Elsevier

Urology

Volume 60, Issue 6, December 2002, Pages 1124-1130
Urology

Basic science
Prognostic value of proliferative activity and nuclear morphometry for progression in TaT1 urothelial cell carcinomas of the urinary bladder

https://doi.org/10.1016/S0090-4295(02)01906-4Get rights and content

Abstract

Objectives

To analyze the predictive power of Ki67 area% (Ki67), mitotic activity index (MAI), p53 area% (p53), and the mean area of the 10 largest nuclei (MNA10) for progression of stage in 195 primary consecutive TaT1 urothelial cell carcinomas of the urinary bladder.

Methods

Ki67- and p53-positive versus negative nuclei, MAI, and MNA10 using motorized systematic random sampling morphometry were determined. Kaplan-Meier curves and multivariate survival analysis (Cox model) were used to assess the prognostic value of the quantitative and classic clinicopathologic risk factors (age, sex, stage, grade, carcinoma in situ, multicentricity).

Results

Thirteen (6.7%) of the 195 patients had progression (0 [0%] of 36 low-risk, 1 [1.1%] of 85 intermediate-risk, and 12 [16.2%] of 74 high-risk patients). In univariate analysis (all variables), the strongest predictors with the highest hazard ratios were Ki67 (threshold 25.0%), MAI (threshold 30), and MNA10 (threshold 170 μm2). In multivariate analysis, the strongest independent combinations for progression—MNA10 (170 μm2) plus MAI (threshold 30) and MNA10 (threshold 170 μm2) plus Ki67 (threshold 25.0%)—overshadowed all other features. p53 was weaker but, combined with Ki67, still predicted progression fairly well. In the total group, the sensitivity, specificity, and positive and negative predictive values of MNA10-MAI and MNA10-Ki67 at the thresholds mentioned were 100%, 89%, 38%, and 100%, respectively. These feature combinations were also strongest prognostically in the high-risk treatment group.

Conclusions

The combined biomarkers MNA10-MAI or MNA10-Ki67 are accurate, well reproducible, and easy to assess progression predictors in all patients with TaT1 urothelial cell carcinomas, as well as in high-risk (bacille Calmette-Guérin-treated) patients.

Section snippets

Material and methods

Tissues from 195 primary consecutive UCCs, diagnosed from 1995 to 1997, were obtained by transurethral resection or biopsy. The mean patient age at the time of diagnosis was 67.6 years (range 34 to 92); all patients were white. The tissues were fixed in 4% formaldehyde, dehydrated, embedded in paraffin, and stained with hematoxylin-eosin; 4-μm sections were made. The worst differentiated area (measurement area, minimally 2 × 2 mm and maximally 5 × 5 mm) was carefully demarcated for the Ki67,

Results

Thirteen (6.7%) of the 195 patients had progression (0 [0%] of 36 low-risk, 1 [1.1%] of 85 intermediate-risk, and 12 [16.2%] of 74 high-risk patients). The median follow-up time in the nonprogression and progression groups was 53.1 months (range 31.0 to 69.6) and 12.1 months (range 2.2 to 31.4), respectively. Table II shows the single-variate progression-free survival results. Most features were significant, but the hazard ratios of the quantitative variables were higher in general than those

Comment

The results showed that quantitative proliferation features and MNA10 are stronger prognosticators than the classic clinicopathologic risk factors and confirmed previously indicated thresholds for MAI and Ki67.25, 26 It is not surprising that these thresholds were not exactly the same, because biologic variation among the patient groups may occur. Furthermore, the sampling and quantitation methods vary slightly (eg, systematic random sampling of nuclei was previously lacking, and the Ki67 and

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    This study was supported by grant 99-87 from the Stichting Bevordering Diagnostische Morfometrie (SBDM).

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