{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T03:19:58Z","timestamp":1785727198132,"version":"3.56.0"},"reference-count":134,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T00:00:00Z","timestamp":1741824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Objectives: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally, with HPV-positive cases emerging as a distinct subtype with unique clinical and molecular characteristics. Current diagnostic methods, including tissue biopsy and imaging, face limitations in terms of invasiveness, static disease assessment, and difficulty in distinguishing recurrence from treatment-related changes. This review aimed to assess the potential of liquid biopsy as a minimally invasive tool for the diagnosis, treatment monitoring, and surveillance of HPV-associated HNSCC. Methods: This systematic review analyzed literature from PubMed\/MEDLINE, Embase, and Web of Science, focusing on original research and reviews related to liquid biopsy applications in HPV-positive HNSCC. Included studies were evaluated based on the robustness of the study design, clinical relevance, and analytical performance of liquid biopsy technologies. Biomarker types, detection methods, and implementation strategies were assessed to identify advancements and challenges in this field. Results: Liquid biopsy technologies, including circulating HPV DNA, ctDNA, and extracellular vesicles, demonstrated high sensitivity (90\u201395%) and specificity (&gt;98%) in detecting HPV-positive HNSCC. These methods enabled real-time monitoring of tumor dynamics, early detection of recurrence, and insights into treatment resistance. Longitudinal analysis revealed that biomarker clearance during treatment correlates strongly with patient outcomes. Conclusions: Liquid biopsy is a transformative diagnostic and monitoring tool for HPV-associated HNSCC, offering minimally invasive, real-time insights into tumor biology. While challenges remain in standardization and clinical implementation, ongoing research and technological innovations hold promise for integrating liquid biopsy into personalized cancer care, ultimately improving patient outcomes.<\/jats:p>","DOI":"10.3390\/cancers17060977","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T12:06:59Z","timestamp":1741867619000},"page":"977","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Liquid Biopsy in HPV-Associated Head and Neck Cancer: A Comprehensive Review"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0998-726X","authenticated-orcid":false,"given":"Federica Maria","family":"Parisi","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d, ENT Section, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8127-5045","authenticated-orcid":false,"given":"Mario","family":"Lentini","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, ASP 7, Ragusa Hospital, 97100 Ragusa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9454-9464","authenticated-orcid":false,"given":"Carlos M.","family":"Chiesa-Estomba","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Hospital Universitario Donostia, 20001 San Sebastian, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1829-6597","authenticated-orcid":false,"given":"Miguel","family":"Mayo-Yanez","sequence":"additional","affiliation":[{"name":"Otorhinolaryngology-Head and Neck Surgery Department, Complexo Hospitalario Universitario A Coru\u00f1a (CHUAC), 15006 La Coru\u00f1a, Spain"},{"name":"Otorhinolaryngology-Head and Neck Surgery Department, Hospital San Rafael (HSR) de A Coru\u00f1a, 15006 La Coru\u00f1a, Spain"},{"name":"Otorhinolaryngology-Head and Neck Surgery Research Group, Institute of Biomedical Research of A Coru\u00f1a, (INIBIC), Complexo Hospitalario Universitario de A Cor\u00f1na (CHUAC), Universidade da Cor\u00f1na (UDC), 15494 La Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome R.","family":"Leichen","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Experimental Oncology, UMONS Research Institute for Health Sciences and Technology, University of Mons (UMons), 7011 Mons, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"White","sequence":"additional","affiliation":[{"name":"Division of Otorhinolaryngology, Head and Neck Surgery, University of Cape Town, Cape Town 8001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4855-8615","authenticated-orcid":false,"given":"Giovanni","family":"Giurdanella","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6135-0958","authenticated-orcid":false,"given":"Salvatore","family":"Cocuzza","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d, ENT Section, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4512-1378","authenticated-orcid":false,"given":"Maria Rita","family":"Bianco","sequence":"additional","affiliation":[{"name":"Otolaryngology-Department of Health Science, University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Fakhry","sequence":"additional","affiliation":[{"name":"Department of Oto-Rhino-Laryngology Head and Neck Surgery, La Conception University Hospital, AP-HM, Aix Marseille Universit\u00e9, 13006 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1251-0185","authenticated-orcid":false,"given":"Antonino","family":"Maniaci","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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