{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T22:33:45Z","timestamp":1790980425514,"version":"4.1.0"},"reference-count":30,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:00:00Z","timestamp":1613088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Middle ear squamous cell carcinoma (MESCC) is rare. Human Papilloma Virus (HPV) infection has been found in a significant number of cases of MESCC. Despite the emerging role of HPV in oncogenesis, its role in the pathogenesis and prognosis of MESCC is not known. This study aims to identify the prognostic impact of alpha and beta HPV in MESCC and its correlation with p16 protein. We retrospectively investigated 33 patients with MESCC surgically treated between 2004 and 2016. HPV DNA was ascertained by polymerase chain reaction (PCR) and P16INK4a detection was performed. Disease-specific survival (DSS) and cumulative incidence of recurrence were calculated in relation to HPV presence and genotype. p16 sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in predicting HPV infection were calculated. HPV was detected in 66.7% of patients (36.4% alpha HPV, 63.6% beta HPV). Five-year DSS was 55.0% and was not statistically related to HPV presence (p = 0.55) or genotype (p = 0.87). Five-year cumulative incidence of recurrence was 46 %, and was not statistically related to HPV presence (p = 0.22) or genotype (p = 0.44). p16 sensitivity, specificity, PPV, and NPV in predicting HPV infection were 27.3%, 36.4%, 46.2%, and 20.0%, respectively. In our experience, beta HPV was more frequent than alpha HPV in MESCC. Neither HPV presence nor HPV genotypes relate to DSS or cumulative incidence of recurrence. p16 expression was not predictive for HPV infection in MESCC. The role of HPV infection in oncogenesis, maintenance, and prognosis of MESCC seems to be different from that in oropharynx and skin cancer.<\/jats:p>","DOI":"10.3390\/jcm10040738","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T22:41:25Z","timestamp":1613169685000},"page":"738","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["HPV Infection in Middle Ear Squamous Cell Carcinoma: Prevalence, Genotyping and Prognostic Impact"],"prefix":"10.3390","volume":"10","author":[{"given":"Giovanni","family":"Cristalli","sequence":"first","affiliation":[{"name":"Otorhinolaryngology Unit, Ospedali Riuniti Padova Sud \u201cMadre Teresa di Calcutta\u201d Hospital, 35043 Monselice, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2322-6857","authenticated-orcid":false,"given":"Aldo","family":"Venuti","sequence":"additional","affiliation":[{"name":"HPV Unit, UOSD Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4160-3479","authenticated-orcid":false,"given":"Fabiola","family":"Giudici","sequence":"additional","affiliation":[{"name":"Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7384-6248","authenticated-orcid":false,"given":"Francesca","family":"Paolini","sequence":"additional","affiliation":[{"name":"HPV Unit, UOSD Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Ferreli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Mercante","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Italy"},{"name":"Otorhinolaringology\u2014Head and Neck Surgery Unit, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Spriano","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Italy"},{"name":"Otorhinolaringology\u2014Head and Neck Surgery Unit, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0758-2376","authenticated-orcid":false,"given":"Francesca","family":"Boscolo Nata","sequence":"additional","affiliation":[{"name":"Otorhinolaryngology Unit, Ospedali Riuniti Padova Sud \u201cMadre Teresa di Calcutta\u201d Hospital, 35043 Monselice, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"ref_1","first-page":"1327","article-title":"Prevalence of human papillomavirus in middle ear carcinoma associated with chronic otitis media","volume":"150","author":"Jin","year":"1997","journal-title":"Am. J. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s12105-018-0908-4","article-title":"Squamous cell carcinoma of the external auditory canal and temporal bone","volume":"12","author":"Allanson","year":"2018","journal-title":"Head Neck Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nature07205","article-title":"Cancer-related inflammation","volume":"454","author":"Mantovani","year":"2008","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature01322","article-title":"Inflammation and cancer","volume":"420","author":"Coussens","year":"2002","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1002\/lary.25822","article-title":"Predictors of High-Risk and Low-Risk Oral HPV Infection in the United States","volume":"126","author":"Orosco","year":"2016","journal-title":"Laryngoscope"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e435","DOI":"10.1016\/j.lpm.2014.08.008","article-title":"Cutaneous HPV and skin cancer","volume":"42","author":"Accardi","year":"2014","journal-title":"Presse Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1093\/infdis\/jir383","article-title":"The oral cavity contains abundant known and novel human papillomaviruses from the Betapapillomavirus and Gammapapillomavirus genera","volume":"204","author":"Bottalico","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jcv.2012.09.016","article-title":"Both mucosal and cutaneous papillomaviruses are in the oral cavity but only alpha genus seems to be associated with cancer","volume":"56","author":"Paolini","year":"2013","journal-title":"J. Clin. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.oraloncology.2019.01.004","article-title":"Beta human papillomaviruses in middle ear squamous cell carcinoma","volume":"90","author":"Paolini","year":"2019","journal-title":"Oral Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3930","DOI":"10.1200\/JCO.2013.54.5228","article-title":"p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma","volume":"32","author":"Chung","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1177\/000348949009900909","article-title":"Staging proposal for external auditory meatus carcinoma based on preoperative clinical examination and computed tomography findings","volume":"99","author":"Arriaga","year":"1990","journal-title":"Ann. Otol. Laryngol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"85","DOI":"10.14639\/0392-100X-486","article-title":"Intraoperative radiation therapy as adjuvant treatment in locally advanced stage tumours involving the middle ear: A hypothesis-generating retrospective study","volume":"36","author":"Cristalli","year":"2016","journal-title":"Acta Otorhinolaryngol. Ital."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1158\/1078-0432.CCR-06-1210","article-title":"Cumulative incidence in competing risks data and competing risks regression analysis","volume":"13","author":"Kim","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/ijc.2910590405","article-title":"Human-papillomavirus DNA in cholesteatomas","volume":"59","author":"Bergmann","year":"1994","journal-title":"Int. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.virol.2004.03.033","article-title":"Classification of papillomaviruses","volume":"324","author":"Fauquet","year":"2004","journal-title":"Virology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1093\/infdis\/jix245","article-title":"Prevalence and concordance of cutaneous beta human papillomavirus infection at mucosal and cutaneous sites","volume":"216","author":"Hampras","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.jcv.2016.07.019","article-title":"Beta-HPV types in patients with head and neck pathology and in healthy subjects","volume":"82","author":"Sabol","year":"2016","journal-title":"J. Clin. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1128\/JVI.06579-11","article-title":"Comparative analysis of transforming properties of E6 and E7 from different beta human papillomavirus types","volume":"86","author":"Cornet","year":"2012","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1001\/jamaoncol.2015.5504","article-title":"Associations of oral \u03b1-, \u03b2-, and \u03b3-human papillomavirus types with risk of incident head and neck cancer","volume":"2","author":"Agalliu","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.virol.2019.10.001","article-title":"Induction of co-inhibitory molecule CTLA-4 by human papillomavirus E7 protein through downregulation of histone methyltransferase JHDM1B expression","volume":"538","author":"Zhoua","year":"2019","journal-title":"Virology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s12070-016-0991-3","article-title":"Detection of Epstein-Barr and Human Papilloma Viruses in the Middle Ear Squamous Cell Carcinoma","volume":"70","author":"Surono","year":"2018","journal-title":"Indian J. Otolaryngol. Head Neck Surg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1002\/(SICI)1097-0215(19970410)71:2<208::AID-IJC14>3.0.CO;2-D","article-title":"High prevalence of human papillomavirus types 16 and 18in middle-ear carcinomas","volume":"71","author":"Tsai","year":"1997","journal-title":"Int. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/S0140-6736(05)67069-9","article-title":"Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: A pooled analysis","volume":"366","author":"Clifford","year":"2005","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1001\/jamaoto.2014.821","article-title":"Prognostic significance of p16 and its relationship with human papillomavirus in pharyngeal squamous cell carcinoma","volume":"140","author":"Wilson","year":"2014","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.oraloncology.2017.01.012","article-title":"Oropharyngeal cancer prognosis by tumour HPV status in France: The multicentric Papillophar study","volume":"67","author":"Rousseau","year":"2017","journal-title":"Oral Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1158\/1055-9965.EPI-19-0038","article-title":"Incidence and Demographic Burden of HPV-Associated Oropharyngeal Head and Neck Cancers in the United States","volume":"28","author":"Mahal","year":"2019","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_27","first-page":"22","article-title":"Investigating the role of human papillomavirus in squamous cell carcinoma of the temporal bone","volume":"5","author":"Masterson","year":"2013","journal-title":"Head Neck Oncol."},{"key":"ref_28","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_29","doi-asserted-by":"crossref","unstructured":"Nopmaneepaisarn, T., Tangjaturonrasme, N., Rawangban, W., Vinayanuwattikun, C., Keelawat, S., and Bychkov, A. (2019). Low prevalence of p16-positive HPV-related head-neck cancers in Thailand: Tertiary referral center experience. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6266-0"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1038\/onc.2010.614","article-title":"p16Ink4a overexpression in cancer: A tumor suppressor gene associated with senescence and high-grade tumors","volume":"30","author":"Romagosa","year":"2011","journal-title":"Oncogene"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/4\/738\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:23:30Z","timestamp":1760160210000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/4\/738"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,12]]},"references-count":30,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["jcm10040738"],"URL":"https:\/\/doi.org\/10.3390\/jcm10040738","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,12]]}}}