Oropharyngeal squamous cell carcinoma (OPSCC) comprises cancers of the tonsils, base of tongue, soft palate and uvula (Fig. 1). Like other head and neck squamous cell carcinomas (HNSCCs), OPSCC has historically been linked to alcohol and tobacco consumption. A reduction in the prevalence of smoking in most high-income countries over the past 20 years has led to a decline in the incidence of HNSCC; however, carcinogenic human papillomavirus (HPV) infection has emerged as an important risk factor that has driven an increase in the incidence of OPSCC over the same period. More specifically, HPV now accounts for 71% and 51.8% of all OPSCCs in the USA and UK, respectively [1][2][3][4] . Of these, 85-96% are caused by HPV-16 infections and are therefore expected to be preventable by prophylactic HPV vaccination, which is known to be effective in preventing HPV-associated cervical neoplasia and is now being administered to both boys and girls in several countries 4,5 . The most recent edition of the American Joint Committee on Cancer (AJCC) staging system defined HPV-positive (HPV + ) and HPV-negative (HPV -) OPSCCs as separate entities, with distinct molecular profiles, tumour characteristics and outcomes 6 (Table 1). Importantly, the former is associated with a more favourable prognosis 7 . In this Review, we provide a comprehensive overview of HPV + OPSCC, focusing on how our increasing knowledge of disease biology has informed clinical practice and is guiding the pursuit of improved treatments.
Epidemiology
Rising incidence, particularly in menAmong all cancers, OPSCC has one of the most rapidly rising incidences in high-income countries 8,9 . An increasing incidence of this disease has been observed in the UK, USA, across Europe, New Zealand and in parts of Asia [9][10][11][12][13][14][15][16][17][18][19] . In both the UK and the USA, the incidence of oropharyngeal cancer in men has surpassed that of cervical cancer in women 8 (Fig. 1). Globally, the percentage of OPSCCs that are HPV + was reported in 2021 to be 33%; however, prevalence varies considerably depending on the geographical region, with estimates ranging from 0% in southern India to 85% in Lebanon 20 .HPV + OPSCC is more prevalent than HPV -OPSCC among those who do not consume tobacco or alcohol; however, a substantial history of tobacco and alcohol use remains prominent in patients with the former and is associated with worse outcomes 21,22 . Furthermore, sexual behaviour is an established risk factor for HPV + OPSCC, with a strong association observed between number of
