ORIGINAL ARTICLE

Proliferation markers and DNA content analysis in urinary bladder TaT1 urothelial cell carcinomas: identification of subgroups with low and high stage progression risks

M G W Bol¹, J P A Baak¹, B van Diermen¹, S Buhr-Wildhagen¹, E A M Janssen¹, K H Kjellevold¹, A J Kruse¹, O Mestad², P Øgreid²

¹ Department of Pathology, SIR Hospital, 4068 Stavanger, Norway
² Department of Urology, SIR Hospital
³ Free University, De Boelelaan 1105, 1081 HV, Amsterdam, The Netherlands

Correspondence to:
Correspondence to:
Professor J P A Baak, Department of Pathology, SIR Hospital, Post Box 8100, Armauer Hansensvei 20, 4068 Stavanger, Norway;
baja{at}sir.no

Aims: To evaluate whether in situ biomarkers Ki67, mitotic activity index (MAI), p53, mean area of the 10 largest nuclei (MNA10), and whole genome DNA ploidy by flow and image cytometry (FCM and ICM, respectively) have independent prognostic value in urinary bladder urothelial cell carcinomas (UCs).

Methods: Ki67 and p53 immunoquantitation was performed in TaT1 consensus diagnosis UCs. MAI and MNA10 were also determined. Single cell suspensions were stained (DAPI for FCM; Feulgen for ICM). There was enough material for all measurements in 171 cases. Kaplan-Meier curves and multivariate survival analysis (Cox) were used to assess the prognostic value of all features (including classic clinicopathological risk factors, such as stage, grade, multicentricity, carcinoma in situ).

Results: Thirteen (7.6%) patients progressed. Of the classic factors, grade was strongly prognostic in univariate analysis, as were all the biomarkers. In multivariate analysis, the strongest independent combinations for progression were MNA10 (threshold (T) = 170.0 µm²) plus MAI (T = 30), or MNA10 (T = 170.0 µm²) plus Ki67(T = 25.0%). p53 (T = 35.2%) plus Ki67 (T = 25.0%) also predicted progression well, with high hazard ratios, but p53 measurements were not as reproducible as the other features. The prognostic value of the quantitative biomarkers exceeded that of the classic risk factors and DNA ploidy. The sensitivity, specificity, positive, and negative predictive values of MNA10/MAI or MNA10/Ki67 at the thresholds mentioned were 100%, 79%, 57%, and 100%, respectively. These feature combinations were also strongest prognostically in the high risk treatment subgroup.

Conclusions: The combined biomarkers MNA10/Ki67 or MNA10/MAI are more accurate and reproducible predictors of stage progression in TaT1 UCs than classic prognostic risk factors and DNA ploidy.

Keywords: urinary bladder carcinoma; progression; proliferation; image cytometry; flow cytometry; morphometry; Ki67; p53

Abbreviations: CV, coefficient of variation; DI, DNA index; FCM, flow cytometry; FOV, field of vision; H&E, haematoxylin and eosin; HR, hazards ratio; ICM, image cytometry; IHC, immunohistochemistry; MAI, mitotic activity index; MNA10, mean area of the 10 largest nuclei; SPF, S phase fraction; T, threshold; UC, urothelial cell carcinoma; WHO, World Health Organisation

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