title: p16-positive lymph node metastases from cutaneous head and neck squamous cell carcinoma: No association with high-risk human papillomavirus or prognosis and implications for the workup of the unknown primary.
abstract: BACKGROUND
  The incidence of p16 overexpression and the role of human papillomavirus (HPV) in cutaneous head and neck squamous cell carcinoma (cHNSCC) are unclear.
  
  
  METHODS
  One hundred forty-three patients with cHNSCC lymph node metastases involving the parotid gland were evaluated for p16 expression by immunohistochemistry. The detection of 18 high-risk HPV subtypes was performed with HPV RNA in situ hybridization for a subset of 59 patients. The results were correlated with clinicopathological features and outcomes.
  
  
  RESULTS
  The median follow-up time was 5.3 years. No differences were observed in clinicopathological factors with respect to the p16 status. p16 was positive, weak, and negative in 45 (31%), 21 (15%), and 77 cases (54%), respectively. No high-risk HPV subtypes were identified, regardless of the p16 status. The p16 status was not prognostic for overall (hazard ratio, 1.08; 95% confidence interval [CI], 0.85-1.36; P = .528), cancer-specific (hazard ratio, 1.12; 95% CI, 0.77-1.64; P = .542), or progression-free survival (hazard ratio, 1.03; 95% CI, 0.83-1.29; P = .783). Distant metastasis-free survival, freedom from locoregional failure, and freedom from local failure were also not significantly associated with the p16 status.
  
  
  CONCLUSIONS
  p16 positivity is common but not prognostic in cHNSCC lymph node metastases. High-risk HPV subtypes are not associated with p16 positivity and do not appear to play a role in this disease. HPV testing, in addition to the p16 status in the unknown primary setting, may provide additional information for determining a putative primary site.
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Lachlan J
authors.initials: LJ
authors.lastname: McDowell
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Young
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Johnston
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Tze-Jian
authors.initials: TJ
authors.lastname: Tan
authors.affiliation: Division of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kleid
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Chen S
authors.initials: CS
authors.lastname: Liu
authors.affiliation: Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Mathias
authors.initials: M
authors.lastname: Bressel
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.|University of Melbourne, Parkville, Australia.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Estall
authors.affiliation: University of Melbourne, Parkville, Australia.|Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Danny
authors.initials: D
authors.lastname: Rischin
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.|University of Melbourne, Parkville, Australia.|Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Solomon
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.|University of Melbourne, Parkville, Australia.
authors.forename: June
authors.initials: J
authors.lastname: Corry
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000556:secondary / Q000821:virology*; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016208:Databases, Factual; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000401:mortality / Q000556:secondary / Q000821:virology*; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009382:Neoplasms, Unknown Primary / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D030361:Papillomavirus Infections / Q000473:pathology* / Q000821:virology; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012737:Sex Factors; D012878:Skin Neoplasms / Q000401:mortality / Q000556:secondary / Q000821:virology*; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D013997:Time Factors
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins
keywords: head and neck cancer; human p16 protein; papillomavirus infections; skin neoplasms; squamous cell neoplasms; unknown primary neoplasms