Periodontitis and Oral and Oropharyngeal Cancer Risk: A Systematic Review and Meta-Analysis with Exploratory Evidence on Tumor-Associated Porphyromonas gingivalis

<b>Background:</b> Periodontitis is a chronic inflammatory condition characterized by progressive destruction of tooth-supporting tissues and sustained microbial dysbiosis. Increasing evidence suggests that chronic oral inflammation may be associated with oral and oropharyngeal carcinogenesis, although findings across epidemiological and prognostic studies remain heterogeneous. <b>Objective:</b> To systematically evaluate the epidemiological association between clinically defined periodontitis and the risk of oral and/or oropharyngeal cancer, and to explore, in a distinct analytical component, the prognostic association between tumor-associated periodontal pathogens, particularly <i>Porphyromonas gingivalis</i>, and survival outcomes in affected patients. <b>Methods:</b> A systematic review and meta-analysis were conducted following PRISMA guidelines and registered in PROSPERO (CRD420251273975). Observational studies evaluating periodontitis and oral/oropharyngeal cancer risk (Arm 1) and prognostic studies assessing tumor-associated periodontal pathogens and survival outcomes (Arm 2) were identified through comprehensive database searches. Random-effects meta-analyses were performed to pool adjusted effect estimates. Risk of bias was assessed using the Newcastle-Ottawa Scale and the QUIPS tool. <b>Results:</b> Six observational studies were included in the epidemiological meta-analysis. Periodontitis was significantly associated with an increased risk of oral and/or oropharyngeal cancer (pooled HR = 2.14; 95% CI: 1.53-2.98), with substantial heterogeneity; trial sequential analysis supported the statistical robustness of this association. In the separate prognostic analysis, three studies evaluating intratumoral <i>Porphyromonas gingivalis</i> were included. A higher presence or expression of <i>P. gingivalis</i> was associated with poorer overall survival (HR = 2.89; 95% CI: 1.93-4.32), with no observed heterogeneity. Sensitivity and influence analyses confirmed the stability of these findings. <b>Conclusions:</b> This systematic review and meta-analysis demonstrate a consistent epidemiological association between periodontitis and an increased risk of oral and/or oropharyngeal cancer. In addition, exploratory prognostic evidence suggests that the presence of <i>Porphyromonas gingivalis</i> within tumor tissue may be associated with adverse survival outcomes. These findings should be interpreted as addressing distinct clinical and microbiological constructs, underscoring the need for further well-designed prospective and mechanistic studies.