{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T22:11:12Z","timestamp":1780092672271,"version":"3.54.0"},"reference-count":105,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:00:00Z","timestamp":1731283200000},"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>Background: The incidence of patients showing neck metastasis and no obvious primary tumor at the initial diagnostic evaluation or neck cancer of unknown primary (NCUP) is rising. It is estimated that a relevant part of these tumors arises in the tonsillar crypts or base of the tongue and are p16+-related. However, today, the detection rate of the primary tumor is suboptimal. Identifying the primary tumor and its biomolecular characterization is essential since it influences the treatment administered, possibly reducing radiation fields and providing de-escalation to primary surgical management. However, p16 IHC (immunohistochemistry) might not be sufficient to diagnose HPV-related OPSCC. The other subset of patients discussed are the HPV-positive patients who have a history of tobacco exposure and\/or p53 mutations. Possible factors that could negatively influence the outcomes of these patients are investigated and discussed below. So, this paper aims to analyze the diagnostic, bio-molecular, clinico-radiological, morphological, prognostic and therapeutical aspects of p16-positive OPSCC, highlighting the possible bias that can occur during the diagnostic and prognostic process. Methods: A narrative review was conducted to investigate the biases in the diagnostic and therapeutic process of two groups of patients: those who are p16-positive but HPV-negative patients, and those who are p16-positive and HPV-positive with exposure to traditional risk factors and\/or p53 mutations. The keywords used for the literature research included the following: NCUP, OPSCC, p16IHC, HPV testing, p16 positive HPV negative OPSCC, p16 positive HPV positive OPSCC, tonsillectomy, tobacco exposure, p53 mutations, cystic neck metastasis, extranodal extension (ENE), radiotherapy, de-escalation and neck neck dissection. Results: HPV-positive OPSCC has specific clinico-radiological features. Bilateral tonsillectomy should be considered for the identification of the primary tumor. P16 IHC alone is not sufficient for diagnosing HPV-related OPSCC; additional detection methods are required. The role of tobacco exposure and p53 mutations should be investigated especially in cases of HPV-positive tumors. Extranodal extension (ENE) must be taken into consideration in the prognostic staging of HPV-positive tumors. Surgical primary treatment involving neck dissection (ND) and bilateral tonsillectomy followed by adjuvant radiation may represent the most appropriate approach for N3 cases. Diagnosis, prognosis and therapeutical implications must be addressed considering clinical, biomolecular and morphological aspects. At least today, the numerous biases that are still present influencing the diagnostic and prognostic process do not permit considering de-escalation protocols. Conclusions: A precise and accurate diagnosis is required in order to adequately stage and manage p16+ OPSCC, particularly with neck metastasis. The role of tobacco exposure and\/or p53 mutations must be considered not only in p16+ OPSCC but especially in HPV-positive OPSCC. Until a more accurate diagnosis is possible, ENE should be considered even in p16+HPV+ OPSCC. Primary surgery with unilateral ND and bilateral tonsillectomy might be the treatment of choice given the numerous diagnostic and prognostic pitfalls. Therefore, it is inappropriate and risky to propose de-escalation protocols in routine clinical practice due to the risk of undertreatment.<\/jats:p>","DOI":"10.3390\/jcm13226773","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T11:34:11Z","timestamp":1731324851000},"page":"6773","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Challenges and Considerations in Diagnosing and Managing p16+-Related Oropharyngeal Squamous Cell Carcinoma (OPSCC) with Neck Metastasis: Implications of p16 Positivity, Tobacco Exposure, and De-Escalation Strategies"],"prefix":"10.3390","volume":"13","author":[{"given":"Giovanni","family":"Motta","sequence":"first","affiliation":[{"name":"ENT Unit, Department of Mental, Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Brandolini","sequence":"additional","affiliation":[{"name":"ENT Unit, Department of Mental, Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonia","family":"Di Meglio","sequence":"additional","affiliation":[{"name":"ENT Unit, Department of Mental, Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4312-4711","authenticated-orcid":false,"given":"Salvatore","family":"Allosso","sequence":"additional","affiliation":[{"name":"Otorhinolaryngology-Head and Neck Surgery Unit, Department of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5081-1552","authenticated-orcid":false,"given":"Massimo","family":"Mesolella","sequence":"additional","affiliation":[{"name":"Otorhinolaryngology-Head and Neck Surgery Unit, Department of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7235-2804","authenticated-orcid":false,"given":"Filippo","family":"Ricciardiello","sequence":"additional","affiliation":[{"name":"Ear, Nose and Throat Unit, AORN \u201cAntonio Cardarelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Bocchetti","sequence":"additional","affiliation":[{"name":"Department of Life and Health Sciences, Link Campus University, Via del Casale di San Pio V 44, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7176-3652","authenticated-orcid":false,"given":"Domenico","family":"Testa","sequence":"additional","affiliation":[{"name":"ENT Unit, Department of Mental, Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Motta","sequence":"additional","affiliation":[{"name":"ENT Unit, Department of Mental, Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/S1470-2045(10)70017-6","article-title":"HPV-associated head and neck cancer: A virus-related cancer epidemic","volume":"11","author":"Marur","year":"2010","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.radonc.2021.01.028","article-title":"Prevalence and Distribution of cervical lymph node metastases in HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma","volume":"157","author":"Bauwens","year":"2021","journal-title":"Radiother. 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