Skip to main content

Advertisement

Log in

Human papillomavirus-positive tonsillar carcinomas: a different tumor entity?

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract.

Human papillomavirus (HPV) infections are thought to be one of the causal factors in the development of head and neck squamous cell carcinomas (HNSCC), particularly in tumors arising from the Waldeyer's tonsillar ring. We screened 98 carefully stratified HNSCC and different control tissues for the presence of HPV DNA by nested polymerase chain reaction (PCR) specific for genital- and Epidermodysplasia verruciformis (EV)-associated HPVs and by HPV16-specific single step PCR. Typing was performed by direct sequencing and/or sequencing of cloned amplimers. On average HNSCC showed rather low HPV DNA prevalences; 18% of the oral cavity cancers, 8% of nasopharyngeal cancers, 25% of hypopharyngeal cancers and 7% of laryngeal cancers were HPV DNA positive. In contrast, HPV sequences could be detected in 45% of the oropharyngeal cancers, particularly tonsillar carcinomas (58%). Tonsillar carcinomas were significantly more likely to be HPV positive than tumors from any other site (P<0.001). All tonsillar cancers contained oncogenic HPV types, predominantly HPV16 (13 of 14; 93%). Unaffected tonsils were available from two of these patients, but both tested negative for HPV DNA. Furthermore, no HPV DNA could be found in tonsillar biopsy specimens from control groups. Localization and load of HPV DNA was determined in HPV16-positive tonsillar carcinomas, their metastases and in unaffected mucosa using laser-assisted microdissection and subsequent real time fluorescence PCR. We demonstrated that the HPV genome is located in the cancer cells, whereas the infection of normal mucosa is a rare event. Quantification of HPV16 DNA in samples of seven patients yielded viral loads from 6 to 153 HPV DNA copies per β-globin gene copy and the load values in both locations were roughly comparable. These loads are comparable with data shown for other HPV-associated lesions. Statistical evaluation of data related to clinicopathological parameters showed a significant correlation of the HPV positivity of tonsillar carcinomas with tumor grading (P=0.008) and alcohol consumption (P=0.029). Taken together our findings show a preferential association of HPV DNA with tonsillar carcinomas. Furthermore our results argue for HPV-positive tonsillar carcinomas representing a separate tumor entity, which is less dependent on conventional HNSCC risk factors.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.

Similar content being viewed by others

References

  1. Andl T, Kahn T, Pfuhl A, Nicola T, Erber R, Conradt C, Klein W, Helbig M, Dietz A, Weidauer H, Bosch FX (1998) Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control. Cancer Res 58:5–13

    Google Scholar 

  2. Brandsma JL, Abramson AL (1989) Association of papillomavirus with cancers of the head and neck. Arch Otolaryngol Head Neck Surg 115:621–625

    Google Scholar 

  3. DeVita VT, Helman S, Rosenberg SA (1997) Principles and practice of oncology. Lippincott Williams & Wilkins, Philadelphia

  4. Frisch M, Biggar RJ (1999) Aetiological parallel between tonsillar and anogenital squamous-cell carcinomas. Lancet 354:1442–1443

    Google Scholar 

  5. Gillison ML, Koch WM, Shah KV (1999) Human papillomavirus in head and neck squamous cell carcinoma: are some head and neck cancers a sexually transmitted disease? Curr Opin Oncol 11:191–199

    Google Scholar 

  6. Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, Zahurak ML, Daniel RW, Viglione M, Symer DE, Shah KV, Sidransky D (2000) Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92:709–720

    Google Scholar 

  7. Gross GE, Barasso R (1997) Human papillomavirus infection. Ullstein Mosby, Wiesbaden

  8. Guay ME, Lavertu P (1995) Tonsillar carcinoma. Eur Arch Otorhinolaryngol 252:259–264

    Google Scholar 

  9. Haraf DJ, Nodzenski E, Brachman D, Mick R, Montag A, Graves D, Vokes EE, Weichselbaum RR (1996) Human papilloma virus and p53 in head and neck cancer: clinical correlates and survival. Clin Cancer Res 2:755–762

    Google Scholar 

  10. Hemminki K, Dong C and Frisch M (2000) Tonsillar and other upper aerodigestive tract cancers among cervical cancer patients and their husbands. Eur J Cancer Prev 9:433–437

    Google Scholar 

  11. Josefsson AM, Magnusson PK, Ylitalo N, Sorensen P, Qwarforth-Tubbin P, Andersen PK, Melbye M, Adami HO, Gyllensten UB (2000) Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case-control study. Lancet 355:2189–2193

    Google Scholar 

  12. Klaes R, Friedrich T, Spitkovsky D, Ridder R, Rudy W, Petry U, Dallenbach-Hellweg G, Schmidt D, Knebel DM von (2001) Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 92:276–284

    Google Scholar 

  13. Klussmann JP, Weissenborn S, Wieland U, Dries V, Kolligs J, Jungehuelsing M, Eckel HE, Dienes HP, Pfister H, Fuchs P (2001) Prevalence, distribution and viral load of human papillomavirus 16 DNA in tonsillar carcinomas. Cancer 92:2875–2884

    Google Scholar 

  14. Klussmann JP, Weissenborn S, Fuchs PG (2001) Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 345:376

    Google Scholar 

  15. Koh J, Enders GH, Dynlacht BD, Harlow E (1995) Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature 375:506–510

    Google Scholar 

  16. McKaig RG, Baric RS, Olshan AF (1998) Human papillomavirus and head and neck cancer: epidemiology and molecular biology. Head Neck 20:250–265

    Google Scholar 

  17. Mork J, Lie AK, Glattre E, Hallmans G, Jellum E, Koskela P, Moller B, Pukkala E, Schiller JT, Youngman L, Lehtinen M, Dillner J (2001) Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344:1125–1131

    Google Scholar 

  18. Parkin DM, Pisani P, Ferlay J (1999) Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer 80:827–841

    Google Scholar 

  19. Paz IB, Cook N, Odom-Maryon T, Xie Y, Wilczynski SP (1997) Human papillomavirus (HPV) in head and neck cancer. An association of HPV 16 with squamous cell carcinoma of Waldeyer's tonsillar ring. Cancer 79:595–604

    Google Scholar 

  20. Pfister H, Schegget J ter (1997) Role of HPV in cutaneous premalignant and malignant tumors. Clin Dermatol 15:335–347

    Google Scholar 

  21. Sakaguchi M, Fujii Y, Hirabayashi H, Yoon HE, Komoto Y, Oue T, Kusafuka T, Okada A, Matsuda H (1996) Inversely correlated expression of p16 and Rb protein in non-small cell lung cancers: an immunohistochemical study. Int J Cancer 65:442–445

    Google Scholar 

  22. Sano T, Oyama T, Kashiwabara K, Fukuda T, Nakajima T (1998) Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 153:1741–1748

    Google Scholar 

  23. Schwartz SM, Daling JR, Doody DR, Wipf GC, Carter JJ, Madeleine MM, Mao EJ, Fitzgibbons ED, Huang S, Beckmann AM, McDougall JK, Galloway DA (1998) Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst 90:1626–1636

    Google Scholar 

  24. Seedorf K, Krammer G, Durst M, Suhai S, Rowekamp WG (1985) Human papillomavirus type 16 DNA sequence. Virology 145:181–185

    Google Scholar 

  25. Shah KV, Howley PM (1996) Papillomaviruses. In: Fields BN, Knipe DM, Howley PM, Channock RM, Melnick JL, Monath TP, Roizman B (eds) Fields virology. Lippincott-Raven, Philadelphia, pp 2077–2109

  26. Sisk EA, Bradford CR, Jacob A, Yian CH, Staton KM, Tang G, Harris MO, Carey TE, Lancaster WD, Gregoire L (2000) Human papillomavirus infection in "young" versus "old" patients with squamous cell carcinoma of the head and neck. Head Neck 22:649–657

    Google Scholar 

  27. Snijders PJ, Cromme FV, Brule AJ van den, Schrijnemakers HF, Snow GB, Meijer CJ, Walboomers JM (1992) Prevalence and expression of human papillomavirus in tonsillar carcinomas, indicating a possible viral etiology. Int J Cancer 51:845–850

    Google Scholar 

  28. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK (1993) Head and neck cancer. N Engl J Med 328:184–194

    Google Scholar 

  29. Wieland U, Jurk S, Weissenborn S, Krieg T, Pfister H, Ritzkowsky A (2000) Erythroplasia of queyrat: coinfection with cutaneous carcinogenic human papillomavirus type 8 and genital papillomaviruses in a carcinoma in situ. J Invest Dermatol 115:396–401

    Google Scholar 

  30. Wilczynski SP, Lin BT, Xie Y, Paz IB (1998) Detection of human papillomavirus DNA and oncoprotein overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma. Am J Pathol 152:145–156

    Google Scholar 

  31. Ylitalo N, Sorensen P, Josefsson AM, Magnusson PK, Andersen PK, Ponten J, Adami HO, Gyllensten UB, Melbye M (2000) Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study. Lancet 355:2194–2198

    Google Scholar 

  32. Zur Hausen H (1999) Papillomaviruses in human cancers. Proc Assoc Am Physicians 111:581–587

    Google Scholar 

Download references

Acknowledgements.

This work was supported by funding from the Jean Uhrmacher Foundation and from the Köln Fortune-Program of the Faculty of Medicine, University of Cologne (No. 63/1999) and a grant from the Center for Molecular Medicine of Cologne (ZMMK).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jens P. Klussmann.

Additional information

Presented in part at the Joint Meeting of the Arbeitsgemeinschaft Dermatologische Infektiologie der Deutschen Dermatologischen Gesellschaft and the Arbeitsgemeinschaft Oralpathologie on "Oral Viral Infection and Oral Tumors" in Rostock, Germany, 6–7 July 2001

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klussmann, J.P., Weissenborn, S.J., Wieland, U. et al. Human papillomavirus-positive tonsillar carcinomas: a different tumor entity?. Med Microbiol Immunol 192, 129–132 (2003). https://doi.org/10.1007/s00430-002-0126-1

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-002-0126-1

Keywords.

Navigation