Tumor Biology

, Volume 37, Issue 2, pp 1521–1525 | Cite as

Determination of malignant potential of cervical intraepithelial neoplasia

  • E. Kudela
  • V. Holubekova
  • A. Farkasova
  • J. Danko


Basic diagnostic procedures in cervical cancer screening are able to set the diagnosis but they do not provide any information about the biological nature and behavior of lesions. The causal link of HPV infection and cervical cancer and discoveries of complex interactions between host and HPV genome opened new possibilities in molecular diagnostics. HPV DNA analysis, determination of viral load, detection of E6 and E7 mRNA transcripts, identifying of methylation profiles, genomic changes, miRNAs, and telomerase activity should be the right choice for exact diagnostics and prediction of behavior of premalignant lesions of the cervix. These findings set a completely new light not only in diagnostic but also in management and treatment of cervical dysplasia and cervical cancer.


Cervical intraepithelial neoplasia Cervical cancer HPV 



This work was supported by the project “Molecular diagnostics of cervical cancer” (ITMS: 26220220113); Project “Increasing opportunities for career growth in research and development in the field of medical sciences;” ITMS 26110230067, Comenius University Grants 303/2011, 242/2012, and 287/2015; and the VEGA Grant 1/0271/12 as well as the APVV-0224-12 Grant.

Compliance with ethical standards

Conflicts of interest



  1. 1.
    Ferlay J. GLOBOCAN 2012. Accessed 3 Dec 2015.
  2. 2.
    Snijders PJ, Steenbergen RD, Heideman DA, et al. HPV-mediated cervical carcinogenesis: concepts and clinical implications. J Pathol. 2006;208(2):152–64.CrossRefPubMedGoogle Scholar
  3. 3.
    Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Pathol. 1993;12(2):186–92.CrossRefGoogle Scholar
  4. 4.
    Munk AC, Kruse AJ, van Diermen B, et al. Cervical intraepithelial neoplasia grade 3 lesions can regress. APMIS. 2007;115(12):1409–14.CrossRefPubMedGoogle Scholar
  5. 5.
    Ovestad IT, Gudlauqsson E, Skaland I, et al. Local immune response in the microenvironment of CIN2-3 with and without spontaneous regression. Mod Pathol. 2010;23(9):1231–40.CrossRefPubMedGoogle Scholar
  6. 6.
    Herbeck G. et al. Atlas kolposkopie. (Book in Czech) Praha: Maxdorf s.r.o; 2011.Google Scholar
  7. 7.
    Discacciati MG, da Silva ID, Villa LL, et al. Outcome of expectant management of cervical intraepithelial neoplasia grade 2 in women followed for three months. Eur J Obstet Gynecol Reprod Biol. 2011;155(2):204–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Guedes AC, Brenna SM, Coelho SA, et al. p16INK4a expression does not predict the outcome of cervical intraepithelial neoplasia grade 2. Int J Gynecol Cancer. 2007;17(5):1099–103.CrossRefPubMedGoogle Scholar
  9. 9.
    Nasiell K, Nasiell M, Vaclavinkova V, et al. Behavior of moderate cervical dysplasia during long-term follow-up. Obstet Gynecol. 1983;61(5):609–14.PubMedGoogle Scholar
  10. 10.
    Castle PE, Schiffman M, Wheeler CM, et al. Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol. 2009;113(1):18–25.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wentzensen N, Walker J, Schiffman M, et al. Heterogenity of high grade cervical intraepithelial neoplasia related to HPV 16: implications for natural history and management. Int J Cancer. 2012;132(1):148–54.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J of Cancer. 2007;121(3):621–32.CrossRefGoogle Scholar
  13. 13.
    Jaisamrarn U, Castellsague X, Garland SM, et al. Natural history of progression of HPV infection to cervical lesion or clearance: analysis of the control arm of the large, randomized PATRICIA study. PLoS One. 2013;8(11):e79260.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Schiffman M, Rodriguez AC, Chen Z, et al. A population-based prospective study of carcinogenic human papillomavirus variant lineages, viral persistence, and cervical neoplasia. Cancer Res. 2010;70(8):3159–69.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chaturvedi AK, Katki HA, Hildesheim A, et al. Human papillomavirus infection with multiple types: pattern of coinfection and risk of cervical disease. J Infect Dis. 2011;203(7):910–20.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Thomsen LT, Frederiksen K, Munk C, et al. Long-term risk of cervical intraepithelial neoplasia grade 3 or worse according to high-risk human papillomavirus genotype and semi-quantitative viral load among 33,228 women with normal cervical cytology. Int J Cancer. 2015;137(1):193–203.CrossRefPubMedGoogle Scholar
  17. 17.
    Lee CH, Peng CY, Li RN, et al. Risk evaluation for the development of cervical intraepithelial neoplasia: development and validation of risk-scoring systems. Int J Cancer. 2015; 136(2):Google Scholar
  18. 18.
    Burger EA, Kornor H, Klemp M, et al. HPV mRNA tests for the detection of cervical intraepithelial neoplasia: a systematic review. Gynecol Oncol. 2011;120(3):430–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Monsonego J, Hudgens MG, Zerat L, et al. Risk assessment and clinical impact of liquid-based cytology, oncogenic human papillomavirus (HPV) DNA and mRNA testing in primary cervical screening (the FASE study). Gynecol Oncol. 2012;125(1):175–80.CrossRefPubMedGoogle Scholar
  20. 20.
    Wentzensen N, Sherman ME, Schiffman M, et al. Utility of methylation markers in cervical cancer early detection: appraisal of the state-of-the-science. Gynecol Oncol. 2009;112(2):293–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Farkas SA, Milutin-Gasperov N, Grce M, et al. Genome-wide DNA methylation assay reveals novel candidate biomarker genes in cervical cancer. Epigenetics. 2013;8(11):1213–25.CrossRefPubMedGoogle Scholar
  22. 22.
    Eijsink JJ, Yang N, Lendvai A, et al. Detection of cervical neoplasia by DNA methylation analysis in cervico-vaginal lavages, a feasibility study. Gynecol Oncol. 2011;120(2):280–3.CrossRefPubMedGoogle Scholar
  23. 23.
    de Wilde J, Kooter J, Overmeer RM, et al. hTERT promoter activity and CpG methylation in HPV-induced carcinogenesis. BMC Cancer. 2010;271(10):1–14.Google Scholar
  24. 24.
    Yin A, Zhang Q, Kong X, et al. JAM3 methylation status as a biomarker for diagnosis of preneoplastic and neoplastic lesions of the cervix. Oncotarget. 2015.Google Scholar
  25. 25.
    Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16:16–21.CrossRefGoogle Scholar
  26. 26.
    Kalantari M, Osann K, Calleja-Macias IE, et al. Methylation of human papillomavirus 16, 18, 31 and 45 L2 and L1 genes and the cellular DAPK gene: considerations for use as biomarkers of the progression of cervical neoplasia. Virology. 2014;448:314–21.CrossRefPubMedGoogle Scholar
  27. 27.
    Kirchhoff M, Rose H, Petersen BL, et al. Comparative genomic hybridization reveals non-random chromosomal aberrations in early preinvasive cervical lesions. Cancer Genet Cytogenet. 2001;129(1):47–51.CrossRefPubMedGoogle Scholar
  28. 28.
    Uhlik K, et al. Fluorescence in situ hybridization (FISH) or other in situ hybridization (ISH) testing of uterine cervical cells to predict precancer and cancer. Technology assessment report. Project ID: CANC0511. 2013. Tufts Evidence-based Practice Center.Google Scholar
  29. 29.
    Heselmeyer-Haddad K, Janz V, Castle PE, et al. Detection of genomic amplification of the human telomerase gene (TERC) in cytologic specimens as a genetic test for the diagnosis of cervical dysplasia. Am J Pathol. 2003;163:1405–16.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Heselmeyer-Haddad K, Sommerfeld K, White NM, et al. Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer. Am J Pathol. 2005;166(4):1229–38.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Andersson S, Sowjanya P, Wangsa D, et al. Detection of genomic amplification of the human telomerase gene TERC, a potential marker for triage of women with HPV-positive, abnormal Pap smears. Am J Pathol. 2009;175(5):1831–47.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kudela E, Farkasova A, Visnovsky J. Amplification of 3q26 and 5p15 regions in cervical intraepithelial neoplasia. Acta Obstet Gynecol Scand. 2014;93(10):997–1002.CrossRefPubMedGoogle Scholar
  33. 33.
    Gimenes F, Souza RP, de Abreu AL, et al. Simultaneous detection of human papillomavirus integration and c-MYC gene amplification in cervical lesions: an emerging marker for the risk to progression. Arch Gynecol Obstet. 2015.Google Scholar
  34. 34.
    Kuglik P, Kasikova K, Smetana J, et al. Molecular cytogenetic analyses of hTERC (3q26) and MYC (8q24) genes amplifications in correlation with oncogenic human papillomavirus infection in Czech patients with cervical intraepithelial neoplasia and cervical carcinomas. Neoplasma. 2015;62(1):130–9.CrossRefPubMedGoogle Scholar
  35. 35.
    de Freitas AC, Coimbra EC, Gomes Leitao MC. Molecular targets of HPV oncoproteins: potentional biomarkers for cervical carcinogenesis. Biochim Biophys Acta. 2014;1845(2):91–103.PubMedGoogle Scholar
  36. 36.
    Deftereos G, Corrie SR, Feng Q, et al. Expression of mir-21 and mir-143 in cervical specimens ranging from histologically normal through to invasive cancer. PLoS One. 2011;6:e28423.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Li B, Hu Y, Ye F, et al. Reduced miR-34a expression in normal cervical tissues and cervical lesions with high-risk human papillomavirus infection. Int J Gynecol Cancer. 2010;20(4):597–604.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • E. Kudela
    • 1
  • V. Holubekova
    • 2
  • A. Farkasova
    • 3
  • J. Danko
    • 1
  1. 1.Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine in MartinComenius UniversityBratislavaSlovak Republic
  2. 2.Biomedical Center Martin, Jessenius Faculty of Medicine in MartinComenius University BratislavaSlovak Republic
  3. 3.Institute of Pathological Anatomy, Jessenius Faculty of Medicine in MartinComenius UniversityBratislavaSlovak Republic

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