Skip to main content
SpringerLink
Log in

HPV Assessment in Oropharynx Cancer: What is the Gold Standard?

  • Chapter
  • First Online:
Critical Issues in Head and Neck Oncology

Abstract

During recent years, evidence of human papillomavirus (HPV) infection emerged as a major prognostic biomarker in head and neck squamous cell carcinomas (HNSCCs), especially those arising from the oropharynx. HPV-associated oropharyngeal carcinomas (OSCCs) represent a clinically distinct form of HNSCC with a different clinical profile, prognosis, and therapeutic options than HPV-non-related HNSCC. Most importantly, the accurate diagnosis of HPV causality in OSCCs is likely to influence therapeutic decisions in affected patients in the near future. Indeed, the clinical significance of detecting HPV in HNSCC has resulted in a growing expectation for HPV testing of HNSCCs. Many different HPV tests exist and much more information about their specific technical, analytical, and clinical properties are available. The objective of this chapter is to address the current state of HPV detection, explain various techniques of HPV detection and analyze the strengths and weaknesses of some of the more commonly used assays. As no single test has been universally accepted as a best method, the challenge for the oncologic community is to implement standardized HPV testing using a method that is highly accurate, technically feasible, cost effective, and readily transferrable to the diagnostic pathology laboratory. Furthermore, in this chapter we will discuss the role of HPV in OSCC and the clinical impact of HPV status as a biomarker for HNSCC.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.

    Article  CAS  PubMed  Google Scholar 

  2. Syrjanen K, Syrjanen S, Lamberg M, Pyrhonen S, Nuutinen J. Morphological and immunohistochemical evidence suggesting human papillomavirus (HPV) involvement in oral squamous cell carcinogenesis. Int J Oral Surg. 1983;12:418–24.

    Article  CAS  PubMed  Google Scholar 

  3. Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92:709–20.

    Article  CAS  PubMed  Google Scholar 

  4. Nelson HH, Pawlita M, Michaud DS, McClean M, Langevin SM, Eliot MN, et al. Immune response to HPV16 E6 and E7 proteins and patient outcomes in head and neck cancer. JAMA Oncol. 2016;3(2):178–85.

    Article  Google Scholar 

  5. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomark Prev. 2005;14:467–75.

    Article  CAS  Google Scholar 

  6. Rampias T, Sasaki C, Weinberger P, Psyrri A. E6 and e7 gene silencing and transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells. J Natl Cancer Inst. 2009;101:412–23.

    Article  CAS  PubMed  Google Scholar 

  7. Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Brandsma J, et al. Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis. J Clin Oncol. 2006;24:736–47.

    Article  CAS  PubMed  Google Scholar 

  8. Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294–301.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Mehanna H, Beech T, Nicholson T, El-Hariry I, McConkey C, Paleri V, et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer--systematic review and meta-analysis of trends by time and region. Head Neck. 2013;35:747–55.

    Article  PubMed  Google Scholar 

  10. Munger K, Baldwin A, Edwards KM, Hayakawa H, Nguyen CL, Owens M, et al. Mechanisms of human papillomavirus-induced oncogenesis. J Virol. 2004;78:11451–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Syrjanen SM, Syrjanen KJ. New concepts on the role of human papillomavirus in cell cycle regulation. Ann Med. 1999;31:175–87.

    Article  CAS  PubMed  Google Scholar 

  12. Khoury R, Sauter S, Butsch Kovacic M, Nelson AS, Myers KC, Mehta PA, et al. Risk of human papillomavirus infection in cancer-prone individuals: what we know. Viruses. 2018;10:47.

    Article  PubMed Central  Google Scholar 

  13. Psyrri A, DiMaio D. Human papillomavirus in cervical and head-and-neck cancer. Nat Clin Pract Oncol. 2008;5:24–31.

    Article  CAS  PubMed  Google Scholar 

  14. Pyeon D, Pearce SM, Lank SM, Ahlquist P, Lambert PF. Establishment of human papillomavirus infection requires cell cycle progression. PLoS Pathog. 2009;5:e1000318.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Adams AK, Wise-Draper TM, Wells SI. Human papillomavirus induced transformation in cervical and head and neck cancers. Cancer. 2014;6:1793–820.

    Article  CAS  Google Scholar 

  16. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci. 2006;110:525–41.

    Article  CAS  Google Scholar 

  17. Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10:550–60.

    Article  CAS  PubMed  Google Scholar 

  18. Rampias T, Sasaki C, Psyrri A. Molecular mechanisms of HPV induced carcinogenesis in head and neck. Oral Oncol. 2014;50:356–63.

    Article  CAS  PubMed  Google Scholar 

  19. Goodwin EC, DiMaio D. Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc Natl Acad Sci U S A. 2000;97:12513–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mellin Dahlstrand H, Lindquist D, Bjornestal L, Ohlsson A, Dalianis T, Munck-Wikland E, et al. P16(INK4a) correlates to human papillomavirus presence, response to radiotherapy and clinical outcome in tonsillar carcinoma. Anticancer Res. 2005;25:4375–83.

    PubMed  Google Scholar 

  21. Li Y, Nichols MA, Shay JW, Xiong Y. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res. 1994;54:6078–82.

    CAS  PubMed  Google Scholar 

  22. Agoff SN, Lin P, Morihara J, Mao C, Kiviat NB, Koutsky LA. p16(INK4a) expression correlates with degree of cervical neoplasia: a comparison with Ki-67 expression and detection of high-risk HPV types. Mod Pathol. 2003;16:665–73.

    Article  PubMed  Google Scholar 

  23. Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR, et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012;30(Suppl 5):F55–70.

    Article  CAS  PubMed  Google Scholar 

  24. Bosch FX, Broker TR, Forman D, Moscicki AB, Gillison ML, Doorbar J, et al. Comprehensive control of human papillomavirus infections and related diseases. Vaccine. 2013;31(Suppl 8):I1–31.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tota JE, Chevarie-Davis M, Richardson LA, Devries M, Franco EL. Epidemiology and burden of HPV infection and related diseases: implications for prevention strategies. Prev Med. 2011;53(Suppl 1):S12–21.

    Article  PubMed  Google Scholar 

  26. Kreimer AR, Pierce Campbell CM, Lin HY, Fulp W, Papenfuss MR, Abrahamsen M, et al. Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study. Lancet. 2013;382:877–87.

    Article  PubMed  PubMed Central  Google Scholar 

  27. D’Souza G, Fakhry C, Sugar EA, Seaberg EC, Weber K, Minkoff HL, et al. Six-month natural history of oral versus cervical human papillomavirus infection. Int J Cancer. 2007;121:143–50.

    Article  PubMed  CAS  Google Scholar 

  28. Pytynia KB, Dahlstrom KR, Sturgis EM. Epidemiology of HPV-associated oropharyngeal cancer. Oral Oncol. 2014;50:380–6.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gillison ML, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307:693–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kreimer AR, Bhatia RK, Messeguer AL, Gonzalez P, Herrero R, Giuliano AR. Oral human papillomavirus in healthy individuals: a systematic review of the literature. Sex Transm Dis. 2010;37:386–91.

    PubMed  Google Scholar 

  31. Chung CH, Bagheri A, D’Souza G. Epidemiology of oral human papillomavirus infection. Oral Oncol. 2014;50:364–9.

    Article  PubMed  Google Scholar 

  32. D’Souza G, Cullen K, Bowie J, Thorpe R, Fakhry C. Differences in oral sexual behaviors by gender, age, and race explain observed differences in prevalence of oral human papillomavirus infection. PLoS One. 2014;9:e86023.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Gillison ML, Castellsague X, Chaturvedi A, Goodman MT, Snijders P, Tommasino M, et al. Eurogin Roadmap: comparative epidemiology of HPV infection and associated cancers of the head and neck and cervix. Int J Cancer. 2014;134:497–507.

    Article  CAS  PubMed  Google Scholar 

  34. Koskimaa HM, Waterboer T, Pawlita M, Grenman S, Syrjanen K, Syrjanen S. Human papillomavirus genotypes present in the oral mucosa of newborns and their concordance with maternal cervical human papillomavirus genotypes. J Pediatr. 2012;160:837–43.

    Article  PubMed  Google Scholar 

  35. Pickard RK, Xiao W, Broutian TR, He X, Gillison ML. The prevalence and incidence of oral human papillomavirus infection among young men and women, aged 18-30 years. Sex Transm Dis. 2012;39:559–66.

    Article  PubMed  Google Scholar 

  36. D’Souza G, Agrawal Y, Halpern J, Bodison S, Gillison ML. Oral sexual behaviors associated with prevalent oral human papillomavirus infection. J Infect Dis. 2009;199:1263–9.

    Article  PubMed  Google Scholar 

  37. Smith EM, Ritchie JM, Summersgill KF, Klussmann JP, Lee JH, Wang D, et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer. 2004;108:766–72.

    Article  CAS  PubMed  Google Scholar 

  38. D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944–56.

    Article  PubMed  Google Scholar 

  39. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wakeham K, Kavanagh K. The burden of HPV-associated anogenital cancers. Curr Oncol Rep. 2014;16:402.

    Article  PubMed  Google Scholar 

  41. de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13:607–15.

    Article  PubMed  Google Scholar 

  42. Hashibe M, Sturgis EM. Epidemiology of oral-cavity and oropharyngeal carcinomas: controlling a tobacco epidemic while a human papillomavirus epidemic emerges. Otolaryngol Clin N Am. 2013;46:507–20.

    Article  Google Scholar 

  43. Bonner JA, Mesia R, Giralt J, Psyrri A, Keilholz U, Rosenthal DI, et al. p16, HPV, and cetuximab: what is the evidence? Oncologist. 2017;22:811–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mork J, Moller B, Dahl T, Bray F. Time trends in pharyngeal cancer incidence in Norway 1981-2005: a subsite analysis based on a reabstraction and recoding of registered cases. Cancer Causes Control. 2010;21:1397–405.

    Article  PubMed  Google Scholar 

  45. Mourad M, Jetmore T, Jategaonkar AA, Moubayed S, Moshier E, Urken ML. Epidemiological trends of head and neck cancer in the United States: a SEER population study. J Oral Maxillofac Surg. 2017;75:2562–72.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health. 2016;4:e609–16.

    Article  PubMed  Google Scholar 

  47. Shah A, Malik A, Garg A, Mair M, Nair S, Chaturvedi P. Oral sex and human papilloma virus-related head and neck squamous cell cancer: a review of the literature. Postgrad Med J. 2017;93:704–9.

    Article  PubMed  Google Scholar 

  48. Spence T, Bruce J, Yip KW, Liu FF. HPV associated head and neck cancer. Cancer. 2016;8:75.

    Article  CAS  Google Scholar 

  49. Psyrri A, Rampias T, Vermorken JB. The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck. Ann Oncol. 2014;25:2101–15.

    Article  CAS  PubMed  Google Scholar 

  50. Huang SH, O’Sullivan B, Xu W, Zhao H, Chen DD, Ringash J, et al. Temporal nodal regression and regional control after primary radiation therapy for N2-N3 head-and-neck cancer stratified by HPV status. Int J Radiat Oncol Biol Phys. 2013;87:1078–85.

    Article  PubMed  Google Scholar 

  51. Huang SH, Xu W, Waldron J, Siu L, Shen X, Tong L, et al. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM stage and prognostic groups for human papillomavirus-related oropharyngeal carcinomas. J Clin Oncol. 2015;33:836–45.

    Article  PubMed  Google Scholar 

  52. O’Sullivan B, Huang SH, Perez-Ordonez B, Massey C, Siu LL, Weinreb I, et al. Outcomes of HPV-related oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation. Radiother Oncol. 2012;103:49–56.

    Article  PubMed  Google Scholar 

  53. Bratman SV, Bruce JP, O’Sullivan B, Pugh TJ, Xu W, Yip KW, et al. Human papillomavirus genotype association with survival in head and neck squamous cell carcinoma. JAMA Oncol. 2016;2:823–6.

    Article  PubMed  Google Scholar 

  54. Goodman MT, Saraiya M, Thompson TD, Steinau M, Hernandez BY, Lynch CF, et al. Human papillomavirus genotype and oropharynx cancer survival in the United States of America. Eur J Cancer. 2015;51:2759–67.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Yete S, D’Souza W, Saranath D. High-risk human papillomavirus in oral cancer: clinical implications. Oncology. 2018;94:133–41.

    Article  PubMed  Google Scholar 

  56. Tanaka TI, Alawi F. Human papillomavirus and oropharyngeal cancer. Dent Clin N Am. 2018;62:111–20.

    Article  PubMed  Google Scholar 

  57. Parfenov M, Pedamallu CS, Gehlenborg N, Freeman SS, Danilova L, Bristow CA, et al. Characterization of HPV and host genome interactions in primary head and neck cancers. Proc Natl Acad Sci U S A. 2014;111:15544–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Campbell JD, Yau C, Bowlby R, Liu Y, Brennan K, Fan H, et al. Genomic, pathway network, and immunologic features distinguishing squamous carcinomas. Cell Rep. 2018;23:194.e6–212.e6.

    Article  CAS  Google Scholar 

  59. Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517:576–82.

    Article  CAS  Google Scholar 

  60. Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005;5:921–9.

    Article  CAS  PubMed  Google Scholar 

  61. Sewell A, Brown B, Biktasova A, Mills GB, Lu Y, Tyson DR, et al. Reverse-phase protein array profiling of oropharyngeal cancer and significance of PIK3CA mutations in HPV-associated head and neck cancer. Clin Cancer Res. 2014;20:2300–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Du L, Chen X, Cao Y, Lu L, Zhang F, Bornstein S, et al. Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGFbeta signaling. Oncogene. 2016;35:4641–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Slebos RJ, Yi Y, Ely K, Carter J, Evjen A, Zhang X, et al. Gene expression differences associated with human papillomavirus status in head and neck squamous cell carcinoma. Clin Cancer Res. 2006;12:701–9.

    Article  CAS  PubMed  Google Scholar 

  64. Schlecht NF, Burk RD, Adrien L, Dunne A, Kawachi N, Sarta C, et al. Gene expression profiles in HPV-infected head and neck cancer. J Pathol. 2007;213:283–93.

    Article  CAS  PubMed  Google Scholar 

  65. Martinez I, Wang J, Hobson KF, Ferris RL, Khan SA. Identification of differentially expressed genes in HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas. Eur J Cancer. 2007;43:415–32.

    Article  CAS  PubMed  Google Scholar 

  66. Keck MK, Zuo Z, Khattri A, Stricker TP, Brown CD, Imanguli M, et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res. 2015;21:870–81.

    Article  CAS  PubMed  Google Scholar 

  67. Zhang Y, Koneva LA, Virani S, Arthur AE, Virani A, Hall PB, et al. Subtypes of HPV-positive head and neck cancers are associated with HPV characteristics, copy number alterations, PIK3CA mutation, and pathway signatures. Clin Cancer Res. 2016;22:4735–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Qureishi A, Mawby T, Fraser L, Shah KA, Moller H, Winter S. Current and future techniques for human papilloma virus (HPV) testing in oropharyngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2017;274:2675–83.

    Article  PubMed  Google Scholar 

  69. Ragin CC, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer. 2007;121:1813–20.

    Article  CAS  PubMed  Google Scholar 

  70. Bonilla-Velez J, Mroz EA, Hammon RJ, Rocco JW. Impact of human papillomavirus on oropharyngeal cancer biology and response to therapy: implications for treatment. Otolaryngol Clin N Am. 2013;46:521–43.

    Article  Google Scholar 

  71. Mallen-St Clair J, Alani M, Wang MB, Srivatsan ES. Human papillomavirus in oropharyngeal cancer: the changing face of a disease. Biochim Biophys Acta. 1866;2016:141–50.

    Google Scholar 

  72. Westra WH. Detection of human papillomavirus (HPV) in clinical samples: evolving methods and strategies for the accurate determination of HPV status of head and neck carcinomas. Oral Oncol. 2014;50:771–9.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Venuti A, Paolini F. HPV detection methods in head and neck cancer. Head Neck Pathol. 2012;6(Suppl 1):S63–74.

    Article  PubMed  Google Scholar 

  74. Mirghani H, Amen F, Moreau F, Guigay J, Ferchiou M, Melkane AE, et al. Human papilloma virus testing in oropharyngeal squamous cell carcinoma: what the clinician should know. Oral Oncol. 2014;50:1–9.

    Article  PubMed  Google Scholar 

  75. Nuovo GJ. In situ detection of human papillomavirus DNA after PCR-amplification. Methods Mol Biol. 2011;688:35–46.

    Article  CAS  PubMed  Google Scholar 

  76. Agoston ES, Robinson SJ, Mehra KK, Birch C, Semmel D, Mirkovic J, et al. Polymerase chain reaction detection of HPV in squamous carcinoma of the oropharynx. Am J Clin Pathol. 2010;134:36–41.

    Article  PubMed  Google Scholar 

  77. Remmerbach TW, Brinckmann UG, Hemprich A, Chekol M, Kuhndel K, Liebert UG. PCR detection of human papillomavirus of the mucosa: comparison between MY09/11 and GP5+/6+ primer sets. J Clin Virol. 2004;30:302–8.

    Article  CAS  PubMed  Google Scholar 

  78. Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012;14:22–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ukpo OC, Flanagan JJ, Ma XJ, Luo Y, Thorstad WL, Lewis JS Jr. High-risk human papillomavirus E6/E7 mRNA detection by a novel in situ hybridization assay strongly correlates with p16 expression and patient outcomes in oropharyngeal squamous cell carcinoma. Am J Surg Pathol. 2011;35:1343–50.

    Article  PubMed  Google Scholar 

  80. Schache AG, Liloglou T, Risk JM, Jones TM, Ma XJ, Wang H, et al. Validation of a novel diagnostic standard in HPV-positive oropharyngeal squamous cell carcinoma. Br J Cancer. 2013;108:1332–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rooper LM, Gandhi M, Bishop JA, Westra WH. RNA in-situ hybridization is a practical and effective method for determining HPV status of oropharyngeal squamous cell carcinoma including discordant cases that are p16 positive by immunohistochemistry but HPV negative by DNA in-situ hybridization. Oral Oncol. 2016;55:11–6.

    Article  CAS  PubMed  Google Scholar 

  82. Bhatia A, Burtness B. Human papillomavirus-associated oropharyngeal cancer: defining risk groups and clinical trials. J Clin Oncol. 2015;33:3243–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hoffmann M, Ihloff AS, Gorogh T, Weise JB, Fazel A, Krams M, et al. p16(INK4a) overexpression predicts translational active human papillomavirus infection in tonsillar cancer. Int J Cancer. 2010;127:1595–602.

    Article  CAS  PubMed  Google Scholar 

  84. Jordan RC, Lingen MW, Perez-Ordonez B, He X, Pickard R, Koluder M, et al. Validation of methods for oropharyngeal cancer HPV status determination in US cooperative group trials. Am J Surg Pathol. 2012;36:945–54.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Smeets SJ, Hesselink AT, Speel EJ, Haesevoets A, Snijders PJ, Pawlita M, et al. A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer. 2007;121:2465–72.

    Article  CAS  PubMed  Google Scholar 

  86. Perrone F, Gloghini A, Cortelazzi B, Bossi P, Licitra L, Pilotti S. Isolating p16-positive/HPV-negative oropharyngeal cancer: an effort worth making. Am J Surg Pathol. 2011;35:774–7. author reply 7-8.

    Article  PubMed  Google Scholar 

  87. Rietbergen MM, Brakenhoff RH, Bloemena E, Witte BI, Snijders PJ, Heideman DA, et al. Human papillomavirus detection and comorbidity: critical issues in selection of patients with oropharyngeal cancer for treatment de-escalation trials. Ann Oncol. 2013;24:2740–5.

    Article  CAS  PubMed  Google Scholar 

  88. Chung CH, Zhang Q, Kong CS, Harris J, Fertig EJ, Harari PM, et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol. 2014;32:3930–8.

    Article  PubMed  PubMed Central  Google Scholar 

  89. El-Naggar AK, Westra WH. p16 expression as a surrogate marker for HPV-related oropharyngeal carcinoma: a guide for interpretative relevance and consistency. Head Neck. 2012;34:459–61.

    Article  PubMed  Google Scholar 

  90. Singhi AD, Westra WH. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer. 2010;116:2166–73.

    PubMed  Google Scholar 

  91. Vermorken JB, Stohlmacher-Williams J, Davidenko I, Licitra L, Winquist E, Villanueva C, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013;14:697–710.

    Article  CAS  PubMed  Google Scholar 

  92. Giralt J, Trigo J, Nuyts S, Ozsahin M, Skladowski K, Hatoum G, et al. Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial. Lancet Oncol. 2015;16:221–32.

    Article  CAS  PubMed  Google Scholar 

  93. Rietbergen MM, Snijders PJ, Beekzada D, Braakhuis BJ, Brink A, Heideman DA, et al. Molecular characterization of p16-immunopositive but HPV DNA-negative oropharyngeal carcinomas. Int J Cancer. 2014;134:2366–72.

    Article  CAS  PubMed  Google Scholar 

  94. Lewis JS Jr, Thorstad WL, Chernock RD, Haughey BH, Yip JH, Zhang Q, et al. p16 positive oropharyngeal squamous cell carcinoma:an entity with a favorable prognosis regardless of tumor HPV status. Am J Surg Pathol. 2010;34:1088–96.

    Article  PubMed  Google Scholar 

  95. Thavaraj S, Stokes A, Guerra E, Bible J, Halligan E, Long A, et al. Evaluation of human papillomavirus testing for squamous cell carcinoma of the tonsil in clinical practice. J Clin Pathol. 2011;64:308–12.

    Article  PubMed  Google Scholar 

  96. Harris SL, Thorne LB, Seaman WT, Hayes DN, Couch ME, Kimple RJ. Association of p16(INK4a) overexpression with improved outcomes in young patients with squamous cell cancers of the oral tongue. Head Neck. 2011;33:1622–7.

    Article  PubMed  Google Scholar 

  97. Holmes BJ, Westra WH. The expanding role of cytopathology in the diagnosis of HPV-related squamous cell carcinoma of the head and neck. Diagn Cytopathol. 2014;42:85–93.

    Article  PubMed  Google Scholar 

  98. Jalaly JB, Lewis JS Jr, Collins BT, Wu X, Ma XJ, Luo Y, et al. Correlation of p16 immunohistochemistry in FNA biopsies with corresponding tissue specimens in HPV-related squamous cell carcinomas of the oropharynx. Cancer Cytopathol. 2015;123:723–31.

    Article  CAS  PubMed  Google Scholar 

  99. Holmes BJ, Maleki Z, Westra WH. The Fidelity of p16 staining as a surrogate marker of human papillomavirus status in fine-needle aspirates and core biopsies of neck node metastases: implications for HPV testing protocols. Acta Cytol. 2015;59:97–103.

    Article  CAS  PubMed  Google Scholar 

  100. Xu B, Ghossein R, Lane J, Lin O, Katabi N. The utility of p16 immunostaining in fine needle aspiration in p16-positive head and neck squamous cell carcinoma. Hum Pathol. 2016;54:193–200.

    Article  CAS  PubMed  Google Scholar 

  101. Bernadt CT, Collins BT. Fine-needle aspiration biopsy of HPV-related squamous cell carcinoma of the head and neck: Current ancillary testing methods for determining HPV status. Diagn Cytopathol. 2017;45:221–9.

    Article  PubMed  Google Scholar 

  102. Bishop JA, Maleki Z, Valsamakis A, Ogawa T, Chang X, Pai SI, et al. Application of the hybrid capture 2 assay to squamous cell carcinomas of the head and neck: a convenient liquid-phase approach for the reliable determination of human papillomavirus status. Cancer Cytopathol. 2012;120:18–25.

    Article  CAS  PubMed  Google Scholar 

  103. Solomides CC, Bibbo M, Wang ZX. Assessment of fine needle aspiration specimen adequacy for high-risk HPV detection and genotyping in oropharyngeal squamous cell carcinoma. Acta Cytol. 2012;56:196–8.

    Article  PubMed  Google Scholar 

  104. Prigge ES, Arbyn M, von Knebel Doeberitz M, Reuschenbach M. Diagnostic accuracy of p16(INK4a) immunohistochemistry in oropharyngeal squamous cell carcinomas: a systematic review and meta-analysis. Int J Cancer. 2017;140:1186–98.

    Article  CAS  PubMed  Google Scholar 

  105. Rischin D, Peters LJ, O’Sullivan B, Giralt J, Fisher R, Yuen K, et al. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol. 2010;28:2989–95.

    Article  CAS  PubMed  Google Scholar 

  106. Rischin D, Young RJ, Fisher R, Fox SB, Le QT, Peters LJ, et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 2010;28:4142–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fu KK, Pajak TF, Trotti A, Jones CU, Spencer SA, Phillips TL, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys. 2000;48:7–16.

    Article  CAS  PubMed  Google Scholar 

  108. Gillison ML, Zhang Q, Ang K, Fu KK, Hammond ME, Jordan R, Trotti A, Spencer S, Rotman M, Chung CH. Analysis of the effect of p16 and tobacco pack-years (p-y) on overall (OS) and progression-free survival (PFS) for patients with oropharynx cancer (OPC) in Radiation Therapy Oncology Group (RTOG) protocol 9003. J Clin Oncol. 2010;28(15_suppl):5510.

    Article  Google Scholar 

  109. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357:1705–15.

    Article  CAS  PubMed  Google Scholar 

  110. Posner MR, Lorch JH, Goloubeva O, Tan M, Schumaker LM, Sarlis NJ, et al. Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Ann Oncol. 2011;22:1071–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Overgaard J, Hansen HS, Overgaard M, Bastholt L, Berthelsen A, Specht L, et al. A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85. Radiother Oncol. 1998;46:135–46.

    Article  CAS  PubMed  Google Scholar 

  112. Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol. 2009;27:1992–8.

    Article  CAS  PubMed  Google Scholar 

  113. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–27.

    Article  CAS  PubMed  Google Scholar 

  114. Vermorken JB, Psyrri A, Mesia R, Peyrade F, Beier F, de Blas B, et al. Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial. Ann Oncol. 2014;25:801–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261–9.

    Article  CAS  PubMed  Google Scholar 

  116. Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, et al. Association of human papillomavirus and p16 status with outcomes in the IMCL-9815 phase III registration trial for patients with locoregionally advanced oropharyngeal squamous cell carcinoma of the head and neck treated with radiotherapy with or without cetuximab. J Clin Oncol. 2016;34:1300–8.

    Article  CAS  PubMed  Google Scholar 

  117. Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J, et al. HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer. Radiother Oncol. 2010;94:30–5.

    Article  CAS  PubMed  Google Scholar 

  118. Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. 2014;32:2940–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Psyrri A, Fortpied C, Koutsodontis G, Avgeris M, Kroupis C, Goutas N, et al. Evaluation of the impact of tumor HPV status on outcome in patients with locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) receiving cisplatin, 5-fluorouracil with or without docetaxel: a subset analysis of EORTC 24971 study. Ann Oncol. 2017;28:2213–8.

    Article  CAS  PubMed  Google Scholar 

  120. Psyrri A, Licitra L, de Blas B, Celik I, Vermorken JB. Safety and efficacy of cisplatin plus 5-FU and cetuximab in HPV-positive and HPV-negative recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): analysis of the phase III EXTREME trial. Ann Oncol. 2012;23:10180.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Section of Medical Oncology, Attikon University Hospital, National Kapodistrian University of Athens, School of Medicine, Athens, Greece

    Panagiota Economopoulou, Ioannis Kotsantis & Amanda Psyrri

Authors
  1. Panagiota Economopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ioannis Kotsantis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amanda Psyrri
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium

    Jan B. Vermorken

  2. Department of Radiation Oncology, Charité University Medicine, Berlin, Germany

    Volker Budach

  3. Department of Otolaryngology , VU University Medical Center, Amsterdam, The Netherlands

    C. René Leemans

  4. Institut Roi Albert II, Université Catholique de Louvain , Louvain-la-Neuve, Belgium

    Jean-Pascal Machiels

  5. Department of Otorhinolarynology, University of Brescia, Brescia, Italy

    Piero Nicolai

  6. Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada

    Brian O'Sullivan

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Economopoulou, P., Kotsantis, I., Psyrri, A. (2018). HPV Assessment in Oropharynx Cancer: What is the Gold Standard?. In: Vermorken, J., Budach, V., Leemans, C., Machiels, JP., Nicolai, P., O'Sullivan, B. (eds) Critical Issues in Head and Neck Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-98854-2_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-98854-2_10

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-98853-5

  • Online ISBN: 978-3-319-98854-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation