{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T00:13:07Z","timestamp":1772842387868,"version":"3.50.1"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background\/Objectives<\/jats:title><jats:p>Cervical squamous cell carcinoma of unknown primary (SCCUP) is a rare entity within head and neck cancer and both treatment regimens as well as identified potential predictors for oncological outcomes vary between published series. In this study, we evaluated oncological outcomes and identified potential prognostic factors for outcome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and methods<\/jats:title><jats:p>This retrospective monocentric cohort study includes 82 SCCUP patients diagnosed and treated between January 2000 and June 2021. Overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS) and locoregional recurrence-free survival (LRFS) were evaluated. The Cox proportional hazards model was used to analyze the prognostic effect of patient and tumor characteristics on oncological outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Five year OS, DSS, DFS and LRFS were respectively 53.9%, 72.2%, 68.9% and 67.3%. The p16 status was evaluated in 55 patients with 40% being p16 positive. On univariable analysis, p16 negative SCCUPs had significantly worse survival and recurrence rates in the presence of clinical extranodal extension (cENE) (OS: p=0.0013, DSS: p=0.0099, DFS: p=0.0164, LRFS: p=0.0099) and radiological extranodal extension (rENE) (OS: p=0.0034, DSS: p=0.0137, DFS: p=0.0167, LRFS: p=0.0100). In p16 positive SCCUP patients, rENE had a significantly negative prognostic effect on DFS (p=0.0345) and LRFS (p=0.0367). Total group multivariate analysis identified rENE as an independent negative predictor for all oncological outcomes. The \u201cnumber of positive lymph nodes\u201d was a second independent predictor for DSS (p=0.0257) and DFS (p=0.0435).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We report favorable oncological outcomes, comparable to previously published results. Although the presence of rENE seems associated with poor oncological outcomes, the differential effect of clinical, radiological and pathological ENE in both p16 positive and negative subgroups remain to be elucidated by further prospective research.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2022.1024414","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T05:20:58Z","timestamp":1668403258000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Cervical squamous cell carcinoma of unknown primary: Oncological outcomes and prognostic factors"],"prefix":"10.3389","volume":"12","author":[{"given":"Jeroen","family":"Meulemans","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Voortmans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Nuyts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Fran\u00e7ois","family":"Daisne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Clement","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annouschka","family":"Laenen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"Delaere","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Van Lierde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent Vander","family":"Poorten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.00275","article-title":"Diagnosis and management of squamous cell carcinoma of unknown primary in the head and neck: ASCO guideline","volume":"38","author":"Maghami","year":"2020","journal-title":"J Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/hed.25522","article-title":"Role of palatine tonsillectomy in the diagnostic workup of head and neck squamous cell carcinoma of unknown primary origin: A systematic review and meta-analysis","volume":"41","author":"Di Maio","year":"2019","journal-title":"Head Neck."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/hed.21898","article-title":"Contemporary management of lymph node metastases from an unknown primary to the neck: I","volume":"35","author":"Strojan","year":"2013","journal-title":"A Rev Diagn approaches. Head Neck."},{"key":"B4","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1001\/jamaoto.2015.3228","article-title":"Changes in unknown primary squamous cell carcinoma of the head and neck at initial presentation in the era of human papillomavirus","volume":"142","author":"Motz","year":"2016","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"key":"B5","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.oraloncology.2016.12.033","article-title":"Transoral robotic surgery for management of cervical unknown primary squamous cell carcinoma: Updates on efficacy, surgical technique and margin status","volume":"66","author":"Geltzeiler","year":"2017","journal-title":"Oral Oncol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ctrv.2016.11.014","article-title":"Neck lymph node metastases from unknown primary","volume":"53","author":"Arosio","year":"2017","journal-title":"Cancer Treat Rev"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2018.11.020","article-title":"Evidence for the approach to the diagnostic evaluation of squamous cell carcinoma occult primary tumors of the head and neck","volume":"88","author":"Golusinski","year":"2019","journal-title":"Oral Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/hed.25858","article-title":"Comprehensive management of HPV-related squamous cell carcinoma of the head and neck of unknown primary","volume":"41","author":"Rassy","year":"2019","journal-title":"Head Neck."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/hed.23514","article-title":"p16 status, pathologic and clinical characteristics, biomolecular signature, and long-term outcomes in head and neck squamous cell carcinomas of unknown primary","volume":"36","author":"Keller","year":"2014","journal-title":"Head Neck."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/hed.24441","article-title":"Impact of p16 expression, nodal status, and smoking on oncologic outcomes of patients with head and neck unknown primary squamous cell carcinoma","volume":"38","author":"Dixon","year":"2016","journal-title":"Head Neck."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.14421","article-title":"Detection and oncologic outcomes of head and neck squamous cell carcinoma of unknown primary origin","volume":"40","author":"Lee","year":"2020","journal-title":"Anticancer Res"},{"key":"B12","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s12105-015-0616-2","article-title":"Approach to metastatic carcinoma of unknown primary in the head and neck: Squamous cell carcinoma and beyond","volume":"9","author":"Chernock","year":"2015","journal-title":"Head Neck Pathology."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/hed.24300","article-title":"Narrow band imaging for the diagnosis of head and neck squamous cell carcinoma: A systematic review","volume":"38","author":"Cosway","year":"2016","journal-title":"Head Neck."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/lary.28350","article-title":"Narrow band imaging in head and neck unknown primary carcinoma: A systematic review and meta-analysis","volume":"130","author":"Di Maio","year":"2020","journal-title":"Laryngoscope"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/lary.25783","article-title":"Role of 18-fludeoxyglucose positron emission tomography-computed tomography and subsequent panendoscopy in head and neck squamous cell carcinoma of unknown primary","volume":"126","author":"Mani","year":"2016","journal-title":"Laryngoscope"},{"key":"B16","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s40463-016-0142-6","article-title":"The role of transoral robotic surgery, transoral laser microsurgery, and lingual tonsillectomy in the identification of head and neck squamous cell carcinoma of unknown primary origin: A systematic review","volume":"45","author":"Fu","year":"2016","journal-title":"J Otolaryngol Head Neck Surg"},{"key":"B17","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.oraloncology.2019.02.018","article-title":"Transoral tongue base mucosectomy for the identification of the primary site in the work-up of cancers of unknown origin: Systematic review and meta-analysis","volume":"91","author":"Farooq","year":"2019","journal-title":"Oral Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.97","article-title":"Precision medicine based on epigenomics: the paradigm of carcinoma of unknown primary","volume":"14","author":"Moran","year":"2017","journal-title":"Nat Rev Clin Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.593164","article-title":"Metastatic squamous cell carcinoma to the cervical lymph nodes from an unknown primary cancer: Management in the HPV era","volume":"10","author":"Civantos","year":"2020","journal-title":"Front Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/hed.25613","article-title":"Ultraviolet light-related DNA damage mutation signature distinguishes cutaneous from mucosal or other origin for head and neck squamous cell carcinoma of unknown primary site","volume":"41","author":"Chan","year":"2019","journal-title":"Head Neck."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjoto.2010.05.004","article-title":"Head and neck squamous cell carcinoma from an unknown primary site","volume":"32","author":"Wallace","year":"2011","journal-title":"Am J Otolaryngol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/hed.23479","article-title":"Head and neck squamous cell carcinoma of unknown primary: Neck dissection and radiotherapy or definitive radiotherapy","volume":"36","author":"Demiroz","year":"2014","journal-title":"Head Neck."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/lary.22424","article-title":"Cancer of unknown primary: Does treatment modality make a difference","volume":"122","author":"Balaker","year":"2012","journal-title":"Laryngoscope"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjoto.2017.06.006","article-title":"Neck dissection for unknown cancer of the head and neck in the era of chemoradiation","volume":"38","author":"Amsbaugh","year":"2017","journal-title":"Am J Otolaryngol"},{"key":"B25","volume-title":"UICC TNM classification of malignant tumours","author":"Sobin","year":"2010"},{"key":"B26","volume-title":"UICC TNM classification of malignant tumours","author":"Brierley","year":"2016"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/hed.26902","article-title":"Transoral robotic surgery (TORS) using the da Vinci xi: prospective analysis of feasibility, safety, and outcomes","volume":"44","author":"Meulemans","year":"2022","journal-title":"Head Neck."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1055\/s-0040-1712106","article-title":"Swedish National multicenter study on head and neck cancer of unknown primary: Prognostic factors and impact of treatment on survival","volume":"25","author":"Axelsson","year":"2021","journal-title":"Int Arch Otorhinolaryngol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00405-019-05338-3","article-title":"Roles of ki-67 and p16 as biomarkers for unknown primary head and neck squamous cell carcinoma","volume":"276","author":"Maebayashi","year":"2019","journal-title":"Eur Arch Otorhinolaryngol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/hed.25028","article-title":"Squamous cell carcinoma of unknown primary of the head and neck: Favorable prognostic factors comparable to those in oropharyngeal cancer","volume":"40","author":"Zhou","year":"2017","journal-title":"Head Neck."},{"key":"B31","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s00405-014-2934-5","article-title":"Management of neck metastases of unknown primary origin united in two European centers","volume":"272","author":"Straetmans","year":"2015","journal-title":"Eur Arch Otorhinolaryngol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.199","article-title":"Human papillomavirus and p53 expression in cancer of unknown primary in the head and neck region in relation to clinical outcome","volume":"3","author":"Sivars","year":"2014","journal-title":"Cancer Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32164","article-title":"Human papillomavirus and p16 immunostaining, prevalence and prognosis of squamous carcinoma of unknown primary in the head and neck region","volume":"145","author":"Ren","year":"2019","journal-title":"Int J Cancer."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-019-03111-x","article-title":"Predictors of survival and recurrence after primary surgery for cervical metastasis of unknown primary","volume":"146","author":"Cho","year":"2020","journal-title":"J Cancer Res Clin Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0205365","article-title":"Treatment outcomes of unknown primary squamous cell carcinoma of the head and neck","volume":"13","author":"Hung","year":"2018","journal-title":"PloS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.oraloncology.2016.01.002","article-title":"Is p16-positive oropharyngeal squamous cell carcinoma associated with favorable prognosis? a systematic review and meta-analysis","volume":"54","author":"Sedghizadeh","year":"2016","journal-title":"Oral Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21389","article-title":"Head and neck cancers-major changes in the American joint committee on cancer eighth edition cancer staging manual","volume":"67","author":"Lydiatt","year":"2017","journal-title":"CA Cancer J Clin"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2012.05.022","article-title":"HPV status in patients with head and neck of carcinoma of unknown primary site: HPV, tobacco smoking, and outcome","volume":"48","author":"Tribius","year":"2012","journal-title":"Oral Oncol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.ejca.2016.12.020","article-title":"Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: A retrospective multicentre study","volume":"74","author":"Schroeder","year":"2017","journal-title":"Eur J Cancer."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/lary.27475","article-title":"HPV status in unknown primary head and neck cancer: Prognosis and treatment outcomes","volume":"129","author":"Cheraghlou","year":"2019","journal-title":"Laryngoscope"},{"key":"B41","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1186\/s12885-015-1598-x","article-title":"PATHOS: A phase II\/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for human papillomavirus (HPV) positive oropharyngeal cancer","volume":"15","author":"Owadally","year":"2015","journal-title":"BMC Cancer."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2006.01.062","article-title":"Meta-analysis of the prognostic significance of perinodal spread in head and neck squamous cell carcinomas (HNSCC) patients","volume":"42","author":"D\u00fcnne","year":"2006","journal-title":"Eur J Cancer."},{"key":"B43","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.oraloncology.2016.10.003","article-title":"Extracapsular spread in head and neck squamous cell carcinoma: A systematic review and meta-analysis","volume":"62","author":"Mermod","year":"2016","journal-title":"Oral Oncol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01394","article-title":"Significance of extranodal extension in surgically treated HPV-positive oropharyngeal carcinomas","volume":"10","author":"Beltz","year":"2020","journal-title":"Front Oncol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1001\/jamaoto.2016.0882","article-title":"Association of extracapsular spread with survival according to human papillomavirus status in oropharynx squamous cell carcinoma and carcinoma of unknown primary site","volume":"142","author":"Kharytaniuk","year":"2017","journal-title":"JAMA Otolaryngolog Head Neck Surg"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1177\/0194599820951176","article-title":"Prognostic significance of extranodal extension in HPV-mediated oropharyngeal carcinoma: A systematic review and meta-analysis","volume":"164","author":"Benchetrit","year":"2021","journal-title":"Otolaryngolog Head Neck Surg"},{"key":"B47","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.radonc.2019.10.011","article-title":"Prognostic importance of radiologic extranodal extension in HPV-positive oropharyngeal carcinoma and its potential role in refining TNM-8 cN-classification","volume":"144","author":"Huang","year":"2020","journal-title":"Radiother Oncol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2020.105167","article-title":"Prognostic value of clinical and radiologic extranodal extension and their role in the 8th edition TNM cN classification for HPV-negative oropharyngeal carcinoma","volume":"114","author":"Pilar","year":"2021","journal-title":"Oral Oncol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1200\/EDBK_320939","article-title":"Assessment criteria and clinical implications of extranodal extension in head and neck cancer","author":"Huang","year":"2021","journal-title":"Am Soc Cli Oncol Educ Book."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2017.07.019","article-title":"Post-operative therapy following transoral robotic surgery for unknown primary cancers of the head and neck","volume":"72","author":"Patel","year":"2017","journal-title":"Oral Oncol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1001\/jamaoto.2016.3419","article-title":"Transoral robotic surgery\u2013assisted endoscopy with primary site detection and treatment in occult mucosal primaries","volume":"143","author":"Hatten","year":"2017","journal-title":"JAMA Otolaryngolog Head Neck Surgery."},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.anl.2019.04.007","article-title":"The emerging role of trans-oral robotic surgery for the detection of the primary tumour site in patients with head-neck unknown primary cancers: A meta-analysis","volume":"46","author":"Meccariello","year":"2019","journal-title":"Auris Nasus Larynx."},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31235","article-title":"Outcomes of patients diagnosed with carcinoma metastatic to the neck from an unknown primary source and treated with intensity-modulated radiation therapy","volume":"124","author":"Kamal","year":"2018","journal-title":"Cancer"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/eci.13583","article-title":"Genomic correlates of response and resistance to immune checkpoint inhibitors in carcinomas of unknown primary","volume":"51","author":"Rassy","year":"2021","journal-title":"Eur J Clin Invest."},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2022.102407","article-title":"Systematic review of the CUP trials characteristics and perspectives for next-generation studies","volume":"107","author":"Rassy","year":"2022","journal-title":"Cancer Treat Rev"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2017-0286-CP","article-title":"Human papillomavirus testing in head and neck carcinomas: Guideline from the college of American pathologists","volume":"142","author":"Lewis","year":"2018","journal-title":"Arch Pathol Lab Med"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.1024414\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T05:21:01Z","timestamp":1668403261000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.1024414\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,14]]},"references-count":56,"alternative-id":["10.3389\/fonc.2022.1024414"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.1024414","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,14]]},"article-number":"1024414"}}