{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:58:56Z","timestamp":1790852336983,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K09635"],"award-info":[{"award-number":["21K09635"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K12721"],"award-info":[{"award-number":["24K12721"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K12722"],"award-info":[{"award-number":["24K12722"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["26K12389"],"award-info":[{"award-number":["26K12389"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background\/Objectives: Inverted sinonasal papilloma (ISP) is a benign tumor with clinically important risks of recurrence and malignant transformation. We investigated factors associated with postoperative recurrence and the clinical significance of human papillomavirus (HPV) DNA detection. Methods: We retrospectively reviewed 104 surgically treated patients with histologically confirmed ISP (2006\u20132024). Clinical and radiological factors, HPV genotype and viral load, and p16, p53, and Ki-67 expression were evaluated. Recurrence analysis included 86 patients with at least 12 months of total clinical follow-up. Results: Seven patients (8.1%) developed recurrence. Median total clinical follow-up in the recurrence-analysis cohort was 46.5 months. Frontal sinus involvement and attachment-site hyperostosis were associated with recurrence in an exploratory two-variable Cox model, with wide confidence intervals. An additional model incorporating Krouse stage failed to converge. HPV DNA was detected in 21\/104 tumors (20.2%): 11 low-risk and 10 high-risk HPV-positive tumors. Viral load was quantifiable in five tumors (0.3\u201365.0 E6 copies\/ng genomic DNA); the remaining 16 were below the quantification limit of 0.25 copies\/ng. No significant association between HPV status and recurrence was demonstrated. Two tumors showed p16 overexpression, including one high-risk HPV-positive tumor; no consistent HPV-related immunohistochemical pattern was identified. Conclusions: Frontal sinus involvement and attachment-site hyperostosis were associated with recurrence in this cohort. With only seven events, the findings are exploratory and require validation. A clinically relevant HPV association cannot be excluded, and HPV transcriptional activity cannot be inferred from these data.<\/jats:p>","DOI":"10.3390\/jcm15197619","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:25:44Z","timestamp":1790850344000},"page":"7619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Factors Associated with Postoperative Recurrence in Inverted Sinonasal Papilloma: A Single-Center Cohort Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9093-4188","authenticated-orcid":false,"given":"Hironori","family":"Nakayoshi","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"software","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1789-8801","authenticated-orcid":false,"given":"Hitoshi","family":"Hirakawa","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9041-7712","authenticated-orcid":false,"given":"Taro","family":"Ikegami","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6421-7279","authenticated-orcid":false,"given":"Shogo","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Tomoyo","family":"Higa","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5978-9910","authenticated-orcid":false,"given":"Masatomo","family":"Toyama","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0092-5812","authenticated-orcid":false,"given":"Hidetoshi","family":"Kinjyo","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Shunsuke","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"given":"Norimoto","family":"Kise","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"given":"Shinya","family":"Agena","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"given":"Naoki","family":"Wada","sequence":"additional","affiliation":[{"name":"Department of Pathology and Oncology, Graduate School of Medicine, University of the Ryukyus, 1076 Kiyuna, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Fumi","family":"Kawakami","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, 1076 Kiyuna, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7743-8666","authenticated-orcid":false,"given":"Mikio","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Ginowan 901-2720, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1177\/1945892418765004","article-title":"Endoscopic resection of sinonasal inverted papilloma: Systematic review and meta-analysis","volume":"32","author":"Goudakos","year":"2018","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.otohns.2005.11.038","article-title":"Endoscopic resection of sinonasal inverted papilloma: A meta-analysis","volume":"134","author":"Busquets","year":"2006","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Syrj\u00e4nen, S., and Syrj\u00e4nen, K. (2021). HPV-associated benign squamous cell papillomas in the upper aero-digestive tract and their malignant potential. Viruses, 13.","DOI":"10.3390\/v13081624"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1097\/00125480-200103000-00001","article-title":"Schneiderian papillomas and carcinomas: A review","volume":"8","author":"Batsakis","year":"2001","journal-title":"Adv. Anat. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1007\/s00405-017-4571-2","article-title":"Malignant transformation of sinonasal inverted papilloma and related genetic alterations: A systematic review","volume":"274","author":"Re","year":"2017","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_6","first-page":"1","article-title":"European position paper on endoscopic management of tumours of the nose, paranasal sinuses and skull base","volume":"22","author":"Lund","year":"2010","journal-title":"Rhinol. Suppl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1002\/lary.28078","article-title":"Morphologic, intraoperative, and histologic risk factors for sinonasal inverted papilloma recurrence","volume":"130","author":"Lee","year":"2020","journal-title":"Laryngoscope"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1097\/PAS.0000000000001411","article-title":"Transcriptionally active HPV and targetable EGFR mutations in sinonasal inverted papilloma: An association between low-risk HPV, condylomatous morphology, and cancer risk?","volume":"44","author":"Mehrad","year":"2020","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/lary.23688","article-title":"Detection of human papillomavirus in sinonasal papillomas: Systematic review and meta-analysis","volume":"123","year":"2013","journal-title":"Laryngoscope"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1002\/lary.29910","article-title":"HPV-positive status is an independent factor associated with sinonasal inverted papilloma recurrence","volume":"132","author":"Viitasalo","year":"2022","journal-title":"Laryngoscope"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e2178","DOI":"10.1002\/rmv.2178","article-title":"The role of human papillomavirus in the pathogenesis of sinonasal inverted papilloma: A narrative review","volume":"31","author":"Gupta","year":"2021","journal-title":"Rev. Med. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1002\/ohn.1108","article-title":"Human papilloma virus infection and sinonasal inverted papilloma recurrence: A meta-analysis","volume":"172","author":"Alqudrah","year":"2025","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hirakawa, H., Ikegami, T., Kise, N., Kinjyo, H., Kondo, S., Agena, S., Hasegawa, N., Kawakami, J., Maeda, H., and Suzuki, M. (2023). Human papillomavirus infection and EGFR exon 20 insertions in sinonasal inverted papilloma and squamous cell carcinoma. J. Pers. Med., 13.","DOI":"10.3390\/jpm13040657"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hirakawa, H., Ikegami, T., Toyama, M., Ooshiro, Y., Higa, T., Kinjyo, H., Kondo, S., Kise, N., Yamashita, Y., and Suzuki, M. (2024). Prospective analysis of squamous cell carcinoma antigen-1 and -2 for diagnosing sinonasal inverted papilloma. J. Clin. Med., 13.","DOI":"10.3390\/jcm13092721"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s00405-025-09585-5","article-title":"Comparative analysis of serum SCC antigen levels in inverted sinonasal papilloma and nasal polyps: A diagnostic meta-analysis","volume":"283","author":"Soltan","year":"2026","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1053\/ajot.2001.22563","article-title":"Endoscopic treatment of inverted papilloma: Safety and efficacy","volume":"22","author":"Krouse","year":"2001","journal-title":"Am. J. Otolaryngol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2500\/ajra.2017.31.4416","article-title":"Transseptal access with crossing multiple incisions for improved pedicle control and septum preservation: \u201cHow I do it\u201d","volume":"31","author":"Omura","year":"2017","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.anl.2019.03.006","article-title":"Direct approach to the anterior and lateral part of the maxillary sinus with an endoscope","volume":"46","author":"Omura","year":"2019","journal-title":"Auris Nasus Larynx"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s12957-025-04130-4","article-title":"Clinical, virological, and immunohistochemical features of laryngeal papilloma with low-risk human papillomavirus infection: Insights from a 13-year institutional cohort","volume":"24","author":"Hirakawa","year":"2026","journal-title":"World J. Surg. Oncol."},{"key":"ref_20","unstructured":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2007). Human Papillomaviruses. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, International Agency for Research on Cancer."},{"key":"ref_21","unstructured":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2012). Biological Agents. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, International Agency for Research on Cancer."},{"key":"ref_22","first-page":"1571","article-title":"Detection of human papillomavirus in branchial cleft cysts","volume":"16","author":"Ikegami","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hirakawa, H., Ikegami, T., Touyama, M., Ooshiro, Y., Higa, T., Higa, T., Agena, S., Kinjyo, H., Kondo, S., and Kise, N. (2023). p16 overexpression in sinonasal squamous cell carcinoma: Association with human papillomavirus and prediction of survival outcomes. J. Clin. Med., 12.","DOI":"10.3390\/jcm12216861"},{"key":"ref_24","first-page":"93","article-title":"The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more \u201cpersonalized\u201d approach to cancer staging","volume":"67","author":"Amin","year":"2017","journal-title":"CA Cancer J. Clin."},{"key":"ref_25","unstructured":"College of American Pathologists (2025). Human Papillomavirus Testing in Head and Neck Carcinomas Guideline Update: Summary of Recommendations, College of American Pathologists."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/j.0006-341X.2001.00114.x","article-title":"A solution to the problem of monotone likelihood in Cox regression","volume":"57","author":"Heinze","year":"2001","journal-title":"Biometrics"},{"key":"ref_27","first-page":"618","article-title":"Focal hyperostosis on CT of sinonasal inverted papilloma as a predictor of tumor origin","volume":"28","author":"Lee","year":"2007","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_28","first-page":"2","article-title":"Association of the human papillomavirus infection with the recurrence of sinonasal inverted papilloma: A systematic review and meta-analysis","volume":"60","author":"Rha","year":"2022","journal-title":"Rhinology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1007\/s12105-019-01125-y","article-title":"Human papillomavirus and factors associated with recurrence in sinonasal inverted papillomas from Poland and Spain","volume":"14","author":"Fulla","year":"2020","journal-title":"Head Neck Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1002\/hed.23034","article-title":"Viral load, physical status, and E6\/E7 mRNA expression of human papillomavirus in head and neck squamous cell carcinoma","volume":"35","author":"Deng","year":"2013","journal-title":"Head Neck"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Ram\u00edrez, I., Carrillo-Garc\u00eda, A., Contreras-Paredes, A., Ortiz-S\u00e1nchez, E., Cruz-Gregorio, A., and Lizano, M. (2018). Regulation of cellular metabolism by high-risk human papillomaviruses. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19071839"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.anorl.2017.10.008","article-title":"Absence of high-risk human papilloma virus in p16 positive inverted sinonasal papilloma","volume":"137","author":"Holm","year":"2020","journal-title":"Eur. Ann. Otorhinolaryngol. Head Neck Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1097\/PAS.0b013e3182698673","article-title":"Human papillomavirus-related carcinomas of the sinonasal tract","volume":"37","author":"Bishop","year":"2013","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1002\/lary.22495","article-title":"Inverted papilloma of the nasal cavity and paranasal sinuses: A Korean multicenter study","volume":"122","author":"Kim","year":"2012","journal-title":"Laryngoscope"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/19\/7619\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:37:43Z","timestamp":1790851063000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/19\/7619"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":34,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["jcm15197619"],"URL":"https:\/\/doi.org\/10.3390\/jcm15197619","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]}}}