Prognostic Value of MIB–1 Antibody Labeling Index to Predict Response to Bacillus Calmette–Guérin Therapy in a High–Risk Selected Population of Patients with Stage T1 Grade G3 Bladder Cancer

Abstract

Purpose: Proliferation rate is an important determinant of bladder tumor progression. However, this factor has not yet been correlated to bacillus Calmette–Guérin (BCG) therapy response in a selected high–risk population of patients with stage T1 grade G3 bladder cancer. To assess the predictive value of the proliferation rate, an immunoreactivity test with monoclonal antibodies MIB–1 was carried out. The aim of this study was to evaluate the prognostic value of an MIB–1 labeling index by selecting a group of responsive patients prior to intravesical therapy.Materials and Methods: After complete transurethral resection, 35 patients with T1G3 bladder carcinoma received 6 weekly installations of BCG (intravesical Pasteur strain: 75 mg in 50 ml course of BCG therapy). After treatment a cystoscopy and randomized biopsies of the bladder mucosa were carried out and all recurrences were systematically resected. All tissue samples were fixed in Bouin’s solution, embedded in paraffin and stained with hematoxylin–eosin–safran. Pathologists had sufficient material to perform immunomarking in 25 patients using peroxidase–antiperoxidase (PAP) technique, with antiprotein monoclonal antibody MIB–1 (Immunotech, Marseilles, France) to study MIB–1 expression before BCG therapy. Consensus was obtained from three independent pathologists for all sections. The results were expressed in a percentage of marked nuclei. Ten percent increment thresholds were established from 10 to 60%. Contingency tables were established, χ2 (p1) and Fisher exact test (p2) were performed for each threshold of 10%.Results: Median follow–up was 57.3 months (range 25–144). Of the 25 patients, 8 (32%) did not respond to BCG therapy, 17 (68%) responded positively. With a 20% threshold, there was a statistical difference (p1 = 0.03, p2 = 0.04) between responder (R) and nonresponder (NR) patients. All the 7 patients with less than 20% of nuclear activity positively responded to BCG. At this threshold level, sensitivity was high but specificity low (positive predictive value = 0.44). If we consider other reactivity thresholds there were no statistical differences between R and NR patients (10%) threshold p1 = 0.13, p2 = 0.19; 30% p1 and p2 = 0.20; 40% p1 = 0.82, p2 = 0.61; 50% p1 = 0.57, p2 = 0.55).Conclusion: Our study indicates that the proliferation rate, assessed by MIB–1 immunoreactivity in Bouin’s solution–fixed primary tissue, could be a useful predictive marker of outcome in T1G3 bladder carcinoma. With a 20% reactivity cut–off, a negative MIB–1 immunomarking appears to predict a positive response to BCG instillations. However, on the other hand, MIB–1 is of limited clinical use because the low specificity of this test cannot predict failure and then select candidates for cystectomies.