Association between human papilloma virus/Epstein-Barr virus coinfection and oral carcinogenesis

J Oral Pathol Med. 2015 Jan;44(1):28-36. doi: 10.1111/jop.12221. Epub 2014 Jul 18.


Background: The recent epidemic of head and neck squamous cell carcinomas associated with human papilloma virus (HPV) has not addressed its association with lymphoid tissue in the oropharynx or the potential role of Epstein-Barr virus (EBV)/HPV coinfection.

Methods: The prevalence of HPV and EBV infection/coinfection and CD21 mRNA expression were determined in normal and cancerous tissues from the oropharynx using in situ hybridization (ISH), p16, and quantitative reverse transcriptase PCR (qRT-PCR). The effects of coinfection on tumorigenicity were evaluated using proliferation and invasion assays.

Results: Normal oropharynx, tonsil, non-cancer base of tongue (BOT), and BOT from sleep apnea patients demonstrated EBV positivity ranging from 7% to 36% depending on the site and methods of detection used (qRT-PCR or ISH). Among non-malignant BOT samples, HPV positivity was noted only in 20%. The percent of tonsil and BOT cancers positive for HPV (up to 63% and 80%, respectively) or coinfected with HPV/EBV (up to 25% and 70%, respectively) were both significantly associated with cancer status. Notably, HPV/EBV coinfection was observed only in malignant tissue originating in lymphoid-rich oropharynx sites (tonsil, BOT). CD21 mRNA (the major EBV attachment receptor) was detected in tonsil and BOT epithelium, but not in soft-palate epithelium. Coinfected cell lines showed a significant increase in invasiveness (P < 0.01).

Conclusions: There is a high prevalence of HPV/EBV infection and coinfection in BOT and tonsil cancers, possibly reflecting their origins in lymphoid-rich tissue. In vitro, cells modeling coinfection have an increased invasive potential.

Keywords: Epstein-Barr virus; coinfection; human papilloma virus; oral carcinogenesis; squamous cell carcinoma; tumorigenesis.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alphapapillomavirus / physiology*
  • Carcinogenesis*
  • Carcinoma, Squamous Cell / virology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / pathology
  • Coinfection / virology*
  • Cyclin-Dependent Kinase Inhibitor p16 / analysis
  • Epstein-Barr Virus Infections / virology*
  • Herpesvirus 4, Human / immunology
  • Humans
  • Neoplasm Invasiveness
  • Oropharyngeal Neoplasms / virology*
  • Oropharynx / virology
  • Palatal Neoplasms / virology
  • Palate, Soft / virology
  • Palatine Tonsil / virology
  • Papillomavirus Infections / virology*
  • Receptors, Complement 3d / analysis
  • Sleep Apnea Syndromes / virology
  • Tongue / virology
  • Tongue Neoplasms / virology
  • Tonsillar Neoplasms / virology


  • Cyclin-Dependent Kinase Inhibitor p16
  • Receptors, Complement 3d