A new and highly prognostic system to discern T1 bladder cancer substage.

BACKGROUND: Management of T1 bladder cancer (BCa) is controversial. OBJECTIVE: Evaluate the impact of substage on the clinical outcome of T1 BCa. DESIGN, SETTING, AND PARTICIPANTS: The T1 diagnosis of 134 first-diagnosis BCa patients from two university hospitals was confirmed. For the T1 substage, we used a new system that discerns T1-microinvasive (T1m) and T1-extensive-invasive (T1e) tumors. We then determined the invasion of the muscularis mucosae-vascular plexus (MM-VP): T1a (invasion above the MM-VP), T1b (invasion in the MM-VP), or T1c (invasion beyond the MM-VP). If the MM-VP was not present at the invasion front, the case was assigned to T1a or T1c. All patients were initially managed conservatively (with bacillus Calmette-Guérin). MEASUREMENTS: Multivariable analyses for progression and disease-specific survival (DSS). RESULTS AND LIMITATIONS: Median follow-up was 6.4 yr (interquartile range: 3.3-9.2 yr). Progression to ≥ T2 was observed in 40 patients (30%), and 19 patients (14%) died of BCa. The MM-VP was not present at the invasion front in 50 patients (37%). T1 substage was as follows: 40 T1m and 94 T1e; 81 T1a, 18 T1b, and 35 T1c. In multivariable analyses, substage (T1m/T1e) was significant for progression (p=0.001) and DSS (p=0.032), whereas substage according to T1a/T1b/T1c was not significant. Female gender (p=0.006) and carcinoma in situ (p=0.034) were also significant predictors of progression. The main limitation to the study is absence of a repeat transurethral resection. CONCLUSIONS: Substage according to the new system (T1m and T1e) was user-friendly, possible in 100% of cases, and very predictive of T1 BCa behavior. Future studies may ultimately lead to the incorporation of this new substaging system in the TNM classification system for urinary BCa.

Long-term prognostic value of the combination of EORTC risk group calculator and molecular markers in non-muscle-invasive bladder cancer patients treated with intravesical Bacille Calmette-Guérin.

BACKGROUND AND OBJECTIVES: To evaluate the long-term prognostic value of the combination of the EORTC risk calculator and proapoptotic, antiapoptotic, proliferation, and invasiveness molecular markers in predicting the outcome of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) treated with intravesical Bacille Calmette-Guérin (BCG) therapy. MATERIALS AND METHODS: This study included 42 patients accrued prospectively presenting with intermediate- to high-risk NMIBC (high-grade T1 tumors or multiple rapidly recurrent tumors refractory to intravesical chemotherapy) treated with transurethral resection (TUR) and BCG. TUR samples were analyzed for the molecular markers p53, p21 waf1/cip, Bcl-2, CyclinD1, and metallothionein 9 (MMP9) using immunohistochemistry. Frequency of positivity, measured as a percentage, was assessed alone or in combination with EORTC risk calculator, for interaction with outcome in terms of recurrence and progression using univariate analysis and Kaplan-Meier survival curves. RESULTS: Median follow-up was 88 months (mean, 99; range, 14-212 months). The overall recurrence rate was 61.9% and progression rate was 21.4%. In univariate analysis, CyclinD1 and EORTC risk groups were significantly associated with recurrence (P value 0.03 and 0.02, respectively), although none of the markers showed a correlation to progression. In combining EORTC risk groups to markers expression status, high-risk group associated with positive MMP9, Bcl-2, CyclinD1, or p21 was significantly correlated to tumor recurrence (log rank P values <0.001, 0.03, 0.02, and 0.006, respectively) and when associated with positive MMP9 or p21, it was significantly correlated to progression (log rank P values 0.01 and 0.04, respectively). CONCLUSION: Molecular markers have a long-term prognostic value when combined with EORTC scoring system and they may be used to improve the predictive accuracy of currently existing scoring system. Larger series are needed to confirm these findings.

Long-term follow-up of T1 high-grade bladder cancer after intravesical bacille Calmette-Guérin treatment.

OBJECTIVE: To report the long-term results of bacille Calmette-Guérin (BCG) intravesical therapy in relation to disease progression and recurrence in primary T1 high-grade (HG) bladder cancer (BC) confirmed by central pathological review. PATIENTS AND METHODS: In all, 136 patients from two university centres (Rotterdam, n = 49; Toronto, n = 87) were diagnosed with primary T1HG BC. One experienced uro-pathologist reviewed all slides, ensuring all cases were indeed HG and that muscle was present in all specimens. Patients were treated with BCG induction (six instillations) after transurethral resection (TUR) of the tumour and followed with cystoscopy and urinary cytology. Predictors for recurrence, progression and survival were assessed with multivariable Cox regression models. RESULTS: Mean (range) follow-up was 6.5 (0.3-21.6) years. There were no significant differences for recurrence (P = 0.52), progression (P = 0.35) and disease-specific survival (DSS) (P = 0.69) between the two centres. Among the cohort, 47 patients (35%) recurred and 42 (30.9%) progressed with a median time to progression of 2.1 years; 16 (38%) of these progressions occurred ≥ 3 years after the initial BCG course; 22 (16%) patients who progressed died from BC. Overall, 96 (71%) patients had no evidence of disease at the last follow-up. Carcinoma in situ was the only independent predictor for recurrence in multivariate analysis (P = 0.011). No independent predictors were found for progression. CONCLUSIONS: Conservative treatment with BCG is a valid option in primary T1HG BC. Nevertheless, the aggressive nature of T1HG BC is evident in the fact that 30% progressed, with a high proportion of these progression events occurring ≥ 3 years after BCG. Caution should be exercised when relying on the long-term effects of BCG, and close follow-up of these patients should not be neglected.

Non-risk-adapted surveillance in clinical stage I nonseminomatous germ cell tumors: the Princess Margaret Hospital's experience.

BACKGROUND: Since 1981 Princess Margaret Hospital has used initial active surveillance (AS) with delayed treatment at relapse as the preferred management for all patients with clinical stage I nonseminomatous germ cell tumors (NSGCT). OBJECTIVE: Our aim was to report our overall AS experience and compare outcomes over different periods using this non-risk-adapted approach. DESIGN, SETTING, AND PARTICIPANTS: Three hundred and seventy-one patients with stage I NSGCT were managed by AS from 1981 to 2005. For analysis by time period, patients were divided into two cohorts by diagnosis date: initial cohort, 1981-1992 (n=157), and recent cohort, 1993-2005 (n=214). INTERVENTION: Patients were followed at regular intervals, and treatment was only given for relapse. MEASUREMENTS: Recurrence rates, time to relapse, risk factors for recurrence, disease-specific survival, and overall survival were determined. RESULTS AND LIMITATIONS: With a median follow-up of 6.3 yr, 104 patients (28%) relapsed: 53 of 157 (33.8%) in the initial group and 51 of 214 (23.8%) in the recent group. Median time to relapse was 7 mo. Lymphovascular invasion (p<0.0001) and pure embryonal carcinoma (p=0.02) were independent predictors of recurrence; 125 patients (33.7%) were designated as high risk based on the presence of one or both factors. In the initial cohort, 66 of 157 patients (42.0%) were high risk and 36 of 66 patients (54.5%) relapsed versus 17 of 91 low-risk patients (18.7%) (p<0.0001). In the recent cohort, 59 of 214 patients (27.6%) were high risk and 29 of 59 had a recurrence (49.2%) versus 22 of 155 low-risk patients (14.2%) (p<0.0001). Three patients (0.8%) died from testis cancer. The estimated 5-yr disease-specific survival was 99.3% in the initial group and 98.9% in the recent one. CONCLUSIONS: Non-risk-adapted surveillance is an effective, simple strategy for the management of all stage I NSGCT.

Pathological stage review is indicated in primary pT1 bladder cancer.

OBJECTIVE: To evaluate the effect of a pathology review on the clinical outcome of patients with primary pT1 bladder cancer (BC), as the clinical course of such patients is variable. PATIENTS AND METHODS: The slides of 164 primary (first diagnosis) pT1 bladder tumours from two university hospitals were reviewed by one pathologist for stage and grade (World Health Organization 1973 and 2004). Patients were initially managed conservatively with bacille Calmette-Guérin (BCG). Uni- and multivariate analyses compared the predictive value of age, gender, hospital, carcinoma in situ (CIS), tumour-size, reviewed grade and reviewed stage. RESULTS: With a mean follow-up of 6.4 years, there was disease progression in 48 (29%) patients and 26 (16%) died from BC. Associated CIS was found in 55 (34%) patients. After reviewing the slides, 24 (15%) tumours were downstaged to pTa, 134 (82%) remained pT1 and six (4%) were upstaged to > or =pT2. The grade review resulted in 74 G2, 90 G3, 37 low-grade and 127 high-grade lesions for the two systems used. In multivariate analyses, reviewed stage (both P < 0.001) and CIS (P = 0.017 and 0.023) had independent significance for progression and disease-specific survival, respectively. CONCLUSION: A stage review is indicated in pT1 BC, as almost 20% of pT1 tumours were up- or downstaged, and the reviewed stage predicted the patient's prognosis. Hence, pathology review identified patients with different prognoses who might benefit from other treatment strategies than BCG. We confirmed that CIS is an unfavourable sign in pT1 bladder cancer.