Significance of bladder biopsies in Ta,T1 bladder tumors: a report from the EORTC Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder Committee.

OBJECTIVES: We investigated to what extent biopsies of normal-appearing urothelium taken from patients with Ta,T1 bladder cancer showed malignant disease: carcinoma in situ, or papillary tumor. We also investigated biopsies underlying the papillary tumor, adjacent to the tumor, and from suspicious-appearing mucosa. METHODS: In EORTC protocol 30863 (low-risk tumors), 393 patients underwent a biopsy of normal-appearing urothelium. In protocol 30911 (intermediate- and high-risk tumors), multiple biopsies were taken from normal- appearing urothelium in 602 patients. RESULTS: No abnormalities were found in the random biopsies of 376 (95.6%) patients with low-risk tumors and in 532 (88.4%) patients with intermediate- and high-risk tumors. Six (1.5%) patients with low-risk tumors and at least 21 (3.5%) patients with higher-risk tumors showed carcinoma in situ in their random biopsies. None of the patients in the low-risk group and 1 (0.2%) patient in higher-risk group had an invasive tumor (T2). CONCLUSIONS: This analysis indicates that biopsies of normal-appearing urothelium in Ta,T1 bladder cancer patients show no abnormalities in about 90% of the patients. Performing such biopsies does not contribute to the staging or to the choice of adjuvant therapy after transurethral resection.     

The significance of random bladder biopsies in superficial bladder cancer

Introduction: Today, there is no consensus about taking random bladder biopsies during transurethral resection of superficial bladder tumors for staging and to determine the urothelial abnormalities like dysplasia and carcinoma in situ. The aim of our study was to evaluate the results and indications of random bladder biopsies for primary superficial bladder cancer.Patients and methods: Random bladder biopsies were taken from 84 patients with primary superficial bladder cancer after transurethral resection. 40 patients had Ta and 44 had T1 tumor. The random biopsies were taken from right and left bladder walls, anterior and posterior walls, dome, trigone and prostatic urethra. The incidence of urothelial abnormalities were evaluated according to the stage and grade of the tumor.Results: None of the patients had carcinoma in situ or dysplasia with Ta tumor. In T1 group, 4 patients (9.1%) had carcinoma in situ and 3 patients (6.8%) had dysplasia. There was a statistically significant difference with regard to urothelial abnormalities between groups Ta and T1. The same difference was also seen between low and high grade tumors.Conclusion: In our study, only 7/84 (8.3%) of patients with primary superficial bladder cancer had urothelial abnormalities like carcinoma in situ or dysplasia. All of these pathologies were seen in T1 tumors. According to our results, we believe that random biopsies are not useful in superficial bladder cancers to detect urothelial abnormalities and also do not help for the planning of further treatment.     

Multiple biopsies of normal‐looking urothelium in patients with superficial bladder cancer: Are they necessary?

BACKGROUND: The objective of the study presented here was to assess the usefulness and indications of multiple biopsies of normal-appearing urothelium in patients with superficial bladder cancer. METHODS: Between December 1996 and December 2002, multiple biopsies of normal-appearing bladder mucosa were performed in 100 patients with superficial bladder transitional cell carcinoma. Biopsy specimens were taken from seven different sites in females and nine different sites in males. RESULTS: In eight of 100 patients, bladder cancers were detected in the biopsy specimens. Three cases were Ta and five were Tis. All of the five patients with carcinoma in situ (CIS) in their biopsy specimens had multiple papillary broad-base tumors and positive urinary cytology. The detection ratio of CIS in patients with these findings was 17.9% (5/28). No concomitant CIS was detected in the 72 patients who had a solitary tumor, pedunculated tumor(s), or negative urinary cytology. CONCLUSION: Multiple mucosal biopsies of normal-appearing urothelium are not necessary for all patients with superficial bladder cancer. They are, however, necessary for patients with multiple papillary broad-base tumors and positive urinary cytology.     

Significance of Random Bladder Biopsies in Non-Muscle Invasive Bladder Cancer

Background/Aims

To evaluate retrospectively the clinical outcome of random bladder biopsies in patients with non-muscle invasive bladder cancer (NMIBC) undergoing transurethral resection (TUR).

Patients and Method

This study included 234 consecutive patients with NMIBC who underwent random biopsies from normal-appearing urothelium of the bladder, including the anterior wall, posterior wall, right wall, left wall, dome, trigone and/or prostatic urethra, during TUR.

Result

Thirty-seven patients (15.8%) were diagnosed by random biopsies as having urothelial cancer. Among several factors available prior to TUR, preoperative urinary cytology appeared to be independently related to the detection of urothelial cancer in random biopsies on multivariate analysis. Urinary cytology prior to TUR gave 50.0% sensitivity, 91.7% specificity, 56.8% positive predictive value and 89.3% negative predictive value for predicting the findings of the random biopsies.

Conclusion

Biopsies of normal-appearing urothelium resulted in the additional detection of urothelial cancer in a definite proportion of NMIBC patients, and it remains difficult to find a reliable alternative to random biopsies. Collectively, these findings suggest that it would be beneficial to perform random biopsies as part of the routine management of NMIBC.Key Words: Non-muscle invasive bladder cancer, Random biopsy, Urinary cytology     

Iatrogenic tumor cell implantation in bladder cancer

J82 monolayer cell cultures and 647 V multicellular tumor spheroids were incubated in Resectal, urine (pH 5.5; 7.5) and distilled water for 5-30 min. In the case of both monolayers and tumor spheroids inhibition of tumor cell growth was achieved by incubation in distilled water. Transurethral resection (TUR) of a primary superficial bladder cancer was performed in 133 patients (Ta, T1). In 60 of these patients selected biopsies of apparently normal bladder mucosa were taken at the same time. There was no significant difference in tumor recurrence between the groups with biopsy and without biopsy. However, all patients with dysplasia in the selected mucosal biopsies developed a tumor recurrence. Between 1969 and 1984 bladder wall perforation occurred in 12 patients during TUR of Ta, T1 bladder cancer. None of the patients who experienced bladder wall perforation developed extraperitoneal or intraperitoneal metastases. Although our clinical results suggest that iatrogenic tumor cell implantation during TUR of a bladder cancer is rather unlikely, this event could be prevented by the use of distilled water during and after TUR.     

Restaging transurethral resection of high risk superficial bladder cancer improves the initial response to bacillus Calmette-Guerin therapy

PURPOSE: This study was an evaluation of whether restaging transurethral resection (TUR) of superficial bladder cancer improves the early response to bacillus Calmette-Guerin (BCG) therapy. MATERIALS AND METHODS: A total of 347 patients with high risk superficial bladder cancer (high grade Ta and T1 tumors associated with carcinoma in situ) underwent a single transurethral resection (TUR, 132 patients) or restaging TUR (215 patients) before receiving 6 weekly intravesical BCG treatments. The patients were evaluated for response (presence or absence of tumor) at first followup cystoscopy, at 6 and 12 months after treatment, and evaluated for disease stage progression within 3 years of followup. RESULTS: Of the 132 patients who underwent a single TUR before BCG therapy, 75 (57%) had residual or recurrent tumor at the first cystoscopy and 45 (34%) later had progression, compared with 62 of 215 patients (29%) who had residual or recurrent tumors and 16 (7%) who had progression after undergoing restaging TUR (p = 0.001). CONCLUSIONS: Restaging TUR of high risk superficial bladder cancer improves the initial response rate to BCG therapy, reduces the frequency of subsequent tumor recurrence and appears to delay early tumor progression.     

Clinical impact of bladder biopsies with TUR-BT according to cytology results in patients with bladder cancer: a case control study

Background

There seems to be no consensus concerning taking bladder biopsies during transurethral resection of bladder tumor (TUR-BT). We investigate the clinical significance of bladder biopsy with TUR-BT and the relationship between urinary cytology and the biopsy results.

Methods

We reviewed a total of 424 patients with non-muscle invasive bladder cancer treated with TUR-BT between 1998 and 2005. Of the total, 293 patients also underwent a bladder biopsy. Biopsies from suspicious-appearing urothelium (N = 59) and those from normal-appearing urothelium (N = 234) were evaluated separately.

Results

Bladder cancer was observed in 23 cases (39.0%) who underwent a biopsy of suspicious-appearing urothelium. Among these 23 cases, 9 cases with visible tumor resection had carcinoma in situ (CIS) only in the biopsies from suspicious-appearing urothelium. Urinary cytology was negative in 3 of the 9 cases. Bladder cancer was observed in 26 cases (11.1%) who underwent a biopsy of normal-appearing urothelium. Of them, 5 cases with visible tumors had CIS only in the multiple biopsies from normal-appearing urothelium. Urinary cytology was positive in all of the 5 cases. No upstaging or upgrading cases were found in these patients by the addition of these two types of biopsy. Furthermore, therapy was not altered in these patients. With or without bladder biopsy was not a significant factor for tumor recurrence in either the univariate or multivariate analysis.

Conclusions

Based on the results, it is concluded the multiple biopsies from normal-appearing urothelium are not necessary in patients with negative cytology results because of the low detection rate and lack of influence on therapeutic decisions. Meanwhile, biopsy of suspicious-appearing urothelium is needed in patients with negative cytology results in order to detect CIS due to staging properties. This result supports a recent EAU guideline.     

Analysis of factors predicting intravesical recurrence of superficial transitional cell carcinoma of the bladder without concomitant carcinoma in situ

BACKGROUND: The objective of this study was to investigate risk factors for intravesical recurrence in patients with superficial bladder cancer without concomitant carcinoma in situ (CIS). METHODS: In this series, we analyzed data from patients with newly diagnosed superficial Ta or T1 transitional cell carcinoma (TCC) of the bladder without concomitant CIS who underwent complete transurethral resection (TUR) without any adjuvant intravesical instillation therapies. Multivariate analysis was used to determine significant risk factors affecting intravesical recurrence after TUR. Differences in clinicopathological features between primary and recurrent tumors were also characterized. RESULTS: Among 341 patients undergoing TUR of Ta or T1 bladder cancer, 187 diagnosed as having concomitant CIS and/or treated with adjuvant intravesical therapy were excluded, and the remaining 154 were evaluated. Intravesical recurrence was detected in 64 of the 154 patients, showing a 5-year recurrence-free survival rate of 58.3%. Among several factors examined, only tumor size was significantly associated with intravesical recurrence. Multivariate analysis identified tumor size as an independent predictor for intravesical recurrence irrespective of other parameters including age, gender, multiplicity, growth pattern, grade and stage. Recurrent tumors were significantly smaller and of a lower grade and lower stage than primary tumors, despite the absence of differences in growth pattern and the multiplicity between them. CONCLUSIONS: These findings suggest that primary tumor size could be used as a potential risk factor for predicting intravesical recurrence following TUR of superficial TCC of the bladder without concomitant CIS, and that the pathological characteristics of recurrent tumors are more favorable than those of primary tumors.     

Phase I pharmacokinetic study of a single intravesical instillation of gemcitabine administered immediately after transurethral resection plus multiple random biopsies in patients with superficial bladder cancer

PURPOSE: In this phase I study we determined the pharmacokinetic and toxicity profiles of a single intravesical instillation of gemcitabine administered immediately after complete transurethral resection (TUR) plus multiple random biopsies. MATERIALS AND METHODS: Ten patients with superficial bladder cancer clinically staged as Ta/T1 with no carcinoma in situ were included. A single dose of gemcitabine was administered intra-vesically immediately after TUR plus 6 random biopsies. Five patients received 1,500 mg and 5 received 2,000 mg diluted in 100 ml saline. Retention time in the bladder was 60 minutes. Concentrations of gemcitabine and dFdU (2',2'-difluoro-2'-deoxyuridine) were determined by high pressure liquid chromatography assay. RESULTS: Treatment was clinically well tolerated in all patients. Two patients in the 1,500 mg group had minimal hipogastric discomfort and 1 in the 2,000 mg group had grade 1 bladder spasms. There was no remarkable systemic toxicity on hematology or biochemistry at any dose level on day 12 or 30. One patient per dose level showed tumor recurrence on 3-month repeat cystourethroscopy. Mean maximum gemcitabine concentration was 1.8 microg/ml and the mean last AUC was 158 microg/ml*minute. There was large interpatient variability but no significant differences between the 2 dose levels. CONCLUSIONS: Single intravesical instillation of gemcitabine immediately after TUR and multiple random biopsies for superficial bladder cancer are a safe and well tolerated treatment. The favorable toxicity and pharmacokinetic profiles of intravesical gemcitabine support future phase II studies with this agent.     

Therapy of superficial bladder carcinomas

Treatment of superficial bladder carcinoma was derived by several large randomized trials. This group of cancers is stratified by differentiation grade and stage in three groups of different risk profiles (Ta G1-2 vs. T1 G1-2 vs. Tis/T1 G3). Standard therapy is fractionated transurethral resection (TUR). Adjuvant therapy after transurethral resection is not indicated in primary Ta G1-2 tumors because there is a low recurrence rate and no risk of tumor progression. The recurrence rate can be decreased up to 15% in recurrent Ta or T1 G1-2 tumors by intravesical therapy with mitomycin C (20 mg/instillation) or adriamycin (50 mg/instillation). Therapy should be limited to early (within 24 h post-TUR) and short-term treatment (4 x weekly, 5 x monthly). Alternatively, patients can be treated by intravesical BCG (strain Connaught or strain RIVM). Maintenance therapy is advantageous according to recurrence rate. Tumors with great malignant ability (Tis or T1 G3) will be treated initially with adjuvant BCG. Patients who fail are candidates for radical cystectomy within 3-6 months after initial diagnosis. There is no need - except in clinical trials - for the administration of unverified or not admitted drugs. Copyright Copyright 1999 S. Karger AG, Basel     

Repeated transurethral resection and intravesical BCG for extensive superficial bladder tumors.

PURPOSE: We report our experience with repeat transurethral resection (TUR) in a group of patients with superficial bladder tumors in whom complete resection in one session was impossible because of the extensive tumor burden. PATIENTS AND METHODS: Only the patients with such extensive (>10 g of resected tissue) tumors that we were unable to perform complete TUR initially were included in the present study. The patients underwent repeat TUR(s) 4 weeks after the previous one until complete resection of the tumor was achieved. After complete TUR, if the pathology examination confirmed superficial disease, the patients received intracavitery immunotherapy and were followed up thereafter. If pathology examination documented muscle-invasive disease, cystectomy was suggested. RESULTS: Of the 43 patients undergoing repeat TUR, 15 needed a second and 5 needed a third session to achieve complete resection. Of the patients, 28 (65%) had stage T1 and 15 (35%) has stage Ta tumor. Eight patients (19%) otherwise regarded as having superficial tumor were found to have muscle-invasive disease following repeat TURs. The mean follow-up of the remaining 35 patients with superficial disease was 34 months (range 1-126 months). Four of the patients with superficial disease progressed to T2 tumor. However, 16 patients achieved a state of complete response with no tumor recurrences during a mean of 38 months (range 4-126 month). The present protocol achieved bladder sparing in a total of 22 (63%) of the 35 patients with superficial disease. CONCLUSIONS: From the presented series, we suggest that one can use the combination of repeat TUR and intravesical immunotherapy in the management of bulky superficial bladder tumors in an effort to preserve the bladder.     

Clinical analysis of bladder cancer

PURPOSE: We report our clinical experiences of treatment for bladder cancer. MATERIAL AND METHODS: Clinical analysis was performed about 282 primary bladder cancer patients who performed first time treatment in our hospital from January 1991 to December 2002. RESULTS: As to T classification, 127 patients were in Ta, 89 in T1, 27 in T2,18 in T3, eight in T4 and 13 in Tis, respectively and among those, there were seven patients with a metastasis. Most patients of superficial cancer were treated by combined use of TUR and instillation therapy. There were few patients of total cystectomy performed as a first time treatment in the case of invasive cancer in our clinic and comparatively many preservation therapies by TUR, systemic chemotherapy and radiotherapy combined use were performed. Cancer recurred to 90 cases in 275 patients, and 18 patients died owing to cancer progression. Five and ten-years-recurrence free rate in the whole were 59.5 and 44.3%, five and ten-years-disease specific survival rate were 92.9 and 85.9%. Furthermore, 5-years-disease specific survival rate classified by T stage were 100, 100, 71.2, 46.7 (3-years-survival), 53.6, 83.3% in Ta, T1, T2, T3, T4, Tis, respectively and the significant difference was observed. The disease specific five-years survival rate of the whole local invasive carcinoma (T2-4N0M0) was 57.5% and 70.2% in the case of preservation therapy performed by TUR, chemotherapy and radiotherapy combined use. CONCLUSIONS: An appropriate treatment according to the each case is needed for bladder cancer.     

Prognosis of bladder tumor patients treated by TUR

One hundred and eleven cases of bladder tumors were treated with transurethral resection (TUR) and transurethral electrocoagulation as the initial treatment from 1974 and 1983. Eighty nine cases were male and 22 cases were female. The average age was 60.1 years old. Of the 111 patients, 57, 33, 2, 1 and 15 patients had a tumor of Ta, T1, T2, T3a and Tx respectively. The number of grades G0, G1, G2, G3, GX cases was 1, 38, 40, 17, 12, respectively. Other than these, 2 cases of squamous cell carcinoma and 1 of adenocarcinoma were included. The actual survival rates for 5 years in Ta and T1 were 84.4 and 88.9% respectively, and the relative survival rates were 99.5 and 109.1%. TUR was recommended for superficial bladder tumor because of good prognosis. The 5-year recurrence rates for single tumors with and without prophylactic bladder instillation were 21.4 and 27.5% respectively, and those for multiple bladder tumors were 58.6 and 51.8%. There was no significant difference between the group with and without bladder instillation.     

Molecular pathways of urothelial development and bladder tumorigenesis

Bladder cancer is the fifth most common human malignancy and the second most frequently diagnosed genitourinary tumor after prostate cancer. The majority of malignant tumors arising in the urinary bladder are urothelial carcinomas. Clinically, superficial bladder tumors (stages Ta and Tis) account for 75% to 85% of neoplasms, while the remaining 15% to 25% are invasive (T1, T2–T4) or metastatic lesions at the time of initial presentation. Several studies have revealed that distinct genotypic and phenotypic patterns are associated with early vs. late stages of bladder cancer. Early superficial disease appears to segregate into 2 main pathways: (1) superficial papillary bladder tumors, which are characterized by gain-of-function mutations affecting oncogenes such as H-RAS, FGFR3, and PI3K, and deletions of the long arm of chromosome 9 (9q); (2) Carcinoma in situ, a “flat” high grade lesion considered to be a precursor of invasive cancer, is characterized by loss-of-function mutations affecting tumor suppressor genes, such as p53, RB, and PTEN. Based on these data, a model for bladder tumor progression has been proposed in which 2 separate genetic pathways characterize the evolution of early bladder neoplasms. Several molecular markers have been correlated with tumor stage, but the rationale for these 2 well-defined genetic pathways still remains unclear.Normal urothelium is a pseudo-stratified epithelium that coats the bladder, composed of 3 cell types: basal, intermediate, and superficial (“umbrella”) cells. We have identified a series of markers that are differently expressed in these distinct cells types, and postulated a novel model for urothelium development and configuration. Briefly, it is our working hypothesis that 2 distinct progenitor cells are responsible for basal/intermediate cells and “umbrella” cells, respectively. Basal and intermediate cells are characterized by a p63 positive phenotype, as well as expression of high molecular weight cytokeratins (CKs), such as CK5, CK10, and CK14. On the contrary, “umbrella” cells display a p63 negative phenotype and are characterized by expression of 2 specific low molecular weight CKs: CK18 and CK20. Neither urothelial stem cells nor bladder cancer stem cells have been identified to date. In this review, we will further expand on the issues discussed above.     

Intravesical bacillus Calmette-Guerin instillation therapy in superficial bladder cancers--clinical study on prognostic factors

Intravesical instillation of Tokyo 172 strain bacillus Calmette-Guerin (BCG) was performed on 137 patients with superficial bladder cancer (Ta and T1) after transurethral tumor resection as a prophylaxis against tumor recurrence. The recurrence rate of tumors was compared with that of historical controls and was estimated by the person-years method. There were statistically significant decreases in recurrent tumors following BCG therapy. To clarify the efficacy of intravesical BCG therapy, prognostic significance of several factors were evaluated in 90 patients with initial bladder cancer treated with TUR and BCG instillation, and compared to those of controls. Prophylactic effects were statistically better for those with multiple tumors, grade 3 lesions or Ta lesions than for control patients. No correlation between purified protein derivative responsiveness and favorable results could detected. There were no marked side effects or fatal complications of BCG therapy during the observation periods. Our results suggest that BCG is able to change the biological behavior of superficial bladder cancers with multiple, high grade or low stage lesions. The intravesical BCG instillation seems to be effective and safe as a prophylaxis against the recurrence of superficial bladder tumors.     

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.     

Difficult decisions in urologic oncology: management of high-grade T1 transitional cell carcinoma of the bladder

Management decisions for a patient with high grade (G3) T1 urothelial cancer of the bladder are critical. These tumors should not be classified as "superficial" since they are not confined to the urothelium. Patients with T1G3 bladder cancers are likely to have recurrence and the tumor will often progress, invade, metastasize, and cause death. Radical cystectomy as well as transurethral resection followed by intravesical BCG are acceptable initial therapies. This article reviews these treatment options and provides recommendations for management of high grade T1 tumors.     

The significance of bladder quadrant biopsies in patients with primary superficial bladder carcinoma

The prognostic significance of dysplasia (D I-III, Tis) based on bladder quadrant biopsies was established in 216 patients with primary urothelial carcinoma of the bladder (stage pTaGI-pTGIII). Collectively within the study, 51 of the 216 patients biopsied (24%) were found with abnormal urothelium. Twelve (6%) have coexistent Tis, and 30 (18%) were found with dysplastic changes D I-III. Further concerns included the incidence of dysplastic changes associated with tumor invasion, tumor dedifferentiation, and the presence of primary multifocal disease. The collective recurrence rate was 43%. However, with inclusion of quadrant biopsies, the predictability of positive biopsy results increased to 63% and the negative rate decreased to 37%.     

pT1 bladder cancer.

pT1 bladder tumors invade the lamina propria and are more aggressive biologically than superficial pTa or in situ carcinomas (Tis). Among patients with pT1 tumors treated by transurethral resection (TUR), 30% develop a muscle-invasive neoplasm within 3-5 years, but intravesical chemotherapy or BCG reduce progression rates to 20 and 14%, respectively. Tumor variables favoring progression include multiple, recurrent pT1 tumors, high grade (G3), solid configuration and associated Tis. Many pT1 tumors can be managed conservatively, but patients failing an adequate trial (3-6 months) of TUR and intravesical therapy are best treated by cystectomy.     

Prospective study of effectiveness. Reoperation (re-TUR) in superficial bladder carcinoma

To assess the rate of residual cancer after transurethral resection (TUR) of superficial bladder cancer, a prospective study was carried out. All patients with transitional cell cancer (TCC) stage pTa-pT1 underwent a repeat TUR (ReTUR) within 6-8 weeks. Sites and rates of tumors found during ReTUR were documented as well as the morbidity of the ReTUR. Of a total of 192 TUR, superficial TCC was found in 124 cases; 83 underwent ReTUR according to the study protocol. Residual tumor was detected in 27% of pTa and 53% of pT1 tumors. Worsening of grading or T stage was found in 8%. Of the tumors detected by ReTUR, 81% were localized at the site of the first TUR. In this prospective study, residual tumor formation was detected in a high percentage. Routine ReTUR is therefore recommended in superficial bladder cancer except solitary pTaGI lesions.