Periodontal Disease and Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis of Risk and Survival Outcomes

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–related 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–control 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–Knapp adjustment, leave-one-out sensitivity analyses, and Trial Sequential Analysis. Results: Five case–control studies were included in the etiological analysis. Periodontal disease was significantly associated with an increased risk of OSCC (pooled OR = 3.17; 95% CI: 1.94–5.21), 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: 1.33–3.47), 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.