Bladder cancer diagnosis by flow cytometry. Correlation between cell samples from biopsy and bladder irrigation fluid

Results of flow cytometry (FCM) examinations of bladder irrigation specimens were compared with those of FCM examinations of cell suspensions from bladder biopsies of 44 urologic patients. The fluorescent dye, acridine orange (AO), was used to stain DNA and RNA differentially and abnormal urothelial cells were identified by their relative content of nucleic acids. Granulocytes and squamous cells could be distinguished from transitional cells in this procedure, and did not interfere with the analyses. Of 28 patients with papillary carcinoma, carcinoma in situ, and invasive carcinoma 27 were identified through FCM examination of irrigation cytology specimens; the one false-negative result was from a low-grade papillary carcinoma. Of 7 patients with papilloma, FCM examinations of irrigation specimens were positive in 4 and negative in 3. Results of FCM studies of biopsy specimens were in good but not complete agreement with those of irrigation specimens. In several cases, irrigation FCM disclosed tumor stemlines that were not identified in biopsy specimens. Discrepancies of this kind seemed most likely due to differences in sampling. Irrigation FCM seems to be a sensitive method for assessing multiple-site bladder tumors, and may be a useful technique for monitoring the course of conservatively managed bladder tumors.     

Flow cytometric analysis of DNA content in human bladder tumors and irrigation fluids

Flow cytometry (FCM) was used to study the DNA distribution of 99 tumor biopsy specimens and 41 bladder irrigation samples from patients with transitional cell carcinoma of the bladder. For tumor biopsy and cystectomy specimens, the frequency of aneuploidy increased with advancing tumor stage and grade. All T0 tumors were diploid. Twenty-seven percent of T1, 71.4% of T2, and 75% of T3 and T4 tumors were aneuploid. All Grade I tumors were diploid. Thirty percent of Grade II and 76.9% of Grade III tumors were aneuploid. The frequency of aneuploidy of tumors in the early stages (Ta, T1) is similar to the incidence of subsequent progression by these tumors described in the literature. For irrigation fluids, the relationship between grade and stage and the frequency of aneuploidy was similar to the relationship seen with tumor specimens. All four patients with only carcinoma in situ had aneuploid cells in their irrigations. The comparison of FCM data of bladder biopsy and bladder irrigation from the same cystoscopic evaluation suggests adequate representation of tumor cells in the irrigation fluids for almost all cases. The authors conclude that DNA ploidy analysis by FCM appears useful in a clinically important group of patients with aneuploid superficial tumors of moderate or high grade. Bladder irrigation analysis appears useful in the follow-up of patients with a history of carcinoma in situ and those with aneuploid tumors.     

Flow cytometry of low stage bladder tumors: correlation with cytologic and cystoscopic diagnosis

Flow cytometry examinations (FCM) were carried out on 110 bladder irrigation specimens from 84 urologic outpatients who had had prior conservative treatment for low stage bladder tumors. The specimens were easily obtained, and adequately cellular in all cases. Of 60 examinations on patients with no cytoscopic abnormalities, FCM and conventional cytology were both negative in 30 and both positive in 12 instances; there were 18 with positive FCM and negative cytology. Of 15 instances with cystoscopically benign appearing papillary lesions, FCM and cytology were both negative in three and both positive in three cases; FCM was positive and cytology negative in nine. Of 35 instances with suspicious cystoscopic findings, FCM and cytology were both positive in 19 and both negative in four; FCM was positive and cytology negative in 12. There were no examples of positive conventional cytology and negative FCM. These findings indicate that, after conservative treatment of low stage tumors, FCM of bladder irrigation specimens may be a more sensitive measure of cytologic abnormalities than is conventional cytology. Specimen collection is feasible as part of the routine urologic examination in an outpatient clinic.     

Monitoring intravesical bacillus Calmette-Guerin treatment of superficial bladder carcinoma by serial flow cytometry

Simultaneous urinary flow cytometry, cytologic, and cystoscopic examinations were performed at 3-month intervals for a minimum of 1 year on 29 patients receiving intravesical bacillus Calmette-Guerin (BCG) treatment of superficial bladder carcinoma. Flow cytometry (FCM) and cytology were concordant in 57 of 103 examinations; both FCM and cytology were positive in 38 instances, and carcinoma was confirmed by biopsy in 35 (92.1%). In 16 instances FCM and cytology were negative, but carcinoma was present on biopsy in 5 (31.3%). Three examinations were suspicious by both techniques. The 46 determinations with discordant FCM and cytology were subdivided into pathologically confirmed recurrences (25 instances) and no evidence of pathologic and/or cystoscopic disease (21 instances). In the 25 instances of recurrences, FCM was positive in 18 (72.0%), suspicious in 3 (12.0%), and negative in 4 (16.0%), while cytology was positive in 3 (12.0%), suspicious in 9 (36.0%), and negative in 13 (52.0%). Most patients had a severe BCG-induced inflammatory response that caused an elevation of the hyperdiploid population, believed secondary to epithelial regeneration and proliferation. In the 21 instances without detectable recurrence, hyperploidy led to a relatively high proportion of positive (15) and suspicious (4) results by FCM, but only eight had distinct aneuploid populations. It is possible that this latter group, at least, is harboring occult carcinoma. Conventional cytology in the nonrecurrent group was positive in 1 (4.8%), suspicious in 7 (33.3%), and negative in 13 (61.9%). In those instances when tumor was confirmed by biopsy, the false-negative rate for FCM was 19.7%; the false-negative rate for cytology was 40.9%. Thus, FCM appears to be more sensitive but less specific than conventional cytology, having a lower false-negative but a higher false-positive rate. Although serial FCM provides an objective quantitative measure of aneuploid stemlines and hyperdiploid populations in bladder irrigation specimens and can be helpful in following intravesical BCG therapy for superficial bladder carcinoma, it should still be used with conventional cytology. The greatest difficulty with FCM at present, as with conventional cytology, is in cases of marked inflammation. The results reported here were obtained under the most stringent conditions and represent the minimum level of accuracy. Potential improvements in the technique, with the addition of immunologic or other markers, hold hope of further increasing the accuracy of FCM.     

Intravesical therapy for superficial bladder cancer

Approximately 54,400 new cases of transitional cell carcinoma of the bladder were reported in the United States in 1999, with an estimated 12,500 deaths attributable to this cancer. Close to 75% of all bladder tumors are confined to the urothelium (stage Ta, or carcinoma in situ), and nearly 30% of papillary tumors invade the lamina propria (stage T1). The majority of superficial tumors are low grade with low rates of progression. Transurethral resection is the standard initial treatment for transitional cell carcinoma. Intravesical therapy is an important adjunct to transurethral resection in patients with superficial bladder cancer, many of whom are at risk for disease recurrence and progression. Cytotoxic and immunomodulating agents and, more recently, photosensitizers have demonstrated utility against superficial transitional cell carcinoma. Many studies have assessed and continue to examine the efficacy of various agents at different doses and in different combinations and schedules. Recently, valrubicin (Valstar) won Food and Drug Administration (FDA) approval only for the treatment of refractory carcinoma in situ. However, bacillus Calmette-Guérin (BCG) and mitomycin (Mutamycin) remain the most commonly used, most effective agents available for prophylaxis against recurrence and subsequent progression of superficial bladder cancer. This article reviews traditional and alternative intravesical agents useful in the therapy and prophylaxis of superficial transitional cell carcinoma of the bladder.     

Heat shock proteins HSP27, HSP60, HSP70, and HSP90: expression in bladder carcinoma

BACKGROUND: Heat shock proteins (HSPs) are synthesized by cells in response to various stress conditions, including carcinogenesis. The expression of HSPs in neoplasia has been implicated in the regulation of apoptosis, and HSPs also can act by increasing immunity. In the current study, the authors attempted to clarify the significance of HSPs in bladder carcinoma and their effect on tumor behavior. METHODS: Expression levels of the 27-kilodalton HSP (HSP27), HSP60, HSP70, and HSP90 were studied using immunohistochemistry on tissue sections from 42 transitional cell carcinomas of the bladder (14 Grade 1 tumors; 13 Grade 2 tumors; 15 Grade 3 tumors, including 3 tumors associated with carcinoma in situ; 30 Stage Ta tumors; 7 Stage T1 tumors; and 5 Stage T2 tumors). Bladder specimens from 10 healthy patients were used as controls in the study. The selected patients had a mean follow-up of 52 months (range, 24-78 months). Among the 37 patients with superficial bladder carcinoma, 17 patients did not have any recurrence after undergoing primary resection, and 20 patients developed recurrent disease, including 4 recurrences with muscle invasion. HSP expression was evaluated according to the percentage of positively stained cells, and loss of expression was defined as < 80% of stained cells. RESULTS: In normal bladder specimens, all four HSPs (HSP27, HSP60, HSP70, and HSP90) were expressed strongly in the cytoplasm and membrane from the basal cell layer to the superficial cell layer. Loss of expression was detected in tumors: respectively, 45.2%, 38.1%, 69.0% and 23.8% of tumors showed a loss of immunostaining for HSP27, HSP60, HSP70, and HSP90. No correlation between HSP expression and grade was found. Low expression levels of HSP27 and HSP60 were correlated with higher tumor stage (87% vs. 6% [P < 0.001] and 78% vs. 9% [P < 0.01], respectively). HSP60 and HSP90 expression levels were correlated with final outcome for patients with superficial bladder carcinoma: loss of expression was associated with the risk of developing an infiltrating recurrence (97% vs. 6.0% [P < 0.001] and 88.2% vs. 52.5% [P = 0.02] for HSP60 and HSP90, respectively). CONCLUSIONS: HSPs were expressed in normal urothelium, and the current results indicated that loss of HSP60 and HSP90 expression may have prognostic relevance in patients with bladder carcinoma. The authors believe that HSP60 may be a very useful marker for patients with superficial bladder carcinoma and may be used for predicting disease progression. If these data are confirmed, low HSP60 expression levels may be usable as a prognostic marker to identify patients for whom local treatment would be insufficient.     

Clinical sensitivity of p53 mutation detection in matched bladder tumor, bladder wash, and voided urine specimens

BACKGROUND: Mutations in the p53 tumor suppressor gene may correlate with an increased risk of recurrence and disease progression in patients with bladder carcinoma. The ability to accurately and sensitively detect p53 mutations in cytology specimens may be of benefit in the treatment of bladder carcinoma patients with superficial, minimally invasive disease. METHODS: Genomic DNA was isolated from 49 cases, each of which was comprised of matched bladder tumor tissue, bladder wash, and voided urine specimens obtained concurrently at a single institution. The genomic DNA was analyzed for mutations in the p53 tumor suppressor gene using a p53 mutation detection assay. Automated dideoxy sequencing of mutant specimens also was performed. RESULTS: Of the 49 cases, 29 (59%) showed no evidence of p53 mutations in the tumor, bladder wash, or voided urine specimens. Of the remaining 20 cases, 19 showed evidence of mutations in the tumor. Of these 19 p53 mutant bladder tumors, 16 (84%) were detected in the matched bladder wash and 16 (84%) were detected in the matched voided urine specimens. One case resulted in the detection of mutant p53 in the voided urine and the bladder wash, but not in the tumor. Analysis of the results between tumor tissue and bladder wash or tumor and voided urine showed 84.2% sensitivity, 96.8% specificity, and 91.8% accuracy. Sequence analysis of the mutant cases showed that the mutations detected in the tumor tissue were the same mutations detected in the bladder wash and the voided urine specimens. CONCLUSIONS: Both voided urine and bladder wash specimens from patients with bladder carcinoma were found to provide a high rate of clinical accuracy for the determination of the p53 gene status in patients with bladder tumors.     

Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation

Urothelial tumors develop along two distinctive phenotypic pathways (superficial papillary non-invasive tumors versus flat carcinoma in situ lesions), with markedly different biological behavior and prognosis. Although multiple genetic alterations have been identified in human bladder cancer, their cause-effect relationship with the two pathways has not been firmly established. Using a urothelium-specific promoter of the uroplakin II gene, we showed earlier in transgenic mice that the urothelial expression of SV40T antigen, which inactivates p53 and pRb, induced carcinoma in situ and invasive and metastatic bladder cancer. In striking contrast, we demonstrate here that the urothelial expression of an activated Ha-ras in transgenic mice caused urothelial hyperplasia and superficial papillary non-invasive bladder tumors. These results provide strong, direct experimental evidence that the two phenotypical pathways of bladder tumorigenesis are caused by distinctive genetic defects. Our results indicate that Ha-ras activation can induce urothelial proliferation in vivo; and that urothelial hyperplasia is a precursor of low-grade, superficial papillary bladder tumors. Our transgenic models provide unique opportunities to study the detailed molecular events underlying different types of bladder neoplasms, and can serve as useful preclinical models for evaluating the in vivo efficacy of preventive and therapeutic agents that act on various signaling pathways in bladder cancer.     

Prognostic significance of thymidine kinase activity in bladder carcinoma

BACKGROUND: Thymidine kinase (TK) plays a key role in the complimentary or alternative salvage pathway of pyrimidine synthesis. Little is known about the significance of TK activity in bladder carcinoma. The authors examined the activity of TK in 55 patients with bladder carcinoma to determine the prognostic significance of TK activity. METHODS: TK activity in nonfixed, fresh-frozen specimens of bladder carcinoma and normal bladder tissue was determined by using the diethylaminoethanol cellulose disc method. RESULTS: The activity of TK was approximately two-fold higher in bladder carcinoma specimens compared with normal bladder tissues. The TK activity in muscle-invasive bladder carcinoma was two-fold higher compared with the activity in superficial bladder carcinoma (Ta and T1). In addition, the activity of TK in T1 tumors was two-fold higher compared with the TK activity in Ta tumors. The level of TK activity in Grade 3 bladder tumors was two-fold higher compared with the activity in Grade 1 and Grade 2 tumors. Patients with Ta and T1 bladder carcinoma who had low TK activity had a longer postoperative tumor free period compared with the patients who had high TK activity during the 2 years of follow-up. TK activity was correlated with the activity of thymidine synthase, which is a key enzyme for pyrimidine synthesis in the de novo pathway. CONCLUSIONS: This study is the first to demonstrate that the level of TK activity is correlated with both disease stage and tumor grade in patients with bladder carcinoma and that elevated TK activity predicts early recurrence in patients with Ta and T1 disease. These results suggest that the level of TK activity may be used as a prognostic parameter and that TK may be a molecular therapeutic target in patients with bladder carcinoma.     

Adjuvant intravesicular pharmacotherapy for superficial bladder cancer.

In 1990, bladder cancer, excluding carcinoma in situ, was estimated to contribute 49,000 cases of cancer. In men 75 years old or older, it became the fifth leading cause of cancer deaths. Of patients with bladder cancer, 75%-80% initially present with superficial bladder tumors. Treatment of these tumors has three objectives: 1) to eradicate existing disease, 2) to provide prophylaxis against tumor recurrence, and 3) to avoid deep invasion into the muscle layers of the bladder. Transurethral resection is the primary treatment to eradicate superficial bladder tumors, but 40%-80% of these tumors recur. Because of these high recurrence rates, adjuvant intravesicular pharmacotherapy with cytotoxic and immunomodulatory drugs has gained widespread use. The past two decades of clinical investigations in superficial bladder cancer have provided valuable information on the biology and treatment of the disease. Multivariate analyses have indicated that tumor grade and stage are the most important prognostic variables commonly available to the clinician to identify the patient at greatest risk of developing muscle-invasive or metastatic bladder cancer. These studies have also identified groups at low risk for tumor recurrence and invasive bladder cancer. Randomized trials have shown that recurrence rates are decreased by adjuvant intravesicular pharmacotherapy with a number of drugs: bacillus Calmette-Guérin vaccine (BCG), doxorubicin, ethoglucid (Epodyl), mitomycin-C, teniposide, and thiotepa. However, few studies indicate that adjuvant intravesicular pharmacotherapy can prevent progression to invasive bladder cancer in the high-risk patient with superficial bladder cancer. Additional clinical trials are needed to determine whether such therapy can prevent invasive and metastatic bladder cancer and improve disease-free survival in this group. In addition, the identification of tests (e.g., monoclonal antibody tests, chromosomal analyses, and tumor marker assays) that can help to identify high-risk patients is needed to better develop therapeutic strategies for superficial bladder cancer.     

Differential expression of progression-related genes in the evolution of superficial to invasive transitional cell carcinoma of the bladder

It is generally accepted that there are dichotomous biologic pathways that lead to the development of either: i) superficial papillary (Ta) transitional cell carcinoma (TCC) or ii) precursor lesions to muscle-invasive (CIS, T1) TCC and muscle-invasive (> or =T2) TCC. We investigated the expression of several progression-related genes to characterize the phenotype of these tumors within these divergent developmental pathways. Using a colorimetric in situ hybridization technique, we examined the expression of mRNAs of several progression-related genes in archival, pathologic specimens from 77 patients with bladder TCC. These genes included basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin (IL)-8, matrix metalloproteinase (MMP)-9, and epidermal growth factor receptor (EGFR). Relative gene expression was quantified using image analysis. Gene expression was normalized using poly (dT) and the expression of each factor in a panel of specimens of normal urothelium. Patients were stratified according to disease stage, and the level of gene expression among the stratified groups was compared. VEGF, bFGF, IL-8, and MMP-9 expression was increased in muscle-invasive compared with superficial papillary tumors, (p<0.05) and VEGF expression was increased in muscle-invasive tumors compared with CIS specimens (p<0. 05). bFGF, IL-8, and EGFR expression was increased in CIS specimens compared with superficial papillary tumors (p<0.05). The pattern of expression of bFGF, VEGF, IL-8, MMP-9, and EGFR represent the divergent developmental pathways in the pathogenesis of bladder TCC, which characterizes superficial or invasive bladder cancer. bFGF, IL-8, and EGFR appear to be upregulated in early precursor lesions (CIS), whereas VEGF appears to be upregulated at later stages in the development of muscle-invasive TCC.     

膀胱癌增殖细胞核抗原与麦胚凝集素受体的相关关系

目的：探讨增殖细胞核抗原（proliferating cell nuclear antigen,PCNA)和麦胚凝集素（wheat germ agglutinin,WGA)在膀胱移行细胞癌（TCC）中表达的相关关系。方法：采用免疫组织化学ABC法对63例TCC标本PCNA WGA受体检测。结果：PCNA与WGA的强阳性表达随着肿瘤的病理分级升高而增高，浸润性肿瘤中的WGA本的强阳性表在显著高于浅表性肿瘤（P＜0．05），PCNA与WGA受体表达一致性良好，呈显著性相关（P＜0．005），结论：我们认为PCNA和WGA受体均可作为TCC的肿瘤标记物，证明了TCC细胞的增殖活性增强将改变其细胞的抗原性。     

MRP-1/CD9和HSP60在膀胱癌中的表达

目的:探讨MRP-1/CD9和HSP60的表达与膀胱癌发生发展的关系.方法:应用免疫组织化学技术(SP法)检测CD9和HSP60在75例膀胱移行细胞癌标本,15例正常膀胱组织中的表达.结果:CD9和HSP60在正常膀胱组织均高表达,41.2%和42.7%的膀胱癌对CD9和HSP60显示了表达减低.不同临床分期和病理分级的膀胱癌中CD9的表达有差异(P＜0.05),根据预后表浅性膀胱癌的复发浸润组和非浸润组中CD9和HSP60表达有差异(P＜0.05).结论:CD9和HSP60可能与膀胱癌的发生发展有关,它们可能作为判断膀胱癌预后的新指标.     

口服卡介苗治疗表浅膀胱肿瘤

口服卡介苗(BCG)治疗表浅膀胱肿瘤6例,其中5例经膀胱镜和组织学复查未发现肿瘤,仅为慢性炎细胞浸润。本组资料说明口服卡介苗免疫疗法对表浅膀胱肿瘤有效。     

147例表浅性膀胱癌预后因素分析

目的 :探讨表浅性膀胱癌各种因素与患者预后的关系。方法 :对 147例表浅性膀胱癌进行回顾性分析。结果 :147例中 ,72例术后复发 ( 4 9% ) ,术后 5年复发率为 35.4 %。初诊时为多发者、直径大于 3cm、分级与分期高的肿瘤术后复发率分别高于单发者、直径小于 3cm者、分级、分期低的肿瘤。术后 6个月内肿瘤复发者经治疗后肿瘤再次复发的机会高 ,术后膀胱内灌药可以预防肿瘤复发。结论 :肿瘤分级与分期高、多发肿瘤、直径大于 3cm者及术后膀胱内未灌药者复发率高     

Bladder cancer as seen in giant histologic sections.

Giant sections from cystectomy specimens in 45 cases of bladder cancer were examined microscopically after en bloc fixation and processing. There were 35 transitional cell, seven squamous cell, and three mixed transitional cell and squamous carcinomas. Broad front invasion was associated with papillary and superficial tumors while tentacular invasion was associated with solid tumors and a generally poorer prognosis. Carcinoma in situ merged with the invasive cancer in 33 cases, and neoplasia in these cases tended to be multifocal. In 10 cases there was no carcinoma in situ next to the invasive lesion, and the cancer was unifocal. These findings support the concept that there may be two pathogenetic types of bladder cancer, one arising in an extensive field of abnormal epithelium and one arising in a focal area of abnormality. The findings also underscore the importance in clinical management of selected mucosal biopsies adjacent to the site of any visible bladder tumors.     

表浅性膀胱癌预后与癌肿数目、病理分级的关系

目的探讨表浅性膀胱癌肿块数目、病理分级与患者预后的关系。方法对122例表浅性膀胱癌进行回顾性分析。结果122例中,40例术后复发,术后5年内的复发率为32.79%。初诊时肿瘤为多发者即3个及3个以上肿瘤、G3级的肿瘤术后复发的平均时间、5年内的复发率分别高于单发或双发者、G1或G2级的肿瘤。结论膀胱癌肿瘤数目、细胞分级是影响表浅性膀胱癌预后的重要因素,多发肿瘤、G3级肿瘤可能在较短时间内复发,及时行膀胱切除更为妥当。     

IMP3 predicts aggressive superficial urothelial carcinoma of the bladder

PURPOSE: In this study, we investigated whether an oncofetal protein, IMP3, can serve as a new biomarker to predict progression and metastasis of early-stage urothelial carcinoma of the bladder. EXPERIMENTAL DESIGN: The expression of IMP3 in 242 patients with primary superficial bladder urothelial carcinoma and metastatic urothelial carcinoma was evaluated by immunohistochemistry. Patients with primary superficial urothelial carcinoma of the bladder were further investigated by use of survival analysis. RESULTS: Twenty percent (42 of 214) of primary superficial urothelial carcinomas and 93% (26 of 28) of metastatic urothelial carcinomas expressed IMP3. Kaplan-Meier plots and log-rank tests showed that patients with IMP3-positive tumors had a much lower progression-free survival (P = 0.0002) and disease-free survival rate (P = 0.0067) than did those with IMP3-negative tumors. The 5-year progression-free and disease-free survival rates were 91% and 94% in IMP3-negative patients versus 64% and 76% in IMP3-positive patients, respectively. Sixty percent of IMP3-positive patients with superficial invasive urothelial carcinoma at initial diagnosis went on to develop metastases, whereas no metastasis was found in IMP3-negative patients (P = 0.0017). In the multivariable Cox analysis, patients with IMP3 expression in their superficial urothelial carcinomas subsequently developed invasive tumors or metastasis at a rate that was about five times greater than cases without expression of IMP3 adjusting for other well-known clinical variables (tumor stage and grade, etc.). CONCLUSIONS: Our findings indicate that IMP3 is an independent prognostic marker that can identify a group of patients with a high potential to develop progression and who might benefit from early aggressive therapy.     

Diagnosis and management of superficial bladder cancer

Bladder cancer is the fourth leading cause of cancer in American men, accounting for more than 12,000 deaths annually. It was one of the first malignancies in which carcinogens were recognized as an important factor in its cause. Currently, cigarette smoking is by far the most common cause of bladder cancer, although occupational exposure to arylamines has been implicated in the past. Gross or microscopic hematuria is the most common sign at presentation. Initial radiologic evaluation usually includes the excretory urography (intravenous pyelography), although further evaluation of the renal parenchyma with ultrasound or computed tomography scanning has been advocated by some. These radiologic studies are unable to provide adequate bladder imaging, and thus cystoscopy is required for the diagnosis of bladder cancer. Most bladder cancers present as "superficial" disease, confined to the bladder mucosa or submucosal layer, without muscle invasion. Superficial tumors consist of papillary tumors that are mucosally confined (Ta), papillary or sessile tumors extending into the lamina propria (T1), and carcinoma in situ, which occurs as "flat" mucosal dysplasia, which can be focal, diffuse, or associated with a papillary or sessile tumor. The natural history of these pathologic subtypes differ significantly. Most superficial tumors (60% to 70%) have a propensity for recurrence after transurethral resection. Some (15% to 25%) are at high risk for progression to muscle invasion. Most superficial tumors can be stratified into high- or low-risk groups depending on tumor stage, grade, size, number, and recurrence pattern. It is important to identify those tumors at risk for recurrence or progression so that adjuvant intravesical therapies can be instituted. Many intravesical chemotherapeutic agents have been shown to reduce tumor recurrence when used in conjunction with transurethral tumor resection. Unfortunately, however, none of these agents have proved to be of benefit in preventing disease progression. Most are given intravesically on a weekly basis, although many studies suggest that a single instillation immediately after transurethral resection may be as good as a longer course of therapy. Although all of these drugs have toxicity, they usually are well tolerated. Intravesical bacille Calmette-Guérin (BCG) is an immunotherapeutic agent that when given intravesically is very effective in the treatment of superficial transitional cell carcinoma. Compared with controls, BCG has a 43% advantage in preventing tumor recurrence, a significantly better rate than the 16% to 21% advantage of intravesical chemotherapy. In addition, BCG is particularly effective in the treatment of carcinoma in situ, eradicating it in more than 80% of cases. In contrast to intravesical chemotherapy, BCG has also been shown to decrease the risk of tumor progression. The optimal course of BCG appears to be a 6-week course of weekly instillations, followed by a 3-week course at 3 months in those tumors that do not respond. In high-risk cancers, maintenance BCG administered for 3 weeks every 6 months may be optimal in limiting recurrence and preventing progression. Unfortunately, adverse effects associated with this prolonged therapy may limit its widespread applicability. In those patients at high risk in whom BCG therapy fails, intravesical interferon-alpha with or without BCG may be beneficial in some. Photodynamic therapy has also been used but is limited by its toxicity. In patients who progress or do not respond to intravesical therapies, cystectomy should be considered. With the development of orthotopic lower urinary tract reconstruction to the native urethra, the quality of life impact of radical cystectomy has been lessened.