Defining molecular phenotypes of human papillomavirus-associated oropharyngeal squamous cell carcinoma: validation of three-class hypothesis

Otolaryngol Head Neck Surg. 2009 Sep;141(3):382-9. doi: 10.1016/j.otohns.2009.04.014.


Objective: The purpose of this study was to determine if oropharyngeal squamous cell carcinoma (OSCC) classified into three groups based on human papillomavirus (HPV) 16 DNA presence and p16 expression display different protein expression patterns.

Study design: Cross-sectional study.

Setting: A laboratory-based study of patients with OSCC treated at a tertiary care academic medical center.

Subjects and methods: Paraffin-embedded OSCC specimens from 77 patients classified into the three-class model (HPV negative, HPV inactive [HPV16+/p16-], and HPV active [HPV16+/p16+]) were queried for the expression of 14 tumor progression proteins using AQUA (HistoRx, New Haven CT). Protein expression between groups was assessed by analysis of variance. Global expression patterns were determined by unsupervised hierarchical clustering.

Results: There were significant differences in expression of beta-catenin (P = 0.009), epidermal growth factor receptor (P = 0.009), and vascular endothelial growth factor (P = 0.028) between groups. HPV-active tumors had overexpression of beta-catenin. Hierarchical clustering showed HPV-negative and HPV-inactive tumors displayed association patterns distinct from HPV-active tumors.

Conclusions: Tumors classified by HPV DNA presence and p16 expression have different molecular phenotypes. This is the first demonstration of overexpression of beta-catenin (also found in HPV-caused cervical cancer) in HPV-active OSCC. HPV-active OSCC may share a similar ontogeny to HPV-caused cervical cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / analysis
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology*
  • DNA Probes, HPV
  • DNA, Viral / genetics*
  • Female
  • Human papillomavirus 16 / genetics*
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Oropharyngeal Neoplasms / metabolism
  • Oropharyngeal Neoplasms / pathology
  • Oropharyngeal Neoplasms / virology*
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / virology*
  • Phenotype
  • Prognosis
  • Reproducibility of Results
  • Retrospective Studies


  • Biomarkers, Tumor
  • DNA Probes, HPV
  • DNA, Viral