{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T08:18:10Z","timestamp":1793521090453,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T00:00:00Z","timestamp":1661817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u2018REVALING\u2019 project","award":["H85J20000030005"],"award-info":[{"award-number":["H85J20000030005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>HPV infection is a clear etiopathogenetic factor in oropharyngeal carcinogenesis and is associated with a markedly better prognosis than in smoking- and alcohol-associated cases, as specified by AJCC classification. The aim of the present work is to evaluate the prevalence of HPV-induced OPSCC in an insular area in the Mediterranean and to assess the reliability of p16 IHC (immunohistochemistry) alone, as accepted by AJCC, in the diagnosis of HPV-driven carcinogenesis in such a setting. All patients with OPSCC consecutively managed by the referral center in North Sardinia of head and neck tumor board of AOU Sassari, were recruited. Diagnosis of HPV-related OPCSS was carried out combining p16 IHC and DNA testing on FFPE samples and compared with the results of p16 IHC alone. Roughly 14% (9\/62) of cases were positive for HPV-DNA and p16 IHC. Three more cases showed overexpression of p16, which has a 100% sensitivity, but only 75% specificity as standalone method for diagnosing HPV-driven carcinogenesis. The Cohen\u2019s kappa coefficient of p16 IHC alone is 0.83 (excellent). However, if HPV-driven carcinogenesis diagnosed by p16 IHC alone was considered the criterion for treatment deintensification, 25% of p16 positive cases would have been wrongly submitted to deintensified treatment for tumors as aggressive as a p16 negative OPSCC. The currently accepted standard by AJCC (p16 IHC alone) harbors a high rate of false positive results, which appears risky for recommending treatment deintensification, and for this aim, in areas with a low prevalence of HPV-related OPSCC, it should be confirmed with HPV nucleic acid detection.<\/jats:p>","DOI":"10.3390\/cancers14174205","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T21:25:18Z","timestamp":1661894718000},"page":"4205","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Low Prevalence of HPV Related Oropharyngeal Carcinogenesis in Northern Sardinia"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6261-2772","authenticated-orcid":false,"given":"Francesco","family":"Bussu","sequence":"first","affiliation":[{"name":"Department of Medicine, Surgery and Pharmacy, University of Sassari-ENT Division, AOU Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3847-870X","authenticated-orcid":false,"given":"Narcisa","family":"Muresu","sequence":"additional","affiliation":[{"name":"Department of Humanities and Social Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1515-1867","authenticated-orcid":false,"given":"Claudia","family":"Crescio","sequence":"additional","affiliation":[{"name":"Otolaryngology Division, Azienda Ospedaliera Universitaria, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3343-2806","authenticated-orcid":false,"given":"Roberto","family":"Gallus","sequence":"additional","affiliation":[{"name":"Otolaryngology, Mater Olbia Hospital, 07026 Olbia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1830-3731","authenticated-orcid":false,"given":"Davide","family":"Rizzo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Pharmacy, University of Sassari-ENT Division, AOU Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cossu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7477-8320","authenticated-orcid":false,"given":"Illari","family":"Sechi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0206-6658","authenticated-orcid":false,"given":"Mariantonietta","family":"Fedeli","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Cossu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Delogu","sequence":"additional","affiliation":[{"name":"Facolt\u00e0 di Medicina e Chirurgia, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6609-8886","authenticated-orcid":false,"given":"Andrea","family":"Piana","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1056\/NEJMoa065497","article-title":"Case-control study of human papillomavirus and oropharyngeal cancer","volume":"356","author":"Kreimer","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1093\/annonc\/mdn372","article-title":"HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: A meta-analysis (1988\u20132007)","volume":"19","author":"Termine","year":"2008","journal-title":"Ann. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"103116","DOI":"10.1016\/j.critrevonc.2020.103116","article-title":"Global prevalence of human papillomavirus-driven oropharyngeal squamous cell carcinoma following the ASCO guidelines: A systematic review and meta-analysis","volume":"156","author":"Mariz","year":"2020","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1002\/ijc.30608","article-title":"Geographic heterogeneity in the prevalence of human papillomavirus in head and neck cancer","volume":"140","author":"Anantharaman","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Carlander, A., Jakobsen, K., Bendtsen, S., Garset-Zamani, M., Lynggaard, C., Jensen, J., Gr\u00f8nh\u00f8j, C., and Buchwald, C. (2021). A Contemporary Systematic Review on Repartition of HPV-Positivity in Oropharyngeal Cancer Worldwide. Viruses, 13.","DOI":"10.3390\/v13071326"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1097\/PPO.0000000000000115","article-title":"Prevalence of Human Papillomavirus in Oropharyngeal Cancer: A Systematic Review","volume":"21","author":"Stein","year":"2015","journal-title":"Cancer J."},{"key":"ref_7","first-page":"27","article-title":"Epidemiology of HPV-Positive Tumors in Europe and in the World","volume":"6","author":"Mena","year":"2017","journal-title":"Recent Results Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1002\/ijc.22980","article-title":"A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen","volume":"121","author":"Smeets","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_9","unstructured":"Amin, M.B., Edge, S., Greene, F., Byrd, D.R., Brookland, R.K., Washington, M.K., Gershenwald, J.E., Compton, C.C., Hess, K.R., and Sullivan, D.C. (2017). AJCC Cancer Staging Manual,  Springer International Publishing,  American Joint Commission on Cancer. [8th ed.]."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1002\/ijc.28580","article-title":"Molecular characterization of p16-immunopositive but HPV DNA-negative oropharyngeal carcinomas","volume":"134","author":"Rietbergen","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1093\/annonc\/mdy060","article-title":"Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing","volume":"29","author":"Nauta","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"224","DOI":"10.6004\/jnccn.2022.0016","article-title":"NCCN Guidelines\u00ae Insights: Head and Neck Cancers, Version 1.2022: Featured Updates to the NCCN Guidelines","volume":"20","author":"Caudell","year":"2022","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_13","unstructured":"(2022, August 08). CINtec\u00aeHistology (50-Test). Available online: http:\/\/reagent-catalog.roche.com\/product\/1875?type=2406."},{"key":"ref_14","unstructured":"(2022, August 08). DNA and RNA Purification Kit. Available online: https:\/\/www.qiagen.com\/it\/products\/discovery-and-translational-research\/dna-rna-purification\/multianalyte-and-virus\/allprep-dnarna-pe-kit\/."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Muresu, N., Sotgiu, G., Saderi, L., Sechi, I., Cossu, A., Marras, V., Meloni, M., Martinelli, M., Cocuzza, C., and Tanda, F. (2020). Distribution of HPV Genotypes in Patients with a Diagnosis of Anal Cancer in an Italian Region. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17124516"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s12985-020-01424-9","article-title":"Italian observational study on HPV infection, E6, and p16 expression in men with penile cancer","volume":"17","author":"Muresu","year":"2020","journal-title":"Virol. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/bjc.2013.55","article-title":"HPV infection in squamous cell carcinomas arising from different mucosal sites of the head and neck region. Is p16 immunohistochemistry a reliable surrogate marker?","volume":"108","author":"Bussu","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.ijrobp.2014.04.044","article-title":"Human papillomavirus (HPV) infection in squamous cell carcinomas arising from the oropharynx: Detection of HPV DNA and p16 immunohistochemistry as diagnostic and prognostic indicators-a pilot study","volume":"89","author":"Bussu","year":"2014","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1002\/hed.25591","article-title":"HPV as a marker for molecular characterization in head and neck oncology: Looking for a standardization of clinical use and of detection method(s) in clinical practice","volume":"41","author":"Bussu","year":"2019","journal-title":"Head Neck"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1038\/s41588-018-0215-8","article-title":"Genomic history of the Sardinian population","volume":"50","author":"Chiang","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1038\/bjc.2015.99","article-title":"Detection of HPV-associated oropharyngeal tumours in a 16-year cohort: More than meets the eye","volume":"112","author":"Melchers","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ejca.2016.10.015","article-title":"Continuing rise in oropharyngeal cancer in a high HPV prevalence area: A Danish population-based study from 2011 to 2014","volume":"70","author":"Carlander","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ejca.2020.04.027","article-title":"The current epidemic of HPV-associated oropharyngeal cancer: An 18-year Danish population-based study with 2169 patients","volume":"134","author":"Zamani","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1093\/carcin\/bgw203","article-title":"Prevalence of HPV Infection in Racial-Ethnic Subgroups of Head and Neck Cancer Patients","volume":"38","author":"Ragin","year":"2017","journal-title":"Carcinogenesis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9","DOI":"10.14639\/0392-100X-1905","article-title":"The evolving landscape of human papillomavirus-related oropharyngeal squamous cell carcinoma at a single institution in Northern Italy","volume":"39","author":"Morbini","year":"2019","journal-title":"Acta Otorhinolaryngol. Ital."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.pvr.2016.07.002","article-title":"Low prevalence of HPV-driven head and neck squamous cell carcinoma in North-East Italy","volume":"2","author":"Baboci","year":"2016","journal-title":"Papillomavirus Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Don\u00e0, M.G., Rollo, F., Pichi, B., Spriano, G., Moretto, S., Covello, R., Pellini, R., and Benevolo, M. (2020). Evolving Profile of HPV-Driven Oropharyngeal Squamous Cell Carcinoma in a National Cancer Institute in Italy: A 10-Year Retrospective Study. Microorganisms, 8.","DOI":"10.3390\/microorganisms8101498"},{"key":"ref_28","first-page":"1","article-title":"Age-independent increasing prevalence of Human Papillomavirus-driven oropharyngeal carcinomas in North-East Italy","volume":"10","author":"Frayle","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tagliabue, M., Mena, M., Maffini, F., Gheit, T., Blasco, B.Q., Holzinger, D., Tous, S., Scelsi, D., Riva, D., and Grosso, E. (2020). Role of Human Papillomavirus Infection in Head and Neck Cancer in Italy: The HPV-AHEAD Study. Cancers, 12.","DOI":"10.3390\/cancers12123567"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1016\/j.ejca.2009.08.018","article-title":"Human papilloma virus in head and neck cancer: The need for a standardised assay to assess the full clinical importance","volume":"45","author":"Braakhuis","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S0959-8049(09)70058-9","article-title":"HPV and prognosis for patients with oropharynx cancer","volume":"45","author":"Gillison","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1080\/00016480701558880","article-title":"Increased viral load correlates with improved survival in HPV-16-associated tonsil carcinoma patients","volume":"128","author":"Cohen","year":"2008","journal-title":"Acta Otolaryngol."},{"key":"ref_33","first-page":"51","article-title":"Significance of p16 in Site-specific HPV Positive and HPV Negative Head and Neck Squamous Cell Carcinoma","volume":"2","author":"Stephen","year":"2013","journal-title":"Cancer Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Miller, D.L., and Sharon Stack, M. (2015). Human Papillomavirus (HPV)-Associated Oropharyngeal Cancer, Springer.","DOI":"10.1007\/978-3-319-21100-8"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1056\/NEJMoa0912217","article-title":"Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer","volume":"363","author":"Ang","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.21037\/atm-20-2984","article-title":"De-intensification strategies in HPV-related oropharyngeal squamous cell carcinoma\u2014A narrative review","volume":"8","author":"Strohl","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"103243","DOI":"10.1016\/j.critrevonc.2021.103243","article-title":"Decreasing treatment burden in HPV-related OPSCC: A systematic review of clinical trials","volume":"160","author":"Iorio","year":"2021","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6213","DOI":"10.1200\/JCO.2009.23.1670","article-title":"Comparative Prognostic Value of HPV16 E6 mRNA Compared With In Situ Hybridization for Human Oropharyngeal Squamous Carcinoma","volume":"27","author":"Shi","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1093\/jjco\/hyv085","article-title":"Prognostic value of p16 expression irrespective of human papillomavirus status in patients with oropharyngeal carcinoma","volume":"45","author":"Saito","year":"2015","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/his.14350","article-title":"Oropharyngeal squamous cell carcinoma: p16\/p53 immunohistochemistry as a strong predictor of HPV tumour status","volume":"79","author":"Benzerdjeb","year":"2021","journal-title":"Histopathology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6262","DOI":"10.1158\/1078-0432.CCR-11-0388","article-title":"Evaluation of human papilloma virus diagnostic testing in oropharyngeal squamous cell carcinoma: Sensitivity, specificity, and prognostic discrimination","volume":"17","author":"Schache","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Oliva, C., Carrillo-Beltr\u00e1n, D., Boettiger, P., Gallegos, I., and Aguayo, F. (2022). Human Papillomavirus Detected in Oropharyngeal Cancers from Chilean Subjects. Viruses, 14.","DOI":"10.3390\/v14061212"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"M\u00e9ndez-Mat\u00edas, G., Vel\u00e1zquez-Vel\u00e1zquez, C., Castro-Oropeza, R., Mantilla-Morales, A., Ocampo-Sandoval, D., Burgos-Gonz\u00e1lez, A., Heredia-Guti\u00e9rrez, C., Alvarado-Cabrero, I., S\u00e1nchez-Sandoval, R., and Barco-Baz\u00e1n, A. (2021). Prevalence of HPV in Mexican Patients with Head and Neck Squamous Carcinoma and Identification of Potential Prognostic Biomarkers. Cancers, 13.","DOI":"10.3390\/cancers13225602"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.radonc.2017.12.007","article-title":"Comparison of detection methods for HPV status as a prognostic marker for loco-regional control after radiochemotherapy in patients with HNSCC","volume":"127","author":"Linge","year":"2018","journal-title":"Radiother. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1002\/ijc.29130","article-title":"p16(INK4a) \/Ki-67 co-expression specifically identifies transformed cells in the head and neck region","volume":"136","author":"Prigge","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1002\/ijc.25889","article-title":"HPV involvement in tonsillar cancer: Prognostic significance and clinically relevant markers","volume":"129","author":"Tachezy","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1002\/ijc.27821","article-title":"Increasing prevalence rates of HPV attributable oropharyngeal squamous cell carcinomas in the Netherlands as assessed by a validated test algorithm","volume":"132","author":"Rietbergen","year":"2013","journal-title":"Int. J. 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