Combined P16 and human papillomavirus testing predicts head and neck cancer survival.
While its prognostic significance remains unclear, p16(INK4a) protein expression is increasingly being used as a surrogate marker for oncogenic human papillomavirus (HPV) infection in head and neck squamous cell carcinomas (HNSCC). To evaluate the prognostic utility of p16 expression in HNSCC, we prospectively collected 163 primary tumor specimens from histologically confirmed HNSCC patients who were followed for up to 9.4 years. Formalin fixed tumor specimens were tested for p16 protein expression by immunohistochemistry (IHC). HPV type-16 DNA and RNA was detected by MY09/11-PCR and E6/E7 RT-PCR on matched frozen tissue, respectively. P16 protein expression was detected more often in oropharyngeal tumors (53%) as compared with laryngeal (24%), hypopharyngeal (8%) or oral cavity tumors (4%; p<0.0001). With respect to prognosis, p16-positive oropharyngeal tumors exhibited significantly better overall survival than p16-negative tumors (log-rank test p=0.04), whereas no survival benefit was observed for nonoropharyngeal tumors. However, when both p16 and HPV DNA test results were considered, concordantly positive nonoropharyngeal tumors had significantly better disease-specific survival than concordantly negative nonoropharyngeal tumors after controlling for sex, nodal stage, tumor size, tumor subsite, primary tumor site number, smoking and drinking [adjusted hazard ratio (HR)=0.04, 0.01-0.54]. Compared with concordantly negative nonoropharyngeal HNSCC, p16(+)/HPV16(-) nonoropharyngeal HNSCC (n=13, 7%) demonstrated no significant improvement in disease-specific survival when HPV16 was detected by RNA (adjusted HR=0.83, 0.22-3.17). Our findings show that p16 IHC alone has potential as a prognostic test for oropharyngeal cancer survival, but combined p16/HPV testing is necessary to identify HPV-associated nonoropharyngeal HNSCC with better prognosis.
Departments of Epidemiology and Population Health, Albert Einstein College of Medicine and Montefiore Medical Center, NY.
Christian R
CR
Salazar
Nicole
N
Anayannis
Richard V
RV
Smith
Yanhua
Y
Wang
Missak
M
Haigentz
Madhur
M
Garg
Bradley A
BA
Schiff
Nicole
N
Kawachi
Jordan
J
Elman
Thomas J
TJ
Belbin
Michael B
MB
Prystowsky
Robert D
RD
Burk
Nicolas F
NF
Schlecht
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000401:mortality* / Q000821:virology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000401:mortality* / Q000821:virology; D061809:Human Papillomavirus DNA Tests; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000401:mortality* / Q000821:virology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D055815:Young Adult
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral
CDKN2A; P16; head and neck neoplasms; human papillomavirus; squamous cell carcinoma; survival