{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:53:08Z","timestamp":1785415988457,"version":"3.56.0"},"reference-count":28,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Otolaryngol Head Neck Surg"],"published-print":{"date-parts":[[2024,2,1]]},"abstract":"Importance<\/jats:title>Patients with suspected head and neck squamous cell carcinoma of unknown primary (HNSCCUP) may undergo tonsillectomy and tongue base mucosectomy (TBM) to help identify clinicoradiologically occult primary disease. It is hypothesized that when these diagnostic specimens are analyzed, conventional histopathological (CH) techniques risk missing small primary tumors that may be hidden in the tissue blocks.<\/jats:p><\/jats:sec>Objective<\/jats:title>To establish the outcomes of a step serial sectioning (SSS) histopathological technique vs CH when analyzing diagnostic tissue specimens from TBM and tonsillectomy performed for HNSCCUP.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>The MOSES prospective multicenter noninterventional cohort study was conducted over a 25-month period from November 2019 at secondary and tertiary care ear, nose, and throat departments in the United Kingdom and included adults with clinicoradiologically occult HNSCCUP who were undergoing TBM.<\/jats:p><\/jats:sec>Intervention<\/jats:title>Conventional histopathological techniques performed on TBM and tonsillectomy specimens at participating centers, followed by SSS performed at the central laboratory.<\/jats:p><\/jats:sec>Main Outcome<\/jats:title>Identification of cancer on central histopathological review of TBM and tonsillectomy specimens.<\/jats:p><\/jats:sec>Results<\/jats:title>Tissue from 58 eligible patients was analyzed (median [range] age, 58 [47-82] years; 10 women [17%]), with 20\u202f480 sections cut in the laboratory and 4096 sections directly examined by a pathologist (median [range], 64 [28-135] per patient). The overall identification rate for TBM following SSS according to study protocol was 50.0% (95% CI, 37.5%-62.5%) and by subgroups was 42.9% (95% CI, 21.4%-67.4%) when performed following a negative bilateral tonsillectomy, 46.7% (95% CI, 24.8%-69.9%) at the same time as bilateral tonsillectomy, and 57.1% (95% CI, 36.5%-75.5%) following historic tonsillectomy. Conventional histopathological techniques at central review identified 2 undiagnosed primary tumors and revised the diagnosis of 2 other cases (1 nonmalignant and another down staged). Step serial sectioning identified a single additional tumor: an ipsilateral synchronous tongue base tumor for which a contralateral tumor had been identified on CH. Multifocal disease was seen in 5 (8.6%); all were human papillomavirus\u2013related and in the tongue base.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this multicenter cohort study of patients undergoing TBM for HNSCCUP, SSS was associated with added considerable histopathological workload with minimal additional diagnostic benefit. A second opinion for conventional histological techniques may be more beneficial. Synchronous primary disease should be considered when planning diagnostic oropharyngeal surgery for these patients.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamaoto.2023.3993","type":"journal-article","created":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T16:01:35Z","timestamp":1703174495000},"page":"118","source":"Crossref","is-referenced-by-count":10,"title":["Step Serial Sectioning in Head and Neck Squamous Cell Carcinoma of Unknown Primary"],"prefix":"10.1001","volume":"150","author":[{"given":"John C.","family":"Hardman","sequence":"first","affiliation":[{"name":"Head and Neck Unit, The Royal Marsden National Health Service Foundation Trust, London, England"},{"name":"The Institute of Cancer Research, London, England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Harrington","sequence":"additional","affiliation":[{"name":"Head and Neck Unit, The Royal Marsden National Health Service Foundation Trust, London, England"},{"name":"The Institute of Cancer Research, London, England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"O\u2019Leary","sequence":"additional","affiliation":[{"name":"Head and Neck Unit, The Royal Marsden National Health Service Foundation Trust, London, England"},{"name":"The Institute of Cancer Research, London, England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Cellular Pathology, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinidh","family":"Paleri","sequence":"additional","affiliation":[{"name":"Head and Neck Unit, The Royal Marsden National Health Service Foundation Trust, London, England"},{"name":"The Institute of Cancer Research, London, England"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"1","key":"ooi230086r3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1053\/j.semnuclmed.2020.07.005","article-title":"Imaging of head and neck cancer with CT, MRI, and US.","volume":"51","author":"Junn","year":"2021","journal-title":"Semin Nucl Med"},{"issue":"22","key":"ooi230086r4","doi-asserted-by":"publisher","first-page":"2570","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"},{"issue":"3","key":"ooi230086r6","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/j.mayocp.2015.12.017","article-title":"Head and neck squamous cell carcinoma: update on epidemiology, diagnosis, and treatment.","volume":"91","author":"Marur","year":"2016","journal-title":"Mayo Clin Proc"},{"issue":"5","key":"ooi230086r7","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/s41571-022-00603-7","article-title":"HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management.","volume":"19","author":"Lechner","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"issue":"7","key":"ooi230086r8","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.3390\/v13071297","article-title":"Human papillomavirus and squamous cell carcinoma of unknown primary in the head and neck region: a comprehensive review on clinical implications.","volume":"13","author":"Larsen","year":"2021","journal-title":"Viruses"},{"issue":"6","key":"ooi230086r9","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1111\/coa.2017.42.issue-6","article-title":"Trans-oral robotic assisted tongue base mucosectomy for investigation of cancer of unknown primary in the head and neck region. The UK experience.","volume":"42","author":"Winter","year":"2017","journal-title":"Clin Otolaryngol"},{"issue":"6","key":"ooi230086r10","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1016\/j.otc.2020.07.008","article-title":"Role of transoral robotic surgery in the work-up of the unknown primary.","volume":"53","author":"de Almeida","year":"2020","journal-title":"Otolaryngol Clin North Am"},{"issue":"10","key":"ooi230086r11","doi-asserted-by":"publisher","first-page":"1832","DOI":"10.1002\/cncr.v119.10","article-title":"Synchronous cancers in patients with head and neck cancer: risks in the era of human papillomavirus-associated oropharyngeal cancer.","volume":"119","author":"Jain","year":"2013","journal-title":"Cancer"},{"issue":"3","key":"ooi230086r12","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"},{"issue":"3","key":"ooi230086r13","doi-asserted-by":"publisher","first-page":"e433","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"},{"issue":"18","key":"ooi230086r14","doi-asserted-by":"publisher","first-page":"2777","DOI":"10.1016\/j.ejca.2015.08.023","article-title":"Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer.","volume":"51","author":"Schilling","year":"2015","journal-title":"Eur J Cancer"},{"key":"ooi230086r15","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2021.105464","article-title":"A complete magnetic sentinel lymph node biopsy procedure in oral cancer patients: a pilot study.","volume":"121","author":"Nieuwenhuis","year":"2021","journal-title":"Oral Oncol"},{"issue":"9","key":"ooi230086r16","doi-asserted-by":"publisher","first-page":"3181","DOI":"10.1007\/s00405-020-06538-y","article-title":"What is the role of sentinel lymph node biopsy in the management of oral cancer in 2020?","volume":"278","author":"de Bree","year":"2021","journal-title":"Eur Arch Otorhinolaryngol"},{"issue":"10","key":"ooi230086r17","doi-asserted-by":"publisher","first-page":"3995","DOI":"10.1007\/s00405-020-06585-5","article-title":"Is the retropharyngeal lymph node the first echelon node for carcinoma tonsil? prospective evaluation and literature review.","volume":"278","author":"Panda","year":"2021","journal-title":"Eur Arch Otorhinolaryngol"},{"issue":"7","key":"ooi230086r18","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1007\/s00405-018-4968-6","article-title":"Robotic lateral oropharyngectomy following diagnostic tonsillectomy is oncologically safe in patients with high risk human papillomavirus related squamous cell cancer.","volume":"275","author":"Siddiq","year":"2018","journal-title":"Eur Arch Otorhinolaryngol"},{"key":"ooi230086r20","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2022.105748","article-title":"Reducing the unknowns: a systematic review & meta-analysis of the effectiveness of trans-oral surgical techniques in identifying head and neck primary cancer in carcinoma unknown primary.","volume":"126","author":"Al-Lami","year":"2022","journal-title":"Oral Oncol"},{"key":"ooi230086r21","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"},{"issue":"2","key":"ooi230086r22","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1111\/coa.2017.42.issue-2","article-title":"Baseline swallowing measures predict recovery at 6 weeks after transoral robotic surgery for head and neck cancer.","volume":"42","author":"Owen","year":"2017","journal-title":"Clin Otolaryngol"},{"issue":"3","key":"ooi230086r23","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1097\/SCS.0000000000001584","article-title":"Oropharyngeal stenosis after transoral robotic lingual tonsillectomy.","volume":"26","author":"Muderris","year":"2015","journal-title":"J Craniofac Surg"},{"issue":"2","key":"ooi230086r24","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1177\/0269216307085341","article-title":"Patients\u2019 experiences of carcinoma of unknown primary site: dealing with uncertainty.","volume":"22","author":"Boyland","year":"2008","journal-title":"Palliat Med"},{"issue":"4","key":"ooi230086r25","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1136\/bmjspcare-2013-000482","article-title":"Uncertainty and anxiety in the cancer of unknown primary patient journey: a multiperspective qualitative study.","volume":"5","author":"Richardson","year":"2015","journal-title":"BMJ Support Palliat Care"},{"issue":"7","key":"ooi230086r26","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1093\/jjco\/hyw048","article-title":"Psychological burden on patients with cancer of unknown primary: from onset of symptoms to initial treatment.","volume":"46","author":"Ishida","year":"2016","journal-title":"Jpn J Clin Oncol"},{"key":"ooi230086r28","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":"ooi230086r2","volume-title":"Diagnosis and Management of Metastatic Malignant Disease of Unknown Primary Origin","author":"National Collaborating Centre for Cancer","year":"2010"},{"key":"ooi230086r1","unstructured":"INTEGRATE (The UK ENT Trainee Research Network). National audit of the Management of Head and Neck Squamous Cell Carcinoma of Unknown Primary. Accessed February 10, 2022. entintegrate.co.uk\/hnsccup"},{"key":"ooi230086r5","unstructured":"National Comprehensive Cancer Network. Head and neck cancer guidelines (version 1.2022) [internet]. Accessed January 6, 2022. https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/head-and-neck.pdf"},{"key":"ooi230086r19","unstructured":"Westra? W, Fujii? S, Bishop? J, . Oropharyngeal tumours (base of tongue, tonsils adenoids), squamous cell carcinoma, HPV associated. Accessed October 8, 2023. https:\/\/tumourclassification.iarc.who.int\/chapters\/52"},{"key":"ooi230086r27","unstructured":"American Joint Committee on Cancer. AJCC cancer staging manual. Accessed March 28, 2017. https:\/\/www.springer.com\/us\/book\/9783319406176"}],"container-title":["JAMA Otolaryngology\u2013Head & Neck Surgery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamaotolaryngology\/articlepdf\/2812748\/jamaotolaryngology_hardman_2023_oi_230086_1706569758.49283.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T16:20:58Z","timestamp":1707409258000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamaotolaryngology\/fullarticle\/2812748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,1]]},"references-count":28,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,2,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamaoto.2023.3993","relation":{},"ISSN":["2168-6181"],"issn-type":[{"value":"2168-6181","type":"print"}],"subject":[],"published":{"date-parts":[[2024,2,1]]}}}