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

Aims: To evaluate whether ki-67 labelling index (LI) has independent prognostic value for survival of patients with bladder urothelial tumours graded according to the 2004 World Health Organisation classification. Methods: Ki-67 LI was evaluated in 164 cases using the grid counting method. Non-invasive (stage Ta) tumours were: papilloma (n = 5), papillary urothelial neoplasia of low malignant potential (PUNLMP; n = 26), and low (LG; n = 34) or high grade (HG; n = 15) papillary urothelial carcinoma. Early invasive (stage T1) tumours were: LG (n = 58) and HG (n = 26) carcinoma. Statistical analysis included Fisher and χ2 tests, and mean comparisons by ANOVA and t test. Univariate and multivariate survival analyses were performed according to the Kaplan–Meier method with log rank test and Cox’s proportional hazard method. Results: Mean ki-67 LI increased from papilloma to PUNLMP, LG, and HG in stage Ta (p<0.0001) and from LG to HG in stage T1 (p = 0.013) tumours. High tumour proliferation (>13%) was related to greater tumour size (p = 0.036), recurrence (p = 0.036), progression (p = 0.035), survival (p = 0.054), and high p53 accumulation (p = 0.015). Ki-67 LI and tumour size were independent predictors of disease free survival (DFS), but only ki-67 LI was related to progression free survival (PFS). Cancer specific overall survival (OS) was related to ki-67 LI, tumour size, and p27kip1 downregulation. Ki-67 LI was the main independent predictor of DFS (p = 0.0005), PFS (p = 0.0162), and cancer specific OS (p = 00195). Conclusion: Tumour proliferation measured by Ki-67 LI is related to tumour recurrence, stage progression, and is an independent predictor of DFS, PFS, and cancer specific OS in TaT1 bladder urothelial cell carcinoma.

[1]  R. Dhir.  Prognostic Factors in Survival of Patients With Stage Ta and T1 Bladder Urothelial Tumors: The Role of G1-S Modulators (p53, p21Waf1, p27Kip1, Cyclin D1, and Cyclin D3), Proliferation Index, and Clinicopathologic Parameters , 2006 .

[2]  R. Montironi,et al.  Prognostic factors in survival of patients with stage Ta and T1 bladder urothelial tumors: the role of G1-S modulators (p53, p21Waf1, p27Kip1, cyclin D1, and cyclin D3), proliferation index, and clinicopathologic parameters. , 2004, American journal of clinical pathology.

[3]  A. Lopez‐Beltran,et al.  Non-invasive urothelial neoplasms: according to the most recent WHO classification. , 2004, European urology.

[4]  R. Montironi,et al.  Prognostic factors in stage T1 grade 3 bladder cancer survival: the role of G1-S modulators (p53, p21Waf1, p27kip1, Cyclin D1, and Cyclin D3) and proliferation index (ki67-MIB1). , 2004, European urology.

[5]  Liang Cheng,et al.  Stage pT1 bladder carcinoma: diagnostic criteria, pitfalls and prognostic significance. , 2003, Pathology.

[6]  A. Borkowski,et al.  P27Kip1 and Ki-67 expression analysis in transitional cell carcinoma of the bladder , 2003, Urological Research.

[7]  A. Nabeeh,et al.  Superficial bladder tumours: analysis of prognostic factors and construction of a predictive index , 2003, BJU international.

[8]  J. Baak,et al.  Proliferation markers and DNA content analysis in urinary bladder TaT1 urothelial cell carcinomas: identification of subgroups with low and high stage progression risks , 2003, Journal of clinical pathology.

[9]  T. H. van der Kwast,et al.  Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  J. Baak,et al.  Reproducibility and prognostic variability of grade and lamina propria invasion in stages Ta, T1 urothelial carcinoma of the bladder. , 2003, The Journal of urology.

[11]  P. Hamilton,et al.  Molecular pathology of non-invasive urothelial carcinomas (part I) , 2003, Virchows Archiv.

[12]  R. Montironi,et al.  Frequent FGFR3 mutations in urothelial papilloma , 2002, The Journal of pathology.

[13]  P. Humphrey,et al.  Patterns of multiple recurrences of superficial (Ta/T1) transitional cell carcinoma of bladder and effects of clinicopathologic and biochemical factors , 2002, Cancer.

[14]  A. Formiconi,et al.  Proliferative activity is the most significant predictor of recurrence in noninvasive papillary urothelial neoplasms of low malignant potential and grade 1 papillary carcinomas of the bladder , 2002, Cancer.

[15]  C. Compton,et al.  AJCC Cancer Staging Manual , 2002, Springer New York.

[16]  J. Epstein,et al.  Correlation of Ki-67 and p53 with the new World Health Organization/International Society of Urological Pathology Classification System for Urothelial Neoplasia. , 2009 .

[17]  C. Dinney,et al.  P53 in bladder cancer: mechanism of action, prognostic value, and target for therapy. , 2001, Urology.

[18]  V. Kosma,et al.  Evaluation of p21WAF1/CIP1 and cyclin D1 expression in the progression of superficial bladder cancer , 2000, Urological Research.

[19]  F. Algaba,et al.  Primary superficial bladder cancer risk groups according to progression, mortality and recurrence. , 2000, The Journal of urology.

[20]  L. Sobin,et al.  World Health Organization classification of tumors , 2000, Cancer.

[21]  A. Smeets,et al.  MIB‐1 as a proliferative marker in transitional cell carcinoma of the bladder , 2000, Cancer.

[22]  P. Lipponen,et al.  Prognostic Value of MIB-1 Score, p53, EGFr, Mitotic Index and Papillary Status in Primary Superficial (Stage pTa/T1) Bladder Cancer: A Prospective Comparative Study , 1999, European Urology.

[23]  C. Busch,et al.  Recurrence and progression in low grade papillary urothelial tumors. , 1999, The Journal of urology.

[24]  A. Cittadini,et al.  Loss of P27Kip1 expression correlates with tumor grade and with reduced disease-free survival in primary superficial bladder cancers. , 1999, Cancer research.

[25]  A. Zlotta,et al.  Correlation and prognostic significance of p53, p21WAF1/CIP1 and Ki-67 expression in patients with superficial bladder tumors treated with bacillus Calmette-Guerin intravesical therapy. , 1999, The Journal of urology.

[26]  J. Köllermann,et al.  Proliferative pattern of exophytic and superficially invasive and noninvasive low-grade urothelial carcinomas. , 1999, Human pathology.

[27]  Lawrence D. True,et al.  The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder , 1998 .

[28]  V. Kosma,et al.  Expression of p21(waf1/cip1) Protein in Transitional Cell Bladder Tumours and Its Prognostic Value , 1998, European Urology.

[29]  S. Groshen,et al.  Effect of p21WAF1/CIP1 expression on tumor progression in bladder cancer. , 1998, Journal of the National Cancer Institute.

[30]  H. Bojar,et al.  WAF1/p21 regulates proliferation, but does not mediate p53-dependent apoptosis in urothelial carcinoma cell lines. , 1998, International journal of oncology.

[31]  S C Chen,et al.  Accumulation of nuclear p53 and tumor progression in bladder cancer. , 1994, The New England journal of medicine.

[32]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[33]  S. Groshen,et al.  p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. , 1993, The American journal of pathology.

[34]  C. Cordon-Cardo,et al.  Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. , 1993, Journal of the National Cancer Institute.

[35]  J. Gerdes,et al.  Immunohistological detection of tumour growth fraction (Ki-67 antigen) in formalin-fixed and routinely processed tissues. , 1992, The Journal of pathology.

[36]  T. H. van der Kwast,et al.  Prognostic factors in bladder carcinoma: Histologic parameters and expression of a cell cycle‐related nuclear antigen (Ki‐67) , 1992, The Journal of pathology.