Oncogenic viruses and their role in oral cavity and oropharyngeal squamous cell carcinoma: a systematic review

Abstract

Oral cavity (OC) and oropharyngeal (OP) squamous cell carcinoma (SCC) represent a major global health concern, accounting for most of head and neck malignancies. These tumors arise from the epithelial lining of the OC and oropharynx and are characterized by aggressive local invasion, lymph node metastasis, and high morbidity and mortality. In addition to known risk factors such as tobacco and alcohol consumption, several oncogenic viruses, including human papillomavirus (HPV), Epstein-Barr virus (EBV), human herpesviruses (HHV) 1 and 2, cytomegalovirus (CMV) and Merkel cell polyomavirus (MCPyV), have been implicated in the development, progression, or prognosis. Detection of viral genomes within tumor tissues suggests a complex interplay between viral oncogenes, host immune responses, and environmental factors in carcinogenesis. This systematic review synthesizes current evidence on the contribution of oncogenic viruses to the etiology of OC and OP SCC. Following the PRISMA 2020 guidelines, observational studies between January 2015 and December 2025 were identified through searches of PubMed, Scopus and Web of Science. Eligible studies were limited to human research and reporting viral detections. The results demonstrate a strong, consistent, and clinically relevant association between HPV infection and OP SCC, while evidence supporting a causal or prognostic role for non-HPV oncogenic viruses in OC and OP SCC remains limited and heterogeneous. Substantial methodological variability in viral detection approaches and epidemiological reporting was observed, underscoring the need for standardized assessment frameworks. Overall, these results support site-specific interpretation of viral oncogenesis and inform the development of targeted prevention, diagnostic stratification, and therapeutic strategies.