Quantitative molecular parameters to identify low-risk and high-risk early CIN lesions: role of markers of proliferative activity and differentiation and Rb availability

Arnold-Jan Kruse, Ivar Skaland, Emiel A Janssen, Suzanne Buhr-Wildhagen, Jan Klos, Mark J Arends, Jan P A Baak

Research output: Contribution to journalArticlepeer-review

Abstract

In early cervical intraepithelial neoplasia (CIN), the Ki67 stratification index 90th percentile (Si90) is a strong predictor of progression. This study was designed to further investigate the mechanisms leading to elevated Ki67 levels in lesions that progress and to try to improve the prognostic accuracy of Ki67-Si90. We studied 90 CIN lesions in which consensus existed regarding the grade between two experienced gynecologic pathologists. All CINs were p16-positive and showed Ki67 cell clusters above the lower third of the epithelium (both features diagnostic for CIN). Ki67 parameters, cell cycle regulators (Rb, p53, Cyclin A, E and D, p16, p21, p27, and telomerase), and cellular differentiation products (involucrin, CK13, CK14) were compared in the basal zone as well as the deeper and upper halves of the epithelium. Fifteen CIN cases (17%) progressed to a higher CIN grade, including 2 of 25 CIN1 (8%) and 13 of 65 CIN2 (20%) (these proportions of progressing CINs are similar to those in a large meta-analysis). Ki67 quantitation effectively predicted CIN progression as 0 of 40 "Ki67 low-risk" and 15 of 50 (30%) "Ki67 high-risk" lesions progressed. CIN progressors showed decreased Rb, CK13, CK14, and involucrin, but increased p21 and p27 expression. Ki67-Si90 and Rb in the deeper half of the epithelium (RbDeep) were the strongest multivariate independent predictors of progression. Ki67-Si90>0.57 was unfavorable, but only if it coexisted with RbDeep 0.57+RbDeep>45% or any Ki67-Si90 value below 0.57 were nonprogressors. In the high-risk progression subgroup (Ki67-Si90>0.57+RbDeep0.57). Increased RbDeep can reduce proliferation, including its upward spread. Combined quantitation of Ki67, Rb, CK13, and CK14 gives accurate information about the progression risk of early CIN lesions.
Original languageEnglish
Pages (from-to)100-9
Number of pages10
JournalInternational Journal of Gynecological Pathology
Volume23
Issue number2
Publication statusPublished - Apr 2004

Keywords

  • Adult
  • Cell Cycle Proteins
  • Cell Division
  • Cervical Intraepithelial Neoplasia
  • Disease Progression
  • Female
  • Humans
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Ki-67 Antigen
  • Neoplasm Invasiveness
  • Predictive Value of Tests
  • Retinoblastoma Protein
  • Risk Factors
  • Sensitivity and Specificity
  • Tumor Markers, Biological
  • Uterine Cervical Neoplasms

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