{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T11:20:22Z","timestamp":1771240822459,"version":"3.50.1"},"reference-count":28,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014NextGenerationEU","award":["SFZG-15-2025"],"award-info":[{"award-number":["SFZG-15-2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Second primary tumors (SPTs) are a major survivorship challenge in oral squamous cell carcinoma (OSCC), yet their biological phenotypes may differ according to exposure status and immune background. Methods: In this retrospective cohort (2011\u20132020), 242 surgically treated primary OSCC patients were classified as non-smoking, non-drinking (NSND; never smokers\/never drinkers) or smoking and\/or drinking (SD; any history of smoking and\/or alcohol consumption). SPTs were categorized as extra-oral SPTs (eoSPTs) or multifocal oral SCC (mOSCC), with mOSCC (\u22653) denoting \u22653 oral primaries. Immune background was assessed by documenting immune-modulating conditions (including oral lichen planus as an immune-mediated mucosal disorder). Multivariable logistic regression was used to evaluate predictors of eoSPTs and mOSCC. Results: SPT occurred in 82\/242 (33.9%), comprising 54 eoSPT (22.3%) and 28 mOSCC (11.6%). Overall SPT prevalence was similar in NSND and SD patients (29.8% vs. 36.1%), but phenotype composition differed significantly (chi-square p = 0.004): eoSPTs were more common in SD (27.8% vs. 11.9%), whereas mOSCC was more common in NSND (17.9% vs. 8.2%); mOSCC (\u22653) occurred in 10.7% of NSND versus 1.3% of SD patients. Immune-modulating conditions were associated with mOSCC but not eoSPTs. Within the immune-modulating spectrum, OLP showed strong phenotype specificity (0\/20 eoSPTs; mOSCC in 7\/20 [35.0%), particularly among NSND patients (38.9% with OLP vs. 12.1% without). In adjusted models, NSND status was associated with lower odds of eoSPT (OR 0.37, 95% CI 0.15\u20130.96), while OLP independently predicted mOSCC (OR 3.47, 95% CI 1.04\u201311.52). Conclusions: SPTs in OSCC comprise distinct phenotypes: SD patients predominantly develop eoSPTs consistent with carcinogen-associated aerodigestive field effects, whereas NSND patients exhibit an immune-associated, oral-restricted pattern with frequent mOSCC, supporting phenotype-tailored surveillance.<\/jats:p>","DOI":"10.3390\/jcm15041563","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T10:14:32Z","timestamp":1771236872000},"page":"1563","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Second Primary Tumor Phenotypes in Oral Squamous Cell Carcinoma According to Exposure Status and Immune Background"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4173-1278","authenticated-orcid":false,"given":"Marko","family":"Tarle","sequence":"first","affiliation":[{"name":"Department of Maxillofacial and Oral Surgery, Dubrava University Hospital, 10000 Zagreb, Croatia"},{"name":"School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9203-7254","authenticated-orcid":false,"given":"Marina","family":"Ragu\u017e","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Dubrava University Hospital, 10000 Zagreb, Croatia"},{"name":"School of Medicine, Catholic University of Croatia, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7058-4123","authenticated-orcid":false,"given":"Koraljka","family":"Hat","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial and Oral Surgery, Dubrava University Hospital, 10000 Zagreb, Croatia"},{"name":"School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1927-9163","authenticated-orcid":false,"given":"Igor","family":"\u010cvrljevi\u0107","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial and Oral Surgery, Dubrava University Hospital, 10000 Zagreb, Croatia"},{"name":"School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8390-8185","authenticated-orcid":false,"given":"Ivan","family":"Salari\u0107","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial and Oral Surgery, Dubrava University Hospital, 10000 Zagreb, Croatia"},{"name":"School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9138-2037","authenticated-orcid":false,"given":"Ivica","family":"Luk\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial and Oral Surgery, Dubrava University Hospital, 10000 Zagreb, Croatia"},{"name":"School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ijom.2021.03.006","article-title":"A population-based study of the epidemiology of oral squamous cell carcinoma in the Netherlands 1989\u20132018, with emphasis on young adults","volume":"51","author":"Helder","year":"2022","journal-title":"Int. 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