Prognostic significance of p16 and its relationship with human papillomavirus in pharyngeal squamous cell carcinomas

JAMA Otolaryngol Head Neck Surg. 2014 Jul;140(7):647-53. doi: 10.1001/jamaoto.2014.821.


Importance: The prognostic significance of p16 in squamous cell carcinoma (SCC) of the hypopharynx (HP) and nasopharynx (NP) and relationship between human papillomavirus (HPV) and p16 is unclear.

Objectives: To evaluate the prognostic significance of p16 in pharyngeal subsites (oropharynx [OP], HP, and NP) and assess the relationship between HPV and p16 in the HP and NP.

Design, setting, and participants: Retrospective medical record review of 172 patients with SCC of the pharynx treated with definitive radiation therapy from 2002 to 2013 at a university tertiary referral center, with tissue available for immunohistochemical analysis. The median follow-up was 30.1 months.

Interventions: A total of 118 patients were treated with chemoradiation, and 54 patients were treated with radiation alone. Immunohistochemical analysis for p16 was performed for all tumors. Hypopharynx and NP tumors were tested for HPV using in situ hybridization, and NP tumors were tested for Epstein-Barr virus.

Main outcomes and measures: Overall survival, locoregional control, and disease-free survival were analyzed according to p16, HPV, and Epstein-Barr virus status.

Results: Thirty-two patients had HP SCC, 127 had OP SCC, and 13 had NP SCC. p16 Was positive in the HP (34%), OP (66%), and NP (46%). Prevalence of HPV was 14% in the HP and 50% in the NP. As a test for HPV, p16 had a positive predictive value of 38% (HP) and 67% (NP) and a negative predictive value of 100% in HP and NP tumors. p16 Status was a significant predictor of all clinical outcomes for patients with OP SCC (P<.001), but not for patients with HP or NP SCC. Patients with Epstein-Barr virus- or HPV-associated NP SCC had improved clinical outcomes.

Conclusions and relevance: p16 Was not associated with improved outcomes in patients with HP or NP SCC. The positive predictive value of p16 as a test for HPV is too low for p16 testing alone in the HP and NP. However, p16 negativity is sufficient to rule out HPV. As a research approach, we recommend p16 immunohistochemistry as a screening test for HPV in NP SCC and HP SCC followed by confirmatory HPV in situ hybridization when p16 positive.

MeSH terms

  • Biomarkers / analysis
  • Carcinoma, Squamous Cell / mortality*
  • Carcinoma, Squamous Cell / therapy
  • Disease-Free Survival
  • Female
  • Genes, p16 / physiology*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Male
  • Middle Aged
  • Nasopharynx / chemistry
  • Oropharynx / chemistry
  • Parainfluenza Virus 1, Human / isolation & purification
  • Pharyngeal Neoplasms / mortality*
  • Pharyngeal Neoplasms / therapy
  • Pharynx / chemistry*
  • Prognosis
  • Radiotherapy Planning, Computer-Assisted
  • Regression Analysis


  • Biomarkers