Abstract

Head and neck squamous-cell carcinoma (HNSCC) includes malignancies of the hypopharynx, nasopharynx, oral cavity, oropharynx, and larynx. Traditionally linked to tobacco and alcohol use, a growing subset—particularly oropharyngeal squamous-cell carcinoma (OPSCC)—is now associated with HPV infection.

Over the past two decades, the incidence of HPV-positive OPSCC has risen significantly, especially in high-income regions such as North America and northern Europe, likely due to changes in sexual behavior. In many European countries, more than 50% of OPSCC cases are HPV-related. According to GLOBOCAN 2022, an estimated 29,800 new cases and 13,027 deaths from oropharyngeal cancer occurred in Europe in 2022.

HPV-related OPSCC follows a distinct molecular pathway. Viral oncoproteins E6 and E7 inactivate tumour suppressor proteins (p53 and Rb), leading to uncontrolled cell proliferation and genomic instability. Additional pathways such as PI3K/AKT/mTOR, Notch, and Wnt/β-catenin are also involved.

Prognosis in HNSCC depends largely on tumour stage and HPV status. Patients with HPV-positive OPSCC generally have better outcomes, although discordance between p16 expression and HPV DNA status (e.g., p16−/HPV+ or p16+/HPV−) is linked to worse survival.

Treatment typically involves a multimodal approach including surgery, radiation, and chemotherapy. Further research is needed to clarify HPV-related carcinogenesis, improve early detection, and personalize treatment. Increasing HPV vaccination coverage—especially among boys—along with better screening, could significantly reduce future cancer burden.

This review summarizes the current status of HPV-driven HNSCC in Europe.