p16 Not a Prognostic Marker for Hypopharyngeal Squamous Cell Carcinoma

Departments of Radiation Oncology, University of Virginia, Charlottesville, VA 22908, USA.
Archives of otolaryngology--head & neck surgery (Impact Factor: 2.33). 06/2012; 138(6):556-61. DOI: 10.1001/archoto.2012.950
Source: PubMed


To investigate the prognostic significance of p16 in patients with hypopharyngeal squamous cell carcinoma (HPSCC) and to evaluate the relationship between p16 and human papillomavirus (HPV). Unlike in oropharyngeal SCC (OPSCC), the prognostic significance of p16 in HPSCC and its association with HPV is unclear.
Retrospective medical chart review.
University tertiary referral center.
A total of 27 patients with HPSCC treated with definitive radiation therapy between 2002 and 2011 whose tissue was available for immunohistochemical analysis.
Twenty-two patients were treated with chemoradiation, and 5 with radiation alone. All tumor biopsy specimens were analyzed for p16 and, when sufficient tissue was available, for HPV DNA.
Overall survival (OS), locoregional control (LRC), disease-free survival (DFS), and laryngoesophageal dysfunction-free survival (LEDFS) were analyzed according to p16 status.
Findings for p16 were positive in 9 tumors and negative in 18 tumors. Median follow-up was 29.3 months. There was no significant difference in OS, LRC, DFS, or LEDFS for patients with p16-positive vs p16-negative tumors. Only 1 of the 19 tumors tested for HPV was found to be HPV positive. When used as a test for HPV, p16 had a positive predictive value of 17%.
In contrast to OPSCC, p16 expression in patients with HPSCC had a low positive predictive value for HPV and did not predict improved OS, LRC, DFS, or LEDFS. Thus, for HPSCC, p16 is not a prognostic biomarker. Caution must be taken when extrapolating the prognostic significance of p16 in patients with OPSCC to patients with head and neck SCC of other subsites.

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    ABSTRACT: To assess the interaction of HPV/p16 status and therapy rendered in patients with locally advanced squamous cell carcinoma of the larynx and hypopharynx. Forty-seven consecutive patients receiving definitive treatment between 2009 and 2011 for locally advanced larynx or hypopharynx cancer with high-risk HPV and/or p16 testing performed were identified and retrospectively investigated. Overall survival (OS), disease-free survival (DFS), and local recurrence-free survival (LRFS) were assessed. Of 47 evaluable patients, there were 38 (81%) with laryngeal and 9 (19%) with hypopharyngeal tumors, 13 (28%) of which were found to be either HPV or p16 positive. At a median follow-up of 24months, comparing HPV/p16+ versus HPV/p16- patients, there was no difference in OS, DFS, or LRFS. There was an improvement in 2-year DFS (60% vs 100%, P=.03) and LRFS (80% vs 100%, P=.08), in HPV/p16+ patients treated with chemo/RT versus surgery. There was an improvement in 2-year DFS (100% vs 68%, P=.04) and LRFS (100% vs 72%, P=.05) in HPV/p16+ versus HPV/p16- patients who received chemo/RT. Patients with HPV/p16+ tumors fared more favorably with chemo/RT than up-front surgery, with improvements in DFS and LRFS. In patients treated with the intent of organ preservation therapy, HPV/p16+ patients had no observed treatment failures. HPV/p16 status should be taken into account when considering organ preservation for locally advanced larynx and hypopharynx cancers.
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    ABSTRACT: Importance The prognostic significance of p16 in squamous cell carcinoma (SCC) of the hypopharynx (HP) and nasopharynx (NP) and relationship between human papillomavirus (HPV) and p16 is unclear.Objectives To evaluate the prognostic significance of p16 in pharyngeal subsites (oropharynx [OP], HP, and NP) and assess the relationship between HPV and p16 in the HP and NP.Design, Setting, and Participants Retrospective medical record review of 172 patients with SCC of the pharynx treated with definitive radiation therapy from 2002 to 2013 at a university tertiary referral center, with tissue available for immunohistochemical analysis. The median follow-up was 30.1 months.Interventions A total of 118 patients were treated with chemoradiation, and 54 patients were treated with radiation alone. Immunohistochemical analysis for p16 was performed for all tumors. Hypopharynx and NP tumors were tested for HPV using in situ hybridization, and NP tumors were tested for Epstein-Barr virus.Main Outcomes and Measures Overall survival, locoregional control, and disease-free survival were analyzed according to p16, HPV, and Epstein-Barr virus status.Results Thirty-two patients had HP SCC, 127 had OP SCC, and 13 had NP SCC. p16 Was positive in the HP (34%), OP (66%), and NP (46%). Prevalence of HPV was 14% in the HP and 50% in the NP. As a test for HPV, p16 had a positive predictive value of 38% (HP) and 67% (NP) and a negative predictive value of 100% in HP and NP tumors. p16 Status was a significant predictor of all clinical outcomes for patients with OP SCC (P<.001), but not for patients with HP or NP SCC. Patients with Epstein-Barr virus– or HPV-associated NP SCC had improved clinical outcomes.Conclusions and Relevance p16 Was not associated with improved outcomes in patients with HP or NP SCC. The positive predictive value of p16 as a test for HPV is too low for p16 testing alone in the HP and NP. However, p16 negativity is sufficient to rule out HPV. As a research approach, we recommend p16 immunohistochemistry as a screening test for HPV in NP SCC and HP SCC followed by confirmatory HPV in situ hybridization when p16 positive.
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    ABSTRACT: While its prognostic significance remains unclear, p16INK4a 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. 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 non-oropharyngeal tumors. However, when both p16 and HPV DNA test results were considered, concordantly positive non-oropharyngeal tumors had significantly better disease-specific survival than concordantly negative non-oropharyngeal 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 non-oropharyngeal HNSCC, p16(+)/HPV16(-) non-oropharyngeal 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 immunohistochemistry alone has potential as a prognostic test for oropharyngeal cancer survival, but combined p16/HPV testing is necessary to identify HPV-associated non-oropharyngeal HNSCC with better prognosis. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Nov 2014 · International Journal of Cancer
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