Combined P16 and human papillomavirus testing predicts head and neck cancer survival

Christian R. Salazar, Nicole Anayannis, Richard V. Smith, Yanhua Wang, Missak Haigentz, Madhur Garg, Bradley A. Schiff, Nicole Kawachi, Jordan Elman, Thomas J. Belbin, Michael B. Prystowsky, Robert D. Burk, Nicolas F. Schlecht

Research output: Contribution to journalArticle

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Abstract

While its prognostic significance remains unclear, p16INK4aprotein 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.

Original languageEnglish (US)
Pages (from-to)2404-2412
Number of pages9
JournalInternational Journal of Cancer
Volume135
Issue number10
DOIs
StatePublished - Nov 15 2014
Externally publishedYes

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Head and Neck Neoplasms
Survival
Neoplasms
Human Papillomavirus DNA Tests
Immunohistochemistry
RNA
Oropharyngeal Neoplasms
Polymerase Chain Reaction
Papillomavirus Infections
Human papillomavirus 16
Formaldehyde
Drinking
Mouth
Carcinoma, squamous cell of head and neck
Proteins
Biomarkers
Smoking

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Salazar, C. R., Anayannis, N., Smith, R. V., Wang, Y., Haigentz, M., Garg, M., ... Schlecht, N. F. (2014). Combined P16 and human papillomavirus testing predicts head and neck cancer survival. International Journal of Cancer, 135(10), 2404-2412. https://doi.org/10.1002/ijc.28876
Salazar, Christian R. ; Anayannis, Nicole ; Smith, Richard V. ; Wang, Yanhua ; Haigentz, Missak ; Garg, Madhur ; Schiff, Bradley A. ; Kawachi, Nicole ; Elman, Jordan ; Belbin, Thomas J. ; Prystowsky, Michael B. ; Burk, Robert D. ; Schlecht, Nicolas F. / Combined P16 and human papillomavirus testing predicts head and neck cancer survival. In: International Journal of Cancer. 2014 ; Vol. 135, No. 10. pp. 2404-2412.
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abstract = "While its prognostic significance remains unclear, p16INK4aprotein 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.",
author = "Salazar, {Christian R.} and Nicole Anayannis and Smith, {Richard V.} and Yanhua Wang and Missak Haigentz and Madhur Garg and Schiff, {Bradley A.} and Nicole Kawachi and Jordan Elman and Belbin, {Thomas J.} and Prystowsky, {Michael B.} and Burk, {Robert D.} and Schlecht, {Nicolas F.}",
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Salazar, CR, Anayannis, N, Smith, RV, Wang, Y, Haigentz, M, Garg, M, Schiff, BA, Kawachi, N, Elman, J, Belbin, TJ, Prystowsky, MB, Burk, RD & Schlecht, NF 2014, 'Combined P16 and human papillomavirus testing predicts head and neck cancer survival', International Journal of Cancer, vol. 135, no. 10, pp. 2404-2412. https://doi.org/10.1002/ijc.28876

Combined P16 and human papillomavirus testing predicts head and neck cancer survival. / Salazar, Christian R.; Anayannis, Nicole; Smith, Richard V.; Wang, Yanhua; Haigentz, Missak; Garg, Madhur; Schiff, Bradley A.; Kawachi, Nicole; Elman, Jordan; Belbin, Thomas J.; Prystowsky, Michael B.; Burk, Robert D.; Schlecht, Nicolas F.

In: International Journal of Cancer, Vol. 135, No. 10, 15.11.2014, p. 2404-2412.

Research output: Contribution to journalArticle

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T1 - Combined P16 and human papillomavirus testing predicts head and neck cancer survival

AU - Salazar, Christian R.

AU - Anayannis, Nicole

AU - Smith, Richard V.

AU - Wang, Yanhua

AU - Haigentz, Missak

AU - Garg, Madhur

AU - Schiff, Bradley A.

AU - Kawachi, Nicole

AU - Elman, Jordan

AU - Belbin, Thomas J.

AU - Prystowsky, Michael B.

AU - Burk, Robert D.

AU - Schlecht, Nicolas F.

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Y1 - 2014/11/15

N2 - While its prognostic significance remains unclear, p16INK4aprotein 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.

AB - While its prognostic significance remains unclear, p16INK4aprotein 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.

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