{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:35:12Z","timestamp":1790127312469,"version":"4.0.1"},"reference-count":72,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) has emerged as a biologically distinct entity, typically affecting younger, non-smoking patients and showing improved survival compared to HPV-negative tumors. Accurate HPV status determination is essential for correct staging, prognostic assessment, and treatment de-escalation. Despite advances, substantial variability persists among diagnostic methods and clinical workflows. A narrative review of PubMed, Scopus, and Web of Science databases was conducted up to July 2025. Studies addressing HPV detection techniques in OPSCC\u2014including p16^INK4a^ immunohistochemistry (IHC), HPV DNA and RNA assays, liquid biopsy approaches, and computational surrogates\u2014were critically analyzed regarding diagnostic accuracy, clinical applicability, and emerging innovations. Tissue-based assays remain the diagnostic reference standard. p16 IHC provides high sensitivity but limited specificity and should be confirmed with nucleic acid-based methods such as DNA PCR, in situ hybridization (ISH), or E6\/E7 mRNA detection. Combined or \u201corthogonal\u201d testing minimizes discordance and refines risk stratification. Liquid biopsy detection of circulating HPV DNA using droplet digital PCR or next-generation sequencing has shown high sensitivity and specificity in cohorts of patients with HPV-associated OPSCC, supporting its potential role as a complementary biomarker for treatment monitoring and surveillance. However, circulating HPV DNA alone does not unequivocally identify the anatomic source of HPV DNA and should be interpreted together with clinical, radiologic, and tissue-based findings. Oral rinse and saliva assays show moderate diagnostic performance, while artificial intelligence-based radiomic and histopathologic models are emerging as complementary tools. Reliable HPV attribution in OPSCC requires a multimodal diagnostic strategy integrating p16 IHC, molecular confirmation, and ctHPV-DNA monitoring. Methodological standardization and prospective validation are essential to implement precision-guided, cost-effective workflows in routine clinical practice.<\/jats:p>","DOI":"10.3390\/diagnostics16071010","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T12:45:53Z","timestamp":1774615553000},"page":"1010","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["HPV Detection in Oropharyngeal Cancer: A Narrative Review of Diagnostic and Emerging Molecular Approaches"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7019-9746","authenticated-orcid":false,"given":"Fernando","family":"L\u00f3pez","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7128-5814","authenticated-orcid":false,"given":"Remco de","family":"Bree","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, 3584 Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. P.","family":"Sreeram","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Oncology, Sri Shankara Cancer Foundation, Bangalore 560004, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5540-4796","authenticated-orcid":false,"given":"Sandra","family":"Nuyts","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, 3000 Leuven, Belgium"},{"name":"Department of Radiation Oncology, Leuven Cancer Institute, University Hospitals Leuven Institution, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3063-0890","authenticated-orcid":false,"given":"Juan Pablo","family":"Rodrigo","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik N.","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Oncology, Sri Shankara Cancer Foundation, Bangalore 560004, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4972-1477","authenticated-orcid":false,"given":"Nabil F.","family":"Saba","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Bradford","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2238-3682","authenticated-orcid":false,"given":"Arlene","family":"Forastiere","sequence":"additional","affiliation":[{"name":"The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0481-156X","authenticated-orcid":false,"given":"Luiz P.","family":"Kowalski","sequence":"additional","affiliation":[{"name":"Head and Neck Surgery Department and LIM 28, University of S\u00e3o Paulo Medical School, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Head and Neck Surgery and Otorhinolaryngology Department, A C Camargo Cancer Center, Sao Paulo 01509-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3725-8051","authenticated-orcid":false,"given":"Anna Lu\u00edza Damaceno","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Suarez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8247-8002","authenticated-orcid":false,"given":"Alfio","family":"Ferlito","sequence":"additional","affiliation":[{"name":"Coordinator of the International Head and Neck Scientific Group, 35100 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105830","DOI":"10.1016\/j.archoralbio.2023.105830","article-title":"Characteristics of human papillomavirus infection among oropharyngeal cancer patients: A systematic review and meta-analysis","volume":"157","author":"Cui","year":"2024","journal-title":"Arch. 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