Asian Pacific Journal of Cancer Prevention

  • 제17권8호
  • /
  • Pages.4049-4057
  • /
  • 2016
  • /
  • 1513-7368(pISSN)
  • /
  • 2476-762X(eISSN)
아시아태평양암예방학회 (Asian Pacific Journal of Cancer Prevention)
권호 표지
DOI QR코드

DOI QR Code

p16 - a Possible Surrogate Marker for High-Risk Human Papillomaviruses in Oral Cancer?

  • Sritippho, Thanun (Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University) ;
  • Pongsiriwet, Surawut (Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University) ;
  • Lertprasertsuke, Nirush (Department of Pathology, Faculty of Medicine, Chiang Mai University) ;
  • Buddhachat, Kittisak (Department of Biology, Faculty of Science, Naresuan University) ;
  • Sastraruji, Thanapat (Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University) ;
  • Iamaroon, Anak (Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University)
  • 발행 : 2016.08.01
⟨ 이전 논문 다음 논문 ⟩

초록

Background: High-risk human papillomaviruses (HR-HPV), particularly types 16 and 18, have been found to play an important role in head and neck cancer, including oropharyngeal squamous cell carcinoma (OPSCC) and oral squamous cell carcinoma (OSCC). p16, a cell cycle inhibitor, has been postulated as a surrogate marker for HR-HPV, since p16 is aberrantly overexpressed in such lesions, especially in HR-HPV-positive OPSCC. However, p16 as a surrogate marker for HR-HPV infection in cancers of the oral cavity remains controversial. Objective: The objectives of the study were to investigate the expression of p16 and the presence of HR-HPV in OSCC and oral verrucous carcinoma (VC) and to determine if p16 could be used as a surrogate marker for HR-HPV. Materials and Methods: Forty one formalin-fixed, paraffin-embedded tissues of OSCC (n=37) or VC (n=4) with clinical and histopathologic data of each case were collected. Expression of p16 was determined by immunohistochemistry, focusing on both staining intensity and numbers of positive cells. The presence of HPV types 16 and 18 was detected by polymerase chain reaction (PCR). Descriptive statistics were employed to describe the demographic, clinical, and histopathologic parameters. Associations between p16 overexpression, HR-HPV and all variables were determined by Fisher's exact test, odds ratios (ORs) and corresponding 95% confidence intervals (CIs). In addition, the use of p16 as a surrogate marker for HR-HPV was analyzed by sensitivity and specificity tests. Results: p16 was overexpressed in 8/37 cases (21.6%) of OSCC and 2/4 cases (50%) of VC. HPV-16 was detected in 4/34 OSCC cases (11.8%) and HPV-18 was detected in 1/34 OSCC cases (2.9%). Co-infection of HPV-16/18 was detected in 1/4 VC cases (25%). Both p16 overexpression and HR-HPV were significantly associated with young patients with both OSCC and VC (p<0.05, OR 20, 95% CI 1.9-211.8; p<0.05, OR 23.3, 95% CI 2.4-229.7, respectively). p16 was able to predict the presence of HPV-16/18 in OSCC with 40% sensitivity and 79.3% specificity and in VC with 100% sensitivity and 66.7% specificity, respectively. Conclusions: p16 overexpression was found in 24.4% of both OSCC and VC. HR-HPV, regardless of type, was detected in 15.8% in cases of OSCC and VC combined. The results of sensitivity and specificity tests suggest that p16 can be used as a surrogate marker for HR-HPV in OSCC and VC.

키워드

참고문헌

  1. Abogunrin S, Di Tanna G, Keeping S, et al (2014). Prevalence of human papillomavirus in head and neck cancers in European populations: a meta-analysis. BMC Cancer, 14, 1-11. https://doi.org/10.1186/1471-2407-14-1
  2. American Cancer Society (2014). Cancer Facts & Figures 2014. American Cancer Society, 1-68.
  3. Antonsson A, Neale RE, Boros S, et al (2015). Human papillomavirus status and p16(INK4A) expression in patients with mucosal squamous cell carcinoma of the head and neck in Queensland, Australia. Cancer Epidemiol, 39, 174-81. https://doi.org/10.1016/j.canep.2015.01.010
  4. Bixofis RB, Sassi LM, Patussi C, et al (2014). Significance of p16 positive expression in oropharyngeal cancers. Asian Pac J Cancer Prev, 15, 10289-92.
  5. Brouwer AF, Eisenberg MC, Meza R (2016). Age effects and temporal trends in HPV-related and HPV-unrelated oral cancer in the United States: a multistage carcinogenesis modeling analysis. PLoS ONE, 11, 1-17.
  6. Cao F, Zhang W, Zhang F, et al (2014). Prognostic significance of high-risk human papillomavirus and p16(INK4A) in patients with esophageal squamous cell carcinoma. Int J Clin Exp Med, 7, 3430-8.
  7. Chandarana SP, Lee JS, Chanowski EJ, et al (2013). Prevalence and predictive role of p16 and epidermal growth factor receptor in surgically treated oropharyngeal and oral cavity cancer. Head Neck, 35, 1083-90. https://doi.org/10.1002/hed.23087
  8. Chung CH, Zhang Q, Kong CS, 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, 3930-8. https://doi.org/10.1200/JCO.2013.54.5228
  9. Dragomir LP, Simionescu C, Margaritescu C, et al (2012). P53, p16 and Ki67 immunoexpression in oral squamous carcinomas. Rom J Morphol Embryol, 53, 89-93.
  10. Elango KJ, Suresh A, Erode EM, et al (2011). Role of human papilloma virus in oral tongue squamous cell carcinoma. Asian Pac J Cancer Prev, 12, 889-96.
  11. Fregonesi PA, Teresa DB, Duarte RA, et al (2003). p16(INK4A) immunohistochemical overexpression in premalignant and malignant oral lesions infected with human papillomavirus. J Histochem Cytochem, 51, 1291-7. https://doi.org/10.1177/002215540305101006
  12. Ghittoni R, Accardi R, Chiocca S, et al (2015). Role of human papillomaviruses in carcinogenesis. Ecancermedicalscience, 9, 526.
  13. Gonzales-Moles MA, Rodriguez-Archilla A, Ruiz-Avila I, et al (2002). p16 Expression in squamous carcinomas of the tongue. Onkologie, 25, 433-6.
  14. Greer RO, Jr., Meyers A, Said SM, et al (2008). Is p16(INK4a) protein expression in oral ST lesions a reliable precancerous marker? Int J Oral Maxillofac Surg, 37, 840-6. https://doi.org/10.1016/j.ijom.2008.05.015
  15. Grobe A, Hanken H, Kluwe L, et al (2013). Immunohistochemical analysis of p16 expression, HPV infection and its prognostic utility in oral squamous cell carcinoma. J Oral Pathol Med, 42, 676-81. https://doi.org/10.1111/jop.12086
  16. Gronhoj Larsen C, Gyldenlove M, Jensen DH, et al (2014). Correlation between human papillomavirus and p16 overexpression in oropharyngeal tumours: a systematic review. Br J Cancer, 110, 1587-94. https://doi.org/10.1038/bjc.2014.42
  17. Hong AM, Grulich AE, Jones D, et al (2010). Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets. Vaccine, 28, 3269-72. https://doi.org/10.1016/j.vaccine.2010.02.098
  18. Hubbers CU, Akgul B (2015). HPV and cancer of the oral cavity. Virulence, 6, 244-8. https://doi.org/10.1080/21505594.2014.999570
  19. Iamaroon A (2016). Targeted therapy of oral cancer: a focus on COX-2 inhibitors. J Dent Assoc Thai, 66, 1-10.
  20. Iamaroon A, Khemaleelakul U, Pongsiriwet S, et al (2004b). Coexpression of p53 and Ki67 and lack of EBV expression in oral squamous cell carcinoma. J Oral Pathol Med, 33, 30-6. https://doi.org/10.1111/j.1600-0714.2004.00192.x
  21. Iamaroon A, Pattanaporn K, Pongsiriwet S, et al (2004a). Analysis of 587 cases of oral squamous cell carcinoma in northern Thailand with a focus on young people. Int J Oral Maxillofac Surg, 33, 84-8. https://doi.org/10.1054/ijom.2003.0503
  22. Isayeva T, Li Y, Maswahu D, et al (2012). Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol, 6, 104-20. https://doi.org/10.1007/s12105-012-0368-1
  23. Johnson NW, Jayasekara P, Amarasinghe AA (2011). Squamous cell carcinoma and precursor lesions of the oral cavity: epidemiology and aetiology. Periodontol 2000, 57, 19-37. https://doi.org/10.1111/j.1600-0757.2011.00401.x
  24. Khovidhunkit SO, Buajeeb W, Sanguansin S, et al (2008). Detection of human papillomavirus in oral squamous cell carcinoma, leukoplakia and lichen planus in Thai patients. Asian Pac J Cancer Prev, 9, 771-5.
  25. Komolmalai N, Chuachamsai S, Tantiwipawin S, et al (2015). Ten-year analysis of oral cancer focusing on young people in northern Thailand. J Oral Sci, 57, 327-34. https://doi.org/10.2334/josnusd.57.327
  26. Kreimer AR, Clifford GM, Boyle P, et al (2005). Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev, 14, 467-75. https://doi.org/10.1158/1055-9965.EPI-04-0551
  27. Laco J, Nekvindova J, Novakova V, et al (2012). Biologic importance and prognostic significance of selected clinicopathological parameters in patients with oral and oropharyngeal squamous cell carcinoma, with emphasis on smoking, protein p16INK4a expression, and HPV status. Neoplasma, 59, 398-408. https://doi.org/10.4149/neo_2012_052
  28. Liu SZ, Zandberg DP, Schumaker LM, et al (2015). Correlation of p16 expression and HPV type with survival in oropharyngeal squamous cell cancer. Oral Oncol, 51, 862-9. https://doi.org/10.1016/j.oraloncology.2015.06.014
  29. Muirhead DM (2006). Correlation of clinicopathological features with immunohistochemical expression of cell cycle regulatory proteins p16 and retinoblastoma: distinct association with keratinisation and differentiation in oral cavity squamous cell carcinoma. J Clin Pathol, 59, 711-5. https://doi.org/10.1136/jcp.2005.030502
  30. Nakahara Y, Shintani S, Mihara M, et al (2001). High frequency of homozygous deletion and methylation of p16(INK4A) gene in oral squamous cell carcinomas. Cancer Lett, 163, 221-8. https://doi.org/10.1016/S0304-3835(00)00699-6
  31. Nasman A, Attner P, Hammarstedt L, et al (2009). Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer, 125, 362-6. https://doi.org/10.1002/ijc.24339
  32. Ndiaye C, Mena M, Alemany L, 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, 1319-31. https://doi.org/10.1016/S1470-2045(14)70471-1
  33. Nemes JA, Deli L, Nemes Z, et al (2006). Expression of p16(INK4A), p53, and Rb proteins are independent from the presence of human papillomavirus genes in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 102, 344-52. https://doi.org/10.1016/j.tripleo.2005.10.069
  34. Pande P, Mathur M, Shukla NK, et al (1998). pRb and p16 protein alterations in human oral tumorigenesis. Oral Oncol, 34, 396-403. https://doi.org/10.1016/S1368-8375(98)00024-4
  35. Pannone G, Santoro A, Papagerakis S, et al (2011). The role of human papillomavirus in the pathogenesis of head & neck squamous cell carcinoma: an overview. Infect Agent Cancer, 6, 1-11. https://doi.org/10.1186/1750-9378-6-1
  36. Patil S, Rao RS, Amrutha N, et al (2014). Analysis of human papilloma virus in oral squamous cell carcinoma using p16: An immunohistochemical study. J Int Soc Prev Community Dent, 4, 61-6. https://doi.org/10.4103/2231-0762.131269
  37. Perez-Sayans M, Suarez-Penaranda JM, Gayoso-Diz P, et al (2011). p16(INK4a)/CDKN2 expression and its relationship with oral squamous cell carcinoma is our current knowledge enough? Cancer Lett, 306, 134-41. https://doi.org/10.1016/j.canlet.2011.02.039
  38. Pirker R, Pereira JR, von Pawel J, et al (2012). EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol, 13, 33-42. https://doi.org/10.1016/S1470-2045(11)70318-7
  39. Prakash P, Khandare M, Kumar M, et al (2013). Immunohistochemical detection of p16(INK4a) in leukoplakia and oral squamous cell carcinoma. J Clin Diagn Res, 7, 2793-5.
  40. Ramshankar V, Soundara VT, Shyamsundar V, et al (2014). Risk stratification of early stage oral tongue cancers based on HPV status and p16 immunoexpression. Asian Pac J Cancer Prev, 15, 8351-9. https://doi.org/10.7314/APJCP.2014.15.19.8351
  41. Rautava J, Syrjanen S (2012). Biology of human papillomavirus infections in head and neck carcinogenesis. Head Neck Pathol, 6, 3-15. https://doi.org/10.1007/s12105-012-0367-2
  42. Sawazaki-Calone I, Rangel A, Bueno AG, et al (2015). The prognostic value of histopathological grading systems in oral squamous cell carcinomas. Oral Dis, 21, 755-61. https://doi.org/10.1111/odi.12343
  43. Shaw R, Robinson M (2011). The increasing clinical relevance of human papillomavirus type 16 (HPV-16) infection in oropharyngeal cancer. Br J Oral Maxillofac Surg, 49, 423-9. https://doi.org/10.1016/j.bjoms.2010.06.023
  44. Shima K, Kobayashi I, Saito I, et al (2000). Incidence of human papillomavirus 16 and 18 infection and p53 mutation in patients with oral squamous cell carcinoma in Japan. Br J Oral Maxillofac Surg, 38, 445-50. https://doi.org/10.1054/bjom.2000.0162
  45. Singhi AD, Westra WH (2010). 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, 116, 2166-73.
  46. 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, 2465-72. https://doi.org/10.1002/ijc.22980
  47. Snietura M, Jaworska M, Piglowski W, et al (2010). High-risk HPV DNA status and p16 (INK4a) expression as prognostic markers in patients with squamous cell cancer of oral cavity and oropharynx. Pol J Pathol, 61, 133-9.
  48. Sritippho T, Chotjumlong P, Iamaroon A (2015). Roles of human papillomaviruses and p16 in oral cancer. Asian Pac J Cancer Prev, 16, 6193-200. https://doi.org/10.7314/APJCP.2015.16.15.6193
  49. Stephen JK, Divine G, Chen KM, et al (2013). Significance of p16 in site-specific HPV positive and HPV negative head and neck squamous cell carcinoma. Cancer Clin Oncol, 2, 51-61.
  50. Suzuki H, Sugimura H, Hashimoto K (2006). p16INK4A in oral squamous cell carcinomas--a correlation with biological behaviors: immunohistochemical and FISH analysis. J Oral Maxillofac Surg, 64, 1617-23. https://doi.org/10.1016/j.joms.2005.11.097
  51. Syrjanen S, Lodi G, von Bultzingslowen I, et al (2011). Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review. Oral Dis, 17, 58-72. https://doi.org/10.1111/j.1601-0825.2011.01792.x
  52. Tarakji B, Kujan O, Nassani MZ (2010). An immunohistochemical study of the distribution of p 16 protein in oral mucosa in smokers, non-smokers and in frictional keratosis. Med Oral Patol Oral Cir Bucal, 15, 681-4.
  53. Vargas-Ferreira F, Nedel F, Etges A, et al (2012). Etiologic factors associated with oral squamous cell carcinoma in non-smokers and non-alcoholic drinkers: a brief approach. Braz Dent J, 23, 586-90. https://doi.org/10.1590/S0103-64402012000500020
  54. Zhang ZY, Sdek P, Cao J, et al (2004). Human papillomavirus type 16 and 18 DNA in oral squamous cell carcinoma and normal mucosa. Int J Oral Maxillofac Surg, 33, 71-4. https://doi.org/10.1054/ijom.2002.0443
  55. Zhao D, Xu QG, Chen XM, et al (2009). Human papillomavirus as an independent predictor in oral squamous cell cancer. Int J Oral Sci, 1, 119-25. https://doi.org/10.4248/IJOS.09015