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The role of high-risk human papillomavirus infections in laryngeal squamous cell carcinoma

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Abstract

The contribution of human papillomavirus (HPV) to the development and clinical outcome of oropharyngeal cancers has been well documented. The association of HPV in laryngeal squamous cell carcinoma (LSCC) has been examined in several studies, but controversy exists regarding its role in carcinogenesis, the outcome of the patients and thus, clinical significance of HPV testing in LSCC. In this review, we give an update of known associations between HPV-positive testing and carcinogenesis in laryngeal cancer. In an early study, the HPV-DNA detection rate in LSCC was documented being 24.0% with significant regional differences. Non-HPV-16 types were more often detected in LSCC when compared to the oropharynx. Later, single institution case series revealed markedly fewer amounts (<10%) of HPV DNA in LSCC and the results suggested that high-risk HPV infections seem to be biologically irrelevant in most LSCC. The significance of p16INK4a (p16) expression as a surrogate marker towards high-risk HPV infection and the outcome in LSCC is doubtful, since only few p16-positive LSCC samples are HPV RNA positive and accordingly there was poor correlation of p16-test results towards the outcome in LSCC. Recent meta-analysis (n = 2739) and large case series (n = 1042) of LSCC revealed the true rate of HPV-driven LSCC being 8.6%, respectively, <5%. In the latter the rate of DNA-, DNA/RNA-, DNA/p16, and DNA/RNA/p16 positivity was 5.7, 3.1, 1.9, and 1.5%, respectively. These results indicate relevant amounts of insignificant/transient HPV infection in LSCC specimen. However, in the same study the rate of transforming HPV infections increased since 2000, and younger patients had higher amounts of HPV-driven LSCC. Serologic testing of E6/E7 antibodies additionally revealed odds ratios between 2 and 5 as a hint for a weak contribution of high-risk HPV infection and the development of LSCC. The contribution of HPV for the development of LSCC needs future investigations, to date, routine HPV testing of LSCC specimen is not warranted.

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References

  1. Parkin DM et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108

    Article  PubMed  Google Scholar 

  2. Chaturvedi AK et al (2008) Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 26(4):612–619

    Article  PubMed  Google Scholar 

  3. Sturgis EM, Cinciripini PM (2007) Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer 110(7):1429–1435

    Article  PubMed  Google Scholar 

  4. Hartwig S et al (2012) Estimation of the epidemiological burden of human papillomavirus-related cancers and non-malignant diseases in men in Europe: a review. BMC Cancer 12:30

    Article  PubMed  PubMed Central  Google Scholar 

  5. Karim-Kos HE et al (2008) Recent trends of cancer in Europe: a combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. Eur J Cancer 44(10):1345–1389

    Article  PubMed  Google Scholar 

  6. Strauss MJ, Shaw EW et al (1949) Crystalline virus-like particles from skin papillomas characterized by intranuclear inclusion bodies. Proc Soc Exp Biol Med 72(1):46–50

    Article  CAS  PubMed  Google Scholar 

  7. Quick CA et al (1980) Relationship between condylomata and laryngeal papillomata. Clinical and molecular virological evidence. Ann Otol Rhinol Laryngol 89(5 Pt 1):467–471

    Article  CAS  PubMed  Google Scholar 

  8. Kreimer AR et al (2005) Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomark Prev 14(2):467–475

    Article  CAS  Google Scholar 

  9. Hoffmann M et al (2010) p16(INK4a) overexpression predicts translational active human papillomavirus infection in tonsillar cancer. Int J Cancer 127(7):1595–1602

    Article  CAS  PubMed  Google Scholar 

  10. Fischer CA et al (2010) Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality? Int J Cancer 126(5):1256–1262

    CAS  PubMed  Google Scholar 

  11. Schache AG et al (2013) Validation of a novel diagnostic standard in HPV-positive oropharyngeal squamous cell carcinoma. Br J Cancer 108(6):1332–1339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Baumann JL et al (2009) Human papillomavirus in early laryngeal carcinoma. Laryngoscope 119(8):1531–1537

    Article  PubMed  Google Scholar 

  13. Halec G et al (2013) Biological evidence for a causal role of HPV16 in a small fraction of laryngeal squamous cell carcinoma. Br J Cancer 109(1):172–183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Klussmann JP et al (2003) Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. Am J Pathol 162(3):747–753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wittekindt C et al (2005) Expression of p16 protein is associated with human papillomavirus status in tonsillar carcinomas and has implications on survival. Adv Otorhinolaryngol 62:72–80

    CAS  PubMed  Google Scholar 

  16. McLaughlin-Drubin ME, Park D, Munger K (2013) Tumor suppressor p16INK4A is necessary for survival of cervical carcinoma cell lines. Proc Natl Acad Sci USA 110(40):16175–16180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ang KK et al (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363(1):24–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lewis JS Jr et al (2010) p16 positive oropharyngeal squamous cell carcinoma: an entity with a favorable prognosis regardless of tumor HPV status. Am J Surg Pathol 34(8):1088–1096

    Article  PubMed  Google Scholar 

  19. Reimers N et al (2007) Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer 120(8):1731–1738

    Article  CAS  PubMed  Google Scholar 

  20. Wagner S et al (2017) Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer. Br J Cancer 116(12):1604–1611

    Article  PubMed  Google Scholar 

  21. Vent J et al (2013) p16 expression in carcinoma of unknown primary: diagnostic indicator and prognostic marker. Head Neck 35(11):1521–1526

    Article  PubMed  Google Scholar 

  22. Isayeva T et al (2012) Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol 6(Suppl 1):S104–S120

    Article  PubMed  Google Scholar 

  23. Mooren JJ et al (2014) p16(INK4A) immunostaining is a strong indicator for high-risk-HPV-associated oropharyngeal carcinomas and dysplasias, but is unreliable to predict low-risk-HPV-infection in head and neck papillomas and laryngeal dysplasias. Int J Cancer 134(9):2108–2117

    Article  CAS  PubMed  Google Scholar 

  24. Gultekin SE et al (2015) p16(INK 4a) and Ki-67 expression in human papilloma virus-related head and neck mucosal lesions. Invest Clin 56(1):47–59

    PubMed  Google Scholar 

  25. Prigge ES et al (2015) p16(INK4a)/Ki-67 co-expression specifically identifies transformed cells in the head and neck region. Int J Cancer 136(7):1589–1599

    Article  CAS  PubMed  Google Scholar 

  26. Lewis JS Jr et al (2012) Transcriptionally-active high-risk human papillomavirus is rare in oral cavity and laryngeal/hypopharyngeal squamous cell carcinomas—a tissue microarray study utilizing E6/E7 mRNA in situ hybridization. Histopathology 60(6):982–991

    Article  PubMed  Google Scholar 

  27. Young RJ et al (2015) Frequency and prognostic significance of p16(INK4A) protein overexpression and transcriptionally active human papillomavirus infection in laryngeal squamous cell carcinoma. Br J Cancer 112(6):1098–1104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chung CH et al (2014) p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol 32(35):3930–3938

    Article  PubMed  PubMed Central  Google Scholar 

  29. Fusconi M et al (2016) Laryngeal cancer, HPV DNA vs E6/E7 mRNA test: a systematic review. J Voice 31(2):248.e1–248.e5

    Article  Google Scholar 

  30. Ndiaye C et al (2014) HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. Lancet Oncol 15(12):1319–1331

    Article  CAS  PubMed  Google Scholar 

  31. Castellsague X et al (2016) HPV involvement in head and neck cancers: comprehensive assessment of biomarkers in 3680 patients. J Natl Cancer Inst 108(6):djv403

    Article  PubMed  Google Scholar 

  32. Mork J et al (2001) Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344(15):1125–1131

    Article  CAS  PubMed  Google Scholar 

  33. Anantharaman D et al (2013) Human papillomavirus infections and upper aero-digestive tract cancers: the ARCAGE study. J Natl Cancer Inst 105(8):536–545

    Article  CAS  PubMed  Google Scholar 

  34. Morshed K (2010) Association between human papillomavirus infection and laryngeal squamous cell carcinoma. J Med Virol 82(6):1017–1023

    Article  CAS  PubMed  Google Scholar 

  35. Scheel A et al (2016) Classification of TP53 mutations and HPV predict survival in advanced larynx cancer. Laryngoscope 126(9):E292–E299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author notes

  1. Claus Wittekindt and Nora Wuerdemann contributed equally to this work.

Authors and Affiliations

  1. Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Klinikstrasse 33, 35392, Giessen, Germany

    Claus Wittekindt, Nora Wuerdemann, Steffen Wagner & Jens Peter Klußmann

  2. Department of Pathology, University of Giessen, Giessen, Germany

    Stefan Gattenlöhner & Alexander Brobeil

  3. Department of Otolaryngology and Laryngological Oncology, University of Medical Sciences, Poznan, Poland

    Malgorzata Wierzbicka

Authors
  1. Claus Wittekindt
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  2. Nora Wuerdemann
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  3. Stefan Gattenlöhner
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  4. Alexander Brobeil
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  5. Malgorzata Wierzbicka
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  6. Steffen Wagner
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  7. Jens Peter Klußmann
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Corresponding author

Correspondence to Nora Wuerdemann.

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The authors declare no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No ethical approval was obtained as tumor samples were immunohistochemically stained in line with pathological diagnostics.

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Informed consent was obtained from all individual participants included in the study.

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Wittekindt, C., Wuerdemann, N., Gattenlöhner, S. et al. The role of high-risk human papillomavirus infections in laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 274, 3837–3842 (2017). https://doi.org/10.1007/s00405-017-4718-1

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  • DOI: https://doi.org/10.1007/s00405-017-4718-1

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