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The references of the publications of interest were also screened for relevant papers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The clinical assessment of HPV\u2010related SCCUP includes a complete clinical examination, an endoscopic evaluation with white\u2010light and narrow band imaging, and radiologic assessment using morphologic and metabolic imaging. If the diagnosis remains unconfirmed, endoscopic examination under anesthesia with tonsillectomy \u00b1 base of tongue mucosectomy is performed. The therapeutic rationale aims to eradicate the involved lymph nodes and potential primary tumor with a sequence of chemoradiotherapy and neck dissection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>As a general approach, p16\u2010negative SCCUP are truly HPV negative, whereas p16\u2010positive specimens require confirmation with HPV in situ hybridization or polymerase chain reaction to confirm HPV infection. If a cervical metastasis is considered HPV positive, the primary lesion is likely in the oropharynx, and further diagnostic interventions such as tonsillectomy seems to be mandatory. Whether the optimal treatment is neck dissection followed by adjuvant radiotherapy or concomitant chemoradiotherapy (CRT) (in case of extranodal extension or advanced lymph node stages) or definitive CRT followed by neck dissection (in case of positive <jats:sup>18<\/jats:sup>F\u2010FDG\u2010PET\/CT) remains a matter of debate. Solid scientific evidence supporting treatment de\u2010escalation in HPV\u2010related SCCUP is lacking, and the results of ongoing trials are at the brink of reporting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Currently, the treatment of patients with HPV\u2010related SCCUP should not differ from the standard treatment of other SCCUP patients and is similarly based on the staging of the disease and general condition of the patient.<\/jats:p><\/jats:sec>","DOI":"10.1002\/hed.25858","type":"journal-article","created":{"date-parts":[[2019,7,13]],"date-time":"2019-07-13T09:49:46Z","timestamp":1563011386000},"page":"3700-3711","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Comprehensive management of HPV\u2010related squamous cell carcinoma of the head and neck of unknown primary"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7906-0991","authenticated-orcid":false,"given":"Elie","family":"Rassy","sequence":"first","affiliation":[{"name":"Department of Medical Oncology Institut Gustave Roussy  Villejuif France"},{"name":"Department of Medical Oncology Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University  Beirut Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Nicolai","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, University of Brescia  Brescia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Pavlidis","sequence":"additional","affiliation":[{"name":"University of Ioannina  Ioannina Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2014.11.007"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-009-0367-1"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3109\/02841869009090048"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdg068"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/00016480500417304"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2015.3228"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2016.12.020"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00066-018-1308-0"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2012.06.019"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21389"},{"key":"e_1_2_8_12_1","unstructured":"NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). 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