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ENE determined by imaging (iENE) is a criterion for upstaging HPV+ HNSCC in the AJCC Cancer Staging System, 9th edition; however, its prognostic value is less than that of pENE, varies between studies, and the correlation between pENE and iENE is less than optimal. This study explores biological characteristics of tumors that can decrease the predictive value of iENE. Methods: Pre-treatment CT scans from patients with HPV-associated HNSCC were evaluated for iENE status. RNA-Seq data from primary tumor samples were analyzed using edgeR v4.6.2 and transcriptional differences were categorized by ssGSEA. Machine learning was applied to refine gene expression changes associated with iENE and survival was analyzed with log-rank tests. Results: Recurrence-free survival did not differ between patients with and without iENE. Both ML-ENE status and enrichment for inflammatory signaling were associated with improved RFS (p &lt; 0.01 and p &lt; 0.0001). When stratified by the ML-ENE signature or the inflammatory signature, iENE status did not further separate outcomes, indicating that its prognostic information was largely captured by these gene sets. These stratified comparisons were exploratory and limited by subgroup size. Conclusions: These analyses suggest that tumor biology associated with an inflamed tumor microenvironment may confound determination of ENE by imaging and that accounting for tumors with inflammatory signaling could improve the correlation of iENE with outcomes.<\/jats:p>","DOI":"10.3390\/cancers18183030","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:50:03Z","timestamp":1789995003000},"page":"3030","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor Inflammation Confounds Radiographic Determination of Extranodal Extension in HPV-Associated Head and Neck Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Sri","family":"Vemulamanda","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\/Head and Neck Surgery, UNC School of Medicine, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2529-2161","authenticated-orcid":false,"given":"Yasine","family":"Mirmozaffari","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\/Head and Neck Surgery, UNC School of Medicine, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Alan H.","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noman","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0855-6444","authenticated-orcid":false,"given":"Wendell G.","family":"Yarbrough","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\/Head and Neck Surgery, UNC School of Medicine, Chapel Hill, NC 27599, USA"},{"name":"Lineberger Comprehensive Cancer Center, UNC School of Medicine, Chapel Hill, NC 27599, USA"},{"name":"Department of Pathology and Laboratory Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5483-6610","authenticated-orcid":false,"given":"Natalia","family":"Issaeva","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\/Head and Neck Surgery, UNC School of Medicine, Chapel Hill, NC 27599, USA"},{"name":"Lineberger Comprehensive Cancer Center, UNC School of Medicine, Chapel Hill, NC 27599, USA"},{"name":"Department of Pathology and Laboratory Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Benjamin Y.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8297-3329","authenticated-orcid":false,"given":"Travis P.","family":"Schrank","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\/Head and Neck Surgery, UNC School of Medicine, Chapel Hill, NC 27599, USA"},{"name":"Lineberger Comprehensive Cancer Center, UNC School of Medicine, Chapel Hill, NC 27599, USA"},{"name":"Department of Pathology and Laboratory Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Barsouk, A., Aluru, J.S., Rawla, P., Saginala, K., and Barsouk, A. 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