Intratumoral Human Papillomavirus in Advanced Prostate Cancer: Systematic Review, Meta-Analysis, and Real-World Evidence from the Largest Cohort to Date.

The etiopathogenesis of prostate cancer (PCa) is complex and involves multiple hormonal and environmental factors. Among these, the role of infectious agents remains controversial. Human papillomavirus (HPV) is known to promote carcinogenesis in epithelial tumors and has also been detected, albeit inconsistently, in PCa tissues. This systematic review, meta-analysis, and real-world cohort study aimed to clarify the prevalence and the prognostic role of intratumoral (IT)-HPV detection in locally advanced and metastatic PCa. We performed a systematic literature search including studies reporting IT-HPV detection in locally advanced (LA-PCa) and metastatic PCa (mPCa). Pooled prevalence estimates were calculated using random-effects models. In parallel, HPV DNA was analyzed using archival tissue in a single-center real-world retrospective cohort of 196 metastatic PCa patients. Twenty-three records met the inclusion criteria, comprising 22 full-text publications and one abstract. Nineteen datasets, encompassing 837 patients, contributed to the quantitative synthesis of stage III-IV disease. Pooled IT-HPV prevalence in mPCa was 18.5% (95% CI, 6.4-34%), while including also LA-PCa was 14.6% (95% CI, 5.2-26.8). Eastern countries showed higher IT-HPV prevalence in both mPCa and LA-PCa (40% and 34.3%, respectively) compared with Western regions (0.8% and 0.3%; p < 0.0001). HPV-positive PCa was associated with a higher Gleason score (>7) in advanced stage (pooled OR 6.32, 95% CI, 3.13-12.78) compared with IT-HPV-negative PCa; however, no studies reported data on its association with survival outcomes. Within our retrospective cohort, IT-HPV DNA was detected in 3.1% of cases (6/196) and exhibited typical PCa driver alterations, such as TP53, SPOP, PIK3CA, and AR amplification. IT-HPV seems to be infrequent in metastatic and locally advanced PCa in Western populations and more prevalent in Asian cohorts and might be associated with a higher Gleason score. IT-HPV-positive advanced PCa seems to exhibit typical PCa driver alterations. Data on the association between IT-HPV status and survival outcomes in PCa are lacking. Standardized molecular assays and multicenter prospective studies are needed to delineate its significance in PCa.