Skip to main content
SpringerLink
Log in

Human Papillomavirus (HPV) Testing of Head and Neck Cancers

  • Chapter
  • First Online:
Molecular Diagnostics in Cytopathology

Abstract

Human papillomavirus (HPV) has been found in approximately 25% of head and neck cancers and in 70% of oropharyngeal squamous cell carcinomas. HPV-associated oropharyngeal squamous cell carcinomas have been found to have a distinctly better prognosis and outcome as compared to conventional squamous cell carcinomas of the head and neck, making the detection of HPV in these tumors integral to patient management. The most common HPV type found in HPV-positive oropharyngeal squamous cell carcinomas is HPV 16. Several different testing modalities have been validated for HPV testing on surgical pathology specimens, including p16 immunohistochemistry, HPV PCR, and in situ hybridization of HPV DNA or RNA. Current guidelines recommend HPV testing in all cases of oropharyngeal squamous cell carcinoma diagnosed on cytology when the HPV status is unknown and in squamous cell carcinomas of unknown primary site. Fine-needle aspiration (FNA) biopsies are increasingly used for diagnosis of oropharyngeal squamous cell carcinoma, which frequently present with a low tumor (T) but high nodal (N) stage, with involved cervical lymph nodes often being amenable to FNA biopsy. There is no specific recommendation for which testing modality to use on cytologic material; therefore, familiarity with these various testing options and their advantages and limitations is essential for the practicing cytopathologist.

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 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight 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

Abbreviations

AJCC:

American Joint Committee on Cancer

CAP:

College of American Pathologists

DNA:

Deoxyribonucleic acid

EBER:

EBV-encoded RNA

EBV:

Epstein-Barr virus

FFPE:

Formalin fixed paraffin embedded

FNA:

Fine-needle aspiration

HPV:

Human papillomavirus

hrHPV:

High-risk HPV

IHC:

Immunohistochemistry

ISH:

In situ hybridization

N:

Nodes (extent of lymph node involvement by metastatic disease in TNM staging)

OPSQCC:

Oropharyngeal squamous cell carcinoma

PCR:

Polymerase chain reaction

Rb:

Retinoblastoma

RNA:

Ribonucleic acid

SQCC:

Squamous cell carcinoma

T:

Tumor (primary tumor description in TNM staging)

References

  1. Kreimer AR, Clifford GM, Boyle P, Kreimer AR, Clifford GM, Boyle P, et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomark Prev. 2005;14(2):467–75.

    Article  CAS  Google Scholar 

  2. 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(4):261–9.

    Article  CAS  Google Scholar 

  3. Chaturvedi AK, Anderson WF, Lortet-Tieulent J, Paula Curado M, Ferlay J, Franceschi S, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol. 2013;31(36):4550–9.

    Article  Google Scholar 

  4. Krane JF. Role of cytology in the diagnosis and management of HPV-associated head and neck carcinoma. Acta Cytol. 2013;57(2):117–26.

    Article  Google Scholar 

  5. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân DF, et al. Human papillomavirus and survival of patients with oropharyngeal Cancer. N Engl J Med. 2010;363(1):24–35.

    Article  CAS  Google Scholar 

  6. 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(9):709–20.

    Article  CAS  Google Scholar 

  7. Isayeva T, Li Y, Maswahu D, Brandwein-Gensler M. Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol. 2012;6(Suppl 1):104–20.

    Article  Google Scholar 

  8. Lewis JS Jr, Beadle B, Bishop JA, Chernock RD, Colasacco C, Lacchetti C, et al. Human papillomavirus testing in head and neck carcinomas. Arch Pathol Lab Med. 2018;142(5):559–97.

    Article  Google Scholar 

  9. O’Sullivan B, Lydiatt WM, Haughey BH, Brandwein-Gensler M, Glastonbury CM, Shah J. HPV-mediated (p16+) oropharyngeal cancer. In: Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al., editors. AJCC cancer staging manual. 8th ed. New York: Springer International Publishing; 2017. p. 113–22.

    Chapter  Google Scholar 

  10. Chernock RD, Lewis JS. Approach to metastatic carcinoma of unknown primary in the head and neck: squamous cell carcinoma and beyond. Head Neck Pathol. 2015;9(1):6–15.

    Article  Google Scholar 

  11. 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  Google Scholar 

  12. Bishop JA, Ogawa T, Chang X, Illei PB, Gabrielson E, Pai SI, et al. HPV analysis in distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma. Am J Surg Pathol. 2012;36(1):142–8.

    Article  Google Scholar 

  13. 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(5):736–47.

    Article  CAS  Google Scholar 

  14. Shelton J, Purgina BM, Cipriani NA, Dupont WD, Plummer D, Lewis JS. P16 immunohistochemistry in oropharyngeal squamous cell carcinoma: a comparison of antibody clones using patient outcomes and high-risk human papillomavirus RNA status. Mod Pathol. 2017;30(9):1194–203.

    Article  CAS  Google Scholar 

  15. Lewis JS, Shelton J, Kuhs KL, Smith D K. p16 immunohistochemistry in oropharyngeal squamous cell carcinoma using the E6H4 antibody clone: a technical method study for optimal dilution. Head Neck Pathol. 2017;0(0):1–8.

    Google Scholar 

  16. Smeets SJ, Hesselink AT, Speel E-JM, Haesevoets A, Snijders PJF, 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(11):2465–72.

    Article  CAS  Google Scholar 

  17. 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(9):2166–73.

    PubMed  Google Scholar 

  18. Schache AG, Liloglou T, Risk JM, Filia A, Jones M, Sheard J, et al. Evaluation of human papillomavirus diagnostic testing in oropharyngeal squamous cell carcinoma: sensitivity, specificity and prognostic discrimination. Clin Cancer Res. 2012;17(19):6262–71.

    Article  CAS  Google Scholar 

  19. Jalaly JB, Lewis JS, 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(12):723–31.

    Article  CAS  Google Scholar 

  20. Grimes R, Garcia-Buitrago MT, Jorda M, Ganjei-Azar P, Ferrell A, Gomez-Fernandez C. P16INKa immunocytochemistry in fine-needle aspiration cytology smears of metastatic head and neck squamous cell carcinoma. Acta Cytol. 2013;57(1):33–7.

    Article  CAS  Google Scholar 

  21. Bishop JA, Westra WH. Human papillomavirus-related small cell carcinoma of the oropharynx. Am J Surg Pathol. 2011;35(11):1679–84.

    Article  Google Scholar 

  22. Wadsworth B, Bumpous JM, Martin AW, Nowacki MR, Jenson AB, Farghaly H. Expression of p16 in sinonasal undifferentiated carcinoma (SNUC) without associated human papillomavirus (HPV). Head Neck Pathol. 2011;5(4):349–54.

    Article  Google Scholar 

  23. Bishop JA, Rooper LM, Chiosea SI, Westra WH. Clear cell carcinoma of salivary glands is frequently p16 positive: a pitfall in the interpretation of oropharyngeal biopsies. Am J Surg Pathol. 2018;42(3):367–71.

    Article  Google Scholar 

  24. Bishop JA, Andreasen S, Hang JF, Bullock MJ, Chen TY, Franchi A, et al. HPV-related multiphenotypic sinonasal carcinoma: an expanded series of 49 cases of the tumor formerly known as HPV-related carcinoma with adenoid cystic carcinoma-like features. Am J Surg Pathol. 2017;41(12):1690–701.

    Article  Google Scholar 

  25. Cao D, Begum S, Ali SZ, Westra WH. Expression of p16 in benign and malignant cystic squamous lesions of the neck. Hum Pathol. 2010;41(4):535–9.

    Article  CAS  Google Scholar 

  26. Asiaf A, Ahmad ST, Mohammad SO, Zargar MA. Review of the current knowledge on the epidemiology, pathogenesis, and prevention of human papillomavirus infection. Eur J Cancer Prev. 2014;23(3):206–24.

    Article  CAS  Google Scholar 

  27. Ukpo OC, Flanagan JJ, Ma XJ, Luo Y, Thorstad WL, Lewis JS. 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(9):1343–50.

    Article  Google Scholar 

  28. Bishop J, Ma X-J, Wang H, Luo Y, Illei PB, Begum S, et al. Detection of transcriptionally active high risk HPV in patients with head and neck squamous cell carcinoma as visualized by a novel E6/E7 mRNA in situ hybridization method. Am J Surg Pathol. 2012;36(12):1874–82.

    Article  Google Scholar 

  29. Mills AM, Dirks DC, Poulter MD, Mills SE, Stoler MH. HR-HPV E6/E7 mRNA in situ hybridization. Am J Surg Pathol. 2017;41(5):607–15.

    Article  Google Scholar 

  30. 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(4):308–12.

    Article  Google Scholar 

  31. Miller JA, Allison DB, Maleki Z. Interpretation of HPV DNA in situ hybridization in HPV-related head and neck squamous cell carcinoma: an achievable task in cell block and small biopsy material. J Am Soc Cytopathol. 2017;6(3):89–95.

    Article  Google Scholar 

  32. 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(1):36–41.

    Article  Google Scholar 

  33. De Roda Husman AM, Walboomers JMM, Van den Brule AJC, Meijer CJLM, Snijders PJF. The use of general primers GP5 and GP6 elongated at their 3′ ends with adjacent highly conserved sequences improves human papillomavirus detection by PCR. J Gen Virol. 1995;76(4):1057–62.

    Article  Google Scholar 

  34. Walline HM, Komarck C, JB MH, Byrd SA, Spector ME, Hauff SJ, et al. High-risk human papillomavirus detection in oropharyngeal, nasopharyngeal, and oral cavity cancers comparison of multiple methods. JAMA Otolaryngol Head Neck Surg. 2013;139(12):1320–7.

    Article  Google Scholar 

  35. Channir HI, Grønhøj Larsen C, Ahlborn LB, van Overeem Hansen T, Gerds TA, Charabi BW, et al. Validation study of HPV DNA detection from stained FNA smears by polymerase chain reaction: improving the diagnostic workup of patients with a tumor on the neck. Cancer Cytopathol. 2016;124(11):820–7.

    Article  CAS  Google Scholar 

  36. Bishop JA, Maleki Z, Valsamakis A, Ogawa T, Chang X, WestraPai 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(1):18–25.

    Article  CAS  Google Scholar 

  37. Guo M, Khanna A, Dhillon J, Patel SJ, Feng J, Williams MD, et al. Cervista HPV assays for fine-needle aspiration specimens are a valid option for human papillomavirus testing in patients with oropharyngeal carcinoma. Cancer Cytopathol. 2014;122(2):96–103.

    Article  CAS  Google Scholar 

  38. Kerr DA, Pitman MB, Sweeney B, Arpin RN, Wilbur DC, Faquin WC. Performance of the roche cobas 4800 high-risk human papillomavirus test in cytologic preparations of squamous cell carcinoma of the head and neck. Cancer Cytopathol. 2014;122(3):167–74.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA

    Eleanor Russell-Goldman & Jeffrey F. Krane

Authors
  1. Eleanor Russell-Goldman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey F. Krane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey F. Krane .

Editor information

Editors and Affiliations

  1. MD Anderson Cancer Center, The University of Texas, Houston, TX, USA

    Sinchita Roy-Chowdhuri

  2. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Paul A. VanderLaan

  3. MD Anderson Cancer Center, The University of Texas, Houston, TX, USA

    John M. Stewart

  4. Department of Laboratory Medicine, University of Toronto, Toronto, ON, Canada

    Gilda da Cunha Santos

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Russell-Goldman, E., Krane, J.F. (2019). Human Papillomavirus (HPV) Testing of Head and Neck Cancers. In: Roy-Chowdhuri, S., VanderLaan, P., Stewart, J., Santos, G. (eds) Molecular Diagnostics in Cytopathology. Springer, Cham. https://doi.org/10.1007/978-3-319-97397-5_9

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-97397-5_9

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-97396-8

  • Online ISBN: 978-3-319-97397-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation