title: Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.
abstract: BACKGROUND
  High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC.
  
  
  METHODS
  Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5-9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPV-positive tumors was determined by proportional hazards regression analysis.
  
  
  RESULTS
  HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%-30%). High-risk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2- 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1-12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPV-positive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05-0.61) and smokers (OR = 0.16; 95% CI = 0.02-1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1-167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01-0. 36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07-0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4- 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4-4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8-2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20-0.88).
  
  
  CONCLUSIONS
  These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.
authors.affiliation: Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Gillison
authors.forename: W M
authors.initials: WM
authors.lastname: Koch
authors.forename: R B
authors.initials: RB
authors.lastname: Capone
authors.forename: M
authors.initials: M
authors.lastname: Spafford
authors.forename: W H
authors.initials: WH
authors.lastname: Westra
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.forename: M L
authors.initials: ML
authors.lastname: Zahurak
authors.forename: R W
authors.initials: RW
authors.lastname: Daniel
authors.forename: M
authors.initials: M
authors.lastname: Viglione
authors.forename: D E
authors.initials: DE
authors.lastname: Symer
authors.forename: K V
authors.initials: KV
authors.lastname: Shah
authors.forename: D
authors.initials: D
authors.lastname: Sidransky
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015139:Blotting, Southern; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000401:mortality / Q000821:virology*; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000209:etiology / Q000401:mortality / Q000821:virology*; D006801:Humans; D017403:In Situ Hybridization; D020014:K562 Cells; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009856:Oncogene Proteins, Viral / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000150:complications*; D016016:Proportional Hazards Models; D012097:Repressor Proteins; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000150:complications*
chemical_list: D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins