Skip to main content

Advertisement

Log in

Human papilloma virus and survival of oropharyngeal cancer patients treated with surgery and adjuvant radiotherapy

  • Head and Neck
  • Published:
European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

Impact of p16 protein, a surrogate marker for human papilloma virus induced cancer, p53 and EGFR as well as clinical factors on survival in a patient cohort with oropharyngeal squamous cell carcinoma (OPSCC) treated by surgical resection and adjuvant radiotherapy (RT) ± concomitant chemotherapy (CT). This is a retrospective analysis of patient’s charts and tumor tissue. 57 patients were consecutively included and their tumor tissue assembled on a tissue microarray following immunohistochemical analysis. Survival times were estimated by means of Kaplan–Meier analysis. The importance of clinical and immunohistochemical factors for outcome was estimated by cox proportional hazard models. With 88 % 5-year overall survival, 91 % 5-year disease-specific survival and 91 % 5-year disease-free survival, respectively, we found excellent survival rates in this surgically treated patient cohort of mainly advanced OPSCC (93 % AJCC stage III or IV). The only factors positively influencing survival were p16 overexpression as well as p53 negativity and even more pronounced the combination of those biomarkers. Survival analysis of patients classified into three risk categories according to an algorithm based on p16, smoking, T- and N-category revealed a low, intermediate and high-risk group with significant survival differences between the low and the high-risk group. Patients with OPSCC can be successfully treated by surgery and adjuvant RT ± CT with a clear survival benefit of p16 positive, p53 negative patients. We recommend considering a combination of immunohistochemical (p16, p53) and clinical factors (smoking, T- and N-category) for risk stratification.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Tschudi D, Stoeckli S, Schmid S (2003) Quality of life after different treatment modalities for carcinoma of the oropharynx. Laryngoscopes 113(11):1949–1954

    Article  Google Scholar 

  2. Broglie MA, Soltermann A, Haile SR, Roosli C, Huber GF, Schmid S et al (2013) Quality of life of oropharyngeal cancer patients with respect to treatment strategy and p16-positivity. Laryngoscope 123(1):164–170

  3. Gillison ML (2006) Human papillomavirus and prognosis of oropharyngeal squamous cell carcinoma: implications for clinical research in head and neck cancers. J Clin Oncol 24(36):5623–5625

    Article  CAS  PubMed  Google Scholar 

  4. Mork J, Lie AK, Glattre E, Hallmans G, Jellum E, Koskela P et al (2001) Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344(15):1125–1131

    Article  CAS  PubMed  Google Scholar 

  5. Olthof NC, Straetmans JM, Snoeck R, Ramaekers FC, Kremer B, Speel EJ (2012) Next-generation treatment strategies for human papillomavirus-related head and neck squamous cell carcinoma: where do we go? Rev Med Virol 22(2):88–105

    Article  CAS  PubMed  Google Scholar 

  6. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H et al (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100(4):261–269

    Article  CAS  PubMed  Google Scholar 

  7. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF et al (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363(1):24–35

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Lindel K, Beer KT, Laissue J, Greiner RH, Aebersold DM (2001) Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. Cancer 92(4):805–813

    Article  CAS  PubMed  Google Scholar 

  9. Lindquist D, Romanitan M, Hammarstedt L, Nasman A, Dahlstrand H, Lindholm J et al (2007) Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7. Mol Oncol 1(3):350–355

    Article  PubMed  Google Scholar 

  10. Butz K, Geisen C, Ullmann A, Spitkovsky D, Hoppe-Seyler F (1996) Cellular responses of HPV-positive cancer cells to genotoxic anti-cancer agents: repression of E6/E7-oncogene expression and induction of apoptosis. Int J Cancer 68(4):506–513

    Article  CAS  PubMed  Google Scholar 

  11. Bristow RG, Benchimol S, Hill RP (1996) The p53 gene as a modifier of intrinsic radiosensitivity: implications for radiotherapy. Radiother Oncol 40(3):197–223

    Article  CAS  PubMed  Google Scholar 

  12. Haughey BH, Hinni ML, Salassa JR, Hayden RE, Grant DG, Rich JT et al (2011) Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: a United States multicenter study. Head Neck 33(12):1683–1694

    Article  PubMed  Google Scholar 

  13. Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R et al (2006) High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 24(36):5630–5636

    Article  CAS  PubMed  Google Scholar 

  14. Fischer CA, Zlobec I, Green E, Probst S, Storck C, Lugli A et al (2010) Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality? Int J Cancer 126(5):1256–1262

    CAS  PubMed  Google Scholar 

  15. Cohen MA, Weinstein GS, O’Malley BW Jr, Feldman M, Quon H (2011) Transoral robotic surgery and human papillomavirus status: oncologic results. Head Neck 33(4):573–580

    Article  PubMed  Google Scholar 

  16. Broglie MA, Tinguely M, Holzman D (2009) How to diagnose sinus fungus balls in the paranasal sinus? An analysis of an institution’s cases from January 1999 to December 2006. Rhinology 47(4):379–384

    CAS  PubMed  Google Scholar 

  17. Roosli C, Tschudi DC, Studer G, Braun J, Stoeckli SJ (2009) Outcome of patients after treatment for a squamous cell carcinoma of the oropharynx. Laryngoscope 119(3):534–540

    Article  PubMed  Google Scholar 

  18. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH et al (2004) Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350(19):1945–1952

    Article  CAS  PubMed  Google Scholar 

  19. Studer G, Huguenin PU, Davis JB, Kunz G, Lutolf UM, Glanzmann C (2006) IMRT using simultaneously integrated boost (SIB) in head and neck cancer patients. Radiat Oncol 1:7

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Studer G, Furrer K, Davis BJ, Stoeckli SS, Zwahlen RA, Luetolf UM et al (2006) Postoperative IMRT in head and neck cancer. Radiat Oncol 1:40

    Article  PubMed Central  PubMed  Google Scholar 

  21. Ragin CC, Taioli E (2007) Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer 121(8):1813–1820

    Article  CAS  PubMed  Google Scholar 

  22. Mehta V, Yu GP, Schantz SP (2010) Population-based analysis of oral and oropharyngeal carcinoma: changing trends of histopathologic differentiation, survival and patient demographics. Laryngoscope 120(11):2203–2212

    Article  PubMed  Google Scholar 

  23. Ernster JA, Sciotto CG, O’Brien MM, Finch JL, Robinson LJ, Willson T et al (2007) Rising incidence of oropharyngeal cancer and the role of oncogenic human papilloma virus. Laryngoscope 117(12):2115–2128

    Article  PubMed  Google Scholar 

  24. Smith EM, Wang D, Rubenstein LM, Morris WA, Turek LP, Haugen TH (2008) Association between p53 and human papillomavirus in head and neck cancer survival. Cancer Epidemiol Biomarkers Prev 17(2):421–427

    Article  CAS  PubMed  Google Scholar 

  25. Mellin H, Dahlgren L, Munck-Wikland E, Lindholm J, Rabbani H, Kalantari M et al (2002) Human papillomavirus type 16 is episomal and a high viral load may be correlated to better prognosis in tonsillar cancer. Int J Cancer 102(2):152–158

    Article  CAS  PubMed  Google Scholar 

  26. Hafkamp HC, Manni JJ, Haesevoets A, Voogd AC, Schepers M, Bot FJ et al (2008) Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas. Int J Cancer 122(12):2656–2664

    Article  CAS  PubMed  Google Scholar 

  27. Maxwell JH, Kumar B, Feng FY, Worden FP, Lee JS, Eisbruch A et al (2010) Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res 16(4):1226–1235

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Kumar B, Cordell KG, Lee JS, Worden FP, Prince ME, Tran HH et al (2008) EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 26(19):3128–3137

    Article  PubMed Central  PubMed  Google Scholar 

  29. Jakobsen J, Hansen O, Jorgensen KE, Bastholt L (1998) Lymph node metastases from laryngeal and pharyngeal carcinomas–calculation of burden of metastasis and its impact on prognosis. Acta Oncol 37(5):489–493

    Article  CAS  PubMed  Google Scholar 

  30. Straetmans JM, Olthof N, Mooren JJ, de Jong J, Speel EJ, Kremer B (2009) Human papillomavirus reduces the prognostic value of nodal involvement in tonsillar squamous cell carcinomas. Laryngoscope 119(10):1951–1957

    Article  PubMed  Google Scholar 

  31. Dahlstrom KR, Calzada G, Hanby JD, Garden AS, Glisson BS, Li G et al (2013) An evolution in demographics, treatment, and outcomes of oropharyngeal cancer at a major cancer center: a staging system in need of repair. Cancer 119(1):81–89

  32. Moore EJ, Olsen SM, Laborde RR, Garcia JJ, Walsh FJ, Price DL et al (2012) Long-term functional and oncologic results of transoral robotic surgery for oropharyngeal squamous cell carcinoma. Mayo Clin Proc 87(3):219–225

    Article  PubMed Central  PubMed  Google Scholar 

  33. Park YM, Kim WS, Byeon HK, Lee SY, Kim SH (2013) Oncological and functional outcomes of transoral robotic surgery for oropharyngeal cancer. Br J Oral Maxillofac Surg 51(5):408–412

  34. Al-Mamgani A, Van Rooij P, Tans L, Teguh DN, Levendag PC (2013) Toxicity and Outcome of Intensity-Modulated Radiotherapy versus 3-Dimensional Conformal Radiotherapy for Oropharyngeal Cancer: a Matched-Pair Analysis. Technol Cancer Res Treat 12(2):123–130

  35. Lok BH, Setton J, Caria N, Romanyshyn J, Wolden SL, Zelefsky MJ et al (2012) Intensity-modulated radiation therapy in oropharyngeal carcinoma: effect of tumor volume on clinical outcomes. Int J Radiat Oncol Biol Phys 82(5):1851–1857

    Article  PubMed  Google Scholar 

  36. Daly ME, Le QT, Maxim PG, Loo BW Jr, Kaplan MJ, Fischbein NJ et al (2010) Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: clinical outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 76(5):1339–1346

    Article  PubMed  Google Scholar 

  37. Hodge CW, Bentzen SM, Wong G, Palazzi-Churas KL, Wiederholt PA, Gondi V et al (2007) Are we influencing outcome in oropharynx cancer with intensity-modulated radiotherapy? An inter-era comparison. Int J Radiat Oncol Biol Phys 69(4):1032–1041

    Article  PubMed  Google Scholar 

  38. Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Brandsma J et al (2006) Molecular classification identifies a subset of human papillomavirus-associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 24(5):736–747

    Article  CAS  PubMed  Google Scholar 

  39. Smeets SJ, Hesselink AT, Speel EJ, Haesevoets A, Snijders PJ, Pawlita M et al (2007) A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer 121(11):2465–2472

    Article  CAS  PubMed  Google Scholar 

  40. Reimers N, Kasper HU, Weissenborn SJ, Stutzer H, Preuss SF, Hoffmann TK et al (2007) Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer 120(8):1731–1738

    Article  CAS  PubMed  Google Scholar 

  41. Hoffmann M, Tribius S, Quabius ES, Henry H, Pfannenschmidt S, Burkhardt C et al (2012) HPV DNA, E6*I-mRNA expression and p16INK4A immunohistochemistry in head and neck cancer—how valid is p16INK4A as surrogate marker? Cancer Lett 323(1):88–96

    Article  CAS  PubMed  Google Scholar 

  42. Rietbergen MM, Snijders PJ, Beekzada D, Braakhuis BJ, Brink A, Heideman DA et al (2014) Molecular characterization of p16-immunopositive but HPV DNA-negative oropharyngeal carcinomas. Int J Cancer 134(10):2366–2372

    Article  CAS  PubMed  Google Scholar 

  43. Ukpo OC, Flanagan JJ, Ma XJ, Luo Y, Thorstad WL, Lewis JS (2011) High-risk human papillomavirus E6/E7 mRNA detection by a novel in situ hybridization assay strongly correlates with p16 expression and patient outcomes in oropharyngeal squamous cell carcinoma. Am J Surg Pathol 35(9):1343–1350

    Article  PubMed  Google Scholar 

  44. Holzinger D, Flechtenmacher C, Henfling N, Kaden I, Grabe N, Lahrmann B et al (2013) Identification of oropharyngeal squamous cell carcinomas with active HPV16 involvement by immunohistochemical analysis of the retinoblastoma protein pathway. Int J Cancer 133(6):1389–1399

    Article  CAS  PubMed  Google Scholar 

  45. Lindel K, Rieken S, Daffinger S, Weber KJ, de Villiers EM, Debus J (2012) The transcriptional regulator gene E2 of the human papillomavirus (HPV) 16 influences the radiosensitivity of cervical keratinocytes. Radiat Oncol 7(1):187

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Pang E, Delic NC, Hong A, Zhang M, Rose BR, Lyons JG (2011) Radiosensitization of oropharyngeal squamous cell carcinoma cells by human papillomavirus 16 oncoprotein E6 *I. Int J Radiat Oncol Biol Phys 79(3):860–865

    Article  CAS  PubMed  Google Scholar 

  47. Mehra R, Ang KK, Burtness B (2012) Management of human papillomavirus-positive and human papillomavirus-negative head and neck cancer. Semin Radiat Oncol 22(3):194–197

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

There are no financial disclosures or conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martina A. Broglie.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Broglie, M.A., Soltermann, A., Haile, S.R. et al. Human papilloma virus and survival of oropharyngeal cancer patients treated with surgery and adjuvant radiotherapy. Eur Arch Otorhinolaryngol 272, 1755–1762 (2015). https://doi.org/10.1007/s00405-014-3099-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00405-014-3099-y

Keywords

Navigation