Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Reviews Clinical Oncology volume 19, pages 306–327 (2022)Cite this article

Subjects

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.

Key points

  • The incidence of human papillomavirus-associated oropharyngeal cancer (HPV+ OPSCC) is expected to continue to rise over the coming decades until the benefits of gender-neutral prophylactic HPV vaccination begin to become manifest.

  • The incidence of HPV+ OPSCC appears to be highest in high-income countries, although more epidemiological data are needed from low- and middle-income countries, in which HPV vaccination coverage remains low.

  • The substantially better prognosis of patients with HPV+ OPSCC compared to those with HPV– OPSCC has been recognized in the American Joint Committee on Cancer TNM8 staging guidelines, which recommend stratification by HPV status to improve staging.

  • The molecular biology and genomic features of HPV+ OPSCC are similar to those of other HPV-associated malignancies, with HPV oncogenes (E6 and E7) acting as key drivers of pathogenesis.

  • Treatment de-intensification is being pursued in clinical trials, although identifying the ~15% of patients with HPV+ OPSCC who have recurrent disease, and who therefore require more intensive treatment, remains a key challenge.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Incidence, anatomical locations and histological appearance of HPV+ oropharyngeal cancers.
Fig. 2: Oncogenesis of HPV+ oropharyngeal cancers.
Fig. 3: Updated model of cell-cycle perturbation by the HPV oncogenes E6 and E7.

Similar content being viewed by others

References

  1. Chaturvedi, A. K. et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J. Clin. Oncol. 29, 4294–4301 (2011).

    PubMed  PubMed Central  Google Scholar 

  2. Gillison, M. L., Chaturvedi, A. K., Anderson, W. F. & Fakhry, C. Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. J. Clin. Oncol. 33, 3235–3242 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Senkomago, V. et al. Human papillomavirus-attributable cancers — United States, 2012–2016. MMWR Morb. Mortal. Wkly Rep. 68, 724–728 (2019).

    PubMed  PubMed Central  Google Scholar 

  4. Schache, A. G. et al. HPV-related oropharynx cancer in the United Kingdom: an evolution in the understanding of disease etiology. Cancer Res. 76, 6598–6606 (2016).

    CAS  PubMed  Google Scholar 

  5. Lei, J. et al. HPV vaccination and the risk of invasive cervical cancer. N. Engl. J. Med. 383, 1340–1348 (2020).

    CAS  PubMed  Google Scholar 

  6. Craig, S. G. et al. Recommendations for determining HPV status in patients with oropharyngeal cancers under TNM8 guidelines: a two-tier approach. Br. J. Cancer 120, 827–833 (2019).

    PubMed  PubMed Central  Google Scholar 

  7. Gillison, M. L. et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J. Natl Cancer Inst. 100, 407–420 (2008).

    PubMed  Google Scholar 

  8. Lechner, M., Jones, O. S., Breeze, C. E. & Gilson, R. Gender-neutral HPV vaccination in the UK, rising male oropharyngeal cancer rates, and lack of HPV awareness. Lancet Infect. Dis. 19, 131–132 (2019).

    PubMed  Google Scholar 

  9. Faraji, F. et al. The prevalence of human papillomavirus in oropharyngeal cancer is increasing regardless of sex or race, and the influence of sex and race on survival is modified by human papillomavirus tumor status. Cancer 125, 761–769 (2019).

    PubMed  Google Scholar 

  10. Argirion, I. et al. Increasing prevalence of HPV in oropharyngeal carcinoma suggests adaptation of p16 screening in Southeast Asia. J. Clin. Virol. 132, 104637 (2020).

    CAS  PubMed  Google Scholar 

  11. Hwang, T. Z., Hsiao, J. R., Tsai, C. R. & Chang, J. S. Incidence trends of human papillomavirus-related head and neck cancer in Taiwan, 1995-2009. Int. J. Cancer 137, 395–408 (2015).

    CAS  PubMed  Google Scholar 

  12. Wittekindt, C. et al. Increasing incidence rates of oropharyngeal squamous cell carcinoma in Germany and significance of disease burden attributed to human papillomavirus. Cancer Prev. Res. 12, 375–382 (2019).

    CAS  Google Scholar 

  13. Zamani, M. et al. The current epidemic of HPV-associated oropharyngeal cancer: an 18-year Danish population-based study with 2,169 patients. Eur. J. Cancer 134, 52–59 (2020).

    CAS  PubMed  Google Scholar 

  14. Del Mistro, A. et al. Age-independent increasing prevalence of human papillomavirus-driven oropharyngeal carcinomas in North-East Italy. Sci. Rep. 10, 1–10 (2020).

    Google Scholar 

  15. Morbini, P. et al. The evolving landscape of human papillomavirus-related oropharyngeal squamous cell carcinoma at a single institution in northern Italy. Acta Otorhinolaryngol. Ital. 39, 9–17 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Haeggblom, L. et al. Changes in incidence and prevalence of human papillomavirus in tonsillar and base of tongue cancer during 2000-2016 in the Stockholm region and Sweden. Head. Neck 41, 1583–1590 (2019).

    PubMed  Google Scholar 

  17. Donà, M. G. et al. Evolving profile of HPV-driven oropharyngeal squamous cell carcinoma in a national cancer institute in Italy: a 10-year retrospective study. Microorganisms 8, 1–12 (2020).

    Google Scholar 

  18. Girardi, F. M., Wagner, V. P., Martins, M. D., Abentroth, A. L. & Hauth, L. A. Prevalence of p16 expression in oropharyngeal squamous cell carcinoma in southern Brazil. Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. 130, 681–691 (2020).

    PubMed  Google Scholar 

  19. Rietbergen, M. M. et al. Epidemiologic associations of HPV-positive oropharyngeal cancer and (pre)cancerous cervical lesions. Int. J. Cancer 143, 283–288 (2018).

    CAS  PubMed  Google Scholar 

  20. Carlander, A. F. et al. A contemporary systematic review on repartition of HPV-positivity in oropharyngeal cancer worldwide. Viruses 13, 1326 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen, S. Y. et al. The association of smoking and outcomes in HPV-positive oropharyngeal cancer: a systematic review. Am. J. Otolaryngol. 41, 102592 (2020).

    PubMed  Google Scholar 

  22. Ang, K. K. et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 363, 24–35 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Gooi, Z., Chan, J. Y. K. & Fakhry, C. The epidemiology of the human papillomavirus related to oropharyngeal head and neck cancer. Laryngoscope 126, 894–900 (2016).

    PubMed  Google Scholar 

  24. D’Souza, G. et al. Sex differences in risk factors and natural history of oral human papillomavirus infection. J. Infect. Dis. 213, 1893–1896 (2016).

    PubMed  Google Scholar 

  25. de Martel, C., Plummer, M., Vignat, J. & Franceschi, S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int. J. Cancer 141, 664–670 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. Blumberg, J., Monjane, L., Prasad, M., Carrilho, C. & Judson, B. L. Investigation of the presence of HPV related oropharyngeal and oral tongue squamous cell carcinoma in Mozambique. Cancer Epidemiol. 39, 1000–1005 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. Rettig, E. M. et al. Oral human papillomavirus infection and head and neck squamous cell carcinoma in rural northwest Cameroon. OTO Open 3, 2473974X18818415 (2019).

    PubMed  PubMed Central  Google Scholar 

  28. Ndiaye, C. et al. The role of human papillomavirus in head and neck cancer in Senegal. Infect. Agent. Cancer 8, 14 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kofi, B. et al. Infrequent detection of human papillomavirus infection in head and neck cancers in the Central African Republic: a retrospective study. Infect. Agent Cancer 14, 9 (2019).

    PubMed  PubMed Central  Google Scholar 

  30. Oga, E. A. et al. Paucity of HPV-related head and neck cancers (HNC) in Nigeria. PLoS ONE 11, e0152828 (2016).

    PubMed  PubMed Central  Google Scholar 

  31. Chaturvedi, A. K. & Zumsteg, Z. S. A snapshot of the evolving epidemiology of oropharynx. cancers Cancer 124, 2893–2896 (2018).

    PubMed  Google Scholar 

  32. Tota, J. E. et al. Evolution of the oropharynx cancer epidemic in the United States: moderation of increasing incidence in younger individuals and shift in the burden to older individuals. J. Clin. Oncol. 37, 1538–1546 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kreimer, A. R. et al. Summary from an international cancer seminar focused on human papillomavirus (HPV)-positive oropharynx cancer, convened by scientists at IARC and NCI. Oral. Oncol. 108, 104736 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mariz BALA, K. L. P. et al. Global prevalence of human papillomavirus-driven oropharyngeal squamous cell carcinoma following the ASCO guidelines: a systematic review and meta-analysis. Crit. Rev. Oncol. Hematol. 156, 103116 (2020).

    PubMed  Google Scholar 

  35. Windon, M. J. et al. Increasing prevalence of human papillomavirus–positive oropharyngeal cancers among older adults. Cancer 124, 2993–2999 (2018).

    CAS  PubMed  Google Scholar 

  36. Rettig, E. M., Fakhry, C., Khararjian, A. & Westra, W. H. Age profile of patients with oropharyngeal squamous cell carcinoma. JAMA Otolaryngol. 144, 538–539 (2018).

    Google Scholar 

  37. Zumsteg, Z. S. et al. Incidence of oropharyngeal cancer among elderly patients in the United States. JAMA Oncol. 2, 1617–1623 (2016).

    PubMed  Google Scholar 

  38. Mahal, B. A. et al. Incidence and demographic burden of HPV-associated oropharyngeal head and neck cancers in the United States. Cancer Epidemiol. Biomark. Prev. 28, 1660–1667 (2019).

    Google Scholar 

  39. Ramer, I. et al. Racial disparities in incidence of human papillomavirus-associated oropharyngeal cancer in an urban population. Cancer Epidemiol. 44, 91–95 (2016).

    PubMed  Google Scholar 

  40. Liederbach, E. et al. The national landscape of human papillomavirus-associated oropharynx squamous cell carcinoma. Int. J. Cancer 140, 504–512 (2017).

    CAS  PubMed  Google Scholar 

  41. Falcaro, M. et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. Lancet 398, 2084–2092 (2021).

    PubMed  Google Scholar 

  42. Masterson, L. & Lechner, M. HPV vaccination in boys — will the UK join the fight? Nat. Rev. Clin. Oncol. 13, 721–722 (2016).

    PubMed  Google Scholar 

  43. HPV Vaccination Uptake. Australia National Control Indicators. Published 2019. https://ncci.canceraustralia.gov.au/prevention/hpv-vaccination-uptake/hpv-vaccination-uptake (2021).

  44. Walker, T. Y. et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13–17 years — United States, 2019. MMWR Morb. Mortal. Wkly Rep. 69, 1109–1116 (2020).

    Google Scholar 

  45. Public Health England. Human papillomavirus (HPV) vaccination coverage in adolescent females and males in England: academic year 2019 to 2020. Heal. Prot. Rep. 14, 1–15 (2020).

    Google Scholar 

  46. Radisic, G., Chapman, J., Flight, I. & Wilson, C. Factors associated with parents’ attitudes to the HPV vaccination of their adolescent sons: a systematic review. Prev. Med. 95, 26–37 (2017).

    PubMed  Google Scholar 

  47. Sonawane, K. et al. Parental intent to initiate and complete the human papillomavirus vaccine series in the USA: a nationwide, cross-sectional survey. Lancet Public Heal. 5, e484–e492 (2020).

    Google Scholar 

  48. Gottvall, M., Stenhammar, C. & Grandahl, M. Parents’ views of including young boys in the Swedish national school-based HPV vaccination programme: a qualitative study. BMJ Open 7, 11–13 (2017).

    Google Scholar 

  49. Thompson, E. L. et al. Awareness and knowledge of HPV and HPV vaccination among adults ages 27–45 years. Vaccine 38, 3143–3148 (2020).

    PubMed  Google Scholar 

  50. Waller, J. et al. Decision-making about HPV vaccination in parents of boys and girls: a population-based survey in England and Wales. Vaccine 38, 1040–1047 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sherman, S. M., Cohen, C. R., Denison, H. J., Bromhead, C. & Patel, H. A survey of knowledge, attitudes and awareness of the human papillomavirus among healthcare professionals across the UK. Eur. J. Public Health 30, 10–16 (2020).

    PubMed  Google Scholar 

  52. Lechner, M. et al. A cross-sectional survey of awareness of human papillomavirus-associated oropharyngeal cancers among general practitioners in the UK. BMJ Open 8, 1–6 (2018).

    Google Scholar 

  53. Katz, J. The impact of HPV vaccination on the prevalence of oropharyngeal cancer (OPC) in a hospital-based population: a cross-sectional study of patient’s registry. J. Oral. Pathol. Med. 50, 47–51 (2021).

    CAS  PubMed  Google Scholar 

  54. Herrero, R. et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS ONE 8, e68329 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Chaturvedi, A. K. et al. Effect of prophylactic human papillomavirus (HPV) vaccination on oral HPV infections among young adults in the United States. J. Clin. Oncol. 36, 262–267 (2018).

    CAS  PubMed  Google Scholar 

  56. Hirth, J. M., Chang, M., Resto, V. A., Guo, F. & Berenson, A. B. Prevalence of oral human papillomavirus by vaccination status among young adults (18–30 years old). Vaccine 35, 3446–3451 (2017).

    PubMed  Google Scholar 

  57. Zhang, Y., Fakhry, C. & D’Souza, G. Projected association of human papillomavirus vaccination with oropharynx cancer incidence in the US, 2020–2045. JAMA Oncol. 7, e212907 (2021).

    PubMed  Google Scholar 

  58. Lechner, M., Breeze, C. E., O’Mahony, J. F. & Masterson, L. Early detection of HPV-associated oropharyngeal cancer. Lancet 393, 2123 (2019).

    PubMed  Google Scholar 

  59. Kreimer, A. R. et al. Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium. Ann. Oncol. 30, 1335–1343 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kreimer, A. R., Clifford, G. M., Boyle, P. & Franceschi, S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systemic review. Cancer Epidemiol. Biomark. Prev. 14, 467–475 (2005).

    CAS  Google Scholar 

  61. Egawa, N., Egawa, K., Griffin, H. & Doorbar, J. Human papillomaviruses; epithelial tropisms, and the development of neoplasia. Viruses 7, 3863–3890 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Doorbar, J. et al. The biology and life-cycle of human papillomaviruses. Vaccine 30, F55–F70 (2012).

    CAS  PubMed  Google Scholar 

  63. Graham, S. V. Keratinocyte differentiation-dependent human papillomavirus gene regulation. Viruses 9, 245 (2017).

    PubMed Central  Google Scholar 

  64. Parfenov, M. et al. Characterization of HPV and host genome interactions in primary head and neck cancers. Proc. Natl Acad. Sci. USA 111, 15544–15549 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Vinokurova, S. et al. Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res. 68, 307–313 (2008).

    CAS  PubMed  Google Scholar 

  66. Ramqvist, T. et al. Studies on human papillomavirus (HPV) 16 E2, E5 and E7 mRNA in HPV-positive tonsillar and base of tongue cancer in relation to clinical outcome and immunological parameters. Oral. Oncol. 51, 1126–1131 (2015).

    CAS  PubMed  Google Scholar 

  67. Koneva, L. A. et al. HPV integration in HNSCC correlates with survival outcomes, immune response signatures, and candidate drivers. Mol. Cancer Res. 16, 90–102 (2018).

    CAS  PubMed  Google Scholar 

  68. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  69. Mesri, E. A., Feitelson, M. A. & Munger, K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe 15, 266–282 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Huibregtse, J. M., Scheffner, M. & Howley, P. M. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J. 10, 4129–4135 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129–1136 (1990).

    CAS  PubMed  Google Scholar 

  72. Scheffner, M., Huibregtse, J. M., Vierstra, R. D. & Howley, P. M. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75, 495–505 (1993).

    CAS  PubMed  Google Scholar 

  73. Huh, K. et al. Human papillomavirus type 16 E7 oncoprotein associates with the Cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor. J. Virol. 81, 9737–9747 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Dyson, N., Howley, P. M., Munger, K. & Harlow, E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243, 934–938 (1986).

    Google Scholar 

  75. Münger, K., Phelps, W. C., Bubb, V., Howley, P. M. & Schlegel, R. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J. Virol. 63, 4417–4421 (1989).

    PubMed  PubMed Central  Google Scholar 

  76. Božinović, K. et al. Genome-wide miRNA profiling reinforces the importance of miR-9 in human papillomavirus associated oral and oropharyngeal head and neck cancer. Sci. Rep. 9, 2306 (2019).

    PubMed  PubMed Central  Google Scholar 

  77. Boscolo-Rizzo, P., Furlan, C., Lupato, V., Polesel, J. & Fratta, E. Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors. Clin. Epigenetics 9, 124 (2017).

    PubMed  PubMed Central  Google Scholar 

  78. Barr, J. A. et al. Long non-coding RNA FAM83H-AS1 is regulated by human papillomavirus 16 E6 independently of p53 in cervical cancer cells. Sci. Rep. 9, 3662 (2019).

    PubMed  PubMed Central  Google Scholar 

  79. Lechner, M. et al. Identification and functional validation of HPV-mediated hypermethylation in head and neck squamous cell carcinoma. Genome Med. 5, 15 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Burgers, W. A. et al. Viral oncoproteins target the DNA methyltransferases. Oncogene 26, 1650–1655 (2007).

    CAS  PubMed  Google Scholar 

  81. Chalertpet, K., Pakdeechaidan, W., Patel, V., Mutirangura, A. & Yanatatsaneejit, P. Human papillomavirus type 16 E7 oncoprotein mediates CCNA1 promoter methylation. Cancer Sci. 106, 1333–1340 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Cicchini, L. et al. Suppression of antitumor immune responses by human papillomavirus through epigenetic downregulation of CXCL14. mBio 7, e00270-16 (2016).

    PubMed  PubMed Central  Google Scholar 

  83. Cicchini, L. et al. High-risk human papillomavirus E7 alters host DNA methylome and represses HLA-E expression in human keratinocytes. Sci. Rep. 7, 3633 (2017).

    PubMed  PubMed Central  Google Scholar 

  84. Munger, K. & Jones, D. L. Human papillomavirus carcinogenesis: an identity crisis in the retinoblastoma tumor suppressor pathway. J. Virol. 89, 4708–4711 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Magaldi, T. G. et al. Primary human cervical carcinoma cells require human papillomavirus E6 and E7 expression for ongoing proliferation. Virology 422, 114–124 (2012).

    CAS  PubMed  Google Scholar 

  86. Weinstein, I. B. Addiction to oncogenes–the Achilles heal of cancer. Science 297, 63–64 (2002).

    CAS  PubMed  Google Scholar 

  87. McLaughlin-Drubin, M. E., Crum, C. P. & Münger, K. Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming. Proc. Natl Acad. Sci. USA 108, 2130–2135 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. McLaughlin-Drubin, M. E., Park, D. & Munger, K. Tumor suppressor p16INK4A is necessary for survival of cervical carcinoma cell lines. Proc. Natl Acad. Sci. USA 110, 16175–16180 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Spring, L. M. et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet 395, 817–827 (2020).

    CAS  PubMed  Google Scholar 

  90. Soto, D. R., Barton, C., Munger, K. & McLaughlin-Drubin, M. E. KDM6A addiction of cervical carcinoma cell lines is triggered by E7 and mediated by p21CIP1 suppression of replication stress. PLoS Pathog. 13, 1–25 (2017).

    Google Scholar 

  91. Ganti, K. et al. The human papillomavirus E6 PDZ binding motif: from life cycle to malignancy. Viruses 7, 3530–3551 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Mittal, S. & Banks, L. Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation. Mutat. Res. 772, 23–35 (2017).

    CAS  Google Scholar 

  93. Roman, A. & Munger, K. The papillomavirus E7 proteins. Virology 445, 138–168 (2013).

    CAS  PubMed  Google Scholar 

  94. Moody, C. A. & Laimins, L. A. Human papillomavirus oncoproteins: pathways to transformation. Nat. Rev. Cancer 10, 550–560 (2010).

    CAS  PubMed  Google Scholar 

  95. Seiwert, T. Y. et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin. Cancer Res. 21, 632–641 (2015).

    CAS  PubMed  Google Scholar 

  96. The Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582 (2015).

    Google Scholar 

  97. Gillison, M. L. et al. Human papillomavirus and the landscape of secondary genetic alterations in oral cancers. Genome Res. 29, 1–17 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Dogan, S. et al. Identification of prognostic molecular biomarkers in 157 HPV-positive and HPV-negative squamous cell carcinomas of the oropharynx. Int. J. Cancer 145, 3152–3162 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Lechner, M. et al. Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV− tumors. Genome Med. 5, 49 (2013).

    PubMed  PubMed Central  Google Scholar 

  100. Hayes, D. N., Van Waes, C. & Seiwert, T. Y. Genetic landscape of human papillomavirus-associated head and neck cancer and comparison to tobacco-related tumors. J. Clin. Oncol. 33, 3227–3234 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Henderson, S., Chakravarthy, A., Su, X., Boshoff, C. & Fenton, T. R. APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Rep. 7, 1833–1841 (2014).

    CAS  PubMed  Google Scholar 

  102. Zhu, B. et al. Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance. Nat. Commun. 11, 1–12 (2020).

    Google Scholar 

  103. Faden, D. L. et al. APOBEC mutagenesis is concordant between tumor and viral genomes in HPV-positive head and neck squamous cell carcinoma. Viruses 13, 1666 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Smith, N. J. & Fenton, T. R. The APOBEC3 genes and their role in cancer: insights from human papillomavirus. J. Mol. Endocrinol. 62, R269–R287 (2019).

    CAS  PubMed  Google Scholar 

  105. Fenton, T. R. Accumulation of host cell genetic errors following high-risk HPV infection. Curr. Opin. Virol. 51, 1–8 (2021).

    CAS  PubMed  Google Scholar 

  106. Warren, C. J., Westrich, J. A., Van Doorslaer, K. & Pyeon, D. Roles of APOBEC3A and APOBEC3B in human papillomavirus infection and disease progression. Viruses 9, 1–20 (2017).

    Google Scholar 

  107. Lui, V. W. Y. et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 3, 761–769 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Nichols, A. C. et al. High frequency of activating PIK3CA mutations in human papillomavirus- positive oropharyngeal cancer. JAMA Otolaryngol. 139, 617–622 (2013).

    Google Scholar 

  109. Hanna, G. J. et al. Improved outcomes in PI3K-pathway-altered metastatic HPV oropharyngeal cancer. JCI Insight 3, e122799 (2018).

    PubMed Central  Google Scholar 

  110. Beaty, B. T. et al. PIK3CA mutation in HPV-associated OPSCC patients receiving deintensified chemoradiation. J. Natl Cancer Inst. 112, 855–858 (2019).

    Google Scholar 

  111. Hedberg, M. L. et al. Use of nonsteroidal anti-inflammatory drugs predicts improved patient survival for PIK3CA-altered head and neck cancer. J. Exp. Med. 216, 419–427 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Cai, Y., Yousef, A., Grandis, J. R. & Johnson, D. E. NSAID therapy for PIK3CA-altered colorectal, breast, and head and neck cancer. Adv. Biol. Regul. 75, 100653 (2020).

    PubMed  Google Scholar 

  113. Paleari, L. et al. PIK3CA mutation, aspirin use after diagnosis and survival of colorectal cancer. a systematic review and meta-analysis of epidemiological studies. Clin. Oncol. 28, 317–326 (2016).

    CAS  Google Scholar 

  114. Nyman, P. E., Buehler, D. & Lambert, P. F. Loss of function of canonical Notch signaling drives head and neck carcinogenesis. Clin. Cancer Res. 24, 6308–6318 (2018).

    PubMed  PubMed Central  Google Scholar 

  115. Kranjec, C. et al. Modulation of basal cell fate during productive and transforming HPV-16 infection is mediated by progressive E6-driven depletion of Notch. J. Pathol. 242, 448–462 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Beglin, M., Melar-New, M. & Laimins, L. Human papillomaviruses and the interferon response. J. Interf. Cytokine Res. 29, 629–635 (2009).

    CAS  Google Scholar 

  117. Dhawan, A. et al. Role of gene signatures combined with pathology in classification of oropharynx head and neck cancer. Sci. Rep. 10, 10226 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. She, Y. et al. Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma. Cancer Cell Int. 20, 22 (2020).

    PubMed  PubMed Central  Google Scholar 

  119. Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30, 44–56 (2019).

    CAS  PubMed  Google Scholar 

  120. McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    CAS  PubMed  Google Scholar 

  122. Steinbach, A. & Riemer, A. B. Immune evasion mechanisms of human papillomavirus: an update. Int. J. Cancer 142, 224–229 (2018).

    CAS  PubMed  Google Scholar 

  123. Ashrafi, G. H., Haghshenas, M. R., Marchetti, B., O’Brien, P. M. & Campo, M. S. E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I. Int. J. Cancer 113, 276–283 (2005).

    CAS  PubMed  Google Scholar 

  124. Ashrafi, G. H., Haghshenas, M., Marchetti, B. & Campo, M. S. E5 protein of human papillomavirus 16 downregulates HLA class I and interacts with the heavy chain via its first hydrophobic domain. Int. J. Cancer 119, 2105–2112 (2006).

    CAS  PubMed  Google Scholar 

  125. Campo, M. S. et al. HPV-16 E5 down-regulates expression of surface HLA class I and reduces recognition by CD8 T cells. Virology 407, 137–142 (2010).

    CAS  PubMed  Google Scholar 

  126. Georgopoulos, N. T., Proffitt, J. L. & Blair, G. E. Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins. Oncogene 19, 4930–4935 (2000).

    CAS  PubMed  Google Scholar 

  127. Li, H., Ou, X., Xiong, J. & Wang, T. HPV16E7 mediates HADC chromatin repression and downregulation of MHC class I genes in HPV16 tumorigenic cells through interaction with an MHC class I promoter. Biochem. Biophys. Res. Commun. 349, 1315–1321 (2006).

    CAS  PubMed  Google Scholar 

  128. Bottley, G. et al. High-risk human papillomavirus E7 expression reduces cell-surface MHC class I molecules and increases susceptibility to natural killer cells. Oncogene 27, 1794–1799 (2008).

    CAS  PubMed  Google Scholar 

  129. Heusinkveld, M. et al. Systemic and local human papillomavirus 16-specific T-cell immunity in patients with head and neck cancer. Int. J. Cancer 131, 74–85 (2012).

    Google Scholar 

  130. Welters, M. J. P. et al. Intratumoral HPV16-specific T cells constitute a type I-oriented tumor microenvironment to improve survival in HPV16-driven oropharyngeal cancer. Clin. Cancer Res. 24, 634–647 (2018).

    CAS  PubMed  Google Scholar 

  131. Santegoets, S. J. et al. The anatomical location shapes the immune infiltrate in tumors of same etiology and affects survival. Clin. Cancer Res. 25, 240–252 (2019).

    CAS  PubMed  Google Scholar 

  132. Santegoets, S. J. et al. CD163+ cytokine-producing cDC2 stimulate intratumoral type 1 T cell responses in HPV16-induced oropharyngeal cancer. J. Immunother. Cancer 8, e001053 (2020).

    PubMed  PubMed Central  Google Scholar 

  133. Hoffmann, T. K. et al. T cells specific for HPV16 E7 epitopes in patients with squamous cell carcinoma of the oropharynx. Int. J. Cancer 118, 1984–1991 (2006).

    CAS  PubMed  Google Scholar 

  134. Masterson, L. et al. CD8+ T cell response to human papillomavirus 16 E7 is able to predict survival outcome in oropharyngeal cancer. Eur. J. Cancer 67, 141–151 (2016).

    CAS  PubMed  Google Scholar 

  135. Laban, S. & Hoffmann, T. K. Human papillomavirus immunity in oropharyngeal cancer: time to change the game? Clin. Cancer Res. 24, 505–507 (2018).

    CAS  PubMed  Google Scholar 

  136. Balermpas, P. et al. CD8+ tumour-infiltrating lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemoradiotherapy: a multicentre study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Int. J. Cancer 138, 171–181 (2016).

    CAS  PubMed  Google Scholar 

  137. Ward, M. J. et al. Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br. J. Cancer 110, 489–500 (2014).

    CAS  PubMed  Google Scholar 

  138. Mandal, R. et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight 1, e89829 (2016).

    PubMed  PubMed Central  Google Scholar 

  139. Chakravarthy, A. et al. Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted to the oropharynx. J. Clin. Oncol. 34, 4132–4141 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Li, H. et al. Association of human papillomavirus status at head and neck carcinoma subsites with overall survival. JAMA Otolaryngol. 144, 519–525 (2018).

    Google Scholar 

  141. Hladíková, K. et al. Tumor-infiltrating B cells affect the progression of oropharyngeal squamous cell carcinoma via cell-to-cell interactions with CD8+ T cells. J. Immunother. Cancer 7, 261 (2019).

    PubMed  PubMed Central  Google Scholar 

  142. Wood, O. et al. Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors. Oncotarget 7, 56781–56797 (2016).

    PubMed  PubMed Central  Google Scholar 

  143. Ou, D. et al. Influence of tumor-associated macrophages and HLA class I expression according to HPV status in head and neck cancer patients receiving chemo/bioradiotherapy. Radiother. Oncol. 130, 89–96 (2019).

    PubMed  Google Scholar 

  144. Welters, M. J. P., Santegoets, S. J. & van der Burg, S. H. The tumor microenvironment and immunotherapy of oropharyngeal squamous cell carcinoma. Front. Oncol. 10, 545385 (2020).

    PubMed  PubMed Central  Google Scholar 

  145. Hong, A. M. et al. Significant association of PD-L1 expression with human papillomavirus positivity and its prognostic impact in oropharyngeal cancer. Oral. Oncol. 92, 33–39 (2019).

    CAS  PubMed  Google Scholar 

  146. Cao, S. et al. Dynamic host immune response in virus-associated cancers. Commun. Biol. 2, 109 (2019).

    PubMed  PubMed Central  Google Scholar 

  147. McIlwain, W. R., Sood, A. J., Nguyen, S. A. & Day, T. A. Initial symptoms in patients with HPV-positive and HPV-negative oropharyngeal cancer. JAMA Otolaryngol. 140, 441–447 (2014).

    Google Scholar 

  148. Khalid, M. B. et al. Initial presentation of human papillomavirus-related head and neck cancer: a retrospective review. Laryngoscope 129, 877–882 (2019).

    PubMed  Google Scholar 

  149. Tham, T., Ahn, S., Frank, D., Kraus, D. & Costantino, P. Anatomical subsite modifies survival in oropharyngeal squamous cell carcinoma: National Cancer Database study. Head. Neck 42, 434–445 (2020).

    PubMed  Google Scholar 

  150. Golusinski, P. et al. Evidence for the approach to the diagnostic evaluation of squamous cell carcinoma occult primary tumors of the head and neck. Oral. Oncol. 88, 145–152 (2019).

    PubMed  Google Scholar 

  151. Zhang, M. Q., El-Mofty, S. K. & Dávila, R. M. Detection of human papillomavirus-related squamous cell carcinoma cytologically and by in situ hybridization in fine-needle aspiration biopsies of cervical metastasis: a tool for identifying the site of an occult head and neck primary. Cancer 114, 118–123 (2008).

    PubMed  Google Scholar 

  152. Begum, S., Gillison, M. L., Nicol, T. L. & Westra, W. H. Detection of human papillomavirus-16 in fine-needle aspirates to determine tumor origin in patients with metastatic squamous cell carcinoma of the head and neck. Clin. Cancer Res. 13, 1186–1191 (2007).

    CAS  PubMed  Google Scholar 

  153. Mehanna, H. et al. Oropharyngeal cancer: United Kingdom National Multidisciplinary Guidelines. J. Laryngol. Otol. 130, S90–S96 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Gage, K. L., Thomas, K., Jeong, D., Stallworth, D. G. & Arrington, J. A. Multimodal imaging of head and neck squamous cell carcinoma. Cancer Control. 24, 172–179 (2017).

    PubMed  Google Scholar 

  155. Schache, A. G. et al. Evaluation of human papilloma virus diagnostic testing in oropharyngeal squamous cell carcinoma: sensitivity, specificity, and prognostic discrimination. Clin. Cancer Res. 17, 6262–6271 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Lewis, J. S. Morphologic diversity in human papillomavirus-related oropharyngeal squamous cell carcinoma: catch me if you can! Mod. Pathol. 30, S44–S53 (2017).

    PubMed  Google Scholar 

  157. Chernock, R. D., Lewis, J. S., Zhang, Q. & El-Mofty, S. K. Human papillomavirus-positive basaloid squamous cell carcinomas of the upper aerodigestive tract: a distinct clinicopathologic and molecular subtype of basaloid squamous cell carcinoma. Hum. Pathol. 41, 1016–1023 (2010).

    CAS  PubMed  Google Scholar 

  158. Cho, K. J. et al. Basaloid squamous cell carcinoma of the head and neck: subclassification into basal, ductal, and mixed subtypes based on comparison of clinico-pathologic features and expression of p53, cyclin D1, epidermal growth factor receptor, p16, and human papilloma. J. Pathol. Transl. Med. 51, 374–380 (2017).

    PubMed  PubMed Central  Google Scholar 

  159. Mehrad, M. et al. Papillary squamous cell carcinoma of the head and neck: clinicopathologic and molecular features with special reference to human papillomavirus. Am. J. Surg. Pathol. 37, 1349–1356 (2013).

    PubMed  PubMed Central  Google Scholar 

  160. Carpenter, D. H., El-Mofty, S. K. & Lewis, J. S. Undifferentiated carcinoma of the oropharynx: a human papillomavirus-associated tumor with a favorable prognosis. Mod. Pathol. 24, 1306–1312 (2011).

    CAS  PubMed  Google Scholar 

  161. Singhi, A. D., Stelow, E. B., Mills, S. E. & Westra, W. H. Lymphoepithelial-like carcinoma of the oropharynx: a morphologic variant of HPV-related head and neck carcinoma. Am. J. Surg. Pathol. 34, 800–805 (2010).

    PubMed  Google Scholar 

  162. Jo, V. Y., Mills, S. E., Stoler, M. H. & Stelow, E. B. Papillary squamous cell carcinoma of the head and neck: frequent association with human papillomavirus infection and invasive carcinoma. Am. J. Surg. Pathol. 33, 1720–1724 (2009).

    PubMed  Google Scholar 

  163. Bryne, M., Koppang, H. S., Lilleng, R. & Kjærheim, Å. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. J. Pathol. 166, 375–381 (1992).

    CAS  PubMed  Google Scholar 

  164. Albergotti, W. G. et al. Defining the prevalence and prognostic value of perineural invasion and angiolymphatic invasion in human papillomavirus-positive oropharyngeal carcinoma. JAMA Otolaryngol. 143, 1236–1243 (2017).

    Google Scholar 

  165. Dirven, R. et al. Tumor thickness versus depth of invasion – analysis of the 8th edition American Joint Committee on Cancer Staging for oral cancer. Oral. Oncol. 74, 30–33 (2017).

    PubMed  Google Scholar 

  166. Zhan, K. Y. et al. Appraisal of the AJCC 8th edition pathologic staging modifications for HPV−positive oropharyngeal cancer, a study of the National Cancer Data Base. Oral. Oncol. 73, 152–159 (2017).

    PubMed  Google Scholar 

  167. Elicin, O. et al. Comparison of contemporary staging systems for oropharynx cancer in a surgically treated multi-institutional cohort. Head. Neck 41, 1395–1402 (2019).

    PubMed  Google Scholar 

  168. Bhattasali, O., Thompson, L. D. R., Schumacher, A. J. & Iganej, S. Radiographic nodal prognostic factors in stage I HPV-related oropharyngeal squamous cell carcinoma. Head. Neck 41, 398–402 (2019).

    PubMed  Google Scholar 

  169. Sinha, P. et al. High metastatic node number, not extracapsular spread or N-classification is a node-related prognosticator in transorally-resected, neck-dissected p16-positive oropharynx cancer. Oral. Oncol. 51, 514–520 (2015).

    PubMed  Google Scholar 

  170. Bauer, E. et al. Extranodal extension is a strong prognosticator in HPV-positive oropharyngeal squamous cell carcinoma. Laryngoscope 130, 939–945 (2020).

    CAS  PubMed  Google Scholar 

  171. Freitag, J. et al. Extracapsular extension of neck nodes and absence of human papillomavirus 16-DNA are predictors of impaired survival in p16-positive oropharyngeal squamous cell carcinoma. Cancer 126, 1856–1872 (2020).

    CAS  PubMed  Google Scholar 

  172. Tian, S. et al. Prognostic value of radiographically defined extranodal extension in human papillomavirus-associated locally advanced oropharyngeal carcinoma. Head. Neck 41, 3056–3063 (2019).

    PubMed  PubMed Central  Google Scholar 

  173. Meyer, M. F. et al. The relevance of the lymph node ratio as predictor of prognosis is higher in HPV-negative than in HPV-positive oropharyngeal squamous cell carcinoma. Clin. Otolaryngol. 43, 192–198 (2018).

    CAS  PubMed  Google Scholar 

  174. Chai, R. L. et al. Accuracy of computed tomography in the prediction of extracapsular spread of lymph node metastases in squamous cell carcinoma of the head and neck. JAMA Otolaryngol. 139, 1187–1194 (2013).

    Google Scholar 

  175. Aiken, A. H. et al. Accuracy of preoperative imaging in detecting nodal extracapsular spread in oral cavity squamous cell carcinoma. Am. J. Neuroradiol. 36, 1776–1781 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Carlton, J. A. et al. Computed tomography detection of extracapsular spread of squamous cell carcinoma of the head and neck in metastatic cervical lymph nodes. Neuroradiol. J. 30, 222–229 (2017).

    PubMed  PubMed Central  Google Scholar 

  177. Douglas, C. et al. Accuracy of contrast-enhanced CT and predictive factors for extracapsular spread in unknown primary head and neck squamous cell cancer. Clin. Radiol. 75, 77.e23–77.e28 (2020).

    CAS  Google Scholar 

  178. O’Sullivan, B. et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol. 17, 440–451 (2016).

    PubMed  Google Scholar 

  179. Cramer, J. D., Hicks, K. E., Rademaker, A. W., Patel, U. A. & Samant, S. Validation of the eighth edition American Joint Committee on Cancer staging system for human papillomavirus-associated oropharyngeal cancer. Head. Neck 40, 457–466 (2018).

    PubMed  Google Scholar 

  180. Geltzeiler, M. et al. Staging HPV-related oropharyngeal cancer: validation of AJCC-8 in a surgical cohort. Oral. Oncol. 84, 82–87 (2018).

    PubMed  PubMed Central  Google Scholar 

  181. Van Gysen, K. et al. Validation of the 8th edition UICC/AJCC TNM staging system for HPV associated oropharyngeal cancer patients managed with contemporary chemo-radiotherapy. BMC Cancer 19, 674 (2019).

    PubMed  PubMed Central  Google Scholar 

  182. Würdemann, N. et al. Prognostic impact of AJCC/UICC 8th edition new staging rules in oropharyngeal squamous cell carcinoma. Front. Oncol. 7, 129 (2017).

    PubMed  PubMed Central  Google Scholar 

  183. Nauta, I. H. et al. Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing. Ann. Oncol. 29, 1273–1279 (2018).

    CAS  PubMed  Google Scholar 

  184. Fakhry, C. et al. Validation of NRG oncology/RTOG-0129 risk groups for HPV-positive and HPV-negative oropharyngeal squamous cell cancer: implications for risk-based therapeutic intensity trials. Cancer 125, 2027–2038 (2019).

    CAS  PubMed  Google Scholar 

  185. Haeggblom, L., Ramqvist, T., Tommasino, M. & Dalianis, T. Time to change perspectives on HPV in oropharyngeal cancer. A systematic review of HPV prevalence per oropharyngeal sub-site the last 3 years. Papillomavirus Res. 4, 1–11 (2017).

    PubMed  PubMed Central  Google Scholar 

  186. Wendt, M. et al. Long-term survival and recurrence in oropharyngeal squamous cell carcinoma in relation to subsites, HPV, and p16-status. Cancers (Basel) 13, 2553 (2021).

    CAS  Google Scholar 

  187. Ellis, M. et al. Post-treatment head and neck cancer care: national audit and analysis of current practice in the United Kingdom. Clin. Otolaryngol. 46, 284–294 (2021).

    PubMed  Google Scholar 

  188. Fakhry, C. et al. Association of oral human papillomavirus DNA persistence with cancer progression after primary treatment for oral cavity and oropharyngeal squamous cell carcinoma. JAMA Oncol. 5, 985–992 (2019).

    PubMed  PubMed Central  Google Scholar 

  189. Chera, B. S. et al. Plasma circulating tumor HPV DNA for the surveillance of cancer recurrence in HPV-associated oropharyngeal cancer. J. Clin. Oncol. 38, 1050–1058 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Holsinger, F. C. & Ferris, R. L. Transoral endoscopic head and neck surgery and its role within the multidisciplinary treatment paradigm of oropharynx cancer: robotics, lasers, and clinical trials. J. Clin. Oncol. 33, 3285–3292 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Sinha, P., Haughey, B. H., Kallogjeri, D. & Jackson, R. S. Long-term analysis of transorally resected p16 + oropharynx cancer: outcomes and prognostic factors. Laryngoscope 129, 1141–1149 (2019).

    CAS  PubMed  Google Scholar 

  192. Mahmoud, O., Sung, K., Civantos, F. J., Thomas, G. R. & Samuels, M. A. Transoral robotic surgery for oropharyngeal squamous cell carcinoma in the era of human papillomavirus. Head Neck 40, 710–721 (2018).

    PubMed  Google Scholar 

  193. Jackson, R. S. et al. Transoral resection of human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx: outcomes with and without adjuvant therapy. Ann. Surg. Oncol. 24, 3494–3501 (2017).

    PubMed  PubMed Central  Google Scholar 

  194. Carey, R. M. et al. Increased rate of recurrence and high rate of salvage in patients with human papillomavirus–associated oropharyngeal squamous cell carcinoma with adverse features treated with primary surgery without recommended adjuvant therapy. Head Neck 43, 1128–1141 (2021).

    PubMed  Google Scholar 

  195. Sethia, R. et al. Quality of life outcomes of transoral robotic surgery with or without adjuvant therapy for oropharyngeal cancer. Laryngoscope 128, 403–411 (2018).

    PubMed  Google Scholar 

  196. Ma, D. J. et al. Phase II evaluation of aggressive dose de-escalation for adjuvant chemoradiotherapy in human papillomavirus-associated oropharynx squamous cell carcinoma. J. Clin. Oncol. 37, 1909–1918 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Hargreaves, S., Beasley, M., Hurt, C., Jones, T. M. & Evans, M. Deintensification of adjuvant treatment after transoral surgery in patients with human papillomavirus-positive oropharyngeal cancer: the conception of the PATHOS study and its development. Front Oncol. 9, 936 (2019).

    PubMed  PubMed Central  Google Scholar 

  198. Ferris, R. L. et al. Updated report of a phase II randomized trial of transoral surgical resection followed by low-dose or standard postoperative therapy in resectable p16+ locally advanced oropharynx cancer: a trial of the ECOG-ACRIN cancer research group (E3311). J. Clin. Oncol. 39, 6010 (2021).

    Google Scholar 

  199. Ferris, R. L. et al. Transoral robotic surgical resection followed by randomization to low- or standard-dose IMRT in resectable p16+ locally advanced oropharynx cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3311). J. Clin. Oncol. 38, 6500 (2020).

    Google Scholar 

  200. Ferris, R. L. et al. Phase II randomized trial of transoral surgery and low-dose intensity modulated radiation therapy in resectable p16+ locally advanced oropharynx cancer: an ECOG-ACRIN Cancer Research Group trial (E3311). J. Clin. Oncol. 40, 138–149 (2022).

    CAS  PubMed  Google Scholar 

  201. Chera, B. S. et al. Phase 2 trial of de-intensified chemoradiation therapy for favorable-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 93, 976–985 (2015).

    PubMed  Google Scholar 

  202. Chera, B. S. et al. Mature results of a prospective study of deintensified chemoradiotherapy for low-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cancer 124, 2347–2354 (2018).

    CAS  PubMed  Google Scholar 

  203. Pearlstein, K. A. et al. Quality of life for patients with favorable-risk HPV-associated oropharyngeal cancer after de-intensified chemoradiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 103, 646–653 (2019).

    PubMed  Google Scholar 

  204. Seiwert, T. Y. et al. Optima: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer. Ann. Oncol. 30, 297–302 (2019).

    CAS  PubMed  Google Scholar 

  205. Marur, S. et al. E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx-ECOG-ACRIN cancer research group. J. Clin. Oncol. 35, 490–497 (2017).

    CAS  PubMed  Google Scholar 

  206. Hegde, J. V. et al. Functional outcomes after de-escalated chemoradiation therapy for human papillomavirus-positive oropharyngeal cancer: secondary analysis of a phase 2 trial. Int. J. Radiat. Oncol. Biol. Phys. 100, 647–651 (2018).

    PubMed  Google Scholar 

  207. Chen, A. M. et al. Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study. Lancet Oncol. 18, 803–811 (2017).

    PubMed  PubMed Central  Google Scholar 

  208. Yamamoto, Y. et al. Radiotherapy alone as a possible de-intensified treatment for human papillomavirus-related locally advanced oropharyngeal squamous cell carcinoma. Int. J. Clin. Oncol. 24, 640–648 (2019).

    PubMed  Google Scholar 

  209. Hall, S. F., Griffiths, R. J., O’Sullivan, B. & Liu, F. F. The addition of chemotherapy to radiotherapy did not reduce the rate of distant metastases in low-risk HPV-related oropharyngeal cancer in a real-world setting. Head Neck 41, 2271–2276 (2019).

    PubMed  PubMed Central  Google Scholar 

  210. Yom, S. S. et al. Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG Oncology HN002). J. Clin. Oncol. 39, 956–965 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Sher, D. J. et al. Radiation therapy for oropharyngeal squamous cell carcinoma: executive summary of an ASTRO evidence-based clinical practice guideline. Pract. Radiat. Oncol. 7, 246–253 (2017).

    PubMed  Google Scholar 

  212. Howard, J. et al. Minimally invasive surgery versus radiotherapy/chemoradiotherapy for small-volume primary oropharyngeal carcinoma. Cochrane Database Syst. Rev. 12, CD010963 (2016).

    PubMed  Google Scholar 

  213. Nichols, A. C. et al. Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial. Lancet Oncol. 20, 1349–1359 (2019).

    CAS  PubMed  Google Scholar 

  214. Ferris, R. L. et al. A novel surgeon credentialing and quality assurance process using transoral surgery for oropharyngeal cancer in ECOG-ACRIN Cancer Research Group trial E3311. Oral. Oncol. 110, 104797 (2020).

    PubMed  PubMed Central  Google Scholar 

  215. de Almeida, J. R. et al. Oncologic outcomes after transoral robotic surgery: a multi-institutional study. JAMA Otolaryngol. 141, 1043–1051 (2015).

    Google Scholar 

  216. Mehanna, H. et al. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet 393, 51–60 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Gillison, M. L. et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet 393, 40–50 (2019).

    CAS  PubMed  Google Scholar 

  218. Oosthuizen, J. C. & Doody, J. De-intensified treatment in human papillomavirus-positive oropharyngeal cancer. Lancet 393, 5–7 (2019).

    PubMed  Google Scholar 

  219. Guo, T. et al. Characterization of functionally active gene fusions in human papillomavirus related oropharyngeal squamous cell carcinoma. Int. J. Cancer 139, 373–382 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Dunn, L. A. et al. Phase I study of induction chemotherapy with afatinib, ribavirin, and weekly carboplatin and paclitaxel for stage IVA/IVB human papillomavirus-associated oropharyngeal squamous cell cancer. Head. Neck 40, 233–241 (2018).

    PubMed  Google Scholar 

  221. Frazer, I. H. & Chandra, J. Immunotherapy for HPV associated cancer. Papillomavirus Res. 8, 100176 (2019).

    PubMed  PubMed Central  Google Scholar 

  222. Barra, F. et al. Advances in therapeutic vaccines for treating human papillomavirus-related cervical intraepithelial neoplasia. J. Obstet. Gynaecol. Res. 46, 989–1006 (2020).

    PubMed  Google Scholar 

  223. Smalley Rumfield, C., Pellom, S. T., Morillon, Y. M., Schlom, J. & Jochems, C. Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine. J. Immunother. Cancer https://doi.org/10.1136/jitc-2020-000612 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Ferris, R. L. et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 375, 1856–1867 (2016).

    PubMed  PubMed Central  Google Scholar 

  225. Cohen, E. E. W. et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393, 156–167 (2019).

    CAS  PubMed  Google Scholar 

  226. Burtness, B. et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394, 1915–1928 (2019).

    CAS  PubMed  Google Scholar 

  227. Xu, Y. et al. Programmed death-1/programmed death-ligand 1-axis blockade in recurrent or metastatic head and neck squamous cell carcinoma stratified by human papillomavirus status: a systematic review and meta-analysis. Front. Immunol. 12, 645170 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Wang, J. et al. HPV-positive status associated with inflamed immune microenvironment and improved response to anti-PD-1 therapy in head and neck squamous cell carcinoma. Sci. Rep. 9, 13404 (2019).

    PubMed  PubMed Central  Google Scholar 

  229. Galvis, M. M. et al. Immunotherapy improves efficacy and safety of patients with HPV positive and negative head and neck cancer: a systematic review and meta-analysis. Crit. Rev. Oncol. Hematol. 150, 102966 (2020).

    PubMed  Google Scholar 

  230. Patel, J. J., Levy, D. A., Nguyen, S. A., Knochelmann, H. M. & Day, T. A. Impact of PD-L1 expression and human papillomavirus status in anti-PD1/PDL1 immunotherapy for head and neck squamous cell carcinoma — systematic review and meta-analysis. Head Neck 42, 774–786 (2019).

    PubMed  PubMed Central  Google Scholar 

  231. Wong, D. J. et al. Abstract CT123: IMvoke010: randomized phase III study of atezolizumab as adjuvant monotherapy after definitive therapy of squamous cell carcinoma of the head and neck. Cancer Res. 79, (Suppl.) 13 (2019).

    Google Scholar 

  232. Leidner, R. et al. Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma. J. Immunother. Cancer 9, e002485 (2021).

    PubMed  PubMed Central  Google Scholar 

  233. Ferris, R. L. et al. Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial. J. Immunother. Cancer 9, e002568 (2021).

    PubMed  PubMed Central  Google Scholar 

  234. Ferrarotto, R. et al. Impact of neoadjuvant durvalumab with or without tremelimumab on CD8+ tumor lymphocyte density, safety, and efficacy in patients with oropharynx cancer: CIAO trial results. Clin. Cancer Res. 26, 3211–3219 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. von Witzleben, A., Wang, C., Laban, S., Savelyeva, N. & Ottensmeier, C. H. HNSCC: tumour antigens and their targeting by immunotherapy. Cells 9, 2103 (2020).

    Google Scholar 

  236. Massarelli, E. et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: a phase 2 clinical trial. JAMA Oncol. 5, 67–73 (2019).

    PubMed  Google Scholar 

  237. Aggarwal, C. et al. Immunotherapy targeting HPV16/18 generates potent immune responses in HPV-associated head and neck cancer. Clin. Cancer Res. 25, 110–124 (2019).

    CAS  PubMed  Google Scholar 

  238. Fakhry, C. et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J. Clin. Oncol. 32, 3365–3373 (2014).

    PubMed  PubMed Central  Google Scholar 

  239. Harbison, R. A. et al. The mutational landscape of recurrent versus nonrecurrent human papillomavirus-related oropharyngeal cancer. JCI insight 3, e99327 (2018).

    PubMed Central  Google Scholar 

  240. Gleber-netto, F. O. et al. Variations in HPV function are associated with survival in squamous cell carcinoma. JCI Insight 4, e124762 (2019).

    PubMed Central  Google Scholar 

  241. King, A. and Broggio, J. Cancer Registration Statistics, England https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/cancerregistrationstatisticsengland/final2016 (2016).

  242. Surveillance Research Program SEER Incidence Data, 1975–2018. https://seer.cancer.gov/data/ (National Cancer Institute, 2020).

  243. Lechner, M. & Fenton, T. R. The genomics, epigenomics, and transcriptomics of HPV-associated oropharyngeal cancer — understanding the basis of a rapidly evolving disease. Adv. Genet. 93, 1–56 (2016).

    CAS  PubMed  Google Scholar 

  244. Machczyński, P., Majchrzak, E., Niewinski, P., Marchlewska, J. & Golusiński, W. A review of the 8th edition of the AJCC staging system for oropharyngeal cancer according to HPV status. Eur. Arch. Otorhinolaryngol. 277, 2407–2412 (2020).

    PubMed  PubMed Central  Google Scholar 

  245. Adelstein, D. J. et al. Role of treatment deintensification in the management of p16+ oropharyngeal cancer: ASCO provisional clinical opinion. J. Clin. Oncol. 37, 1578–1589 (2019).

    PubMed  Google Scholar 

  246. Posner, M. R. et al. Survival (OS) and progression-free survival (PFS) results after induction chemotherapy (IC) followed by de-escalated chemoradiotherapy (RDCRT) for locally advanced (LA) HPV positive oropharynx cancer (HPVOPC). J. Clin. Oncol. 39, 6058 (2021).

    Google Scholar 

  247. Palma, D. A. et al. A randomized trial of radiotherapy vs. trans-oral surgery for treatment de-escalation in HPV-associated oropharyngeal squamous cell carcinoma (ORATOR2). Int. J. Rad. Oncol. Biophys. 111, 1324–1325 (2021).

    Google Scholar 

  248. Miles, B. A. et al. De-escalated adjuvant therapy after transoral robotic surgery for human papillomavirus-related oropharyngeal carcinoma: the Sinai robotic surgery (SIRS) trial. Oncologist 26, 504–513 (2021).

    PubMed  PubMed Central  Google Scholar 

  249. Swisher–McClure, S. et al. A phase 2 trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): omission of the resected primary tumor bed after transoral robotic surgery for human papilloma virus-related squamous cell carcinoma of the oropharynx. Int. J. Radiat. Oncol. Biol. Phys. 106, 725–732 (2020).

    PubMed  Google Scholar 

Download references

Acknowledgements

Work on HPV-positive OPSCC in T.R.F’s lab has been supported by the Rosetrees Trust (CM229-CD1) and the Paul Southgate Fund. The authors thank A. Jay (Department of Histopathology, University College London Hospital) for the micrographs shown in Fig. 1.

Author information

Authors and Affiliations

  1. UCL Cancer Institute, University College London, London, UK

    Matt Lechner & Jacklyn Liu

  2. Division of Surgery and Interventional Science, University College London, London, UK

    Matt Lechner

  3. Department of ENT, Barts Health NHS Trust, London, UK

    Matt Lechner

  4. Department of ENT, Cambridge University Hospitals NHS Trust, Cambridge, UK

    Liam Masterson

  5. School of Biosciences, University of Kent, Canterbury, UK

    Tim R. Fenton

  6. School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton, UK

    Tim R. Fenton

Authors
  1. Matt Lechner
    View author publications

    Search author on:PubMed Google Scholar

  2. Jacklyn Liu
    View author publications

    Search author on:PubMed Google Scholar

  3. Liam Masterson
    View author publications

    Search author on:PubMed Google Scholar

  4. Tim R. Fenton
    View author publications

    Search author on:PubMed Google Scholar

Contributions

All authors made a substantial contribution to all aspects of the preparation of this manuscript.

Corresponding authors

Correspondence to Matt Lechner or Tim R. Fenton.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Clinical Oncology thanks T. Dalianis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lechner, M., Liu, J., Masterson, L. et al. HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clin Oncol 19, 306–327 (2022). https://doi.org/10.1038/s41571-022-00603-7

Download citation

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41571-022-00603-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer