John P. Stein

PURPOSE: To evaluate our long-term experience with patients treated uniformly with radical cystectomy and pelvic lymph node dissection for invasive bladder cancer and to describe the association of the primary bladder tumor stage and regional lymph node status with clinical outcomes. PATIENTS AND METHODS: All patients undergoing radical cystectomy with bilateral pelvic iliac lymphadenectomy, with the intent to cure, for transitional-cell carcinoma of the bladder between July 1971 and December 1997, with or without adjuvant radiation or chemotherapy, were evaluated. The clinical course, pathologic characteristics, and long-term clinical outcomes were evaluated in this group of patients. RESULTS: A total of 1,054 patients (843 men [80%] and 211 women) with a median age of 66 years (range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years (range, 0 to 28 years). There were 27 (2.5%) perioperative deaths, with a total of 292 (28%) early complications. Overall recurrence-free survival at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5- and 10-year recurrence-free survival for patients with organ-confined, lymph node-negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node-negative tumors had 89% and 87% and 78% and 76% 5- and 10-year recurrence-free survival, respectively. Patients with nonorgan-confined (P3b, P4), lymph node-negative tumors demonstrated a significantly higher probability of recurrence compared with those with organ-confined bladder cancers (P <.001). The 5- and 10-year recurrence-free survival for P3b tumors was 62% and 61%, and for P4 tumors was 50% and 45%, respectively. A total of 246 patients (24%) had lymph node tumor involvement. The 5- and 10-year recurrence-free survival for these patients was 35%, and 34%, respectively, which was significantly lower than for patients without lymph node involvement (P <.001). Patients could also be stratified by the number of lymph nodes involved and by the extent of the primary bladder tumor (p stage). Patients with fewer than five positive lymph nodes, and whose p stage was organ-confined had significantly improved survival rates. Bladder cancer recurred in 311 patients (30%). The median time to recurrence among those patients in whom the cancer recurred was 12 months (range, 0.04 to 11.1 years). In 234 patients (22%) there was a distant recurrence, and in 77 patients (7%) there was a local (pelvic) recurrence. CONCLUSION: These data from a large group of patients support the aggressive surgical management of invasive bladder cancer. Excellent long-term survival can be achieved with a low incidence of pelvic recurrence.

BACKGROUND: We have previously demonstrated a strong association between nuclear accumulation of p53 protein, as determined by immunohistochemical analysis, and mutations in the p53 gene. The purpose of this study was to determine the relation between nuclear accumulation of p53 and tumor progression in transitional-cell carcinoma of the bladder. METHODS: Histologic specimens of transitional-cell carcinoma of the bladder (stages Pa, noninvasive disease, to P4, disease with direct extension into adjacent organs or structures) from 243 patients who were treated by radical cystectomy were examined for the immunohistochemical detection of p53 protein. Nuclear p53 reactivity was then analyzed in relation to time to recurrence and overall survival. RESULTS: The detection of nuclear p53 was significantly associated with an increased risk of recurrence of bladder cancer (P < 0.001) and with decreased overall survival (P < 0.001). In patients with cancer confined to the bladder, the rates of recurrence for stage P1, P2, and P3a tumors that had no detectable nuclear p53 reactivity at five years were 7, 12, and 11 percent, respectively, as compared with 62, 56, and 80 percent, respectively, for tumors that had p53 immunoreactivity. Similar results were obtained when the presence or absence of p53 in the nuclei of the tumor cells was studied in relation to overall survival. In a multivariable analysis stratified according to grade, pathological stage, and lymph-node status, nuclear p53 status was an independent predictor (and in cancer confined to the bladder, the only independent predictor) of recurrence and overall survival (P < 0.001). CONCLUSIONS: In patients with transitional-cell carcinoma confined to the bladder, an accumulation of p53 in the tumor-cell nuclei detected by immunohistochemical methods predicts a significantly increased risk of recurrence and death, independently of tumor grade, stage, and lymph-node status. Patients with transitional-cell carcinoma confirmed to the bladder that demonstrates nuclear p53 reactivity should be considered for protocols of adjuvant treatment.

PURPOSE: We evaluated the clinical outcomes and risk factors for progression in a large cohort of patients with lymph node metastases following en bloc radical cystectomy and bilateral pelvic lymphadenectomy. MATERIALS AND METHODS: From July 1971 through December 1997, 1,054 patients underwent radical cystectomy and bilateral pelvic-iliac lymphadenectomy for high grade, invasive transitional cell carcinoma of the bladder. Of these patients 244 (23%) with a median age of 66 years (range 36 to 90) had pathological lymph node metastases. Overall 139 of the 244 patients (57%) received some form of chemotherapy. At a median followup of greater than 10 years (range 0 to 28) outcomes data were analyzed in univariate analysis according to tumor grade, carcinoma in situ, primary bladder tumor stage, pathological subgroups, total number of lymph nodes removed and involved with tumor, and lymph node density (total number of positive lymph nodes/total number removed). In addition, the form of urinary diversion and the administration of chemotherapy were also evaluated. Multivariate analysis was then performed to analyze these variables independently. RESULTS: The incidence of positive lymph nodes increased with higher p stage and pathological subgroups. Of 669 patients 75 (11%) with organ confined primary tumors and 169 of 385 (44%) with extravesical tumor extension had involved lymph nodes. The median number of lymph nodes removed in the 244 lymph node positive cases was 30 (range 1 to 96), while the median number of positive lymph nodes was 2 (range 1 to 63). Overall recurrence-free survival at 5 and 10 years for the 244 patients with lymph node positive disease was 35% and 34%, respectively. Patients with lymph node positive disease and an organ confined primary bladder tumor had significantly improved 10-year recurrence-free survival compared with those with extravesical tumor extension (44% vs 30%, p = 0.003). The total number of lymph nodes removed at surgery was also prognostic. Patients with 15 or less lymph nodes removed had 25% 10-year recurrence-free survival compared with 36% when greater than 15 lymph nodes were removed. Recurrence-free survival at 10 years for patients with 8 or less positive lymph nodes was significantly higher than in those with greater than 8 positive lymph nodes (40% vs 10%, p <0.001). The novel concept of lymph node density was also a significant prognostic factor. Patients with a lymph node density of 20% or less had 43% 10-year recurrence-free survival compared with only 17% survival at 10 years when lymph node density was greater than 20% (p <0.001). On multivariate analysis the total number of lymph nodes involved, pathological subgroups of the primary bladder tumor, lymph node density and adjuvant chemotherapy remained significant and independent risk factors for recurrence-free and overall survival. CONCLUSIONS: Patients with lymph node tumor involvement following radical cystectomy may be stratified into high risk groups based on the primary bladder tumor, pathological subgroup, number of lymph nodes removed and total number of lymph nodes involved. Lymph node density, which is a novel prognostic indicator, may better stratify lymph node positive cases because this concept collectively accounts for the total number of positive lymph nodes (tumor burden) and the total number of lymph nodes removed (extent of lymphadenectomy). Future staging systems and the application of adjuvant therapies in clinical trials should consider applying lymph node density to help standardize this high risk group of patients following radical cystectomy.