Comparing Outcomes for Patients with Human Papillomavirus (HPV) Type 16 versus Other High-Risk HPV Types in Oropharyngeal Squamous Cell Carcinoma


Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is related to improved treatment outcomes. What remains unclear is whether all HPV DNA genotypes carry similar prognostic relevance. We aimed to evaluate disease control and survival outcomes by HPV DNA genotype. Patients with primary OPSCC without distant metastases treated with curative intent were retrospectively identified from an IRB-approved institutional database. Patients that underwent HPV DNA polymerase chain reaction (PCR) testing with available genotype were included and dichotomized by the presence of HPV type 16 (HPV-16) or other high-risk HPV genotype (HPV-non16). Overall survival (OS), disease-free survival (DFS), locoregional control (LRC) and distant control (DC) were determined using the Kaplan–Meier method and compared using the log-rank test. In our cohort of 193 patients treated from 2012 to 2018 with HPV DNA PCR, 10% were detected as HPV-non16 high-risk types. Patients with HPV-16 were significantly younger than those with HPV-non16, but no other baseline factors were associated with HPV-non16. With a median follow-up of 42.9 months, there were no significant differences in outcomes between the HPV-16 and HPV-non16 groups for 3-year OS (87.7% v. 73.6%), DFS (82.9% v. 68.7%), LRC (92.8% v. 88.5%) or DC (91% v. 89.2%). There is no statistically significant difference in outcomes between OPSCC with HPV-16 and HPV-non16 high-risk genotypes in our cohort, though trends of overall worse survival and disease-free survival in HPV-non 16 OPSCC were seen. Further studies with larger cohorts of patients with HPV-non 16-associated OPSCC are required to make definitive conclusions regarding the prognostic and clinical significance of HPV type.

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

Fig. 1
Fig. 2


  1. 1.

    Gillison ML. Human papillomavirus-related diseases: oropharynx cancers and potential implications for adolescent HPV vaccination. J Adolesc Health. 2008;43(4 Suppl):S52-60.

    Article  Google Scholar 

  2. 2.

    Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60.

    CAS  Article  Google Scholar 

  3. 3.

    Dayyani F, et al. Meta-analysis of the impact of human papillomavirus (HPV) on cancer risk and overall survival in head and neck squamous cell carcinomas (HNSCC). Head Neck Oncol. 2010;2:15.

    Article  Google Scholar 

  4. 4.

    Westra WH. The morphologic profile of HPV-related head and neck squamous carcinoma: implications for diagnosis, prognosis, and clinical management. Head Neck Pathol. 2012;6(Suppl 1):S48-54.

    Article  Google Scholar 

  5. 5.

    Gillison ML, et al. Eurogin Roadmap: comparative epidemiology of HPV infection and associated cancers of the head and neck and cervix. Int J Cancer. 2014;134(3):497–507.

    CAS  Article  Google Scholar 

  6. 6.

    Ang KK, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.

    CAS  Article  Google Scholar 

  7. 7.

    Mallen-St Clair J, et al. Human papillomavirus in oropharyngeal cancer: the changing face of a disease. Biochim Biophys Acta. 2016;1866(2):141–50.

    CAS  PubMed  Google Scholar 

  8. 8.

    Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, et al, editors. AJCC cancer staging manual. 8th ed. Springer International Publishing, American Joint Commission on Cancer; 2017.

  9. 9.

    Chera BS, Amdur RJ. Current status and future directions of treatment deintensification in human papilloma virus-associated oropharyngeal squamous cell carcinoma. Semin Radiat Oncol. 2018;28(1):27–34.

    Article  Google Scholar 

  10. 10.

    Keck MK, et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res. 2015;21(4):870–81.

    CAS  Article  Google Scholar 

  11. 11.

    Grce M, Mravak-Stipetic M. Human papillomavirus-associated diseases. Clin Dermatol. 2014;32(2):253–8.

    Article  Google Scholar 

  12. 12.

    de Villiers EM, Gissmann L, Zur Hausen H. Molecular cloning of viral DNA from human genital warts. J Virol. 1981;40(3):932–5.

    Article  Google Scholar 

  13. 13.

    Munger K, et al. Mechanisms of human papillomavirus-induced oncogenesis. J Virol. 2004;78(21):11451–60.

    Article  Google Scholar 

  14. 14.

    Harris PA, et al. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81.

    Article  Google Scholar 

  15. 15.

    Nagatsuka M, et al. Omitting elective irradiation of the contralateral retropharyngeal nodes in oropharyngeal squamous cell carcinoma treated with intensity-modulated radiotherapy. Cureus. 2019;11(1):e3825.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Elrefaey S, et al. HPV in oropharyngeal cancer: the basics to know in clinical practice. Acta Otorhinolaryngol Ital. 2014;34(5):299–309.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Varier I, et al. Clinical characteristics and outcomes of oropharyngeal carcinoma related to high-risk non-human papillomavirus16 viral subtypes. Head Neck. 2016;38(9):1330–7.

    Article  Google Scholar 

  18. 18.

    St Guily JL, et al. Human papillomavirus genotype distribution in oropharynx and oral cavity cancer in France-The EDiTH VI study. J Clin Virol. 2011;51(2):100–4.

    Article  Google Scholar 

  19. 19.

    Chaturvedi AK, et al. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612–9.

    Article  Google Scholar 

  20. 20.

    Misiukiewicz K, et al. Standard of care vs reduced-dose chemoradiation after induction chemotherapy in HPV+ oropharyngeal carcinoma patients: the quarterback trial. Oral Oncol. 2019;95:170–7.

    CAS  Article  Google Scholar 

  21. 21.

    Weinberger PM, et al. Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. J Clin Oncol. 2006;24(5):736–47.

    CAS  Article  Google Scholar 

  22. 22.

    Semrau R, et al. Prognostic impact of human papillomavirus status, survivin, and epidermal growth factor receptor expression on survival in patients treated with radiochemotherapy for very advanced nonresectable oropharyngeal cancer. Head Neck. 2013;35(9):1339–44.

    Article  Google Scholar 

  23. 23.

    Driessen CM, et al. Toxicity and efficacy of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. Head Neck. 2016;38(Suppl 1):E559–65.

    Article  Google Scholar 

  24. 24.

    Lewis JS Jr, et al. Human papillomavirus testing in head and neck carcinomas: guideline from the college of American pathologists. Arch Pathol Lab Med. 2018;142(5):559–97.

    Article  Google Scholar 

  25. 25.

    El-Mofty SK, Patil S. Human papillomavirus (HPV)-related oropharyngeal nonkeratinizing squamous cell carcinoma: characterization of a distinct phenotype. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101(3):339–45.

    Article  Google Scholar 

  26. 26.

    Westra WH. The pathology of HPV-related head and neck cancer: implications for the diagnostic pathologist. Semin Diagn Pathol. 2015;32(1):42–53.

    Article  Google Scholar 

  27. 27.

    Fonmarty D, et al. Study of the concordance between p16 immunohistochemistry and HPV-PCR genotyping for the viral diagnosis of oropharyngeal squamous cell carcinoma. Eur Ann Otorhinolaryngol Head Neck Dis. 2015;132(3):135–9.

    CAS  Article  Google Scholar 

  28. 28.

    Pannone G, et al. Evaluation of a combined triple method to detect causative HPV in oral and oropharyngeal squamous cell carcinomas: p16 immunohistochemistry, consensus PCR HPV-DNA, and In Situ Hybridization. Infect Agent Cancer. 2012;7:4.

    CAS  Article  Google Scholar 

  29. 29.

    Albers AE, et al. Meta analysis: HPV and p16 pattern determines survival in patients with HNSCC and identifies potential new biologic subtype. Sci Rep. 2017;7(1):16715.

    Article  Google Scholar 

  30. 30.

    Liu JC, et al. High prevalence of discordant human papillomavirus and p16 oropharyngeal squamous cell carcinomas in an African American cohort. Head Neck. 2016;38(Suppl 1):E867–72.

    Article  Google Scholar 

  31. 31.

    Froberg M, et al. Impact of the human papillomavirus status on the development of high-grade cervical intraepithelial neoplasia in women negative for intraepithelial lesions or malignancy at the baseline: a 9-year Swedish nested case-control follow-up study. Cancer. 2019;125(2):239–48.

    PubMed  Google Scholar 

  32. 32.

    Hopenhayn C, et al. Prevalence of human papillomavirus types in invasive cervical cancers from 7 US cancer registries before vaccine introduction. J Low Genit Tract Dis. 2014;18(2):182–9.

    Article  Google Scholar 

Download references


This work was supported by the Wake Forest Baptist Medical Center and National Center for Advancing Translational Sciences (NCATS), National Institutes of Health funded Wake Forest Clinical and Translational Science Institute (WF CTSI) through Grant Award Number UL1TR001420.

Author information



Corresponding author

Correspondence to Rachel F. Shenker.

Ethics declarations

Conflict of interest

There are no conflicts of interest to be declared.

Ethical Approval

This study was reviewed by the Wake Forest Clinical and Translational Science Institute IRB and approved by ethical standards.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shenker, R.F., May, N.H., Waltonen, J.D. et al. Comparing Outcomes for Patients with Human Papillomavirus (HPV) Type 16 versus Other High-Risk HPV Types in Oropharyngeal Squamous Cell Carcinoma. Head and Neck Pathol (2021).

Download citation


  • Oropharyngeal carcinoma
  • Human papillomavirus
  • Head and neck neoplasms
  • Squamous cell carcinoma
  • HPV testing