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p16INK4A Is a Strong Biomarker for Cervical Intraepithelial Neoplasia and Invasive Cervical Carcinoma: A Reappraisal

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Abstract

To assess the role of p16INK4A, bcl–2, and p53 in cervical cancer screening, we conducted a retrospective trial of prospectively collected data. Sixty two women with abnormal Pap smears were subjected to colposcopy and biopsies from any abnormal lesion. Human papillomavirus (HPV)-DNA typing, histology, and immunochemistry for p16INK4A, bcl-2, and p53 were performed or these women. Histologic diagnosis was that of low grade squamous intraepithelial lesion (LSIL), high grade squamous intraepithelial lesion (HSIL), or cancer in all cases. Human papillomavirus strains were identified in 56 patients (90.3%). All HSIL and invasive cancer cases were HPVpositive. p16INK4A immunostaining yielded 100% sensitivity, 76% specificity, 61% positive predictive value, and 100% negative predictive value in cancer patients. The corresponding peformance indicators forHSIL patients were 75%, 62%, 32%, and 91%. bcl-2 and p53 expression did not correlate with worsening grades of cervical disease. We conclude that p16INK4A seems to be a sensitive biomarker o high grade cervical intraepithelial neoplasia and cancer.

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References

  1. Sano T, Oyama T, Kashiwabara K, Fukuda T, Nakajima T. Immunohistochemical overexpression of p16 protein associated with intact retinoblastoma protein expression in cervical cancer and cervical intraepithelial neoplasia. Pathol Int. 1998;48(8): 580–585.

    Article  CAS  PubMed  Google Scholar 

  2. Klaes R, Benner A, Friedrich T, et al. p16INK4a immunohis-tochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. Am J Surg Pathol. 2002;26(11):1389–1399.

    Article  PubMed  Google Scholar 

  3. Katsumata M, Siegel RM, Louie DC, et al. Differential effects of Bcl–2 on T and B cells in transgenic mice. Proc Natl Acad Sci U S A. 1992;89(23):11376–11380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tjalma W, Weyler J, Goovaerts G, De Pooter C, Van Marck E, van Dam P. Prognostic value of bcl–2 expression in patients with operable carcinoma of the uterine cervix. J Clin Pathol. 1997;50(1):33–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Crawford RA, Caldwell C, Iles RK, Lowe D, Shepherd JH, Chard T. Prognostic significance of the bcl–2 apoptotic family of proteins in primary and recurrent cervical cancer. Br J Cancer. 1998;78(2):210–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Spitkovsky D, Aengeneyndt F, Braspenning J, von Knebel Doeberitz M. p53-independent growth regulation of cervical cancer cells by the papillomavirus E6 oncogene. Oncogene. 1996;13(5):1027–1035.

    CAS  PubMed  Google Scholar 

  7. Scheffner M. Ubiquitin, E6-AP, and their role in p53 inacti-vation. Pharmacol Ther. 1998;78(3):129–139.

    Article  CAS  PubMed  Google Scholar 

  8. Zheng PS, Li SR, Iwasaka T, Song J, Cui MH, Sugimori H. Simultaneous detection by concensus multiplex PCR of high and low-risk and other types of human papilloma virus in clinical samples. Gynecol Oncol. 1995;58(2):179–183.

    Article  CAS  PubMed  Google Scholar 

  9. Bernard HU, Chan SY, Manos MM, et al. Identification and assesment of known and novel human papillomavirus by poly-merase chain reaction amplification, restriction fragment length polymorphism nucleotide sequence, and phylogenetic algorithms. J Infect Dis. 1994;170(5):1077–1085.

    Article  CAS  PubMed  Google Scholar 

  10. Vernon SD, Unger ER, Williams S. Comparison of human papillomavirus detection and typing by cycle sequencing, line blotting, and hybrid capture. J Clin Microbiol. 2000;38(2): 651–655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. DeMay RM. Failure of the Pap smear. In: The art & science of 3 cytopathology, Philip Rogers (Ed), Chicago: American Society for Clinical Pathology Press (ASCP Press); 1996:141–147.

  12. de Vet HC, Knipschild PG, Schouten HJ, et al. Interobserver variation in histopathological grading of cervical dysplasia. J Clin Epidemiol. 1990;43(12):1395–1398.

    Article  PubMed  Google Scholar 

  13. Robertson AJ, Anderson JM, Beck JS, et al. Observer variability in histopathological reporting of cervical biopsy specimens. J Clin Pathol. 1989;42(3):231–238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dehn D, Torkko KC, Shroyer KR. Human papillomavirus testing and molecular markers of cervical dysplasia and carcinoma. Cancer. 2007;111(1):1–14.

    Article  CAS  PubMed  Google Scholar 

  15. Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer. 2001;92(2): 276–284.

    Article  CAS  PubMed  Google Scholar 

  16. Murphy N, Ring M, Killalea AG, et al. p16INK4A as a marker for cervical dyskaryosis: CIN and cGIN in cervical biopsies and ThinPrep smears. J Clin Pathol. 2003;56(1): 56–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Volgareva G, Zavalishina L, Andreeva Y, et al. Protein p16 as a marker of dysplastic and neoplastic alterations in cervical epithelial cells. BMC Cancer. 2004;4:58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Guo M, Hu L, Baliga M, He Z, Hughson MD. The predictive value of p16(INK4a) and hybrid capture 2 human papilloma-virus testing for high-grade cervical intraepithelial neoplasia. Am J Clin Pathol. 2004;122(6):894–901.

    Article  CAS  PubMed  Google Scholar 

  19. Hu L, Guo M, He Z, Thornton J, McDaniel LS, Hughson MD. Human papillomavirus genotyping and p16INK4a expression in cervical intraepithelial neoplasia of adolescents. Mod Pathol. 2005;18(2):267–273.

    Article  CAS  PubMed  Google Scholar 

  20. Qiao X, Bhuiya TA, Spitzer M. Differentiating high-grade cervical intraepithelial lesion from atrophy in postmenopausal women using Ki–67, cyclin E, and p16 immunohistochemical analysis. J Low Genit Tract Dis. 2005;9(2):100–107.

    Article  PubMed  Google Scholar 

  21. Lin ZH, Shen XH, Jin Z, et al. Human papillomavirus geno-typing by oligonucleotide microarray and p16 expression in uterine cervical intraepithelial neoplasm and in invasive carcinoma in Korean women. Pathol Int. 2005;55(8):491–496.

    Article  CAS  PubMed  Google Scholar 

  22. Lambert AP, Anschau F, Schmitt VM. p16INK4A expression in cervical premalignant and malignant lesions. Exp Mol Pathol. 2006;80(2):192–196.

    Article  CAS  PubMed  Google Scholar 

  23. Queiroz C, Silva TC, Alves VA, et al. p16(INK4a) expression as a potential prognostic marker in cervical pre-neoplastic and neoplastic lesions. Pathol Res Pract. 2006;202(2):77–83.

    Article  CAS  PubMed  Google Scholar 

  24. Benevolo M, Mottolese M, Marandino F, et al. Immunohis-tochemical expression of p16(INK4a) is predictive of HR-HPV infection in cervical low-grade lesions. Mod Pathol. 2006;19(3):384–391.

    Article  CAS  PubMed  Google Scholar 

  25. Ishikawa M, Fujii T, Saito M, et al. Overexpression of p16 INK4a as an indicator for human papillomavirus oncogenic activity in cervical squamous neoplasia. Int J Gynecol Cancer. 2006;16(1):347–353.

    Article  CAS  PubMed  Google Scholar 

  26. Eleutério J Jr, Giraldo PC, Gonçalves AK, et al. Prognostic markers of high-grade squamous intraepithelial lesions: the role of p16INK4a and high-risk human papillomavirus. Acta Obstet Gynecol Scand. 2007;86(1):94–98.

    Article  PubMed  Google Scholar 

  27. Guedes AC, Brenna SM, Coelho SA, Martinez EZ, Syrjänen KJ, Zeferino LC. p16(INK4a) Expression does not predict the outcome of cervical intraepithelial neoplasia grade 2. Int J Gynecol Cancer. 2007;17(5):1099–1103.

    Article  CAS  PubMed  Google Scholar 

  28. Focchi GR, Silva ID, Nogueira-de-Souza NC, Dobo C, Oshima CT, Stavale JN. Immunohistochemical expression of p16(INK4A) in normal uterine cervix, nonneoplastic epithelial lesions, and low-grade squamous intraepithelial lesions. J Low Genit Tract Dis. 2007;11(2):98–104.

    Article  PubMed  Google Scholar 

  29. Bahnassy AA, Zekri AR, Saleh M, Lotayef M, Moneir M, Shawki O. The possible role of cell cycle regulators in multi-step process of HPV-associated cervical carcinoma. BMC Clin Pathol. 2007;7:4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Yildiz IZ, Usubütün A, Firat P, Ayhan A, Küçükali T. Efficiency of immunohistochemical p16 expression and HPV typing in cervical squamous intraepithelial lesion grading and review of the p16 literature. Pathol Res Pract. 2007;203(6): 445–449.

    Article  CAS  PubMed  Google Scholar 

  31. Monsonego J, Pollini G, Evrard MJ, et al. p16(INK4a) immu-nocytochemistry in liquid-based cytology samples in equivocal Pap smears: added value in management of women with equivocal Pap smear. Acta Cytol. 2007;51(5):755–766.

    Article  PubMed  Google Scholar 

  32. Liu H, Shi J, Wilkerson M, Huang Y, et al. Immunohisto-chemical detection of p16INK4a in liquid-based cytology specimens on cell block sections. Cancer. 2007;111(2):74–82.

    Article  CAS  PubMed  Google Scholar 

  33. Feng W, Xiao J, Zhang Z, et al. Senescence and apoptosis in carcinogenesis of cervical squamous carcinoma. Mod Pathol. 2007;20(9):961–966.

    Article  CAS  PubMed  Google Scholar 

  34. El-Ghobashy AA, Shaaban AM, Innes J, Prime W, Herrington CS. Differential expression of cyclin-dependent kinase inhibitors and apoptosis-related proteins in endocervi-cal lesions. Eur J Cancer. 2007;43(13):2011–2018.

    Article  CAS  PubMed  Google Scholar 

  35. Milde-Langosch K, Albrecht K, Joram S, Schlechte H, Giessing M, Loning T. Presence and persistence of HPV infection and p53 mutation in cancer of the cervix uteri and the vulva. Int J Cancer. 1995;63(5):639–645.

    Article  CAS  PubMed  Google Scholar 

  36. Avall-Lundqvist EH, Silfeverswand C, Aspenblad U, Nilsson BR, Auer GU. The impact of tumor angiogenesis, p53 overexpression and proliferative activity (MIB-1) on survival in squamous cervical carcinoma. Eur J Cancer. 1997;33(11):1799–1804.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to George A. Partsinevelos MD.

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Haidopoulos, D., Partsinevelos, G.A., Vlachos, G.D. et al. p16INK4A Is a Strong Biomarker for Cervical Intraepithelial Neoplasia and Invasive Cervical Carcinoma: A Reappraisal. Reprod. Sci. 16, 685–693 (2009). https://doi.org/10.1177/1933719109334259

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