{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:51:06Z","timestamp":1787028666025,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Oral squamous cell carcinoma (OSCC) accounts for over 90% of oral malignancies and remains associated with substantial global morbidity and mortality. Although tobacco and alcohol are established risk factors, they do not fully explain OSCC incidence, highlighting the need to explore additional contributors such as chronic inflammatory conditions. Periodontal disease, characterized by persistent inflammation and microbial dysbiosis, has emerged as a plausible factor in oral carcinogenesis and tumor progression. To systematically evaluate the association between periodontal disease and the risk of developing OSCC, and to assess the prognostic impact of periodontal disease\u2013related factors, particularly intratumoral Porphyromonas gingivalis, on survival outcomes in patients with OSCC. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines and prospectively registered in PROSPERO (CRD420261296479). Comprehensive searches were performed in PubMed, EMBASE, Web of Science, Scopus, the Cochrane Library, ClinicalTrials.gov, and World Health Organization regional databases. Case\u2013control studies evaluating OSCC risk and cohort studies assessing survival outcomes were included. Random-effects meta-analyses using inverse-variance models were applied. Heterogeneity was assessed using the I2 statistic, and robustness was evaluated through Hartung\u2013Knapp adjustment, leave-one-out sensitivity analyses, and Trial Sequential Analysis. Results: Five case\u2013control studies were included in the etiological analysis. Periodontal disease was significantly associated with an increased risk of OSCC (pooled OR = 3.17; 95% CI: 1.94\u20135.21), with moderate heterogeneity (I2 = 58.7%). Two cohort studies were included in the prognostic analysis. High intratumoral expression of P. gingivalis was significantly associated with poorer overall survival (pooled HR = 2.15; 95% CI: 1.33\u20133.47), with no detected heterogeneity (I2 = 0%). Conclusions: Periodontal disease is strongly associated with an increased risk of OSCC, and intratumoral P. gingivalis appears to be an adverse prognostic marker. These findings underscore the relevance of periodontal inflammation and microbial factors across the OSCC continuum, from carcinogenesis to clinical outcomes, and support their consideration as potential targets for risk stratification and prevention strategies.<\/jats:p>","DOI":"10.3390\/jcm15083161","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T11:42:45Z","timestamp":1776771765000},"page":"3161","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Periodontal Disease and Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis of Risk and Survival Outcomes"],"prefix":"10.3390","volume":"15","author":[{"given":"Gabriela Guadalupe","family":"Zambrano Manzaba","sequence":"first","affiliation":[{"name":"School of Dentistry, Universidad Cat\u00f3lica de Santiago de Guayaquil (UCSG), Guayaquil 090101, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8713-951X","authenticated-orcid":false,"given":"Luis","family":"Chauca-Baja\u00f1a","sequence":"additional","affiliation":[{"name":"College Dentistry, University of Guayaquil, Guayaquil 090101, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Andr\u00e9s","family":"Guim Mart\u00ednez","sequence":"additional","affiliation":[{"name":"School of Dentistry, Universidad Cat\u00f3lica de Santiago de Guayaquil (UCSG), Guayaquil 090101, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3881-431X","authenticated-orcid":false,"given":"Sara Isabel","family":"Marcalupo Llerena","sequence":"additional","affiliation":[{"name":"College Dentistry, University of Guayaquil, Guayaquil 090101, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6559-4597","authenticated-orcid":false,"given":"Andrea","family":"Ordo\u00f1ez Balladares","sequence":"additional","affiliation":[{"name":"College Dentistry, University of Guayaquil, Guayaquil 090101, Ecuador"},{"name":"College Dentistry, Universidad Bolivariana del Ecuador, Dur\u00e1n 092406, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5660-3941","authenticated-orcid":false,"given":"Byron","family":"Velasquez Ron","sequence":"additional","affiliation":[{"name":"Carrera de Odontolog\u00eda, Department Prosthesis Research, Universidad de Las Am\u00e9ricas (UDLA), Quito 170102, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2759-8984","authenticated-orcid":false,"given":"Carlos Enrique","family":"Cuevas-Su\u00e1rez","sequence":"additional","affiliation":[{"name":"Dental Materials Laboratory, Academic Area of Dentistry, Autonomous University of Hidalgo State, San Agust\u00edn Tlaxiaca 42160, Mexico"},{"name":"Dental Materials and Biomaterials Laboratory, Faculty of Stomatology, Meritorious Autonomous University of Puebla, Puebla 72590, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8136-4820","authenticated-orcid":false,"given":"Abigailt","family":"Flores-Ledesma","sequence":"additional","affiliation":[{"name":"Dental Materials and Biomaterials Laboratory, Faculty of Stomatology, Meritorious Autonomous University of Puebla, Puebla 72590, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica Natalia","family":"Maroto Hidalgo","sequence":"additional","affiliation":[{"name":"School of Dentistry, Universidad Cat\u00f3lica de Santiago de Guayaquil (UCSG), Guayaquil 090101, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0520-6492","authenticated-orcid":false,"given":"Gina Fernanda","family":"V\u00e1squez Armas","sequence":"additional","affiliation":[{"name":"School of Dentistry, Universidad Cat\u00f3lica de Santiago de Guayaquil (UCSG), Guayaquil 090101, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"ref_1","first-page":"394","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"17","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.oraloncology.2008.06.002","article-title":"Global epidemiology of oral and oropharyngeal cancer","volume":"45","author":"Warnakulasuriya","year":"2009","journal-title":"Oral Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e2023092","DOI":"10.4178\/epih.e2023092","article-title":"Cancer risk based on alcohol consumption levels: A comprehensive systematic review and meta-analysis","volume":"45","author":"Jun","year":"2023","journal-title":"Epidemiol. Health"},{"key":"ref_5","first-page":"3282","article-title":"Smoking and drinking in relation to oral and pharyngeal cancer","volume":"48","author":"Blot","year":"1988","journal-title":"Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17038","DOI":"10.1038\/nrdp.2017.38","article-title":"Periodontal diseases","volume":"3","author":"Kinane","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_7","first-page":"225","article-title":"Immunoinflammatory response in periodontal diseases","volume":"76","author":"Brozek","year":"2025","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1177\/0022034512457373","article-title":"Prevalence of periodontitis in adults in the United States: 2009 and 2010","volume":"91","author":"Eke","year":"2012","journal-title":"J. Dent. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nature07205","article-title":"Cancer-related inflammation","volume":"454","author":"Mantovani","year":"2008","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nri3785","article-title":"Periodontitis: From microbial immune subversion to systemic inflammation","volume":"15","author":"Hajishengallis","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1038\/nrc3610","article-title":"The microbiome and cancer","volume":"13","author":"Schwabe","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1126\/science.aaa4972","article-title":"Cancer and the microbiota","volume":"348","author":"Garrett","year":"2015","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6306","DOI":"10.1002\/cam4.3206","article-title":"Role of the oral microbiota in cancer evolution and progression","volume":"9","author":"Sun","year":"2020","journal-title":"Cancer Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1111\/j.1462-5822.2007.00931.x","article-title":"Intrinsic apoptotic pathways of gingival epithelial cells modulated by Porphyromonas gingivalis","volume":"9","author":"Mao","year":"2007","journal-title":"Cell Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Groeger, S., and Meyle, J. (2019). Oral Mucosal Epithelial Cells. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00208"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1001\/archotol.133.5.450","article-title":"Chronic periodontitis and the risk of tongue cancer","volume":"133","author":"Tezal","year":"2007","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1746-160X-9-39","article-title":"Chronic periodontitis and its possible association with oral squamous cell carcinoma\u2014A retrospective case control study","volume":"9","author":"Moergel","year":"2013","journal-title":"Head Face Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1177\/0022034519827565","article-title":"Association of Periodontitis with Oral Cancer: A Case-Control Study","volume":"98","author":"Shin","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/prd.12425","article-title":"Role of Porphyromonas gingivalis in oral and orodigestive squamous cell carcinoma","volume":"89","author":"Lamont","year":"2022","journal-title":"Periodontology 2000"},{"key":"ref_21","first-page":"100438","article-title":"Biomimetic nanotherapy for P. gingivalis-infected oral squamous cell carcinoma: Photothermal therapy and immunoactivation via precise intracellular bacterial elimination","volume":"10","author":"Dai","year":"2025","journal-title":"Int. J. Pharm. X"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1002\/ijc.30201","article-title":"Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe Life study","volume":"139","author":"Laprise","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1590\/0103-6440201600754","article-title":"Association Between Chronic Periodontitis and Oral\/Oropharyngeal Cancer","volume":"27","author":"Dias","year":"2016","journal-title":"Braz. Dent. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"189","DOI":"10.3892\/ol.2021.12450","article-title":"Bioinformatics and immunohistochemistry analyses of expression levels and clinical significance of CXCL2 and TANs in an oral squamous cell carcinoma tumor microenvironment of Prophyromonas gingivalis infection","volume":"21","author":"Guo","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Li, C., Li, M., Wei, W., Wang, Z., Yu, J., and Gong, Z. (2024). Association of DOK3 and infiltrated tumor-associated macrophages with risk for the prognosis of Porphyromonas gingivalis-infected oral cancer: A 12-year data analysis of 200 patients from a tertiary teaching hospital, Urumqi, China. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-12300-y"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s10654-010-9491-z","article-title":"Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses","volume":"25","author":"Stang","year":"2010","journal-title":"Eur. J. Epidemiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"280","DOI":"10.7326\/0003-4819-158-4-201302190-00009","article-title":"Assessing bias in studies of prognostic factors","volume":"158","author":"Hayden","year":"2013","journal-title":"Ann. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7073","DOI":"10.1007\/s13277-014-1951-8","article-title":"Association of periodontal disease with oral cancer: A meta-analysis","volume":"35","author":"Yao","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.critrevonc.2015.08.018","article-title":"Is there a relationship between periodontal disease and oral cancer? A systematic review of currently available evidence","volume":"97","author":"Javed","year":"2016","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Koml\u00f3s, G., Csurgay, K., Horv\u00e1th, F., Pelyhe, L., and N\u00e9meth, Z. (2021). Periodontitis as a risk for oral cancer: A case-control study. BMC Oral Health, 21.","DOI":"10.1186\/s12903-021-01998-y"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"40478","DOI":"10.2340\/aos.v83.40478","article-title":"Periodontitis and the risk of oral cancer: A meta-analysis of case-control studies","volume":"83","author":"Ma","year":"2024","journal-title":"Acta Odontol. Scand."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1007\/s12672-025-02528-w","article-title":"Causal association between periodontitis and oral cancer: A two-sample Mendelian randomization study","volume":"16","author":"Xiao","year":"2025","journal-title":"Discov. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e13198","DOI":"10.1016\/j.heliyon.2023.e13198","article-title":"Microbial dysbiosis in oral squamous cell carcinoma: A systematic review and meta-analysis","volume":"9","author":"Yu","year":"2023","journal-title":"Heliyon"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sukmana, B.I., Saleh, R.O., Najim, M.A., Al-Ghamdi, H.S., Achmad, H., Al-Hamdani, M.M., Taher, A.A., Alsalamy, A., Khaledi, M., and Javadi, K. (2024). Oral microbiota and oral squamous cell carcinoma: A review of their relation and carcinogenic mechanisms. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1319777"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1021\/acsinfecdis.9b00032","article-title":"Porphyromonas gingivalis Infection Promoted the Proliferation of Oral Squamous Cell Carcinoma Cells through the miR-21\/PDCD4\/AP-1 Negative Signaling Pathway","volume":"5","author":"Chang","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7870","DOI":"10.1038\/s41598-021-86816-9","article-title":"Prognostic value of intratumoral Fusobacterium nucleatum and association with immune-related gene expression in oral squamous cell carcinoma patients","volume":"11","author":"Neuzillet","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_38","first-page":"127","article-title":"Periodontal pathogens promote epithelial-mesenchymal transition in oral squamous carcinoma cells in vitro","volume":"12","author":"Abdulkareem","year":"2018","journal-title":"Cell Adhes. Migr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1177\/00220345211067401","article-title":"Treponema denticola Promotes OSCC Development via the TGF-\u03b2 Signaling Pathway","volume":"101","author":"Peng","year":"2022","journal-title":"J. Dent. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/omi.12334","article-title":"sRNA23392 packaged by Porphyromonas gingivalis outer membrane vesicles promotes oral squamous cell carcinomas migration and invasion by targeting desmocollin-2","volume":"36","author":"Liu","year":"2021","journal-title":"Mol. Oral Microbiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2482924","DOI":"10.1080\/20002297.2025.2482924","article-title":"Porphyromonas gingivalis-OMVs promote the epithelial-mesenchymal transition of oral squamous cell carcinoma by inhibiting ferroptosis through the NF-\u03baB pathway","volume":"17","author":"Liao","year":"2025","journal-title":"J. Oral Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"128296","DOI":"10.1016\/j.micres.2025.128296","article-title":"Porphyromonas gingivalis outer membrane vesicles promote oral tumorigenesis through suppressing innate immune surveillance","volume":"301","author":"Chen","year":"2025","journal-title":"Microbiol. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e0046922","DOI":"10.1128\/msystems.00469-22","article-title":"Oral Microbiota from Periodontitis Promote Oral Squamous Cell Carcinoma Development via \u03b3\u03b4 T Cell Activation","volume":"7","author":"Wei","year":"2022","journal-title":"mSystems"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Nicoar\u0103, A., Roi, C., Roi, A., Motofelea, A.C., Rakitovan, M., Zar\u0103, F., and Rivi\u0219, M. (2024). Systemic Immune-Inflammatory Index and Other Inflammatory Marker Variations in Oral Squamous Cell Carcinoma Management. Medicina, 60.","DOI":"10.3390\/medicina60111840"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/8\/3161\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T12:25:02Z","timestamp":1776774302000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/8\/3161"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,21]]},"references-count":44,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["jcm15083161"],"URL":"https:\/\/doi.org\/10.3390\/jcm15083161","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,21]]}}}