title: Poor prognosis in human papillomavirus-positive oropharyngeal squamous cell carcinomas that overexpress hypoxia inducible factor-1α.
abstract: Hypoxia induces stabilization of the transcription factor HIF-1alpha (HIF-1α), associated with (chemo-)radiotherapy resistance in oropharyngeal squamous cell carcinoma (SCC). We investigated the effect of HIF-1α expression on survival in relation to human papillomavirus (HPV) status in oropharyngeal SCC.
  
  
  
  We conducted an immunohistochemical analysis of HIF-1α protein expression and downstream targets carbonic anhydrase-IX (CA-IX) and glucose transporter-1 (GLUT-1) in 274 patients with oropharyngeal SCC. Overall survival (OS) was analyzed in total and stratified for HPV status and treatment.
  
  
  
  In HPV-positive tumors (n = 44), HIF-1α overexpression predicted worse OS (hazard ratio [HR] = 6.23; p = .012), whereas TNM classification or treatment modality did not. In HPV-negative tumors (n = 218), advanced T and N classification and HIF-1α overexpression all independently predicted worse OS. However, the effect of HIF-1α overexpression on OS was lower in HPV-negative (HR = 1.50; p = .024) than in HPV-positive tumors.
  
  
  
  HIF-1α overexpression is associated with worse OS and characterized a subgroup of patients with HPV-positive oropharyngeal SCC with poor prognosis. Possibly, patients with HIF-1α overexpressing HPV-positive tumors should not be eligible for treatment dose deescalation. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1338-1346, 2016.
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Justin Egidius
authors.identifier: 0000-0003-4288-0803
authors.initials: JE
authors.lastname: Swartz
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ajit Joe
authors.initials: AJ
authors.lastname: Pothen
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Pauline Maria Wilhelmina
authors.initials: PM
authors.lastname: van Kempen
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.|Brain Center Rudolph Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: Stegeman
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Fleurieke Karlijn
authors.initials: FK
authors.lastname: Formsma
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ellen Maria Van
authors.initials: EM
authors.lastname: Cann
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Stefan Martin
authors.initials: SM
authors.lastname: Willems
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.|Brain Center Rudolph Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Wilko
authors.initials: W
authors.lastname: Grolman
mesh_terms: D000046:Academic Medical Centers; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001707:Biopsy, Needle; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000821:virology*; D016208:Databases, Factual; D005260:Female; D006258:Head and Neck Neoplasms / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000821:virology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D009959:Oropharyngeal Neoplasms / Q000097:blood* / Q000401:mortality / Q000473:pathology / Q000821:virology*; D027383:Papillomaviridae / Q000302:isolation & purification*; D011379:Prognosis; D012189:Retrospective Studies; D000077195:Squamous Cell Carcinoma of Head and Neck; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: biomarkers; human papillomavirus; hypoxia; oropharyngeal carcinoma; tumor microenvironment