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Ki67 Expression has Prognostic Significance in Relation to Human Papillomavirus Status in Oropharyngeal Squamous Cell Carcinoma

  • Head and Neck Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Human papillomavirus (HPV) is the major predictor of outcome in oropharyngeal squamous cell carcinoma (OSCC) but the disease is heterogeneous and there is limited understanding of the prognostic significance of other molecular markers in relation to HPV. This multi-institutional, retrospective study examined the prognostic significance of Ki67 expression in association with HPV status in OSCC.

Methods

The 105 patients recruited had a median follow-up of 70 months. Tumor HPV status was determined by HPV E6-targeted multiplex real-time polymerase chain reaction/p16 semiquantitative immunohistochemistry and Ki67 expression by semiquantitative immunohistochemistry. Determinants of recurrence and mortality hazards were modelled using Cox regression with censoring at dates of last follow-up.

Results

HPV and Ki67 positivity rates were 46 and 44 %, respectively. HPV-positive cancers were more likely to be Ki67-positive. On multivariate analysis, both HPV and Ki67 were predictors of outcome. Ki67-positive cancers were associated with a 3.13-fold increased risk of disease-related death compared with Ki67-negative cancers. Among HPV-negative patients, Ki67-positive disease was associated with 5.6-fold increased risk of oropharyngeal cancer-related death (p = 0.002), 5.5-fold increased risk of death from any cause (p = 0.001), and 2.9-fold increased risk of any event (p = 0.013). The risk of locoregional failure was lowest in patients with HPV-positive/Ki67-positive cancers.

Conclusions

Ki67 predicts disease-related death in oropharyngeal cancer independent of HPV status. A combination of Ki67 and HPV status provides improved prognostic information relative to HPV status alone. Our data suggest, for the first time, that Ki67 status has prognostic value, particularly in HPV-negative oropharyngeal cancer.

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REFERENCES

  1. Hong AM, Dobbins TA, Lee CS, et al. Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy. Br J Cancer. 2010;103(10):1510–1517.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. 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(12):1992–1998.

    Article  CAS  PubMed  Google Scholar 

  3. Gillison ML. Human papillomavirus and prognosis of oropharyngeal squamous cell carcinoma: implications for clinical research in head and neck cancers. J Clin Oncol. 2006;24(36):5623–5625.

    Article  CAS  PubMed  Google Scholar 

  4. Gillison ML. Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity. Semin Oncol. 2004;31(6):744–754.

    Article  PubMed  Google Scholar 

  5. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. J Clin Oncol. 2006;24(5):736–747.

    Article  CAS  PubMed  Google Scholar 

  6. Hong AM, Martin A, Chatfield M, et al. Human papillomavirus, smoking status and outcomes in tonsillar squamous cell carcinoma. Int J Cancer. 2013;132(12):2748–2754.

    Article  CAS  PubMed  Google Scholar 

  7. Rainsbury JW, Ahmed W, Williams HK, Roberts S, Paleri V, Mehanna H. Prognostic biomarkers of survival in oropharyngeal squamous cell carcinoma: systematic review and meta-analysis. Head Neck. 2013;35(7):1048–1055.

    Article  PubMed  Google Scholar 

  8. Schliephake H. Prognostic relevance of molecular markers of oral cancer: a review. Int J Oral Maxillofac Surg. 2003;32(3):233–245.

    Article  CAS  PubMed  Google Scholar 

  9. Brown DC, Gatter KC. Ki67 protein: the immaculate deception? Histopathology. 2002;40(1):2–11.

    Article  CAS  PubMed  Google Scholar 

  10. van Diest PJ, van der Wall E, Baak JP. Prognostic value of proliferation in invasive breast cancer: a review. J Clin Pathol. 2004;57(7):675–681.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Pich A, Chiusa L, Navone R. Prognostic significance of cell proliferation in head and neck tumors. Ann Oncol. 2004;15:1319–1329.

    Article  CAS  PubMed  Google Scholar 

  12. Ritta M, De Andrea M, Mondini M, et al. Cell cycle and viral and immunologic profiles of head and neck squamous cell carcinoma as predictable variables of tumor progression. Head Neck. 2009;31(3):318–327.

    Article  PubMed  Google Scholar 

  13. De Petrini M, Ritta M, Schena M, et al. Head and neck squamous cell carcinoma: role of the human papillomavirus in tumour progression. New Microbiol. 2006;29(1):25–33.

    PubMed  Google Scholar 

  14. Grabenbauer GG, Muhlfriedel C, Rodel F, et al. Squamous cell carcinoma of the oropharynx: Ki-67 and p53 can identify patients at high risk for local recurrence after surgery and postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 2000;48(4):1041–1050.

    Article  CAS  PubMed  Google Scholar 

  15. Klussmann JP, Gultekin E, Weissenborn SJ, et al. Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. Am J Pathol. 2003;162(3):747–753.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Smeets SJ, Hesselink AT, Speel EJ, 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):2465–2472.

    Article  CAS  PubMed  Google Scholar 

  17. Stanley KK, Szewczuk E. Multiplexed tandem PCR: gene profiling from small amounts of RNA using SYBR Green detection. Nucleic Acids Res. 2005;33(20):e180.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Hong AM, Dobbins TA, Lee CS, et al. Use of cyclin D1 in conjunction with human papillomavirus status to predict outcome in oropharyngeal cancer. Int J Cancer. 2011;128(7):1532-1545.

    Article  CAS  PubMed  Google Scholar 

  19. Hong A, Jones D, Chatfield M, et al. HPV status of oropharyngeal cancer by combination HPV DNA/p16 testing: biological relevance of discordant results. Ann Surg Oncol. 2013;20 Suppl 3:S450-458.

    Article  PubMed  Google Scholar 

  20. Hong A, Jones D, Chatfield M, et al. HPV status of oropharyngeal cancer by combination HPV DNA/p16 testing: biological relevance of discordant results. Ann Surg Oncol. 2013;20 Suppl 3:450–458.

    Article  Google Scholar 

  21. Homma A, Furuta Y, Oridate N, et al. Prognostic significance of clinical parameters and biological markers in patients with squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy. Clin Cancer Res. 1999;5(4):801–806.

    CAS  PubMed  Google Scholar 

  22. Lavertu P, Adelstein DJ, Myles J, Secic M. P53 and Ki-67 as outcome predictors for advanced squamous cell cancers of the head and neck treated with chemoradiotherapy. Laryngoscope. 2001;111(11 Pt 1):1878–1892.

    Article  CAS  PubMed  Google Scholar 

  23. Roland NJ, Caslin AW, Bowie GL, Jones AS. Has the cellular proliferation marker Ki67 any clinical relevance in squamous cell carcinoma of the head and neck? Clin Otolaryngol Allied Sci. 1994;19(1):13–18.

    Article  CAS  PubMed  Google Scholar 

  24. Barber BR, Biron VL, Klimowicz AC, Puttagunta L, Cote DW, Seikaly H. Molecular predictors of locoregional and distant metastases in oropharyngeal squamous cell carcinoma. J Otolaryngol Head Neck Surg. 2013;42(1):53.

    Article  Google Scholar 

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ACKNOWLEDGMENT

The authors gratefully acknowledge the financial support of the Sydney Head and Neck Cancer Institute, Cure Cancer Australia, and Cancer Australia. We would also like to thank the clinicians at all the participating hospitals.

DISCLOSURE

The authors have no conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. Central Clinical School, The University of Sydney, Sydney, NSW, Australia

    Jia Liu PhD, Mei Zhang MD, Xiaoying Zhang PhD, Chris Milross MD & Angela Hong PhD

  2. Department of Radiation Oncology, Lifehouse, Sydney, NSW, Australia

    Jia Liu PhD, Mei Zhang MD, Chris Milross MD & Angela Hong PhD

  3. Prince of Wales Clinical School and Lowy Cancer Research Centre, University of NSW, Sydney, NSW, Australia

    Jia Liu PhD

  4. Department of Infectious Diseases and Immunology, The University of Sydney, Sydney, NSW, Australia

    Barbara Rose PhD, Deanna Jones BAppSci & Xiaoying Zhang PhD

  5. NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia

    Anne-Sophie Veillard MS

  6. Department of Anatomical Pathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia

    C. Soon Lee MD

  7. Bosch Institute, The University of Sydney, Sydney, NSW, Australia

    C. Soon Lee MD

Authors
  1. Jia Liu PhD
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  2. Mei Zhang MD
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  3. Barbara Rose PhD
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  4. Anne-Sophie Veillard MS
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  5. Deanna Jones BAppSci
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  6. Xiaoying Zhang PhD
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  7. C. Soon Lee MD
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  8. Chris Milross MD
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  9. Angela Hong PhD
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Corresponding author

Correspondence to Angela Hong PhD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10434_2014_4237_MOESM1_ESM.tif

Supplementary material 1 (TIFF 2701 kb) Representative images of immunohistochemical expression of Ki67 fromhigh-expressing (Left; Ki67-positive) and low-expressing (Right; Ki67-negative) OSCC. Immunohistochemical staining shows positive cells in brown colour,counterstained with Harris’ hematoxylin

Supplementary material 2 (DOCX 124 kb)

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Liu, J., Zhang, M., Rose, B. et al. Ki67 Expression has Prognostic Significance in Relation to Human Papillomavirus Status in Oropharyngeal Squamous Cell Carcinoma. Ann Surg Oncol 22, 1893–1900 (2015). https://doi.org/10.1245/s10434-014-4237-x

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  • DOI: https://doi.org/10.1245/s10434-014-4237-x

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