[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-405778-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-405778-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","spatial-and-temporal-heterogeneity-of-digestive-neuroendocrine-neoplasms","Spatial and temporal heterogeneity of digestive neuroendocrine neoplasms","","Neuroendocrine neoplasms (NENs) begin as monoclonal tumors and gradually become polyclonal, producing substantial genotypic and phenotypic diversity that shapes biological behavior. While inter-patient heterogeneity is well documented, intra-tumor spatial and temporal heterogeneity has received less attention. NEN subclones can differ by Ki-67 proliferation, hormonal marker expression, and metabolic imaging uptake intensity, which relates to prognosis. Tumor grade may evolve over time, yet guidance is limited on systematic biopsy of recurrence or progression lesions. This review synthesizes current knowledge, hypotheses, and implications.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/spatial-and-temporal-heterogeneity-of-digestive-neuroendocrine-neoplasms/405778/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/spatial-and-temporal-heterogeneity-of-digestive-neuroendocrine-neoplasms/405778.png","ImageObject",300,407,{"name":42,"@type":43},"Jake","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-04","2026-09-28",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",6,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"How does intra-tumor heterogeneity arise in digestive neuroendocrine neoplasms?","Question",{"text":63,"@type":64},"NENs progress from monoclonal to polyclonal states as tumor subclones with different behaviors emerge, creating spatial and temporal differences within the same tumor and across lesions.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"Which features help distinguish NEN subclones?",{"text":68,"@type":64},"Subpopulations can be distinguished by Ki-67 proliferation index, expression of hormonal markers, and differences in metabolic imaging uptake intensity on modalities such as 68Ga-somatostatin receptor imaging and 18F-FDG PET.",{"name":70,"@type":61,"acceptedAnswer":71},"What challenges exist in biopsy decisions for recurrence or progression?",{"text":72,"@type":64},"The review notes there is no recommendation on systematic biopsy of NEN recurrence or progression, including which specific lesion should be sampled to best represent tumor 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Couvelard, Maxime Ronot, Rachida Lebtahi, Olivia Hentic, Philippe Ruszniewski, Jérôme Cros and Louis de Mestier  \nAbstract: Neuroendocrine neoplasms (NENs) are initially monoclonal neoplasms that progressively become polyclonal, with very different genotypic and phenotypic characteristics leading to biological differences, including the Ki-67 proliferation index, morphology, or sensitivity to treatments. Whereas inter-patient heterogeneity has been well described, intra-tumor heterogeneity has been little studied. However, NENs present a high degree of heterogeneity, both spatially within the same location or between different lesions, and through time. This can be explained by the emergence of tumor subclones with different behaviors. These subpopulations can be distinguished by the Ki-67 index, but also by the expression of hormonal markers or by differences in the intensity of uptake on metabolic imaging, such as 68 Ga-somatostatin receptor and Fluorine-18 fluorodeoxyglucose positron emission tomography. As these features are directly related to prognosis, it seems mandatory to move toward a standardized, improved selection of the tumor areas to be studied to be as predictive as possible. The temporal evolution of NENs frequently leads to changes in tumor grade over time, with impact on prognosis and therapeutic decision-making. However, thereis no recommendation regarding systematic biopsy of NEN recurrence or progression, and which lesion to sample. This review aims to summarize the current state of knowledge, the main hypotheses, and the main implications regarding intra-tumor spatial and temporal heterogeneity in digestive NENs.  \nKeywords: clonal selection, evolution, heterogeneity, neuroendocrine neoplasms  \nReceived: 28 February 2023; revised manuscript accepted: 11 May 2023.  \nIntroduction: NENs are heterogeneous neoplasms  \nNeuroendocrine neoplasms (NENs) are rare malignancies arising from neuroendocrine cells organized as glandular organs (e.g. pancreas) or as the diffuse endocrine system (e.g. in the digestive and bronchial tracts) .1 NENs can present very variable histopathological characteristics, functioning profile, aspect on imaging and molecular abnormalities. These differences are important as they can impact prognosis and influence therapeutic decision-making.  \nNENs encompass well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) .2,3 These entities are very different in molecular landscape, prognosis,  \nand treatment. Beyond cell differentiation, NENscan have heterogeneous histopathological features, notably variable architecture including nested, trabecular, and/or pseudo-glandular patterns in NETs, and organoid or diffuse patterns in NECs.4 In addition, NENs show very variable degree of proliferation, measured by the Ki-67 index and mitotic count, which constitutes the basis of their histoprognostic classification.2,3  \nNENs have variable functioning profile, corresponding to their ability to produce, store, and secrete hormones and peptides, such as chromogranin A which is clinically inert, and serotonin, insulin, glucagon, and gastrin, whose hypersecretion can lead to functioning syndromes. Hormone production can be primarily  \nTherAdv Med Oncol 2023, Vol. 15: 1–12  \nDOI: 10. 1177/ 17588359231179310  \n© The Author(s), 2023. Article reuse guidelines: [sagepub.com/journals](sagepub.com/journals)permissions  \nCorrespondence to:  \nLouis de Mestier  \nDepartment of Pancreatology and Digestive Oncology, Beaujon Hospital (APHP. Nord), Université ParisCité, Clichy, France Centre de Recherche sur l’Inflammation, INSERMUMR1149, FHU MOSAIC, Paris, France  \n[louis.demestier@aphp.fr](louis.demestier@aphp.fr)[ ](louis.demestier@aphp.fr)Pauline Bourdeleau Olivia Hentic  \nDepartment of Pancreatology and Digestive Oncology, Beaujon Hospital (APHP. Nord), Université P","cbCaihlJS9W9cEhS","https://ap.wps.com/l/cbCaihlJS9W9cEhS","pdf",957262,12,"English","# Introduction\n## NENs are heterogeneous neoplasms\n# Key mechanisms of spatial and temporal heterogeneity\n## Subclones and tumor heterogeneity\n## Imaging and biomarker features","[{\"question\":\"How does intra-tumor heterogeneity arise in digestive neuroendocrine neoplasms?\",\"answer\":\"NENs progress from monoclonal to polyclonal states as tumor subclones with different behaviors emerge, creating spatial and temporal differences within the same tumor and across lesions.\"},{\"question\":\"Which features help distinguish NEN subclones?\",\"answer\":\"Subpopulations can be distinguished by Ki-67 proliferation index, expression of hormonal markers, and differences in metabolic imaging uptake intensity on modalities such as 68Ga-somatostatin receptor imaging and 18F-FDG PET.\"},{\"question\":\"What challenges exist in biopsy decisions for recurrence or progression?\",\"answer\":\"The review notes there is no recommendation on systematic biopsy of NEN recurrence or progression, including which specific lesion should be sampled to best represent tumor behavior.\"}]","Spatial and temporal heterogeneity of digestive neuroendocrine neoplasms | PDF",1790561772]