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膀胱TaT1尿路上皮细胞癌中的增殖标志物与DNA含量分析：低、高分期进展风险亚组的识别

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

作者信息

Bol M G W, Baak J P A, van Diermen B, Buhr-Wildhagen S, Janssen E A M, Kjellevold K H, Kruse A J, Mestad O, Øgreid P

机构信息

Department of Pathology, SIR Hospital, 4068 Stavanger, Norway.

出版信息

J Clin Pathol. 2003 Jun;56(6):447-52. doi: 10.1136/jcp.56.6.447.

DOI:10.1136/jcp.56.6.447
PMID:12783972
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1769973/
Abstract

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 micro m(2)) plus MAI (T = 30), or MNA10 (T = 170.0 micro m(2)) 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.

摘要

目的：评估原位生物标志物Ki67、有丝分裂活性指数（MAI）、p53、10个最大细胞核的平均面积（MNA10）以及分别通过流式细胞术和图像细胞术（FCM和ICM）检测的全基因组DNA倍性在膀胱尿路上皮癌（UCs）中是否具有独立的预后价值。 方法：对TaT1共识诊断的UCs进行Ki67和p53免疫定量分析。同时测定MAI和MNA10。制备单细胞悬液并进行染色（FCM用DAPI染色；ICM用福尔根染色）。171例患者有足够的样本用于所有测量。采用Kaplan-Meier曲线和多因素生存分析（Cox）评估所有特征（包括经典的临床病理危险因素，如分期、分级、多中心性、原位癌）的预后价值。 结果：13例（7.6%）患者病情进展。在单因素分析中，经典因素中的分级以及所有生物标志物均具有较强的预后意义。在多因素分析中，进展的最强独立组合是MNA10（阈值（T）=170.0μm²）加MAI（T = 30），或MNA10（T = 170.0μm²）加Ki67（T = 25.0%）。p53（T = 35.2%）加Ki67（T = 25.0%）也能很好地预测进展，风险比很高，但p53测量的重复性不如其他特征。定量生物标志物的预后价值超过了经典危险因素和DNA倍性。上述阈值下MNA10/MAI或MNA10/Ki67的敏感性、特异性、阳性和阴性预测值分别为100%、79%、57%和100%。这些特征组合在高风险治疗亚组中预后意义也最强。 结论：与经典预后危险因素和DNA倍性相比，联合生物标志物MNA10/Ki67或MNA10/MAI是TaT1期UCs更准确、可重复的分期进展预测指标。

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[1]
Proliferation markers and DNA content analysis in urinary bladder TaT1 urothelial cell carcinomas: identification of subgroups with low and high stage progression risks.

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[2]
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引用本文的文献

[1]
Study of Proliferating cell nuclear antigen expression and Angiogenesis in Urothelial neoplasms: Correlation with tumor grade and stage.

Urol Ann. 2018

[2]
High Ki-67 Immunohistochemical Reactivity Correlates With Poor Prognosis in Bladder Carcinoma: A Comprehensive Meta-Analysis with 13,053 Patients Involved.

Medicine (Baltimore). 2016-4

[3]
Role of morphometry and proliferative parameters in grading of urothelial neoplasms.

Cent European J Urol. 2015

[4]
Cell-cycle control in urothelial carcinoma: large-scale tissue array analysis of tumor tissue from Maine and Vermont.

Cancer Epidemiol Biomarkers Prev. 2012-7-3

[5]
Diagnostic algorithm for papillary urothelial tumors in the urinary bladder.

Virchows Arch. 2008-4

[6]
Ki-67 MIB1 labelling index and the prognosis of primary TaT1 urothelial cell carcinoma of the bladder.

J Clin Pathol. 2006-1

[7]
DNA ploidy as a prognostic factor in muscle invasive transitional cell carcinoma of the bladder.

Urol Res. 2005-2

本文引用的文献

[1]
Reproducibility and prognostic variability of grade and lamina propria invasion in stages Ta, T1 urothelial carcinoma of the bladder.

J Urol. 2003-4

[2]
Prognostic value of proliferative activity and nuclear morphometry for progression in TaT1 urothelial cell carcinomas of the urinary bladder.

Urology. 2002-12

[3]
The framework of pathology: good laboratory practice by quantitative and molecular methods.

J Pathol. 2002-11

[4]
Ki67 protein: the immaculate deception?

Histopathology. 2002-1

[5]
Improved objectivity of grading of T(A,1) transitional cell carcinomas of the urinary bladder by quantitative nuclear and proliferation related features.

J Clin Pathol. 2001-11

[6]
Diagnosis of bladder cancer with urinary cytology, immunocytology and DNA-image-cytometry.

Anal Cell Pathol. 2001

[7]
Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade.

J Pathol. 2001-7

[8]
Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy.

J Urol. 2001-4

[9]
Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma.

Cancer. 2000-12-1

[10]
Evaluation of P53 protein overexpression, Ki67 proliferative activity and mitotic index as markers of tumour recurrence in superficial transitional cell carcinoma of the bladder.

Eur Urol. 2000-9

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