title: Prognostic significance of p16 and its relationship with human papillomavirus in pharyngeal squamous cell carcinomas.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville.
authors.forename: David D
authors.initials: DD
authors.lastname: Wilson
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville.
authors.forename: Edwin F
authors.initials: EF
authors.lastname: Crandley
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville.
authors.forename: Austin
authors.initials: A
authors.lastname: Sim
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stelow
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville.
authors.forename: Neil
authors.initials: N
authors.lastname: Majithia
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Virginia, Charlottesville.
authors.forename: David C
authors.initials: DC
authors.lastname: Shonka
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Virginia, Charlottesville.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Jameson
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Virginia, Charlottesville.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Levine
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Read
mesh_terms: D015415:Biomarkers / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000401:mortality* / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D019942:Genes, p16 / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009305:Nasopharynx / Q000737:chemistry; D009960:Oropharynx / Q000737:chemistry; D010222:Parainfluenza Virus 1, Human / Q000302:isolation & purification; D010610:Pharyngeal Neoplasms / Q000401:mortality* / Q000628:therapy; D010614:Pharynx / Q000737:chemistry*; D011379:Prognosis; D011880:Radiotherapy Planning, Computer-Assisted; D012044:Regression Analysis
chemical_list: D015415:Biomarkers