{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:47:29Z","timestamp":1792723649763,"version":"4.5.0"},"reference-count":34,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007435","name":"\u00c5ke Wiberg Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007435","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004047","name":"Karolinska Institutet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007232","name":"Radiumhemmets Forskningsfonder","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007232","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2026,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Human papillomavirus (HPV)\u2010associated tonsillar squamous cell carcinoma (TSCC) is suggested to arise in tonsillar crypts. It also constitutes a rare exception in the literature of carcinoma development, as carcinoma in situ (CIS) is not a recognized entity and dysplastic stages are not evident. Here we investigated the evidence of this. Hence, a systematic review and meta\u2010analysis was performed to study tumor origin. MEDLINE was searched and all original studies reporting tumor origin in HPV\u2010associated oropharyngeal cancer were included. We also used spatial transcriptomics (10\u00d7 Visium) on HPV\u2010associated TSCC, cervical, and HPV\u2010independent oral cancer cases. We compared tonsillar CIS to cervical high\u2010grade intraepithelial lesion (HSIL). We studied epithelial cell gene expression across the sample types and epithelial cellular states. A trajectory analysis was performed in HPV\u2010associated tumors. In total, 14% of all TSCC were of surface origin in the systematic review. Spatial transcriptomics revealed that tonsillar CIS and HSIL clustered with a high correlation when using a pseudo\u2010bulk approach. Moreover, when all epithelial cells were analyzed unsupervised, ten epithelial cell clusters that correlated to histology were identified. Two of these clusters were dysplastic and occurred in all samples. A sequential progression from dysplasia to invasion was observed in both TSCC and cervical cancer in the trajectory analysis. We conclude that a subset of HPV\u2010associated TSCC may arise from the surface and that there is a sequential progression toward invasive disease in HPV\u2010associated TSCC, similar to that of cervical cancer. The findings suggest that pure tonsillar dysplastic lesions should hypothetically exist.<\/jats:p>","DOI":"10.1002\/ijc.70207","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T16:59:27Z","timestamp":1761238767000},"page":"1080-1092","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Spatial evidence for\n                    <i>carcinoma<\/i>\n                    in situ (\n                    <scp>CIS<\/scp>\n                    ) as an entity in human papillomavirus (\n                    <scp>HPV<\/scp>\n                    )\u2010associated tonsillar squamous cell carcinoma (\n                    <scp>TSCC<\/scp>\n                    )"],"prefix":"10.1002","volume":"158","author":[{"given":"Tobias","family":"N\u00e4sman","sequence":"first","affiliation":[{"name":"Department of Oncology\u2010Pathology Karolinska Institutet, Karolinska University Hospital  Stockholm Sweden"},{"name":"Department of Clinical Pathology and Cancer Diagnostics Karolinska University Laboratory (KUL), Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5876-0710","authenticated-orcid":false,"given":"Madeleine","family":"Birgersson","sequence":"additional","affiliation":[{"name":"Department of Oncology\u2010Pathology Karolinska Institutet, Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Marklund","sequence":"additional","affiliation":[{"name":"Medical Unit Head, Neck, Lung, and Skin Cancer, Theme Cancer Karolinska University Hospital  Stockholm Sweden"},{"name":"Department of Clinical Sciences, Intervention and Technology, Division of ENT Diseases Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Surgical Sciences, Section of Otolaryngology and Head and Neck Surgery Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4602-4297","authenticated-orcid":false,"given":"Anders","family":"N\u00e4sman","sequence":"additional","affiliation":[{"name":"Department of Oncology\u2010Pathology Karolinska Institutet, Karolinska University Hospital  Stockholm Sweden"},{"name":"Department of Clinical Pathology and Cancer Diagnostics Karolinska University Laboratory (KUL), Karolinska University Hospital  Stockholm 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