Cancer Causes & Control

, Volume 25, Issue 4, pp 461–471 | Cite as

Human papillomavirus (HPV) 16 and the prognosis of head and neck cancer in a geographical region with a low prevalence of HPV infection

  • Rossana Verónica Mendoza LópezEmail author
  • José Eduardo Levi
  • José Eluf-Neto
  • Rosalina Jorge Koifman
  • Sergio Koifman
  • Maria Paula Curado
  • Pedro Michaluart-Junior
  • David Livingstone Alves Figueiredo
  • Fabiano Pinto Saggioro
  • Marcos Brasilino de Carvalho
  • Luiz Paulo Kowalski
  • Márcio Abrahão
  • Francisco de Góis-Filho
  • Eloiza Helena Tajara
  • Tim Waterboer
  • Paolo Boffetta
  • Paul Brennan
  • Victor Wünsch-Filho
Original paper



The role of human papillomavirus (HPV) on head and neck squamous cell carcinoma (HNSCC) survival in regions with low HPV prevalence is not yet clear. We evaluated the HPV16 infection on survival of HNSCC Brazilian patient series.


This cohort comprised 1,093 HNSCC cases recruited from 1998 to 2008 in four Brazilian cities and followed up until June 2009. HPV16 antibodies were analyzed by multiplex Luminex assay. In a subset of 398 fresh frozen or paraffin blocks of HNSCC specimens, we analyzed for HPV16 DNA by L1 generic primer polymerase chain reaction. HNSCC survival according to HPV16 antibodies was evaluated through Kaplan–Meier method and Cox regression.


Prevalence of HPV16 E6 and E6/E7 antibodies was higher in oropharyngeal cancer than in other head and neck tumor sites. HPV16 DNA positive in tumor tissue was also higher in the oropharynx. Seropositivity for HPV16 E6 antibodies was correlated with improved HNSCC survival and oropharyngeal cancer. The presence of HPV16 E6/E7 antibodies was correlated with improved HNSCC survival and oropharyngeal cancer survival. The death risk of oropharyngeal squamous cell carcinoma patients HPV16 E6/E7 antibodies positive was 78 % lower than to those who test negative.


Oropharyngeal squamous cell carcinoma is less aggressive in the HPV16 E6/E7 positive serology patients. HPV16 E6/E7 antibody is a clinically sensible surrogate prognostic marker of oropharyngeal squamous cell carcinoma.


Human papillomavirus Serology Prognosis Head and neck cancer Prevalence 



This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) [10/50733-6; 09/52031-1 and 04/12054-9] and by the European Commission [IC18-CT97-0222].

Conflict of interest

None declared.


  1. 1.
    Argiris A, Karamouzis MV, Raben D, Ferris RL (2008) Head and neck cancer. Lancet 371:1695–1709PubMedCrossRefGoogle Scholar
  2. 2.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No 10 [Internet]. Lyon, France: International Agency for Research on Cancer; [cited 2012 Aug 30].
  3. 3.
    Carvalho AL, Ikeda MK, Magrin J, Kowalski LP (2004) Trends of oral and oropharyngeal cancer survival over five decades in 3267 patients treated in a single institution. Oral Oncol 40:71–76PubMedCrossRefGoogle Scholar
  4. 4.
    Szymanska K, Hung RJ, Wünsch Filho V, Eluf Neto J, Curado MP, Koifman S et al (2011) Alcohol and tobacco, and the risk of cancers of the upper aerodigestive tract in Latin America: a case–control study. Cancer Causes Control 22:1037–1046PubMedCrossRefGoogle Scholar
  5. 5.
    Human papillomaviruses (2007) Lyon, France: International Agency for Research on Cancer- IARC Monograph on the Evaluation of Carcinogenic Risks to HumansGoogle Scholar
  6. 6.
    Herrero R, Castellsagué X, Pawlita M, Lissowska J, Kee F, Balaram P et al (2003) Human papillomavirus and oral cancer: The International Agency for Research on Cancer Multicenter Study. J Natl Cancer Inst 95:1772–1783PubMedCrossRefGoogle Scholar
  7. 7.
    Smith EM, Ritchie JM, Pawlita M, Rubenstein LM, Haugen TH, Turek LP et al (2006) Human papillomavirus seropositivity and risks of head and neck cancer. Int J Cancer 120:825–832CrossRefGoogle Scholar
  8. 8.
    D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM et al (2007) Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356:1944–1956PubMedCrossRefGoogle Scholar
  9. 9.
    Näsman A, Attner P, Hammarstedt L, Du J, Eriksson M, Giraud G et al (2009) Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 125:362–366PubMedCrossRefGoogle Scholar
  10. 10.
    Ribeiro KB, Levi JE, Pawlita M, Koifman S, Matos E, Eluf-Neto J et al (2011) Low human papillomavirus prevalence in head and neck cancer: results from two large case–control studies in high-incidence regions. Int J Epidemiol 40:489–502PubMedCrossRefGoogle Scholar
  11. 11.
    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 100:261–269PubMedCrossRefGoogle Scholar
  12. 12.
    Smith EM, Rubenstein LM, Ritchie JM, Lee JH, Haugen TH, Hamsikova E et al (2008) Does treatment seropositivity to human papillomavirus have prognostic significance for head and neck cancers? Cancer Epidemiol Biomarkers Prev 17:2087–2096PubMedCrossRefGoogle Scholar
  13. 13.
    Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF et al (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24–35PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Liang C, Marsit CJ, McClean MD, Nelson HH, Christensen BC, Haddad RI et al (2012) Biomarkers of HPV in head and neck squamous cell carcinoma. Cancer Res 72:5004–5013PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    World Health Organization (1992) International statistical classification of diseases and related health problems. 10th rev. World Health Organization, Washington, DCGoogle Scholar
  16. 16.
    Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP et al (2007) Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst 99:777–789PubMedCrossRefGoogle Scholar
  17. 17.
    Sobin LH, Wittekind C (2002) TNM classification of malignant tumours. International Union Against Cancer, 6th edn. Wiley-Liss, New YorkGoogle Scholar
  18. 18.
    Kleter B, Van Doorn LJ, Schrauwen L, Molijn A, Sastrowijoto S, Ter Schegget J et al (1999) Development and clinical evaluation of a highly sensitive PCR-reverse hybridization line probe assay for detection and identification of anogenital human papillomavirus. J Clin Microbiol 37:2508–2517PubMedCentralPubMedGoogle Scholar
  19. 19.
    Coutlée F, Gravitt P, Kornegay J, Hankins C, Richardson H, Lapointe N et al (2002) Use of PGMY primers in L1 consensus PCR improves detection of human papillomavirus DNA in genital samples. J Clin Microbiol 40:902–907PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Bernard HU, Chan SY, Manos MM, Ong CK, Villa LL, Delius H et al (1994) Identification and assessment of known and novel human papillomaviruses by polymerase chain reaction amplification, restriction fragment length polymorphisms, nucleotide sequence, and phylogenetic algorithms. J Infec Dis 170:1077–1085CrossRefGoogle Scholar
  21. 21.
    Sehr P, Zumbach K, Pawlita M (2001) A generic capture ELISA for recombinant proteins fused to glutathione-S-transferase: validation for HPV serology. J Immunol Methods 253:153–162PubMedCrossRefGoogle Scholar
  22. 22.
    Waterboer T, Sehr P, Michael KM, Franceschi S, Nieland JD, Joos TO et al (2005) Multiplex human papillomavirus serology based on in situ-purified glutathione s-transferase fusion proteins. Clin Chem 51:1845–1853PubMedCrossRefGoogle Scholar
  23. 23.
    Clifford GM, Shin HR, Oh JK, Waterboer T, Ju YH, Vaccarella S et al (2007) Serologic response to oncogenic human papillomavirus types in male and female university students in Busan, South Korea. Cancer Epidemiol Biomarkers Prev 16:1874–1879PubMedCrossRefGoogle Scholar
  24. 24.
    Kreimer AR, Clifford GM, Boyle P, Franceschi S (2005) Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 14:467–475PubMedCrossRefGoogle Scholar
  25. 25.
    Dayyani F, Etzel CJ, Liu M, Ho CH, Lippman SM, Tsao AS (2010) Meta-analysis of the impact of human papillomavirus (HPV) on risk and overall survival in head and neck squamous cell carcinomas (HNSCC). Head Neck Oncol 2:15. doi: 10.1186/1758-3284-2-15 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Smith EM, Pawlita M, Rubenstein LM, Haugen TH, Hamsikova E, Turek LP (2010) Risk factors and survival by HPV-16 E6 and E7 antibody status in human papillomavirus positive head and neck cancer. Int J Cancer 127:111–117PubMedCrossRefGoogle Scholar
  27. 27.
    Rotnáglová E, Tachezy R, Saláková M, Procházka B, Košl’abová E, Veselá E et al (2011) HPV involvement in tonsillar cancer: prognostic significance and clinically relevant markers. Int J Cancer 129:101–110PubMedCrossRefGoogle Scholar
  28. 28.
    Rubenstein LM, Smith EM, Pawlita M, Haugen TH, Hamsikova E, Turek LP (2011) Human papilomavírus serologic follow-up response and relationship to survival in head and neck cancer: a case-comparison study. Infec Agent Cancer 6:9. doi: 10.1186/1750-9378-6-9 CrossRefGoogle Scholar
  29. 29.
    Smith EM, Rubenstein LM, Haugen TH, Pawlita M, Turek LP (2012) Complex etiology underlies risk and survival in head and neck cancer human papillomavirus, tobacco, and alcohol: a case for multifactor disease. J Oncol. doi: 10.1155./2012/571862 PubMedCentralPubMedGoogle Scholar
  30. 30.
    Méndez E (2012) Biomarkers of HPV infection in oropharyngeal carcinomas: can we find simplicity in the puzzle of complexity? Cancer Res 72:4896–4898PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Rossana Verónica Mendoza López
    • 1
    • 2
    Email author
  • José Eduardo Levi
    • 3
  • José Eluf-Neto
    • 4
  • Rosalina Jorge Koifman
    • 5
  • Sergio Koifman
    • 5
  • Maria Paula Curado
    • 6
    • 7
  • Pedro Michaluart-Junior
    • 8
  • David Livingstone Alves Figueiredo
    • 9
  • Fabiano Pinto Saggioro
    • 9
  • Marcos Brasilino de Carvalho
    • 10
  • Luiz Paulo Kowalski
    • 11
  • Márcio Abrahão
    • 12
  • Francisco de Góis-Filho
    • 13
  • Eloiza Helena Tajara
    • 14
  • Tim Waterboer
    • 15
  • Paolo Boffetta
    • 7
    • 16
  • Paul Brennan
    • 17
  • Victor Wünsch-Filho
    • 1
  1. 1.Faculdade de Saúde PúblicaUniversidade de São PauloSão PauloBrazil
  2. 2.Instituto de Ensino e PesquisaHospital de Câncer de BarretosBarretosBrazil
  3. 3.Instituto de Medicina TropicalUniversidade de São PauloSão PauloBrazil
  4. 4.Faculdade de MedicinaUniversidade de São PauloSão PauloBrazil
  5. 5.Escola Nacional de Saúde PúblicaFundação Oswaldo CruzRio de JaneiroBrazil
  6. 6.Hospital Araujo JorgeGoiâniaBrazil
  7. 7.International Prevention Research InstituteLyonFrance
  8. 8.Hospital das Clínicas, Faculdade de MedicinaUniversidade de São PauloSão PauloBrazil
  9. 9.Hospital das Clínicas, Faculdade de Medicina de Ribeirão PretoUniversidade de São PauloRibeirão PretoBrazil
  10. 10.Hospital HeliópolisSão PauloBrazil
  11. 11.Hospital do Câncer A.C. CamargoSão PauloBrazil
  12. 12.Hospital São PauloUniversidade Federal de São PauloSão PauloBrazil
  13. 13.Instituto do Câncer Arnaldo Viera de CarvalhoSão PauloBrazil
  14. 14.Faculdade de Medicina de São José do Rio PretoSão PauloBrazil
  15. 15.German Cancer Research Center (DKFZ)HeidelbergGermany
  16. 16.The Tisch Cancer InstituteMount Sinai School of MedicineNew YorkUSA
  17. 17.International Agency for Research on CancerLyonFrance

Personalised recommendations