neurological manifestations, including early-onset Parkinson's disease (PD). While the juvenile-onset DM1 proband presented with a 10-fold repeat expansion with associated hypermethylation, her partially hypermethylated asymptomatic protomutation father transmitted a 1.8-fold contracted allele in the younger premutation sibling. Adult-onset symptomatic DM1 and PD phenotypic paternal aunts showed significant genome-wide copy number alteration, including PD-associated chr19 aneuploidy loss, with additional losses on chr16, 17, and 22. In the absence of potentially pathogenic <i>de novo</i> or maternally inherited structural variants, the proband presented with large paternally inherited aberrations impacting gene candidates <i>CASC15</i>, <i>CBFA2T3</i>, <i>GPHN</i>, <i>H3F3A</i>, <i>SDK1</i>, and <i>SPAG16</i>, with advanced global hypomethylation. Here we suggest that inherited genomic instability may contribute to phenotypic variability, including multi-neurological presentations and single-generation repeat expansion or contraction. By providing a landscape of inherited large structural variants, this single-family study expands knowledge of this broad and growing class of diseases. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 1","pages":"83-97"},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipodystrophy and adipose tissue recovery are mediated by the Wnt/lipogenesis axis during skin fibrosis","authors":"Suneeti R Madhavan,&nbsp;Piper Moore,&nbsp;Rohan Varshney,&nbsp;Miles Montegut,&nbsp;Qiannan Ma,&nbsp;Kayla Klatt,&nbsp;Reshmi Parameswaran,&nbsp;Elif G Ertugral,&nbsp;Chandrasekhar R Kothapalli,&nbsp;Michael C Rudolph,&nbsp;Radhika P Atit","doi":"10.1002/path.70086","DOIUrl":"10.1002/path.70086","url":null,"abstract":"<p>Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is an early phenotype of skin fibrosis, followed by the accumulation of extracellular matrix (ECM). Lipodystrophy syndromes are estimated to affect 1 in 20,000 people and are associated with metabolic comorbidities. Recently, we showed that fibrosis-associated lipodystrophy depended on sustained Wnt signaling, although the mechanism remains unclear. Transcriptomic profiling of mature dermal adipocytes <i>in vivo</i> revealed that Wnt activation downregulated the <i>de novo</i> lipogenesis (DNL) axis enzymes within 48 h. We further found that expression of fatty acid synthase (FASN), a key DNL enzyme, depends on sustained Wnt activation <i>in vitro</i> and <i>in vivo</i>. In a bleomycin model, and in human systemic sclerosis (&lt; 1 year disease duration) and keloids, FASN was significantly downregulated. Notably, inhibition of FASN in mice during reversal of Wnt-induced fibrosis impaired the recovery of DWAT lipid content and ECM architecture. Collectively, these findings demonstrate that acquired lipodystrophy in skin fibrosis is mediated by a previously unrecognized role of the Wnt–DNL axis. These findings underscore the importance of this pathway in lipodystrophy and fibrosis and highlight its potential as a therapeutic target in skin fibrosis. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 1","pages":"98-113"},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148256639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Invasive Border Index (TIBI) in colorectal cancer: linking infiltrative morphology to molecular insights","authors":"Akseli Kehusmaa,&nbsp;Jouni Härkönen,&nbsp;Huayi Li,&nbsp;Päivi Sirniö,&nbsp;Ville K Äijälä,&nbsp;Henna Karjalainen,&nbsp;Meeri Kastinen,&nbsp;Vilja V Tapiainen,&nbsp;Tuomo Mantere,&nbsp;Vesa-Matti Pohjanen,&nbsp;Hanna Elomaa,&nbsp;Onni Sirkiä,&nbsp;Nicolas Pasquier,&nbsp;Maarit Ahtiainen,&nbsp;Olli Helminen,&nbsp;Erkki-Ville Wirta,&nbsp;Taneli T Mattila,&nbsp;Outi Lindgren,&nbsp;Janette Savela,&nbsp;Jukka Rintala,&nbsp;Sanna Meriläinen,&nbsp;Juha Saarnio,&nbsp;Tero Rautio,&nbsp;Toni T Seppälä,&nbsp;Jan Böhm,&nbsp;Jukka-Pekka Mecklin,&nbsp;Markus J Mäkinen,&nbsp;Anne Tuomisto,&nbsp;Johanna Ivaska,&nbsp;Juha P Väyrynen","doi":"10.1002/path.70087","DOIUrl":"10.1002/path.70087","url":null,"abstract":"<p>Tumor border configuration influences colorectal cancer (CRC) prognosis, yet its molecular determinants remain unclear and existing assessment criteria have faced challenges with reproducibility. We introduce the Tumor Invasive Border Index (TIBI), a novel and reproducible method that quantifies the proportion of tumor stroma and adipose tissue within a hotspot at the deepest point of invasion. TIBI was evaluated in two CRC cohorts (<i>n</i> = 1,100 and <i>n</i> = 776) and analyzed in relation to tumor and patient features. Molecular correlates of an infiltrative growth pattern were explored in The Cancer Genome Atlas (TCGA) CRC cohorts (<i>n</i> = 350), with key features validated independently. High TIBI, indicating an infiltrative border, was associated with advanced disease, tumor budding, lymphovascular invasion, and an immune microenvironment characterized by lower M1-like macrophage and granulocyte densities. High TIBI independently predicted higher CRC-specific mortality, with multivariable hazard ratios of 1.52 (95% CI 1.07–2.17) in cohort 1 and 2.45 (95% CI 1.37–4.37) in cohort 2. Molecular analysis revealed associations with mismatch repair proficiency, <i>TP53</i> and <i>KRAS</i> mutations, MYC signaling downregulation, and epithelial-mesenchymal transition upregulation. <i>L1CAM</i> and <i>DSG3</i> were among the genes showing high expression in infiltrative tumors. As experimental validation, we identified a CRC cell line with high expression of <i>L1CAM</i> and <i>DSG3</i> and demonstrated that silencing them reduced invasion <i>in vitro</i>. A TIBI-associated gene signature also predicted infiltrative growth and adverse outcome in the TCGA gastric cancer cohort. These findings highlight molecular characteristics of tumor border configuration and establish TIBI as a clinically relevant tumor biomarker. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 1","pages":"114-128"},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148269841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knowledge gaps in tubular gut tumours: a critical appraisal of the 6th edition of the World Health Organization classification of tumours","authors":"Iris D Nagtegaal,&nbsp;Elizabeth A Montgomery,&nbsp;Alexandros D Polydorides,&nbsp;Anthony J Gill,&nbsp;Motohiro Kojima,&nbsp;Mark J Arends","doi":"10.1002/path.70089","DOIUrl":"10.1002/path.70089","url":null,"abstract":"<p>Gastrointestinal 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 precursors of the 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. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 1","pages":"4-22"},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}