p53 Positivity Predicts Poor Survival in Oropharyngeal Squamous Cell Carcinoma Dependent on HPV Status

Background: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) generally has a more favorable prognosis compared to HPV-negative cases. Overexpression of p16INK4a is widely used as a surrogate marker for HPV-induced carcinogenesis, and it also represents an important tumor suppressor gene, the second most frequently altered after TP53. In turn, mutations in TP53 are characteristic of tumors linked to smoking and alcohol consumption and p53 expression is consistently associated with worse clinical outcomes. Aims: Investigate the impact of p53 immunohistochemical expression on prognosis of OPSCC. Methods: This retrospective study included 155 OPSCC patients with longitudinal follow-up exceeding 10 years. Immunohistochemistry was used to evaluate p53 protein expression. Clinicopathological associations were performed to evaluate the prognostic impact of p53 protein expression in OPSCC HPV-positive and HPV-negative tumors. Results: Among the 155 OPSCC cases, 90 (58.1%) were classified as HPV-positive and 65 (41.9%) as HPV-negative. HPV status was inversely associated with p53 positivity, with HPV-negative tumors showing a higher frequency of p53 expression (p < 0.0001). Patients with HPV-positive tumors experienced better clinical outcomes than those with HPV-negative disease, including cancer-specific survival (CSS; HR: 3.47, 95% CI 1.16–10.4, p = 0.02) and disease-free survival (DFS; HR: 3.73, 95% CI 1.29–10.7, p = 0.01), whereas p53 positivity alone was not independently associated with survival. Notably, individuals with HPV-negative and p53-positive tumors exhibited the poorest outcomes, in contrast to patients with HPV-positive OPSCC, regardless of p53 expression. Conclusions: Patients with HPV-negative and p53-positive OPSCC showed inferior clinical outcomes compared with their HPV-positive counterparts, independent of p53 status. These findings underscore the prognostic relevance of jointly evaluating HPV status and p53 expression in OPSCC and support more refined risk stratification and personalized therapeutic strategies.