HNO

, Volume 57, Issue 2, pp 113–122

Humane Papillomviren und Oropharynxkarzinome

Molekulare Interaktion und klinische Auswirkung
Leitthema

Zusammenfassung

Ein Drittel aller Oropharynxkarzinome (OSCC) enthalten onkogene humane Papillomviren (HR-HPV). Epidemiologische und molekulare Untersuchungen belegen, dass HR-HPV bei diesen Tumoren ursächlich sind; sie können als HPV-assoziierte OSCC bezeichnen werden. Sexuelle Risikofaktoren scheinen von Bedeutung zu sein. Wenig ist bekannt über die natürliche Infektion und Persistenz von HR-HPV im Oropharynx. Die HPV-assoziierten OSCC unterscheiden sich von denen durch die klassischen Noxen verursachten OSCC grundlegend. Dies betrifft das Expressionsmuster verschiedener Zellzyklusproteine sowie genetische Veränderungen. Das unterschiedliche biologische Verhalten zeigt sich klinisch durch eine günstigere Prognose der HPV-assoziierten OSCC. Die Ursachen sind noch unklar, eine höhere Empfindlichkeit für Strahlen- und Chemotherapie ist aber denkbar. Für Studien bei OSCC ist in Zukunft eine Stratifizierung nach dem HPV-Status sinnvoll. Ob zukünftig die Patienten nach Bestimmung ihres HPV-Status einer entsprechenden maßgeschneiderten Therapie zuzuführen sind, muss in Therapiestudien geklärt werden.

Schlüsselwörter

Kopf-Hals-Karzinome Tonsillenkarzinom Oropharynxkarzinom Humane Papillomaviren (HPV) Prognose 

Abkürzungen

CGH

„Comparative genomic hybridization“

CIS

Carcinoma in situ

DNA

Desoxyribonukleinsäure

EGFR

„Epidermal growth factor receptor“, epidermaler Wachstumsfaktorrezeptor

FISH

Fluoreszenz-in-situ-Hybridisierung

HPV

Humane Papillomaviren

HR-HPV

Hochrisiko-HPV

OR

Odds-Ratio

PCR

Polymerasekettenreaktion

pRb

Retinoblastomprotein

URR

„Upper regulatory region“

Human papillomavirus and cancer of the oropharynx

Molecular interaction and clinical implications

Abstract

One-third of the cases of oropharyngeal squamous cell carcinoma (OSCC) contain oncogenic human papillomavirus (HR-HPV). Epidemiologic and molecular evidence underlines the causal role of HR-HPV in these tumors, which can be defined as HPV-related OSCC. These tumors differ from chemical/toxin-induced OSCC in several biological aspects, including specific molecular and genetic alterations. This leads to a characteristic clinical profile of HPV-related OSCC. Sexual risk factors play a role; however, the knowledge about natural infection and the rate of persistence of HR-HPV in the oropharynx is marginal. It is shown that the distinct biological behavior of the HPV-related subset of oropharyngeal tumors results in a more favorable prognosis. This might be the result of a better response to chemotherapy and radiotherapy. However, further studies are needed to show whether it will be possible to reliably select patients for individualized therapy depended on the HPV status of their tumors. Therefore, we think it will be mandatory to consider and stratify HPV status in the design of prospective clinical trials in the future.

Keywords

Head and neck squamous cell carcinomas (HNSCC) Tonsillar carcinoma Oropharyngeal carcinoma Human papillomavirus (HPV) Prognosis 

Literatur

  1. 1.
    Altieri DC (2003) Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 22: 8581–8589PubMedCrossRefGoogle Scholar
  2. 2.
    Altieri DC (2008) Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8: 61–70PubMedCrossRefGoogle Scholar
  3. 3.
    Andl T, Kahn T, Pfuhl A et al (1998) Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control. Cancer Res 58: 5–13PubMedGoogle Scholar
  4. 4.
    Begum S, Cao D, Gillison M et al (2005) Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clin Cancer Res 11: 5694–5699PubMedCrossRefGoogle Scholar
  5. 5.
    Borbely AA, Murvai M, Konya J et al (2006) Effects of human papillomavirus type 16 oncoproteins on survivin gene expression. J Gen Virol 87: 287–294PubMedCrossRefGoogle Scholar
  6. 6.
    Bosch FX, Lorincz A, Munoz N et al (2002) The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55: 244–265PubMedGoogle Scholar
  7. 7.
    Braakhuis BJ, Leemans CR, Brakenhoff RH (2004) A genetic progression model of oral cancer: current evidence and clinical implications. J Oral Pathol Med 33: 317–322PubMedGoogle Scholar
  8. 8.
    Branca M, Ciotti M, Giorgi C et al (2008) Predicting high-risk human papillomavirus infection, progression of cervical intraepithelial neoplasia, and prognosis of cervical cancer with a panel of 13 biomarkers tested in multivariate modeling. Int J Gynecol Pathol 27: 265–273PubMedGoogle Scholar
  9. 9.
    Capalbo G, Rodel C, Stauber RH et al (2007) The role of survivin for radiation therapy. Prognostic and predictive factor and therapeutic target. Strahlenther Onkol 183: 593–599PubMedCrossRefGoogle Scholar
  10. 10.
    Chaturvedi AK, Engels EA, Anderson WF, Gillison ML (2008) Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 26: 612–619PubMedCrossRefGoogle Scholar
  11. 11.
    Ciardiello F, Tortora G (2001) A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 7: 2958–2970PubMedGoogle Scholar
  12. 12.
    Cruz IB, Snijders PJ, Steenbergen RD et al (1996) Age-dependence of human papillomavirus DNA presence in oral squamous cell carcinomas. Eur J Cancer B Oral Oncol 32B: 55–62PubMedCrossRefGoogle Scholar
  13. 13.
    Dassonville O Formento JL, Francoual M et al (1993) Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 11(10): 1873–1878PubMedGoogle Scholar
  14. 14.
    D’Souza G, Fakhry C, Sugar EA et al (2007) Six-month natural history of oral versus cervical human papillomavirus infection. Int J Cancer 121: 2897–2904Google Scholar
  15. 15.
    D’Souza G, Kreimer AR, Viscidi R et al (2007) Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356: 1944–1956CrossRefGoogle Scholar
  16. 16.
    Fakhry C, Westra WH, Li S et al (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100: 261–269PubMedCrossRefGoogle Scholar
  17. 17.
    Franceschi S, Munoz N, Bosch XF et al (1996) Human papillomavirus and cancers of the upper aerodigestive tract: a review of epidemiological and experimental evidence. Cancer Epidemiol Biomarkers Prev 5: 567–575PubMedGoogle Scholar
  18. 18.
    Frisch M, Hjalgrim H, Jaeger AB, Biggar RJ (2000) Changing patterns of tonsillar squamous cell carcinoma in the United States. Cancer Causes Control 11: 489–495PubMedCrossRefGoogle Scholar
  19. 19.
    Fuchs PG, Pfister H (1994) Transcription of papillomavirus genomes. Intervirology 37: 159–167PubMedGoogle Scholar
  20. 20.
    Galloway DA, McDougall JK (1996) The disruption of cell cycle checkpoints by papillomavirus oncoproteins contributes to anogenital neoplasia. Semin Cancer Biol 7: 309–315PubMedCrossRefGoogle Scholar
  21. 21.
    Gillison ML (2006) Human papillomavirus and prognosis of oropharyngeal squamous cell carcinoma: implications for clinical research in head and neck cancers. J Clin Oncol 24: 5623–5625PubMedCrossRefGoogle Scholar
  22. 22.
    Gillison ML, D’Souza G, Westra W et al (2008) Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 100: 407–420PubMedCrossRefGoogle Scholar
  23. 23.
    Gillison ML, Koch WM, Capone RB et al (2000) Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92: 709–720PubMedCrossRefGoogle Scholar
  24. 24.
    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: 191–199PubMedCrossRefGoogle Scholar
  25. 25.
    Hafkamp HC, Manni JJ, Haesevoets A et al (2008) Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas. Int J Cancer 122: 2656–2664PubMedCrossRefGoogle Scholar
  26. 26.
    Hafkamp HC, Speel EJ, Haesevoets A et al (2003) A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5–8. Int J Cancer 107: 394–400PubMedCrossRefGoogle Scholar
  27. 27.
    Herrero R, Castellsagué X, Pawlita M et al. and IARC Multicenter Oral Cancer Study Group (2003) Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 95(23): 1772–1783PubMedGoogle Scholar
  28. 28.
    Hoffmann M, Gorogh T, Gottschlich S et al (2005) Human papillomaviruses in head and neck cancer: 8 year-survival-analysis of 73 patients. Cancer Lett 218: 199–206PubMedCrossRefGoogle Scholar
  29. 29.
    Hoffmann TK, Arsov C, Schirlau K et al (2006) T cells specific for HPV16 E7 epitopes in patients with squamous cell carcinoma of the oropharynx. Int J Cancer 118: 1984–1991PubMedCrossRefGoogle Scholar
  30. 30.
    Jemal A, Tiwari RC, Murray T et al (2004) Cancer statistics. CA Cancer J Clin 54: 8–29PubMedCrossRefGoogle Scholar
  31. 31.
    Kim SH, Koo BS, Kang S et al (2007) HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation. Int J Cancer 120: 1418–1425PubMedCrossRefGoogle Scholar
  32. 32.
    Klaes R, Friedrich T, Spitkovsky D et al (2001) Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 92: 276–284PubMedCrossRefGoogle Scholar
  33. 33.
    Klaes R, Woerner SM, Ridder R et al (1999) Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res 59: 6132–6136PubMedGoogle Scholar
  34. 34.
    Klingenberg B, Hafkamp HC, Haesevoets A et al. (2009) p16INK4A overexpression is frequently detected in tumor-free tonsil tissue without association with HPV. Mod Pathol (submitted)Google Scholar
  35. 35.
    Klussmann JP, Claesson MH, Preuss SF et al (2007) Die genetische Analyse (CGH) von HPV-positiven und HPV-negativen Oropharynxkarzinomen zeigt signifikante Unterschiede mit Bedeutung für die Prognose. German Medical Science GMS Publishing House (Abstract)Google Scholar
  36. 36.
    Klussmann JP, Dinh S, Guntinas-Lichius O et al (2004) HPV-associated tonsillar cancer. An update. HNO 52: 208–218PubMedCrossRefGoogle Scholar
  37. 37.
    Klussmann JP, Gultekin E, Weissenborn SJ et al (2003) Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. Am J Pathol 162: 747–753PubMedGoogle Scholar
  38. 38.
    Klussmann JP, Weissenborn S, Wieland U et al (2001) Prevalence, distribution and viral load of human papillomavirus 16 DNA in tonsillar carcinomas. Cancer 92: 2875–2884PubMedCrossRefGoogle Scholar
  39. 39.
    Klussmann JP, Weissenborn SJ, Wieland U et al (2003) Human papillomavirus-positive tonsillar carcinomas: a different tumor entity? Med Microbiol Immunol 192: 129–132PubMedCrossRefGoogle Scholar
  40. 40.
    Knauer SK, Bier C, Habtemichael N, Stauber RH (2006) The Survivin-Crm1 interaction is essential for chromosomal passenger complex localization and function. EMBO Rep 7: 1259–1265PubMedCrossRefGoogle Scholar
  41. 41.
    Knauer SK, Kramer OH, Knosel T et al (2007) Nuclear export is essential for the tumor-promoting activity of survivin. FASEB J 21: 207–216PubMedCrossRefGoogle Scholar
  42. 42.
    Kreimer AR, Clifford GM, Boyle P, Franceschi S (2005) Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 14: 467–475PubMedCrossRefGoogle Scholar
  43. 43.
    Licitra L, Perrone F, Bossi P et al (2006) High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 24: 5630–5636PubMedCrossRefGoogle Scholar
  44. 44.
    Lindel K, Beer KT, Laissue J et al (2001) Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. Cancer 92: 805–813PubMedCrossRefGoogle Scholar
  45. 45.
    Lippert BM, Knauer SK, Fetz V et al (2007) Dynamic survivin in head and neck cancer: molecular mechanism and therapeutic potential. Int J Cancer 121: 1169–1174PubMedCrossRefGoogle Scholar
  46. 46.
    Lo ML, Campisi G, Giovannelli L et al (2004) HPV DNA and survivin expression in epithelial oral carcinogenesis: a relationship? Oral Oncol 40: 736–741CrossRefGoogle Scholar
  47. 47.
    Loning T, Ikenberg H, Becker J et al (1985) Analysis of oral papillomas, leukoplakias and invasive carcinomas for human papillomavirus type related DNA. J Invest Dermatol. 84: 417–420Google Scholar
  48. 48.
    Mantovani F, Banks L (2001) The human papillomavirus E6 protein and its contribution to malignant progression. Oncogene 20: 7874–7887PubMedCrossRefGoogle Scholar
  49. 49.
    Mao L, Hong WK, Papadimitrakopoulou VA (2004) Focus on head and neck cancer. Cancer Cell 5: 311–316PubMedCrossRefGoogle Scholar
  50. 50.
    Mellin H, Dahlgren L, Munck-Wikland E et al (2002) Human papillomavirus type 16 is episomal and a high viral load may be correlated to better prognosis in tonsillar cancer. Int J Cancer 102: 152–158PubMedCrossRefGoogle Scholar
  51. 51.
    Mellin H, Friesland S, Lewensohn R et al (2000) Human papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse and survival. Int J Cancer 89: 300–304PubMedCrossRefGoogle Scholar
  52. 52.
    Mendelsohn J (2002) Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 20: 1S–13SPubMedGoogle Scholar
  53. 53.
    Mooren J, Manni JJ, Hafkamp HC et al (2008) Cell cycle protein expression patterns in HPV-containing and -lacking tonsillar squamous cell carcinomas and association with prognosis: a role for p21? Oral Oncol 2: 84 (Abstract)Google Scholar
  54. 54.
    Mork J, Lie AK, Glattre E et al (2001) Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344: 1125–1131PubMedCrossRefGoogle Scholar
  55. 55.
    Pfister H, Fuchs PG (1994) Anatomy, taxonomy and evolution of papillomaviruses. Intervirology 37: 143–149PubMedGoogle Scholar
  56. 56.
    Pfister H, ter Schegget J (1997) Role of HPV in cutaneous premalignant and malignant tumors. Clin Dermatol 15: 335–347PubMedCrossRefGoogle Scholar
  57. 57.
    Pizem J, Cor A, Gale N (2004) Survivin expression is a negative prognostic marker in laryngeal squamous cell carcinoma and is associated with p53 accumulation. Histopathology 45: 180–186PubMedCrossRefGoogle Scholar
  58. 58.
    Preuss S, Enbert I, Valter M et al (2008) Die Prävalenz onkogener HPV-Viren im Oropharynx bei Frauen und mögliche Risikofaktoren. German Medical Science GMS Publishing (Abstract)Google Scholar
  59. 59.
    Preuss SF, Weinell A, Molitor M et al (2008) Nuclear survivin expression is associated with HPV-independent carcinogenesis and is an indicator of poor prognosis in oropharyngeal cancer. Br J Cancer 98: 627–632PubMedCrossRefGoogle Scholar
  60. 60.
    Preuss SF, Weinell A, Molitor M et al (2008) Survivin and epidermal growth factor receptor expression in surgically treated oropharyngeal squamous cell carcinoma. Head Neck 30: 1318–1324PubMedCrossRefGoogle Scholar
  61. 61.
    Ragin CC, Taioli E (2007) Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: Review and meta-analysis. Int J Cancer 121: 1813–1820PubMedCrossRefGoogle Scholar
  62. 62.
    Reimers N, Kasper HU, Weissenborn SJ et al (2007) Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer 120: 1731–1738PubMedCrossRefGoogle Scholar
  63. 63.
    Ritchie JM, Smith EM, Summersgill KF et al (2003) Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer 104: 336–344PubMedCrossRefGoogle Scholar
  64. 64.
    Roussel MF (1999) The INK4 family of cell cycle inhibitors in cancer. Oncogene 18: 5311–5317PubMedCrossRefGoogle Scholar
  65. 65.
    Rubin GJ, Melhem MF, Gooding WE et al (1998) Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90: 824–832CrossRefGoogle Scholar
  66. 66.
    Sano T, Oyama T, Kashiwabara K et al (1998) Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 153: 1741–1748PubMedGoogle Scholar
  67. 67.
    Schwartz SM, Daling JR, Doody DR et al (1998) Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst 90: 1626–1636PubMedCrossRefGoogle Scholar
  68. 68.
    Shiboski CH, Schmidt BL, Jordan RC (2005) Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20-44 years. Cancer 103: 1843–1849PubMedCrossRefGoogle Scholar
  69. 69.
    Smeets SJ, Hesselink AT, Speel EJ et al (2007) A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer 121: 2465–2472PubMedCrossRefGoogle Scholar
  70. 70.
    Smith EM, Ritchie JM, Summersgill KF et al (2004) Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer 108: 766–772PubMedCrossRefGoogle Scholar
  71. 71.
    Smith EM, Ritchie JM, Summersgill KF et al (2004) Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst 96: 449–455PubMedCrossRefGoogle Scholar
  72. 72.
    Speel EJ, Klingenberg B, Hafkamp HC et al (2005) Is p16INK4A overexpression a reliable biomarker for oncogenic human papillomavirus infection in normal tonsils? German Medical Science (Abstract)Google Scholar
  73. 73.
    Stauber RH, Mann W, Knauer SK (2007) Nuclear and cytoplasmic survivin: molecular mechanism, prognostic and therapeutic potential. Cancer Res 67: 5999–6002PubMedCrossRefGoogle Scholar
  74. 74.
    Syrjanen S (2005) Human papillomavirus (HPV) in head and neck cancer. J Clin Virol 32(Suppl 1): S59–S66PubMedCrossRefGoogle Scholar
  75. 75.
    Syrjanen S (2007) Human papillomaviruses in head and neck carcinomas. N Engl J Med 356: 1993–1995PubMedCrossRefGoogle Scholar
  76. 76.
    Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ et al (2004) Genetically altered fields as origin of locally recurrent head and neck cancer: a retrospective study. Clin Cancer Res 10: 3607–3613PubMedCrossRefGoogle Scholar
  77. 77.
    Termine N, Panzarella V, Falaschini S et al (2008) HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988-2007). Ann Oncol 19: 1681–1690PubMedCrossRefGoogle Scholar
  78. 78.
    Vokes EE, Weichselbaum RR, Lippman SM, Hong WK (1993) Head and neck cancer. N Engl J Med 328: 184–194PubMedCrossRefGoogle Scholar
  79. 79.
    Weinberger PM, Yu Z, Haffty BG et al (2006) Molecular classification identifies a subset of human papillomavirus-associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 24: 736–747PubMedCrossRefGoogle Scholar
  80. 80.
    Wentzensen N, Vinokurova S, von Knebel DM (2004) Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res 64: 3878–3884PubMedCrossRefGoogle Scholar
  81. 81.
    Wiest T, Schwarz E, Enders C et al (2002) Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control. Oncogene 21: 1510–1517PubMedCrossRefGoogle Scholar
  82. 82.
    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: 145–156PubMedGoogle Scholar
  83. 83.
    Worden FP, Kumar B, Lee JS et al (2008) Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol 26: 3138–3146PubMedCrossRefGoogle Scholar
  84. 84.
    Zumbach K, Hoffmann M, Kahn T et al (2000) Antibodies against oncoproteins E6 and E7 of human papillomavirus types 16 and 18 in patients with head-and-neck squamous-cell carcinoma. Int J Cancer 85: 815–818PubMedCrossRefGoogle Scholar
  85. 85.
    zur Hausen H (1996) Papillomavirus infections-a major cause of human cancers. Biochim Biophys Acta 1288: 55–78Google Scholar

Copyright information

© Springer Medizin Verlag 2009

Authors and Affiliations

  1. 1.Klinik und Poliklinik für Hals-Nasen-Ohren-HeilkundeKlinikum der Universität zu KölnKölnDeutschland
  2. 2.Department of Molecular Cell Biology, Research Institute Growth and DevelopmentUniversity of MaastrichtMaastrichtNiederlande

Personalised recommendations