The 'Triple Threat': Extracapsular Extension, Perineural Invasion, and Lymphovascular Invasion as Predictors of Adjuvant Chemoradiation Failure in Head and Neck Squamous Cell Carcinoma

The 'Triple Threat': Extracapsular Extension, Perineural Invasion, and Lymphovascular Invasion as Predictors of Adjuvant Chemoradiation Failure in Head and Neck Squamous Cell Carcinoma | 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 The 'Triple Threat': Extracapsular Extension, Perineural Invasion, and Lymphovascular Invasion as Predictors of Adjuvant Chemoradiation Failure in Head and Neck Squamous Cell Carcinoma Ashmita Ghosh This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8898146/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The current standard of care for high-risk Head and Neck Squamous Cell Carcinoma (HNSCC) involves surgical resection followed by adjuvant concurrent chemoradiation (CCRT). Despite this aggressive multimodal approach, a subset of patients experiences early locoregional recurrence and distant metastasis. This study aims to define the "Triple Threat" phenotype—the coexistence of Extracapsular Extension (ECE), Perineural Invasion (PNI), and Lymphovascular Invasion (LVI)—and evaluate its utility as a predictor of CCRT failure, thereby identifying a cohort suitable for novel therapeutic intensification. Methods: We performed a retrospective analysis of 52 consecutive patients with pathologically confirmed HNSCC of the oral cavity and oropharynx treated with curative-intent surgery and adjuvant radiotherapy/chemoradiotherapy at a tertiary cancer center. Patients were stratified based on the presence of isolated high-risk features vs. the "Triple Threat" combination. The primary endpoint was Disease-Free Interval (DFI). Secondary endpoints included the pattern of failure (locoregional vs. systemic) and the impact of adjuvant chemotherapy compliance on outcomes. Results: The prevalence of high-risk features was: ECE (23%), PNI (38%), and LVI (19%). Patients exhibiting the "Triple Threat" phenotype (N=9) demonstrated a significantly inferior median DFI of 2.1 years compared to 4.8 years in patients with zero or one risk factor (Log-Rank p = 0.004). Multivariate Cox regression analysis identified the coexistence of ECE and PNI as an independent predictor of treatment failure (Hazard Ratio 3.4, 95% CI 1.2–8.9). Notably, 66% of "Triple Threat" patients recurred despite receiving guideline-concordant Platinum-based CCRT, suggesting intrinsic resistance to cytotoxic therapy. Conclusion: The coexistence of ECE, PNI, and LVI defines an "ultra-high-risk" subgroup of HNSCC patients who derive suboptimal benefit from standard adjuvant CCRT. This "Triple Threat" phenotype serves as a robust biomarker for selecting patients for adjuvant immunotherapy trials (e.g., PD-1 inhibitors), addressing a critical unmet need in current oncological practice. Oncology Head and Neck Squamous Cell Carcinoma Extracapsular Extension Perineural Invasion Lymphovascular Invasion Adjuvant Chemoradiotherapy Treatment Failure Immunotherapy. Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8898146","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":592533376,"identity":"6c33e26d-6714-491d-901d-fedffddad827","order_by":0,"name":"Ashmita Ghosh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYFACHgaGBAYGO3725oMPQFw+4rQkMCRL9hxLNgBx2YjSArSGccONHDMJEJ+gFv7+s0c3PPxhx8xwI8Gs8muOnQwbA/PDRzfwaJG4kZd2IyEhmY+x50HabdltyUCHsRkb5+Cz5gaPGVALMzMze8Kx25LbmIFaeNik8WmRP38GpKWesY0hsa1Ycls9YS0GB3JAWg4z9nAkszF+3HaYsBbDGyAtaceTJXiOMUszbjvOw8ZMwC9yQIfd/GFTbWd/vP/jx5/bqu2BcfrwMV7vIwNmHjBJrHIQYPxBiupRMApGwSgYMQAAmvFJP5aFIsMAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0008-5550-2960","institution":"Institute of Post Graduate Medical Education and Research","correspondingAuthor":true,"prefix":"","firstName":"Ashmita","middleName":"","lastName":"Ghosh","suffix":""}],"badges":[],"createdAt":"2026-02-17 06:30:22","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8898146/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8898146/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102963363,"identity":"091e792c-96d1-418f-8711-09329537cc8f","added_by":"auto","created_at":"2026-02-19 04:16:11","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":380012,"visible":true,"origin":"","legend":"","description":"","filename":"tripplethreatfinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8898146/v1_covered_e8882499-68fd-4b57-b624-d6fa30b147aa.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eThe 'Triple Threat': Extracapsular Extension, Perineural Invasion, and Lymphovascular Invasion as Predictors of Adjuvant Chemoradiation Failure in Head and Neck Squamous Cell Carcinoma\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Institute of Post Graduate Medical Education and Research","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Head and Neck Squamous Cell Carcinoma; Extracapsular Extension; Perineural Invasion; Lymphovascular Invasion; Adjuvant Chemoradiotherapy; Treatment Failure; Immunotherapy.","lastPublishedDoi":"10.21203/rs.3.rs-8898146/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8898146/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e The current standard of care for high-risk Head and Neck Squamous Cell Carcinoma (HNSCC) involves surgical resection followed by adjuvant concurrent chemoradiation (CCRT). Despite this aggressive multimodal approach, a subset of patients experiences early locoregional recurrence and distant metastasis. This study aims to define the \"Triple Threat\" phenotype—the coexistence of Extracapsular Extension (ECE), Perineural Invasion (PNI), and Lymphovascular Invasion (LVI)—and evaluate its utility as a predictor of CCRT failure, thereby identifying a cohort suitable for novel therapeutic intensification.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We performed a retrospective analysis of 52 consecutive patients with pathologically confirmed HNSCC of the oral cavity and oropharynx treated with curative-intent surgery and adjuvant radiotherapy/chemoradiotherapy at a tertiary cancer center. Patients were stratified based on the presence of isolated high-risk features vs. the \"Triple Threat\" combination. The primary endpoint was Disease-Free Interval (DFI). Secondary endpoints included the pattern of failure (locoregional vs. systemic) and the impact of adjuvant chemotherapy compliance on outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The prevalence of high-risk features was: ECE (23%), PNI (38%), and LVI (19%). Patients exhibiting the \"Triple Threat\" phenotype (N=9) demonstrated a significantly inferior median DFI of 2.1 years compared to 4.8 years in patients with zero or one risk factor (Log-Rank p = 0.004). Multivariate Cox regression analysis identified the coexistence of ECE and PNI as an independent predictor of treatment failure (Hazard Ratio 3.4, 95% CI 1.2–8.9). Notably, 66% of \"Triple Threat\" patients recurred despite receiving guideline-concordant Platinum-based CCRT, suggesting intrinsic resistance to cytotoxic therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The coexistence of ECE, PNI, and LVI defines an \"ultra-high-risk\" subgroup of HNSCC patients who derive suboptimal benefit from standard adjuvant CCRT. This \"Triple Threat\" phenotype serves as a robust biomarker for selecting patients for adjuvant immunotherapy trials (e.g., PD-1 inhibitors), addressing a critical unmet need in current oncological practice.\u003c/p\u003e","manuscriptTitle":"The 'Triple Threat': Extracapsular Extension, Perineural Invasion, and Lymphovascular Invasion as Predictors of Adjuvant Chemoradiation Failure in Head and Neck Squamous Cell Carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-18 03:20:12","doi":"10.21203/rs.3.rs-8898146/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5dd1dfb2-6e6b-4934-87e9-6bf506e83ba1","owner":[],"postedDate":"February 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":63103140,"name":"Oncology"}],"tags":[],"updatedAt":"2026-02-18T03:20:12+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-18 03:20:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8898146","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8898146","identity":"rs-8898146","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}