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

被引:47
作者
Kruse, AJ
Skaland, I
Janssen, EA
Buhr-Wildhagen, S
Klos, J
Arends, MJ
Baak, JPA
机构
[1] Free Univ Amsterdam, Amsterdam, Netherlands
[2] Univ Cambridge, Cambridge, England
[3] Rogaland Cent Hosp SIR, Dept Pathol, N-4068 Stavanger, Norway
关键词
CIN progression; Ki67; Rb; CK13; CK14; cell-cycle regulators; differentiation;
D O I
10.1097/00004347-200404000-00003
中图分类号
R71 [妇产科学];
学科分类号
100211 ;
摘要
In early cervical intraepithelial neoplasia (CIN), the M67 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, p 16, 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 <45% (progression risk = 47%). All early CINs with combined Si90>0.57+RbDeep>45% or any Ki(67)-Si-90 value below 0.57 were nonprogressors. In the high-risk progression subgroup (Ki(67)Si(90)>0.57+RbDeep<45%), all cases with combined CK14<50% and CK13<80% (both in the basal cell layer) (4% of all lesions) progressed. We hypothesize that onco-HPV E7 expression reduces Rb, causing increased and upward proliferation (Ki67-Si90>0.57). 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.
引用
收藏
页码:100 / 109
页数:10
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