title: Prognostic significance of p53, bcl-2 and Ki-67 in high risk superficial bladder cancer.
abstract: BACKGROUND
  Although tumor grade and stage are the most accurate prognostic factors in the evaluation of transitional cell bladder cancer, they cannot always predict the true tumor biological potential since superficial tumors of the same stage and grade may have completely different clinical courses. This study was performed in order to examine whether p53, bcl-2 and Ki-67 have any validity in predicting the course of superficial bladder tumors, with high risk for recurrence or progression, over the traditional prognostic factors that are currently used. Furthermore, we investigated whether any one of these markers maintains its prognostic capability after one course of intravesical instillations of IFN gamma.
  
  
  METHODS
  The immunohistochemical evaluation of bladder tumor specimens, that were obtained transurethrally for the expression of p53, bcl-2 and Ki-67, was performed in 58 patients. After meticulous selection of cut-off values for the expression of the aforementioned markers, twenty-eight patients were treated only with transurethral resection (TURBT only group) while 30 patients received adjuvantly intravesical instillations of interferon gamma. The times to first recurrence and progression were recorded during the follow-up period which ranged from 3 to 36 months (mean 11.7 months). The prognostic significance of tumor stage, grade, presence of CIS, p53, bcl-2 and Ki-67 in determining the risk for recurrence, was studied with both univariate (log-rank test) and multivariate (Cox regression) methods of analysis, separately for the TURBT only group of patients and for those who received instillations. The same analysis was employed for the risk of progression in the overall number of progressed patients.
  
  
  RESULTS
  According to both uni- and multivariate analysis of the prognostic significance for tumor stage (T), grade (G), presence of CIS, p53, Ki-67 and bcl-2 in each group of patients, the Ki-67 index was the only independent prognostic factor for recurrence in patients treated with TURBT only (p = 0.0044 univariate, p = 0.031 multivariate). None of the factors which were studied proved to have prognostic significance for recurrence in the group of patients who received adjuvant intravesical instillation with the immunomodulating agent. Although in the univariate analysis all the studied parameters except tumor stage seem to be associated in a statistically significant manner with higher risk for progression, the multivariate analysis did not yield any independent significant prognosticator. The same evaluation was performed only for the patients with grade 2 disease (28) and yielded statistically significantly higher risk for recurrence, both in uni- (p = 0.0081) and in multivariate analysis (p = 0.044) only in the patients with overexpression of Ki-67 who were treated with TURBT alone.
  
  
  CONCLUSIONS
  The Ki-67 proliferative index has an independent validity in predicting those patients with high risk superficial bladder tumors who may recur in a short follow-up period. A similar relationship of Ki-67 overexpression to progression was not detected. The expression of p53 and bcl-2 does not seem to offer any prognostic information in predicting either recurrence or progression over the prognostic factors that are currently used in clinical practice.
authors.affiliation: Department of Urology, G. Hatzikosta General Hospital, Makriyianni Ave., 45001 Ioannina, Greece. nstavrop@otenet.gr
authors.forename: Nikolaos E
authors.initials: NE
authors.lastname: Stavropoulos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Filiadis
authors.forename: Elli
authors.initials: E
authors.lastname: Ioachim
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Hastazeris
authors.forename: Ioannis
authors.initials: I
authors.lastname: Tsimaris
authors.forename: Demetrios
authors.initials: D
authors.lastname: Kalogeras
authors.forename: Stella
authors.initials: S
authors.lastname: Stefanaki
authors.forename: Nicki J
authors.initials: NJ
authors.lastname: Agnantis
mesh_terms: D000283:Administration, Intravesical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000008:administration & dosage; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D012189:Retrospective Studies; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma