Molecular Tumor Subtypes of HPV-Positive Head and Neck Cancers: Biological Characteristics and Implications for Clinical Outcomes

Simple Summary Human papillomavirus (HPV) infections are responsible for a continually growing number of head and neck cancer (HNC) cases, with the incident rate overtaking that of HPV-related cervical cancers in the United States. Most HPV-related HNC cases arise in the oropharynx, and although they have a better 5-year survival rate than non-HPV-related HNC patients (80% compared to 50%), de-escalating treatment in all HPV(+) patients in an attempt to improve quality of life led to unacceptable results. Studying molecular subtypes of HPV(+) HNC can help to identify treatment regimens tailored to each patient's tumor characteristics. We synthesized information from several studies of HPV(+) HNC subtypes, and describe three main groups that differ by their immune cell content, level of keratinocyte differentiation, degree of epithelial-to-mesenchymal transition, probability of HPV integration, oxidoreductase activity and stromal cell (e.g., cancer-associated fibroblast) content. The differences have important implications for local or distant recurrence, treatment response and survival. Until recently, research on the molecular signatures of Human papillomavirus (HPV)-associated head and neck cancers mainly focused on their differences with respect to HPV-negative head and neck squamous cell carcinomas (HNSCCs). However, given the continuing high incidence level of HPV-related HNSCC, the time is ripe to characterize the heterogeneity that exists within these cancers. Here, we review research thus far on HPV-positive HNSCC molecular subtypes, and their relationship with clinical characteristics and HPV integration into the host genome. Different omics data including host transcriptomics and epigenomics, as well as HPV characteristics, can provide complementary viewpoints. Keratinization, mesenchymal differentiation, immune signatures, stromal cells and oxidoreductive processes all play important roles.