Skip to main content

Advertisement

SpringerLink
Log in

Evidence That Alpha-9 Human Papillomavirus Infections are a Major Etiologic Factor for Oropharyngeal Carcinoma in Black South Africans

  • Original Paper
  • Published:
Head and Neck Pathology Aims and scope Submit manuscript

Abstract

Human papillomavirus (HPV) infection, most commonly genotype 16 of the alpha-9 family, is implicated in the etiology of a subset of oropharyngeal squamous cell carcinomas (OPSC) worldwide. Data are scarce regarding OPSC in South Africans, and three prior studies suggest no significant etiologic role for HPV. We aimed to investigate for evidence of HPV etiology in OPSCs from black South Africans by polymerase chain reaction (PCR) methodologies with determination of HPV subtype by sequencing, in situ hybridization (ISH), and p16INK4a immunohistochemistry (IHC), as a surrogate marker for an HPV-driven tumor. It was hypothesized that HPV-driven tumors would be positive by PCR plus IHC and/or ISH whereas OPSCs with HPV background infections (HPV-passenger) would be positive by PCR alone. Formalin-fixed, paraffin-embedded tissues from 51 OPSCs collected between 2005 and 2010 from 41 patients were analyzed for HPV by GP5+6+ PCR (targeting the HPV L1 region), pU-1M/pU-2R PCR (targeting the HPV E6/E7 region) and HPV-31 specific PCR (targeting the E5 region), chromogenic ISH, and p16INK4a IHC. All cases positive by PCR were subject to sequencing to determine HPV genotype. The patient mean age was 58.0 years and 88 % were male. Of the 51 evaluable tumors, 48 (94.1 %) were positive for HPV DNA by PCR: 25 (49.1 %) met criteria for an HPV-driven tumor, 23 (45.1 %) for HPV-passenger, and 3 (5.9 %) were HPV-unrelated. Sequencing of the PCR-positive cases revealed the following genotypes: combined HPV-16 and 31 (41.7 %), HPV-31 (25.0 %), HPV-16 (22.9 %), combined HPV-16 and 18 (6.3 %), and a single case each of HPV 18 and HPV 33. Studies via ISH were negative in all cases. In accordance with worldwide trends but contrary to prior South African data, HPV likely plays an etiologic role in a significant subset (at least 49.1 %) of OPSC in black South Africans. We found that the alpha-9 HPV family, particularly HPV-16 and 31 either in combination or separately, to predominate in our sample tumors. The use of multiple PCR primers increased sensitivity of viral detection, and a HPV-31 specific primer confirmed the presence of this genotype in many samples. Further studies including HPV E6/E7 mRNA assays are needed to better elucidate the pathogenic role of HPV in black South African OPSCs.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.

    Article  PubMed  CAS  Google Scholar 

  2. Slootweg PJ, Eveson JW. Tumours of the oral cavity and oropharynx. In: Barnes L, Eveson JW, Reichart P, editors. Pathology and genetics of head and neck tumours. Lyon: IARC Press; 2005. p. 165–210.

    Google Scholar 

  3. Braakhuis BJM, Leemans CR, Brakenhoff RH. A genetic progression model of oral cancer: current evidence and clinical implications. J Oral Pathol Med. 2004;33:317–22.

    Article  PubMed  CAS  Google Scholar 

  4. Leemans CR, Braakhuis BJM, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011;11:9–22.

    Article  PubMed  CAS  Google Scholar 

  5. Lewis JS, Thorstad WL, Chernock RD, et al. p16 positive oropharyngeal squamous cell carcinoma: an entity with a favorable prognosis regardless of tumor HPV status. Am J Surg Path. 2010;34(8):1088–96.

    Article  PubMed  Google Scholar 

  6. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261–9.

    Article  PubMed  CAS  Google Scholar 

  7. Ragin CC, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer. 2007;121(8):1813–20.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  9. Kumar B, Cordell KG, Lee JS, et al. 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. 2008;26(19):3128–37.

    Article  PubMed  Google Scholar 

  10. Braakhuis BJ, Snijders PJ, Keune WJ, et al. Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst. 2004;96(13):998–1006.

    Article  PubMed  CAS  Google Scholar 

  11. Chen SF, Yu FS, Chang YC, et al. Role of human papillomavirus infection in carcinogenesis of oral squamous cell carcinoma with evidences of prognostic association. J Oral Pathol Med. 2012;41(1):9–15.

    Article  PubMed  Google Scholar 

  12. Maxwell JH, Kumar B, Feng FY, et al. Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res. 2010;16(4):1226–35.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Smith EM, Rubenstein LM, Haugen TH, et al. Tobacco and alcohol use increases the risk of both HPV-associated and HPV-independent head and neck cancers. Cancer Causes Control. 2010;21(9):1369–78.

    Article  PubMed  Google Scholar 

  15. Chernock RD, El-Mofty SK, Thorstad WL, et al. HPV-related nonkeratinizing squamous cell carcinoma of the oropharynx: utility of microscopic features in predicting patient outcomes. Head Neck Pathol. 2009;3:186–94.

    Article  PubMed  Google Scholar 

  16. 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;101:339–45.

    Article  PubMed  Google Scholar 

  17. Van Rensburg EJ, van Heerden WF, Venter EH, et al. Detection of human papillomavirus DNA with in situ hybridisation in oral squamous carcinoma in a rural black population. S Afr Med J. 1995;85(9):894–6.

    PubMed  Google Scholar 

  18. Van Rensburg EJ, Engelbrecht S, Van Heerden WF, et al. Human papillomavirus DNA in oral squamous cell carcinomas from an African population sample. Anticancer Res. 1996;16(2):969–73.

    PubMed  Google Scholar 

  19. Boy S, Van Rensburg EJ, Engelbrecht S, et al. HPV detection in primary intra-oral squamous cell carcinomas–commensal, aetiological agent or contamination? J Oral Pathol Med. 2006;35(2):86–90.

    Article  PubMed  CAS  Google Scholar 

  20. Postma TC, Van Heerden WF. Is the human papillomavirus a mutual aetiological agent in oral and cervical squamous cell carcinoma? Anticancer Res. 2003;23(4):3509–12.

    PubMed  CAS  Google Scholar 

  21. Tran N, Rose BR, O’Brien CJ. Role of human papillomavirus in the etiology of head and neck cancer. Head Neck. 2007;29(1):64–70.

    Article  PubMed  Google Scholar 

  22. Syrjänen S. Human papillomavirus (HPV) in head and neck cancer. J Clin Virol. 2005;32(Suppl 1):S59–66.

    Article  PubMed  Google Scholar 

  23. Fischer CA, Kampmann M, Zlobec I, et al. p16 expression in oropharyngeal cancer: its impact on staging and prognosis compared with the conventional clinical staging parameters. Ann Oncol. 2010;10:1961–6.

    Article  Google Scholar 

  24. Termine N, Panzarella V, Falaschini S, et al. HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988–2007). Ann Oncol. 2008;19(10):1681–90.

    Article  PubMed  CAS  Google Scholar 

  25. Hobbs CG, Sterne JA, Bailey M, et al. Human papillomavirus and head and neck cancer: a systematic review and meta-analysis. Clin Otolaryngol. 2006;31(4):259–66.

    Article  PubMed  CAS  Google Scholar 

  26. Kreimer AR, Clifford GM, Boyle P, et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14(5):467–75.

    Article  PubMed  CAS  Google Scholar 

  27. Chernock RD, Zhang Q, El-Mofty SK, et al. Human papillomavirus-related squamous cell carcinoma of the oropharynx: a comparative study in whites and African Americans. Arch Otolaryngol Head Neck Surg. 2011;137(2):163–9.

    Article  PubMed  Google Scholar 

  28. Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer. 2007;110(7):1429–35.

    Article  PubMed  Google Scholar 

  29. Syrjänen S. HPV infections and tonsillar carcinoma. J Clin Path. 2004;57:449–55.

    Article  PubMed  Google Scholar 

  30. Evans MF, Adamson CS, Schned LM, et al. HPV is detectable in virtually all abnormal cervical cytology samples after reinvestigation of HPV negatives with multiple alternative PCR tests. Diagn Mol Pathol. 2010;19(3):144–50.

    Article  PubMed  CAS  Google Scholar 

  31. Chan PK, Cheung TH, Tam AO, et al. Biases in human papillomavirus genotype prevalence assessment associated with commonly used consensus primers. Int J Cancer. 2006;118(1):243–5.

    Article  PubMed  CAS  Google Scholar 

  32. Chan PK, Picconi MA, Cheung TH, et al. Laboratory and clinical aspects of human papillomavirus testing. Crit Rev Clin Lab Sci. 2012;49(4):117–36.

    Article  PubMed  CAS  Google Scholar 

  33. Karlsen F, Kalantari M, Jenkins A, et al. Use of multiple PCR primer sets for optimal detection of human papillomavirus. J Clin Microbiol. 1996;34(9):2095–100.

    PubMed  CAS  Google Scholar 

  34. Klussmann JP, Gültekin E, Weissenborn SJ, et al. Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. Am J Pathol. 2003;162(3):747–53.

    Article  PubMed  CAS  Google Scholar 

  35. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709–20.

    Article  PubMed  CAS  Google Scholar 

  36. Braakhuis BJM, Brakenhoff RH, Meijer CJ, et al. Human papillomavirus in head and neck cancer: the need for a standardized assay to assess the full clinical importance. Eur J Cancer. 2009;45:2935–9.

    Article  PubMed  Google Scholar 

  37. Smeets SJ, Hesselink AT, Speel EJ, et al. A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer. 2007;121(11):2465–72.

    Article  PubMed  CAS  Google Scholar 

  38. Singhi AD, Westra WH. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer. 2010;116(9):2166–73.

    Google Scholar 

  39. Romagosa C, Simonetti S, López-Vicente L, et al. p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011;30(18):2087–97.

    Article  PubMed  CAS  Google Scholar 

  40. Evans MF, Matthews A, Kandil D, et al. Discrimination of ‘driver’ and ‘passenger’ HPV in tonsillar carcinomas by the polymerase chain reaction, chromogenic in situ hybridization, and p16INK4a immunohistochemistry. Head Neck Pathol. 2011;5(4):344–8.

    Article  PubMed  Google Scholar 

  41. Matsukura T, Sugase M. Pitfalls in the epidemiologic classification of human papillomavirus types associated with cervical cancer using polymerase chain reaction: driver and passenger. Int J Gynecol Cancer. 2008;18:1042–50.

    Article  PubMed  CAS  Google Scholar 

  42. de Roda Husman AM, Snijders PJ, Stel HV, et al. Processing of long-stored archival cervical smears for human papillomavirus detection by the polymerase chain reaction. Br J Cancer. 1995;72:412–7.

    Article  PubMed  Google Scholar 

  43. Fujinaga Y, Shimada M, Okazawa K, et al. Simultaneous detection and typing of genital human papillomavirus DNA using the polymerase chain reaction. J Gen Virol. 1991;72(Pt 5):1039–44.

    Article  PubMed  CAS  Google Scholar 

  44. Evans MF, Adamson CS, Simmons-Arnold L, et al. Touchdown General Primer (GP5+/GP6+) PCR and optimized sample DNA concentration support the sensitive detection of human papillomavirus. BMC Clin Pathol. 2005;5:10.

    Article  PubMed  Google Scholar 

  45. Evans MF, Mount SL, Beatty BG, et al. Biotinyl-tyramide-based in situ hybridization signal patterns distinguish human papillomavirus type and grade of cervical intraepithelial neoplasia. Mod Pathol. 2002;15:1339–47.

    Article  PubMed  Google Scholar 

  46. Evans MF, Aliesky HA, Cooper K. Optimization of biotinyl tyramide- based in situ hybridization for sensitive background-free applications on formalin-fixed, paraffin-embedded tissue specimens. BMC Clin Pathol. 2003;3(1):2.

    Article  PubMed  Google Scholar 

  47. Cooper K, Herrington CS, Stickland JE, et al. Episomal and integrated human papillomavirus in cervical neoplasia shown by non-isotopic in situ hybridisation. J Clin Pathol. 1991;44:990–6.

    Article  PubMed  CAS  Google Scholar 

  48. St Guily JL, Jacquard AC, Prétet 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  PubMed  Google Scholar 

  49. WHO/ICO Information Centre on HPV and cervical cancer. Human Papillomavirus and Related Cancers: South Africa. Summary Report Update. September 15, 2010. Available from: http://apps.who.int/hpvcentre/statistics/dynamic/ico/country_pdf/ZAF.pdf?CFID=6593267&CFTOKEN=21680899. Accessed 3/1/2012.

  50. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–9.

    Article  PubMed  CAS  Google Scholar 

  51. Chen Z, Schiffman M, Herrero R, et al. Evolution and taxonomic classification of human papillomavirus 16 (HPV16)-related variant genomes: HPV31, HPV33, HPV35, HPV52, HPV58, and HPV67. PLoS ONE. 2011;6(5):e20183.

    Article  PubMed  CAS  Google Scholar 

  52. Bernard HU, Burk RD, Chen Z, et al. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology. 2010;401(1):70–9.

    Article  PubMed  CAS  Google Scholar 

  53. CANSA—Cancer Association of South Africa. Available from: http://www.cansa.org.za/cause_data/images/1056/NCRTables_2001.pdf. Accessed 6/20/2011.

  54. Altini M, Kola AH. Age-specific and age-standardised incidence rates for intraoral squamous cell carcinoma in blacks on the Witwatersrand, South Africa. Community Dent Oral Epidemiol. 1985;13:334–9.

    Article  PubMed  CAS  Google Scholar 

  55. Walbeek C. Recent trends in smoking prevalence in South Africa: some evidence from AMPS data. Available from: http://archive.idrc.ca/ritc//sarelease3.pdf. Accessed 6/18/2011.

  56. Zhao N, Ang M-K, Yin X-Y, et al. Different cellular p16INK4a localisation may signal different survival outcomes in head and neck cancer. Br J Cancer. 2012;107:482–90.

    Article  PubMed  CAS  Google Scholar 

  57. Schache AG, Liloglou T, Risk JM, et al. Validation of a novel diagnostic standard in HPV-positive oropharyngeal squamous cell carcinoma. Br J Cancer. 2013;108:1332–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Vermont Cancer Center DNA Analysis Core Facility

Author information

Authors and Affiliations

  1. Fletcher Allen Health Care, Burlington, VT, USA

    Cherie Paquette & Kumarasen Cooper

  2. University of Vermont College of Medicine, Burlington, VT, USA

    Cherie Paquette, Mark F. Evans, Vanitha Rajendran, Christine S-C. Adamson & Kumarasen Cooper

  3. University of the Witwatersrand, Johannesburg, South Africa

    Shabnum S. Meer

Authors
  1. Cherie Paquette
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark F. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shabnum S. Meer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vanitha Rajendran
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christine S-C. Adamson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kumarasen Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cherie Paquette.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paquette, C., Evans, M.F., Meer, S.S. et al. Evidence That Alpha-9 Human Papillomavirus Infections are a Major Etiologic Factor for Oropharyngeal Carcinoma in Black South Africans. Head and Neck Pathol 7, 361–372 (2013). https://doi.org/10.1007/s12105-013-0453-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12105-013-0453-0

Keywords

Search

Navigation