Evaluation of P53 protein overexpression, Ki67 proliferative activity and mitotic index as markers of tumour recurrence in superficial transitional cell carcinoma of the bladder

OBJECTIVES: To confirm the interrelationship between p53, ki67, mitotic index with others known prognostic factors such us stage, grade, multifocality, tumour size, history of recurrence in transitional cell carcinoma (TCC) of the bladder and to determine the prognostic impact of p53, Ki67 and mitotic index in predicting recurrence in superficial bladder cancer. METHODS: Two hundred and fourteen patients with apparently superficial TCC of the bladder underwent TURBT and the 192 histologically Ta-T1 were divided into 104 primary lesions (group 1, mean follow-up 26 months) and 88 recurrent tumours (group 2, mean follow-up 28 months). Data concerning focality, tumour size, number of recurrences and recurrence-free survival were considered in each patients. All samples were immunohistochemically stained with p53 and Ki67 monoclonal antibodies. Mitotic index (MI) was calculated on haematoxylin and eosin stained sections. RESULTS: Recurrence-free survival was significantly lower in superficial recurrent tumours (group 2) compared with primary tumours (group 1). P53 staining was correlated with grade and stage for both 5 and 20% positivity thresholds. Ki67 and MI were significantly different over strata defined by stage, grade and focality in both patients groups but only Ki67 showed a correlation with p53 status. Recurrence-free survival could not be predicted either by p53 status or MI. A 20% cut-off level of Ki67 staining resulted a good predictor of recurrence in group 1 Ta-T1/G1-G2 tumours (p = 0.03). Only Ki67 and multifocality were found to be independent prognostic factors of recurrence in multivariate analysis. Stratifying Ta-T1/G1-G2 patients according to these variables, Ki67 provided a useful tool to predict early recurrence in monofocal lesions from both groups. CONCLUSIONS: P53 and MI despite a fairly good correlation with traditional prognostic factors in bladder TCC seem to play no role in the prediction of tumoural recurrence. A Ki67 index over 20% predicts those single well-differentiated (Ta-T1/G1-G2) tumours which are likely to recur within one year of treatment.     

Urothelial atypia concomitant with primary bladder tumour. Incidence in a consecutive series of 500 unselected patients

A consecutive series of 500 primary bladder tumours from a single clinic is presented, with distribution of the tumours according to T category and histologic type and grade. Mucosal biopsies were obtained from pre-selected sites at initial cystoscopy or initial transurethral resection of the tumour in 396 cases. In 54% of the patients with grade III tumour there was concomitant urothelial atypia, either carcinoma in situ (urothelial atypia grade III, 30%) or urothelial atypia grade II (24%). In 30% of the patients with invasive grade II bladder tumour and in 14% of those with noninvasive grade II tumour there was concomitant urothelial atypia, mostly grade II. Since concomitant urothelial atypia predicts new tumour growth after successful transurethral surgery or radiotherapy, mucosal biopsies should be performed at preselected sites during initial cystoscopy or transurethral tumour resection in order to identify high-risk patients.     

Prognostic significance of biopsy results of normal-looking mucosa in cases of superficial bladder cancer

Quadrant biopsies of normal-looking mucosa were used as part of the assessment of cases with superficial Ta,T1 transitional cell cancer of the bladder. Patients with one or more abnormal biopsies were shown to have a significantly greater chance of developing recurrent tumour compared to patients with normal mucosal biopsy findings. Other factors noted at the time of initial assessment, such as size, number of tumours, Ta,T1 category or grade of tumour did not predict recurrence, although recurrences that invaded muscle were associated with G3 histology in the primary tumour. The results of mucosal biopsy identified patients at risk for recurrence and it is possible that this group would derive particular benefit from adjuvant chemotherapy.     

Risk factors for mucosal prostatic urethral involvement in superficial transitional cell carcinoma of the bladder

Objective:Prostatic transitional cell carcinoma (TCC) may involve urethral mucosa, ducts, acini and stroma of the gland. In this study, we evaluated the risk factors for mucosal prostatic urethral (PU) involvement in superficial TCC of the bladder.Methods:The data of 340 consecutive male patients with the diagnosis of primary superficial TCC of the bladder who were treated at our institution were reviewed. Median age of the patients was 64 years and median follow-up was 66 months. The impact of pathological stage, grade, tumour multiplicity and presence of carcinoma in situ (CIS) on mucosal PU involvement were evaluated.Results:Twenty one patients (6.2%) had mucosal involvement of the PU and concomitant multifocal TCC of the bladder. Of those, 12 patients (3.5%) had macroscopic mucosal involvement of the PU while the other 9 patients (2.7%) had microscopic tumour. Increased pathological stage, grade and tumour multiplicity were found to be risk factors for mucosal PU involvement in patients with superficial bladder cancer. Multivariate analysis showed that only the tumour multiplicity was found to be an independent risk factor for mucosal PU involvement by TCC (p = 0.001).Conclusions:The incidence of mucosal PU involvement increases as the stage, grade and number of tumours increase in patients with superficial TCC of the bladder. We recommend PU sampling particularly in patients with multiple bladder tumours which may have an impact on further management of these patients.     

Random bladder biopsies and the risk of recurrent superficial bladder cancer: a prospective study in 1026 patients

Summary We prospectively studied random bladder biopsies of normal-looking mucosa in 1026 unselected patients with primary superficial papillary transitional-cell carcinoma of the bladder. In a univariate analysis, the risk for recurrent disease was only slightly higher in patients with an abnormal biopsy result, the 2-year actuarial risk for recurrent disease being 47.5% in these subjects vs 44.5% in patients with a normal biopsy result (P=0.09, log-rank test). However, after correction for other prognostic factors using the Cox proportional-hazards model, an abnormal biopsy result had no prognostic value additional to that of conventional histo-pathology of the tumour with regard to the risk for recurrent disease. Additional therapy after transurethral resection of the tumour (P<0.001), tumour stage (P<0.001), the number of bladder areas affected by tumour (P<0.01) and tumour multiplicity (P=0.09) had significant prognostic value. We conclude that random biopsies of normal-looking mucosa during transurethral resection of superficial papillary bladder tumours are of little additional prognostic value with respect to the risk for recurrent disease.This study was financially supported by three regional Dutch comprehensive cancer centres: IKO, IKZ, and IKA/stedendriehoek Twente     

Studies on multiple mucosal biopsy in patients with bladder cancer. 1. Evaluation of the results of multiple mucosal biopsy in patients with bladder cancer and in vivo methylene blue staining

Between March, 1980 and July, 1984, 165 multiple mucosal biopsies were performed in 111 patients with bladder cancer. Of these 165 multiple mucosal biopsies, 87 were performed in new cases and 78 in recurrent cases: 147 were performed under in vivo staining with intravesical methylene blue. Before endoscopic tumor resection, biopsies were taken with a flexible cup biopsy forceps from non-tumorous urothelium lateral to the ureteral orifices, in the midline posteriorly, from both lateral wall and bladder neck, adjacent to the tumor and from the tumor itself. Histological abnormalities in this paper indicate transitional cell carcinoma, microinvasion of carcinoma in situ, carcinoma in situ, dysplasia and hyperplasia. In the total 955 biopsy specimens, transitional cell carcinoma was found in 45 (4.7%), microinvasion of carcinoma in situ in 30 (3.1%), carcinoma in situ in 55 (5.8%), dysplasia in 27 (2.8%), hyperplasia in 141 (1.5%), squamous metaplasia in 4 (0.4%), proliferative cystitis in 58 (6.1%), inflammation in 230 (24.1%) and normal epithelium in 492 (51.5%). The frequency of histological abnormalities in biopsied specimens was 14.8% in new cases, 21.1% in recurrent cases, the difference being statistically significant (P less than 0.01). Transitional cell carcinoma and dysplasia were more common in mucosal biopsies of recurrent cases than those of new cases (P less than 0.001, P less than 0.05). The frequency of histological abnormalities was 11.5% in 836 biopsy specimens from cystoscopically normal-looking mucosa, while 65.5% in 119 biopsy specimens from grossly abnormal mucosa, the difference being statistically significant (P less than 0.001). Of histological abnormalities, transitional cell carcinoma, microinvasion of carcinoma in situ and carcinoma in situ were more common in biopsy specimens from grossly abnormal mucosa than those from normal-looking mucosa (P less than 0.001). The frequency of histological abnormalities in mucosal biopsy was 11.4% in patients who exhibited a single tumor, and 26.7% in those with multiple tumors, the difference being significant (P less than 0.005). Biopsies of mucosa adjacent to a visible tumor were abnormal most frequently (26.9%), while those taken lateral to the ureteral orifices, from the midline posteriorly and from both lateral wall revealed a slightly lower rate of abnormal findings. The frequency of histological abnormalities in mucosal biopsy was 7.7% in patients with G1 tumor, 15.8% in those with G2 tumor and 36.0% in those with G3 tumor. The histological abnormalities increased with the increase in the grade of main tumor; this correlation was statistically significant (P less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)     

The remnant urothelium after reconstructive bladder surgery

The pathology of the remnant urinary tract in an increasing population of cystectomy patients with orthotopic and heterotopic bladder substitution due to primary bladder carcinoma, and its management is discussed. The incidence of urethral tumours in primary or recurrent bladder cancer in long-term studies is approximately 6% for male and 2% for female patients. Risk factors for urethral tumour occurrence are tumours at the bladder neck and recurrent multifocal tumours. CIS of the bladder not involving the bladder neck, and muscle invasive tumours with or without lymph node involvement are not significantly correlated with urethral cancer. Those patients at risk for urethral tumours need additional work-up (multiple urethral biopsies and/or urethral brushings, frozen section of the membranous urethra) before an orthotopic lower urinary tract reconstruction to the urethra should be considered. In a large series of male patients, the majority of patients with urethral tumours had a single conservative treatment session, and did not recur thereafter demonstrating the feasibility of a conservative approach for superficial urethral tumour recurrences in patients with an orthotopic neo-bladder to the urethra. The incidence of upper tract tumours following cystectomy and lower urinary tract reconstruction lies between 2.4-17%. In a group of 258 patients with an orthotopic bladder substitution, we have seen an incidence of 3.5%. Tumour multifocality, carcinoma in situ in the bladder and/or distal ureter, locally advanced bladder tumour stage, and invasion of the intramural ureter were seen as risk factors in some series. A tendency for a higher incidence can be seen in those series with longer follow-up. The median time between cystectomy and diagnosis of upper tract tumours lies between 8 and 69 months in most series. A longer observation period in larger numbers of patients with an orthotopic neo-bladder and longer survival rates in general after cystectomy may reveal an increase in the incidence of upper tract tumours over the next decade.     

Intravenous urography in patients with transitional cell carcinoma of the bladder. The incidence and implications of ureteral obstruction.

In order to study the value of excretory urography in the diagnosis of transitional cell carcinoma of the bladder, and also the incidence and implications of ureteral obstruction, 100 consecutive patients were studied. Of 73 patients with superficial tumours (stages Tis, Ta, T1) only 1 (1,4%) had hydronephrosis as a result of the bladder tumour. However, 2 further patients had hydronephrosis secondary to synchronous ureteral tumours. Of the 27 patients with muscle-invasive tumours, 10 (37%) had hydronephrosis at the time of diagnosis. Four patients who had normal upper tracts initially, developed hydronephrosis during follow-up: 1 due to progression of a superficial tumour to stage T3, 1 due to the development of an ureteral tumour, and 2 due to fibrosis of the intramural ureter after transurethral resection of superficial tumours. The presence of ureteral obstruction at the time of diagnosis most often implies a muscle-invasive tumour, but the possibility of a synchronous ureteral tumour must also be considered. Fibrous strictures of the distal ureter can occur after transurethral resection of superficial bladder tumours.     

Immunohistochemical analysis of Ki-67, p21waf1/cip1 and apoptosis in marker lesions from patients with superficial bladder tumours treated with vinorelbine intravesical therapy in a preliminary phase I trial

OBJECTIVE: To investigate Ki-67 and p21Waf1/Cip1 expression and apoptosis, before and after treatment, in tumour biopsies obtained from patients with superficial bladder cancer who underwent vinorelbine intravesical therapy. PATIENTS AND METHODS: Twenty patients with high-risk superficial bladder cancer (including one or more of the following parameters: tumour diameter > 3 cm, histological grade 3, or multicentric tumours) were treated 1-6 times (weekly) with intravesical vinorelbine (50 mg/mL) instillations. Transurethral tumour marker biopsies were obtained one week before the first instillation of the drug and one week after the last. The biopsies were immunostained for Ki-67 and p21Waf1/Cip1 with monoclonal antibodies, on tissue sections derived from paraffin-embedded samples obtained before and after vinorelbine treatments. In addition, apoptosis was determined using a terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labelling (TUNEL) technique. RESULTS: There were no significant differences in the cell proliferation marker Ki-67 in biopsies taken before or after treatment. However, p21Waf1/Cip1 showed significantly higher expression in biopsies obtained after vinorelbine treatment, with median (range) values of 40 (20-90)% before and 70 (50-80)% after (P < 0.001, paired nonparametric Wilcoxon test). The apoptotic index was significantly higher after vinorelbine therapy, with median (range) values of 0.89 (0.06-3.8)% before and 2.25 (0.17-18.7)% after treatment (P < 0.001, paired nonparametric Wilcoxon test). Despite the brief treatment and few patients there was a clinical response in nine patients, together with low toxicity in all. CONCLUSION: The intravesical treatment of tumours with vinorelbine affects p21Waf1/Cip1 expression without blocking cell proliferation, although increasing apoptosis. The preliminary results suggest that vinorelbine may be useful for treating superficial bladder tumours, and thus a phase II study is warranted.     

The significance of urothelial dysplasia as diagnosed by cup biopsies

A prospective study was carried out in which four quadrant cold cup biopsies of the bladder were taken from patients with either a bladder tumour (57) or irritative bladder symptoms (44), and a control group (23). Five histopathological patterns were recognized: normal urothelium, mild, moderate and severe dysplasia, and carcinoma in situ (CIS). In the control group, 22 of the 23 patients had normal urothelium, giving a 4% incidence of mild dysplasia. Of the 57 patients with all stages and grades of transitional cell carcinoma, 38 (67%) had dysplastic urothelium. This association is significant (P less than 0.01, chi-squared). Thirty-seven patients had Ta or T1 tumours, and 24 (65%) of these had dysplasia, including four (11%) with CIS. Twenty patients had T2-T4, Grade 111 tumours and 14 (70%) of these had dysplasia, including five (25%) with CIS. There was no statistical difference between these two groups. The recurrence rate was evaluated for all patients presenting with a first bladder tumour. Seventy-three percent of patients with normal cup biopsies remained recurrence free during a mean follow-up of 3 years (s.d. 1.15 years). Of patients with dysplastic urothelium, 72% remained recurrence free over a mean follow-up of 3.25 years (s.d. 1.23 years). Hence, the presence of dysplasia did not predict the likelihood of tumour recurrence. Thirty patients had dysuria or suprapubic pain for which there was no explanation. Sixteen (53%) had dysplasia on cup biopsy including three (10%) with CIS (P less than 0.01, chi-squared). It seems clear, therefore, that the dysplasia was the cause of these symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Results of second-look resection after primary resection of T1 tumour of the urinary bladder

OBJECTIVE: To study residual tumours at second-look resection in patients resected 4-8 weeks earlier for T1 tumours of the urinary bladder. MATERIAL AND METHODS: All patients randomized in the ongoing Nordic T1G2-G3 Bladder Sparing Study with monitored data available were included in the study. Data on residual tumours at second-look resection were compared to basic patient and tumour characteristics. RESULTS: There were 72 patients (56%) without and 57 with residual exophytic tumours. In the former group, 20 patients (28%) had carcinoma in situ, compared to 19 (33%) in the latter group. Potentially dangerous tumours (either carcinoma in situ, T1 or Ta grade 3) were observed in 55 patients (43%). Multiple tumours at primary resection were more prone to residual tumour at second-look resection than single tumours. No other tumour or patient characteristics could predict the occurrence of a residual tumour. CONCLUSIONS: Residual tumours are frequently observed at second-look resection 4-8 weeks after primary resection of T1 tumours. The majority of residual tumours detected at this stage are potentially dangerous; therefore, early second-look resection followed by intravesical instillation therapy is mandatory in patients with T1 tumours of the urinary bladder.     

Urodynamic parameters in preoperative evaluation of patients with bladder tumours

Urodynamic evaluation was done in 28 patients with various staged bladder tumours. In 12 patients with superficial bladder tumours all urodynamic parameters were in normal range. Thirteen patients of 16 with invasive bladder tumours had low capacity of bladder and 5 of them also had involuntary contractions. In this study we suggest that urodynamic parameters in patients with bladder tumour became significantly abnormal when the first tumour invasion is seen at the muscular layer of the bladder (p<0.05); so compliance significantly decreased and the other pathological conditions were followed (p<0.05).     

Urinary fibrin/fibrinogen degradation products in transitional cell carcinoma of the bladder

Urinary fibrin/fibrinogen degradation products (FDPs) were measured in 210 specimens from 174 patients with newly or previously diagnosed transitional cell carcinoma of the bladder. They were detected in 94% of patients with deeply invasive bladder tumours (pT2-4) compared with 17% of superficial tumours. Microalbuminuria (greater than 50 micrograms/g creatinine) was also found in 80% of patients with pT2-4 lesions. Both were compared with urine cytology. Urinary FDPs are markers of bladder tumour invasion. Our results suggest that urinary FDPs are not of value in screening for the presence of bladder neoplasia but their role may be in following patients with superficial bladder tumours to detect those tumours which become invasive. The mode of excretion of the FDPs in the urine is discussed.     

A re-staging transurethral resection predicts early progression of superficial bladder cancer

OBJECTIVE: To determine whether pathology on a re-staging transurethral resection (TUR) predicts the early progression of superficial bladder cancer. PATIENTS AND METHODS: In all, 710 patients presenting with multiple superficial bladder cancers were evaluated by re-staging TUR and followed for 5 years. Tumours were classified by stage as confined to mucosa (Ta) or invading submucosa (T1), and by grade (low- or high-grade). Pathology on re-staging TUR was correlated with the endpoints of tumour recurrence and stage progression. RESULTS: Of the 710 patients, 490 (69%) had a recurrence and 149 (21%) progressed over 5 years. Eighty patients had high-grade invasive (T1G3) cancer on re-staging TUR and 61 (76%) progressed to muscle invasion (median time to progression 15 months), compared with 88 of 630 (14%) who had no evidence of tumour (T0) or other than T1 tumours detected on re-staging TUR. CONCLUSION: A re-staging TUR identifies patients with superficial bladder cancer who are at high risk of early tumour progression.     

Urothelial atypia and survival rate of 500 unselected patients with primary transitional-cell tumour of the urinary bladder

In a consecutive series of 500 unselected patients with primary urinary bladder tumours the influence of urothelial atypia on the 5 years survival-rate was examined. All tumours were transitional-cell tumours categorized according to the T-classification. Mucosal biopsies from 7 pre-selected sites were taken at the initial cystoscopy in 391 patients (78%) to identify urothelial atypia. The over-all cumulative 5 years survival-rate was 48%. Submucosal and muscle invasion had major influence on survival, whereas tumour grade was less important. Patients with urothelial atypia fared significantly worse than those with normal bladder mucosa (5 years survival 42% versus 62%). This difference in survival-rate became apparent first after two years of observation. Grade II atypia in the bladder mucosa and grade III (carcinoma in situ) had equal significance assessed by the survival-rates.     

Studies on multiple mucosal biopsy in patients with bladder cancer. 2. Evaluation on the relationship between the results of multiple mucosal biopsy and recurrence, and the clinical course of cases with carcinoma in situ and micro-invasion of carcinoma in situ

The predictive value of grade, number of tumor and histology of mucosal biopsy for tumor recurrence, the course of carcinoma in situ and microinvasion of carcinoma in situ were examined. The Kaplan-Meier's method was used for the estimation of the recurrence-free rate in the patients who had undergone transurethral resection (TUR) and the logrank test for testing the significance of difference in recurrence-free rate. The 5-year recurrence-free rate was 32.2%. The recurrence-free rate was 51.0% after 40 months postoperatively in patients with a single tumor, 12.8% after 42 months postoperatively in those with multiple tumors. The patients with a single tumor had a significantly higher recurrence-free rate than those with multiple tumors (P less than 0.001). The recurrence-free rate was analyzed according to the grade of main tumor, but significantly difference was not present. The recurrence-free rate was 44.4% after 42 months postoperatively in patients with normal histology of mucosal biopsy and 9.5% after 34 months postoperatively in those with abnormal histology. The patients showing normal histology in mucosal biopsy had a significantly higher recurrence-free rate than those with abnormal findings (P less than 0.001). the recurrence-free rate at the same area of biopsy site was analyzed according to the histologies of 537 mucosal biopsies. The recurrence-free rate was 76.7% after 42 months post operatively in areas with a normal biopsy, 44.3% after 35 months postoperatively in those with abnormal histology and the difference was statistically significant (P less than 0.001). Of the 15 patients found to have carcinoma in situ, 4 were primary carcinoma in situ, 6 were associated with superficial papillary tumors and 5 were associated with invasive tumors. Thirteen of the 15 patients were alive and free of disease 18 to 42 months later. Two patients associated with invasive tumor died 5 and 18 months after transcatheter embolization of internal iliac arteries. Of the 13 patients who were found to have microinvasion of carcinoma in situ, 4 were not associated with visible tumor, 6 were associated with superficial papillary tumor and 3 were associated with invasive tumors. Nine of the 13 patients are alive and free of disease 7 to 53 months later. A patient without any visible tumor who was treated with TUR and intravesical chemotherapy died and three patients with invasive tumor died irrespective of the mode of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Matrix metalloproteinases (MMPs) in bladder cancer: the induction of MMP9 by epidermal growth factor and its detection in urine

OBJECTIVES: To investigate the matrix metalloproteinases (MMPs) 2 and 9 in bladder cancer cell lines stimulated with epidermal growth factor (EGF), and to investigate the presence of gelatinases in the urine of patients with bladder tumours, in relation to the stage and grade of tumour and the EGF receptor (EGFR) status. PATIENTS, SUBJECTS AND METHODS: Conditioned media from cultured tumour cells were analysed by zymography. Urine samples from 28 patients with transitional cell carcinoma and 12 normal volunteers were also analysed. Western blotting was used to verify the bands of gelatinolytic activity. The EGFR status of the tumours was assessed by immunohistochemistry. RESULTS: MMP9 was induced by EGF in the RT112 but not the RT4 bladder tumour cell line, whereas MMP2 production was unaffected by EGF. Gelatin zymography of urine samples from patients with bladder tumours showed high levels of MMP activity, with 78% positive for MMP9 and 28% positive for MMP2. The total gelatinolytic and MMP9 activity were significantly higher in patients with high-stage invasive tumours than in those with superficial tumours (P < 0.05), and were higher than in normal controls. Gelatinolytic activity at 130 and 200 kDa in urine was identified as MMP9 and MMP2. There was no significant relationship of urinary MMP9 activity to EGFR status of the tumour. CONCLUSION: EGF induces MMP9 but not MMP2 in bladder cells. Analysis of urinary gelatinases is a useful noninvasive technique and both total gelatinase and MMP9 activity are associated with high stages of bladder tumours.     

The optimum timing of radical cystectomy for patients with recurrent high-risk superficial bladder tumour

OBJECTIVE: To establish the optimum time of radical cystectomy (RC) for patients with recurrent high-risk superficial bladder tumours after the failure of intravesical therapy. PATIENTS AND METHODS: Among 318 patients with transitional cell carcinoma treated with RC and with no neoadjuvant therapy, there were 46 with clinical stage Ta, T1 or Tis refractory to transurethral resection associated with intravesical therapy. These patients had at least one of: (i) high-risk superficial bladder tumours after failure of two consecutive induction courses of intravesical therapy; (ii) superficial bladder tumours with prostatic stromal invasion; (iii) superficial bladder tumours with mucosa/ducts involvement after failure of one course of intravesical therapy; (iv) uncontrolled superficial tumours with transurethral resection associated or not with intravesical therapy. Progression and cause-specific survival of these patients were compared to those with muscle-invasive tumours. Univariate and multivariate analyses of predictive factors for cause-specific survival were also used in patients with superficial tumours. The incidence of significant prognostic factors was compared in both superficial and muscle-invasive tumours, as were the progression pattern and survival. RESULTS: The progression-free and cause-specific survival of patients with superficial tumours was 54% and 67%, respectively, with no significant difference from those with muscle-invasive tumours. In multivariate analysis, positive lymph-nodes and prostatic stromal invasion were significant and independent variables for survival. The incidence of positive lymph nodes was 15% vs 30% (P < 0.05) and of stromal invasion was 32% vs 1.5% (P < 0.001) in patients with superficial and muscle-invasive tumours, respectively. Accounting for the progression pattern in patients with superficial tumours, extravesical urothelial recurrence prevailed over local or distant recurrences (30% vs 15%), whereas in patients with muscle-invasive tumours the opposite occurred (5% vs 33%, respectively). The cause-specific survival of patients with superficial tumour and prostatic stromal invasion was one of three, and in those who developed extravesical urothelial recurrence was 28.5%. CONCLUSION: In patients with recurrent high-risk superficial bladder cancer after intravesical therapy, our criteria for RC were inappropriate, and patients had a survival rate similar to those with muscle-invasive tumours. RC might have been used too late, as there was a high incidence of prostatic stromal invasion and extravesical urothelial recurrence after RC. Both events seem to be responsible of the low cause-specific survival. Predictive factors for progression are needed to indicate early RC in patients with recurrent high-risk superficial tumours. From a previous analysis the pathological pattern of the clinical lack of response (T1, G3, bladder carcinoma in situ and prostate involvement) to intravesical therapy evaluated at 3 months might be important for predicting progression, and an early RC at that time might be useful.     

p53 expression predicts progression and poor survival in T1 bladder tumours

OBJECTIVES: Histological grade (G) is the only parameter proved to have prognostic value for progression in T1 transitional cell carcinoma (TCC) of the bladder, although it is considered inaccurate to make clinical decisions on individuals. The aim of the present study was to evaluate the prognostic relevance of p53 expression in T1 TCC of the bladder. METHODS: Clinical records of 207 patients with T1 TCC of the bladder were reviewed for clinical parameters reported to influence the evolution of superficial bladder cancer. Among these 207 patients, 40 developed muscle-invasive disease (20 G2 and 20 G3). A retrospective case-control study was then carried out comparing the latter 40 tumours with 40 control tumours matched by grade, sex, age, number and size of the tumours, chemical exposure and presence of carcinoma in situ. p53 immunostaining with monoclonal antibody was performed in these two groups. RESULTS: Histological grade was the only clinical parameter that influenced evolution. p53 expression correlated with tumour progression, since it was observed in 21 out of 24 p53-positive tumours and in only 20 of 56 p53-negative tumours (p<0.0001), showing a specificity of 93. 5% and a sensitivity of 53%. p53 expression correlated as well with patient survival, being 39% in patients with p53-positive tumours and 80% in patients with p53-negative tumours at 60 months (p<0. 0001). CONCLUSIONS: p53 protein expression has prognostic value for survival and progression in T1 bladder tumours and can be used for early detection of poor-prognosis T1 bladder tumours.     

The best management of superficial bladder tumours: Comparing TUR alone versus TUR combined with intravesical chemotherapy modalities?

To compare retrospectively the recurrence rates of TUR alone versus different intravesical chemotherapy modalities in superficial bladder cancer cases, 187 patients with stage Ta and T₁ bladder tumours were treated with transurethral resection followed by adjuvant intravesical chemotherapy with mitomycin, BCG or epirubicin or by transurethral resection alone. All patients in this study had historically proven transurethrally resectable primary, category Ta and T₁ transitional cell carcinoma (TCC) of the bladder. Group I included transurethral resection alone, and the other groups included intravesical mitomycin-C(Group II), BCG (Group III) and epirubicin (Group IV) therapies after transurethral resection. 146 male and 41 female patients (78% male and 22% female patients) in this study were diagnosed as primary TCC bladder tumours. Only 52 of them were stage Ta and 135 of them were stage T₁ bladder tumours. Examining the histological grade of the bladder tumours, 88 (47%) of the patients had grade I, 53 (28%) had grade IIa, 30 (16%) had grade IIb and remaining 16 (9%) had grade III bladder cancers. The recurrence rates were 25% for Group I, 23.8% for Group II, 26.2% for Group III and 22.7% for Group IV. These values were given with disregarding the grade and volume of the bladder tumours. For solitary, less than 3 cm low grade tumours (grade I, IIa) recurrence rates were 16% for Group I, 15.4% for Group II, 17.8% for Group III, 17.2% for Group IV (p> 0.05). As a result of this retrospective study, for patients with low grade, stage Ta and T₁ tumours TUR alone may be the best treatment modality. Although intravesical chemotherapy is effective in decreasing short-term incidences of tumour recurrence, it has not decreased long-term incidences of tumour recurrence. The high cost and adverse side effects of intravesical chemotherapy should also be taken into consideration in superficial, single, low grade tumours of bladder. This revised version was published online in August 2006 with corrections to the Cover Date.