HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management

Abstract

Human papillomavirus (HPV)-positive (HPV⁺) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the UICC/AJCC staging system separates HPV⁺ OPSCC from its HPV-negative (HPV^-) counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment de-intensification as a means to improve quality of life while maintaining acceptable survival outcomes. In addition, owing to the distinct biology of HPV⁺ OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage owing to a lack of symptoms in the early stages; therefore, a need exists to identify and validate possible diagnostic biomarkers to aid in earlier detection. In this Review, we provide a summary of the epidemiology, molecular biology and clinical management of HPV⁺ OPSCC in an effort to highlight important advances in the field. Ultimately, a need exists for improved understanding of the molecular basis and clinical course of this disease to guide efforts towards early detection and precision care, and to improve patient outcomes.

Fig. 1. Incidence, anatomical locations and histological appearance of HPV⁺ oropharyngeal cancers.

a | Directly age-standardized rates per 100,000 population of newly diagnosed cases of cervical and oropharyngeal cancer in the UK and the USA. For male oropharyngeal cancers (pink dotted line) and cervical cancers (pink solid line) in the UK from 1995 to 2016, data are sourced from the UK Office for National Statistics cancer data. Male oropharyngeal cancers include those of the base of tongue, uvula, tonsil and oropharynx, stratified for different types of squamous cell carcinoma (SCC) (as for the US data). Observed age-standardized rates per 100,000 population of newly diagnosed cases of cancer; for oropharyngeal cancers among men (yellow dotted line) and cervical cancers (yellow solid line) from 1995 to 2014 obtained from registries within the Surveillance, Epidemiology, and End Results (SEER) programme. Oropharyngeal cancers included those of the base of tongue, lingual tonsil, soft palate not otherwise specified, uvula, tonsil, oropharynx and Waldeyer’s ring. Cervical cancers include all histological subtypes. b | Basic anatomy of the oropharynx, with inset images from top to bottom depicting human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV⁺ OPSCC) located at the base of tongue (the anterior two-thirds), the soft palate and the tonsil. c | Histological appearance, clockwise from top left. i | Non-keratinizing SCC. ii | Non-keratinizing SCC with immunohistochemical staining for p16; morphology is monomorphic, ovoid, hyperchromatic with inconspicuous cytoplasm. This sample also features increased mitosis, apoptosis and comedo-type necrosis. iii | Keratinizing SCC, featuring filiform projections, a thickened, nonmalignant-appearing stratified squamous epithelium, hyperparakeratosis and keratin plugging. iv | Basaloid SCC featuring variable foci of squamous differentiation. v | Papillary SCC with early invasion, featuring predominant filiform processes with minimal or absent keratinization, frequent mitosis and full-thickness dysplasia with a basaloid cell morphology. vi | Spindle-cell carcinoma, featuring a biphasic tumour composed of SCC and malignant spindle-cell component, exhibits polypoid growth. All images in c shown at 40× magnification.

Fig. 2. Oncogenesis of HPV⁺ oropharyngeal cancers.

a | Major events in the development of human papillomavirus (HPV)-driven malignancy based on the established stepwise model of cervical carcinogenesis. HPV infection is established in the basal layer of the epithelium, with access facilitated either through micro-abrasions or, in the case of the oropharynx, potentially owing to the reticulated nature of the epithelium of the tonsillar crypts. Productive infections are usually cleared by the immune system but if not, deregulation of E6 and E7 expression can occur, causing exit from the productive viral life cycle and the development of neoplasia (in the cervix this is evident as lesions detectable by screening but no such lesions have been identified in the oropharynx). E6 and E7 suppress important mechanisms of tumour suppression and cause epigenetic changes, which can combine with somatic alterations in the host cell genome to cause transformation and progression to malignancy. In the cervix, these events typically occur over the course of 10–20 years after the causative HPV infection^,. b | Schematic showing how HPV-driven oncogenic processes act to enable seven of the eight hallmarks of cancer originally defined by Hanahan and Weinberg and how experimental therapies are able to disable one or more of these hallmarks^,,.

Fig. 3. Updated model of cell-cycle perturbation by the HPV oncogenes E6 and E7.

As proposed by McLaughlin-Drubin, Munger and colleagues, E7 induces the expression of lysine demethylases KDM6A and KDM6B, which in turn leads to the upregulation of CDKN1A (p21^CIP) and CDKN2A (p14^ARF and p16^INK4A), respectively. HPV⁺ cancer cells become dependent on the ongoing expression of p16^INK4A and p21^CIP, with the former acting to limit CDK4/6–cyclin D activity and the latter restraining proliferating cell nuclear antigen (PCNA) activity to avoid lethal replication stress (refs^,,,). Cell-cycle inhibitory proteins (p16^INK4A and p21^CIP1), upon which human papillomavirus (HPV)-transformed cells become dependent, are starred.