{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:34:23Z","timestamp":1790814863193,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T00:00:00Z","timestamp":1770508800000},"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":["Cancers"],"abstract":"<jats:p>Background: Non-smoking, non-drinking (NSND) oral squamous cell carcinoma (OSCC) is increasingly recognized, yet its clinicopathologic and immune-related correlates remain incompletely defined. Methods: We retrospectively studied 243 surgically treated patients with previously untreated primary OSCC (2011\u20132020). Patients were classified as NSND or smoking and\/or drinking (SD). Immune-modulating conditions and preoperative systemic immune\u2013inflammatory indices (NLR, LMR, SIRI, AISI) were assessed, and overall (OS) and disease-specific survival (DSS) were analyzed. Results: Eighty-five patients (35.0%) were NSND. NSND patients were more often female (58.8% vs. 12.7%) and slightly older (median 54 vs. 50 years). Subsite distribution differed (p &lt; 0.001): tongue (52.9%), buccal mucosa (15.3%), and floor of mouth (3.5%) in NSND versus a predominance of floor of mouth tumors in SD (34.8%). NSND tumors showed smaller diameter, lower depth of invasion, less perineural invasion (40.5% vs. 55.1%), and more frequent inflammatory infiltrate (73.8% vs. 60.1%). Immune-modulating conditions were enriched in NSND (67.1% vs. 17.7%; p &lt; 0.001; adjusted OR 6.25, 95% CI 3.23\u201312.11), particularly among NSND patients &gt;50 years (79.2%). NSND patients showed lower NLR (p = 0.01), lower SIRI and AISI (p &lt; 0.001), and higher LMR (p &lt; 0.001). Median OS was 81.2 months; NSND showed a trend toward improved OS (p = 0.083) and improved OS after age\/sex adjustment (HR 0.64, 95% CI 0.42\u20130.98), but not after full clinicopathologic adjustment; DSS did not differ (p = 0.59). Conclusions: NSND OSCC exhibits a distinct clinicopathologic presentation and is strongly associated with immune-modulating comorbidity and lower tumor-associated systemic inflammatory indices, consistent with an immune-modulated clinical phenotype.<\/jats:p>","DOI":"10.3390\/cancers18040553","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T12:42:42Z","timestamp":1770640962000},"page":"553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Non-Smoking, Non-Drinking Oral Squamous Cell Carcinoma Is Associated with an Immune-Modulated Clinical Phenotype"],"prefix":"10.3390","volume":"18","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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davor","family":"Brajdi\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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41368-023-00249-w","article-title":"Oral squamous cell carcinomas: State of the field and emerging directions","volume":"15","author":"Tan","year":"2023","journal-title":"Int. J. Oral. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S204","DOI":"10.4103\/jpbs.jpbs_593_25","article-title":"A Narrative Review on Oral Squamous Cell Carcinoma","volume":"17","author":"Muralidharan","year":"2025","journal-title":"J. Pharm. Bioallied Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Tarle, M., and Luksic, I. (2024). Pathogenesis and Therapy of Oral Carcinogenesis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126343"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Dolens, E.D.S., Dourado, M.R., Almangush, A., Salo, T.A., Gurgel Rocha, C.A., da Silva, S.D., Brennan, P.A., and Coletta, R.D. (2021). The Impact of Histopathological Features on the Prognosis of Oral Squamous Cell Carcinoma: A Comprehensive Review and Meta-Analysis. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.784924"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"104112","DOI":"10.1016\/j.critrevonc.2023.104112","article-title":"Oral cavity cancer in young, non-smoking, and non-drinking patients: A contemporary review","volume":"190","author":"Tran","year":"2023","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Koo, K., Mouradov, D., Angel, C.M., Iseli, T.A., Wiesenfeld, D., McCullough, M.J., Burgess, A.W., and Sieber, O.M. (2021). Genomic Signature of Oral Squamous Cell Carcinomas from Non-Smoking Non-Drinking Patients. Cancers, 13.","DOI":"10.3390\/cancers13051029"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/hed.27266","article-title":"No survival benefit in never-smoker never-drinker patients with oral cavity cancer","volume":"45","author":"Yan","year":"2023","journal-title":"Head Neck"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1002\/hed.27398","article-title":"Characteristics of oral squamous cell carcinoma focusing on cases unaffected by smoking and drinking: A multicenter retrospective study","volume":"45","author":"Harada","year":"2023","journal-title":"Head Neck"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Chang Sing Pang, K.J.W., Mur, T., Collins, L., Rao, S.R., and Faden, D.L. (2020). Human Papillomavirus in Sinonasal Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. Cancers, 13.","DOI":"10.3390\/cancers13010045"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1002\/ijc.33514","article-title":"The unveiled reality of human papillomavirus as risk factor for oral cavity squamous cell carcinoma","volume":"149","author":"Nauta","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Niklander, S.E. (2021). Inflammatory Mediators in Oral Cancer: Pathogenic Mechanisms and Diagnostic Potential. Front. Oral Health, 2.","DOI":"10.3389\/froh.2021.642238"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ali, A., Molska, G.R., Yeo, H., Esfandiari, N., Jeong, W., Huang, M., and Magalhaes, M. (2025). Immune Microenvironment in Oral Potentially Malignant Disorders and Oral Cancer: A Narrative Review. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202501.0149.v1"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1002\/hed.26006","article-title":"Potentially malignant disorders of the oral cavity and oral dysplasia: A systematic review and meta-analysis of malignant transformation rate by subtype","volume":"42","author":"Iocca","year":"2020","journal-title":"Head Neck"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.oooo.2017.12.011","article-title":"Oral potentially malignant disorders: Risk of progression to malignancy","volume":"125","author":"Speight","year":"2018","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Fiedler, M., Off, A., Eichberger, J., Spoerl, S., Schuderer, J.G., Taxis, J., Bauer, R.J., Schreml, S., Reichert, T.E., and Ettl, T. (2023). OSCC in Never-Smokers and Never-Drinkers Is Associated with Increased Expression of Tumor-Infiltrating Lymphocytes and Better Survival. Cancers, 15.","DOI":"10.3390\/cancers15102688"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1093\/annonc\/mdx210","article-title":"The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1\/PD-L1 blockade","volume":"28","author":"Foy","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ruiz-Ranz, M., Lequerica-Fernandez, P., Rodriguez-Santamarta, T., Suarez-Sanchez, F.J., Lopez-Pintor, R.M., Garcia-Pedrero, J.M., and de Vicente, J.C. (2022). Prognostic implications of preoperative systemic inflammatory markers in oral squamous cell carcinoma, and correlations with the local immune tumor microenvironment. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.941351"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e822","DOI":"10.4317\/medoral.26779","article-title":"Prognostic value of systemic immune-inflammation index and systemic inflammation response index for oral cancers: A systematic review and meta-analysis","volume":"29","author":"Yang","year":"2024","journal-title":"Med. Oral Patol. Oral Cir. Bucal"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1475-2867-13-31","article-title":"Oral squamous cell carcinoma in relation to field precancerisation: Pathobiology","volume":"13","author":"Feller","year":"2013","journal-title":"Cancer Cell Int."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Eltohami, Y., and Suleiman, A. (2024). Survival analysis of Sudanese oral squamous cell carcinoma patients with field of cancerization. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-12197-7"},{"key":"ref_21","first-page":"122","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":"ref_22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10006-025-01337-3","article-title":"Non-smoking, non-drinking, oral squamous cell carcinoma patients are a distinct and clinically significant group","volume":"29","author":"Capanni","year":"2025","journal-title":"Oral. Maxillofac. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.oraloncology.2019.07.012","article-title":"Malignant transformation risk of oral lichen planus: A systematic review and comprehensive meta-analysis","volume":"96","author":"Ayen","year":"2019","journal-title":"Oral Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/odi.12885","article-title":"Rate of malignant transformation of oral lichen planus: A systematic review","volume":"25","author":"Giuliani","year":"2019","journal-title":"Oral Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1111\/odi.12337","article-title":"Oral mucosal lesions in older people: Relation to salivary secretion, systemic diseases and medications","volume":"21","author":"Nauntofte","year":"2015","journal-title":"Oral Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41577-020-00488-6","article-title":"Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities","volume":"21","author":"Hajishengallis","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102357","DOI":"10.1016\/j.tranon.2025.102357","article-title":"Frequent PD-L1 expression in oral squamous cell carcinoma of non-smokers and non-drinkers, and association of tumor infiltrating lymphocytes with favorable prognosis","volume":"55","author":"Mulder","year":"2025","journal-title":"Transl. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Theofilou, V.I., Ghita, I., Elnaggar, M., Chaisuparat, R., Papadimitriou, J.C., Bentzen, S.M., Dyalram, D., Lubek, J.E., Ord, R.A., and Younis, R.H. (2024). Histological pattern of tumor inflammation and stromal density correlate with patient demographics and immuno-oncologic transcriptional profile in oral squamous cell carcinoma. Front. Oral Health, 5.","DOI":"10.3389\/froh.2024.1408072"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Battista, R.A., Pini, G.M., Finco, A., Corso, F., Galli, A., Arrigoni, G., Doglioni, C., Callea, M., Paccagnella, M., and Porcu, L. (2024). From Tumor Macroenvironment to Tumor Microenvironment: The Prognostic Role of the Immune System in Oral and Lung Squamous Cell Carcinoma. Cancers, 16.","DOI":"10.3390\/cancers16152759"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1111\/odi.15235","article-title":"Non-smoking and Non-drinking Oral Cancer Patients Are at Higher Risk of Second Primary Tumours","volume":"31","author":"Witjes","year":"2025","journal-title":"Oral Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1002\/hed.26824","article-title":"\u201cFact or fiction?\u201d: Oral cavity cancer in nonsmoking, nonalcohol drinking patients as a distinct entity-Scoping review","volume":"43","author":"Adeoye","year":"2021","journal-title":"Head Neck"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/j.1601-0825.2006.01274.x","article-title":"Non-smoking and non-drinking patients with head and neck squamous cell carcinoma: A distinct population","volume":"13","author":"Farshadpour","year":"2007","journal-title":"Oral Dis."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Perot, P., Falguieres, M., Arowas, L., Laude, H., Foy, J.P., Goudot, P., Corre-Catelin, N., Ungeheuer, M.N., Caro, V., and Heard, I. (2020). Investigation of viral etiology in potentially malignant disorders and oral squamous cell carcinomas in non-smoking, non-drinking patients. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232138"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1002\/hed.27330","article-title":"Prognostic value and clinicopathological status of PD-L1 expression and CD8+ TILs in oral squamous cell cancer patients with or without traditional risk factors","volume":"45","author":"Soopanit","year":"2023","journal-title":"Head Neck"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/4\/553\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T12:13:34Z","timestamp":1770984814000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/4\/553"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,8]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cancers18040553"],"URL":"https:\/\/doi.org\/10.3390\/cancers18040553","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,8]]}}}