A Novel Nodal Staging Paradigm for Gallbladder Cancer Integrating Anatomical Hierarchy and Nodal Burden

A Novel Nodal Staging Paradigm for Gallbladder Cancer Integrating Anatomical Hierarchy and Nodal Burden | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Novel Nodal Staging Paradigm for Gallbladder Cancer Integrating Anatomical Hierarchy and Nodal Burden Wenkai Cui, Yuda Gong, Jie Wang, Xiaobo Bo, Changcheng Wang, Yueqi Wang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8528460/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Accurate lymph node (LN) staging is essential for prognostic stratification in gallbladder cancer (GBC). However, current staging systems are largely one-dimensional, relying exclusively on either nodal counts or anatomical location, and therefore fail to reflect the biological heterogeneity and hierarchical nature of lymphatic dissemination. To address this limitation, we developed a novel nodal classification—the D classification—that integrates anatomical hierarchy with nodal metastatic burden. Methods We retrospectively analyzed 370 patients with GBC who underwent curative-intent resection at Zhongshan Hospital, Fudan University, between 2013 and 2018. The D classification was established based on anatomical lymphatic drainage patterns and further refined by incorporating the number of metastatic lymph nodes within each anatomical tier. Prognostic performance was assessed using Kaplan–Meier survival analysis, multivariable Cox regression, and time-dependent receiver operating characteristic (ROC) curve analysis. Results The anatomy-based D classification independently stratified overall survival, demonstrating a stepwise deterioration in prognosis with involvement of deeper anatomical nodal stations. Incorporation of nodal burden within each anatomical tier further enhanced prognostic discrimination. When integrated with T and M categories, the refined D classification achieved robust predictive accuracy, with area under the curve (AUC) values of 0.750, 0.814, and 0.812 for 1-, 3-, and 5-year overall survival, respectively, outperforming the AJCC 8th edition N classification. Conclusions By jointly modeling anatomical hierarchy and nodal metastatic burden, the D classification introduces a biologically informed and surgically relevant framework for nodal staging in GBC. This integrated approach improves prognostic accuracy and provides a practical foundation for refining future staging systems and guiding individualized clinical decision-making. Gallbladder Neoplasms Lymphatic Metastasis Neoplasm Staging Prognosis Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 05 Feb, 2026 Editor invited by journal 07 Jan, 2026 Editor assigned by journal 07 Jan, 2026 Submission checks completed at journal 07 Jan, 2026 First submitted to journal 06 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8528460","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":587047249,"identity":"161c76dc-aa7b-4529-9b32-0eb98ae0bcdf","order_by":0,"name":"Wenkai Cui","email":"","orcid":"","institution":"Zhongshan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenkai","middleName":"","lastName":"Cui","suffix":""},{"id":587047250,"identity":"a0858f05-b5fe-4fe8-80b9-b881985e97a6","order_by":1,"name":"Yuda Gong","email":"","orcid":"","institution":"Zhongshan 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Burden","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gallbladder Neoplasms, Lymphatic Metastasis, Neoplasm Staging, Prognosis","lastPublishedDoi":"10.21203/rs.3.rs-8528460/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8528460/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAccurate lymph node (LN) staging is essential for prognostic stratification in gallbladder cancer (GBC). However, current staging systems are largely one-dimensional, relying exclusively on either nodal counts or anatomical location, and therefore fail to reflect the biological heterogeneity and hierarchical nature of lymphatic dissemination. To address this limitation, we developed a novel nodal classification\u0026mdash;the D classification\u0026mdash;that integrates anatomical hierarchy with nodal metastatic burden.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed 370 patients with GBC who underwent curative-intent resection at Zhongshan Hospital, Fudan University, between 2013 and 2018. The D classification was established based on anatomical lymphatic drainage patterns and further refined by incorporating the number of metastatic lymph nodes within each anatomical tier. Prognostic performance was assessed using Kaplan\u0026ndash;Meier survival analysis, multivariable Cox regression, and time-dependent receiver operating characteristic (ROC) curve analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe anatomy-based D classification independently stratified overall survival, demonstrating a stepwise deterioration in prognosis with involvement of deeper anatomical nodal stations. Incorporation of nodal burden within each anatomical tier further enhanced prognostic discrimination. When integrated with T and M categories, the refined D classification achieved robust predictive accuracy, with area under the curve (AUC) values of 0.750, 0.814, and 0.812 for 1-, 3-, and 5-year overall survival, respectively, outperforming the AJCC 8th edition N classification.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eBy jointly modeling anatomical hierarchy and nodal metastatic burden, the D classification introduces a biologically informed and surgically relevant framework for nodal staging in GBC. This integrated approach improves prognostic accuracy and provides a practical foundation for refining future staging systems and guiding individualized clinical decision-making.\u003c/p\u003e","manuscriptTitle":"A Novel Nodal Staging Paradigm for Gallbladder Cancer Integrating Anatomical Hierarchy and Nodal Burden","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-09 20:34:50","doi":"10.21203/rs.3.rs-8528460/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-02-05T06:50:44+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-07T17:00:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-07T11:07:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-07T11:05:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-01-06T07:52:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ef08cfd6-4321-48c5-8ddf-3ba453d427f8","owner":[],"postedDate":"February 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T20:34:50+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-09 20:34:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8528460","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8528460","identity":"rs-8528460","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}