Abstract
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.
Highlights
Human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCC) represent a distinct set of tumors that exhibit better prognosis than their HPV-negative counterparts[1,2]
When we compared p16 with HPV16 positivity, there was moderate agreement across all HNSCC
Concordance was substantially higher in the oropharynx between p16 and HPV16 DNA, as well as between p16 and HPV16 RNA
Summary
Human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCC) represent a distinct set of tumors that exhibit better prognosis than their HPV-negative counterparts[1,2]. While the majority of HPV-positive head and neck cancers originate in the oropharynx, a subset of non-oropharyngeal head and neck cancers present with HPV3. HPV DNA detected in these tumors is predominantly of genotype 16, a high-risk type found in cervical cancer, and is often transcriptionally active, expressing the viral oncogenes E6 and E7. P16INK4 immunohistochemistry is increasingly being used as a surrogate for oncogenically active HPV infection to characterize HNSCC, in the oropharynx. While p16 overexpression may be useful as a surrogate marker for HPV infection in oropharyngeal SCC where HPV prevalence can be high, it has low positive predictive value (i.e., poorly discriminates falsepositive from true-positive cases) in non-oropharyngeal HNSCC where HPV prevalence is much lower 10,11
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