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Purpose: Studies indicate that molecular subtypes in muscle invasive bladder cancer predict the clinical outcome. We evaluated whether subtyping by a simplified method and established classifications could predict the clinical outcome., Materials and Methods: We subtyped institutional cohort 1 of 52 patients, including 39 with muscle invasive bladder cancer, an Oncomine™ data set of 151 with muscle invasive bladder cancer and TCGA (The Cancer Genome Atlas) data set of 402 with muscle invasive bladder cancer. Subtyping was done using simplified panels (MCG-1 and MCG-Ext) which included only transcripts common in published studies and were analyzed for predicting metastasis, and cancer specific, overall and recurrence-free survival. TCGA data set was further analyzed using the Lund taxonomy, the Bladder Cancer Molecular Taxonomy Group Consensus and TCGA 2017 mRNA subtype classifications., Results: Muscle invasive bladder cancer specimens from cohort 1 and the Oncomine data set showed intratumor heterogeneity for transcript and protein expression. MCG-1 subtypes did not predict the outcome on univariate or Kaplan-Meier analysis. On multivariate analysis N stage (p ≤0.007), T stage (p ≤0.04), M stage (p=0.007) and/or patient age (p=0.01) predicted metastasis, cancer specific and overall survival, and/or the cisplatin based adjuvant chemotherapy response. In TCGA data set publications showed that subtypes risk stratified patients for overall survival. Consistently the MCG-1 and MCG-Ext subtypes were associated with overall but not recurrence-free survival on univariate and Kaplan-Meier analyses. TCGA data set included 21 low grade specimens of the total of 402 and subtypes associated with tumor grade (p=0.005). However, less than 1% of muscle invasive bladder cancer cases are low grade. In only high grade specimens the MCG-1 and MCG-Ext subtypes could not predict overall survival. On univariate analysis subtypes according to the Bladder Cancer Molecular Taxonomy Group Consensus, TCGA 2017 and the Lund taxonomy were associated with tumor grade (p <0.0001) and overall survival (p=0.01 to <0.0001). Regardless of classification, subtypes had about 50% to 60% sensitivity and specificity to predict overall and recurrence-free survival. On multivariate analyses N stage and lymphovascular invasion consistently predicted recurrence-free and overall survival (p=0.039 and 0.003, respectively)., Conclusions: Molecular subtypes reflect bladder tumor heterogeneity and are associated with tumor grade. In multiple cohorts and subtyping classifications the clinical parameters outperformed subtypes for predicting the outcome.

Purpose: To update current recommendations on prevention, screening, diagnosis, and evaluation of bladder cancer (BC) based on a thorough assessment of the most recent literature on these topics., Methods: A non-systematic review was performed, including articles until June 2017. A variety of original articles, reviews, and editorials were selected according to their epidemiologic, demographic, and clinical relevance. Assessment of the level of evidence and grade of recommendations was performed according to the International Consultation on Urological Diseases grading system., Results: BC is the ninth most common cancer worldwide with 430,000 new cases in 2012. Currently, approximately 165,000 people die from the disease annually. Absolute incidence and prevalence of BC are expected to rise significantly during the next decades because of population ageing. Tobacco smoking is still the main risk factor, accounting for about 50% of cases. Smoking cessation is, therefore, the most relevant recommendation in terms of prevention, as the risk of developing BC drops almost 40% within 5 years of cessation. BC screening is not recommended for the general population. BC diagnosis remains mainly based on cystoscopy, but development of new endoscopic and imaging technologies may rapidly change the diagnosis algorithm. The same applies for local, regional, and distant staging modalities., Conclusions: A thorough understanding of epidemiology, risk factors, early detection strategies, diagnosis, and evaluation is essential for correct, evidence-based management of BC patients. Recent developments in endoscopic techniques and imaging raise the hope for providing better risk-adopted approaches and thereby improving clinical outcomes.

Context: Bladder cancer (BCa) is the fourth most common cancer in men. Survival from the disease has not improved in the last 25 yr. Population-based screening theoretically provides the best opportunity to improve the outcomes of aggressive BCa., Objective: To review the current literature regarding the usefulness and feasibility of screening for bladder cancer., Evidence Acquisition: We conducted a nonsystematic review restricted to English using the keywords urinary bladder neoplasms, mass screening, mandatory testing, and early detection of cancer. We retrieved 184 articles and selected 22., Evidence Synthesis: There was no level 1 evidence (obtained from a randomised controlled trial [RCT]) addressing the impact of screening on BCa survival or tumour downstaging. No study assessed the diagnostic performance of urinary markers in the context of screening. Two case-control series suggested a benefit of screening on survival, and a third found a nonsignificant beneficial trend in favour of screening. Two studies suggested downstaging of BCa at diagnosis. Other reports concluded that most cancers detected with screening were of low grade and that current urinary testing cannot detect all tumours. Screening is likely to be of benefit in high-risk populations using cost-efficient high-performing urinary biomarkers. There was insufficient evidence to define an efficient screening protocol., Conclusions: Although BCa screening is theoretically feasible in a high-risk population, there is currently insufficient evidence to recommend it. This is due to insufficient data to define an efficient screening protocol with selection of an appropriate population and the lack of accurate and cost-effective urinary markers able to discriminate low-risk from high-risk cancers. Major improvements are needed in the evaluation of urinary biomarkers before evaluation in a RCT can be achieved., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Pathology standards for the diagnosis of bladder cancer (BCa) have recently evolved to better reflect patient diagnosis and clinical outcomes., Objective: To update pathology reporting standards for BCa., Evidence Acquisition: We searched the international medical literature and reviewed all articles that addressed BCa gross dissection, pathologic diagnosis, staging, and reporting as of June 6, 2012. We also reviewed the proceedings from the recent Second International Consultation on Bladder Cancer (Vienna, Austria). The literature selected for review focuses on evidence-based studies that address histopathologic factors in BCa, with emphasis placed on factors that influence patient diagnosis and clinical outcomes., Evidence Synthesis: We separated data into three main components for analysis based on the type of specimen obtained: (1) transurethral resection specimens, with an emphasis on pathologic staging, variants of urothelial carcinoma, angiolymphatic invasion, and relevant ancillary techniques such as immunohistochemistry in assessing these features; (2) cystectomy specimens, with an emphasis on pT0 disease, prostatic involvement by urothelial carcinoma and lymph node dissection and analysis; and (3) cytology correlates, with recommendations for the use of cytology paired with tissue-based sampling. Areas of controversy are described and recommendations based on existing guidelines are provided. The value of a multidisciplinary team is highlighted., Conclusions: Ongoing international collaborations amongst pathologists have led to emerging standards in the reporting and microscopic diagnosis of BCa specimens. Although some areas remain controversial, we present the most up-to-date data and guidelines relevant to neoplastic pathology of the urinary bladder., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: Prostate cancer is the most common cancer diagnosed in men and remains the second most lethal malignancy. Most patients undergoing treatment elect for radical prostatectomy or radiation. As the number of patients treated has increased and survival improved, delayed complications of these modalities has assumed increased importance. Recent studies report an increased risk of certain cancers after radiation for prostate cancer. This review aims to summarize recent data., Recent Findings: Recent studies have confirmed the association of prostate radiation with secondary cancers. The most common secondary malignancy is bladder carcinoma. We have treated 44 patients with bladder cancer who had radiation therapy for prostate cancer. At diagnosis, 60% had tumor, which invaded the bladder muscle (T2 or greater disease). The mean latency from radiation to diagnosis of bladder cancer was 5.5 years., Summary: Radiation therapy for prostate cancer is associated with an increased risk of bladder cancer. In our series, patients presented at higher stage than expected from population-based studies of bladder cancer. Patients and their physicians should be aware of such risks when choosing therapy for prostate cancer. Hematuria following radiation therapy for prostate cancer should be investigated rather than being attributed to radiation-induced cystitis.

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.

Objectives: To evaluate the risk of long-term recurrence for patients who received cell-salvaged blood during radical cystectomy (RC)., Methods: We retrospectively analyzed an RC database and compared those who did and did not receive cell-salvaged blood according to baseline parameters, pathologic outcomes, and recurrence., Results: A total of 378 patients underwent RC between 1992 and 2005 by one surgeon. Of these, 65 (17.2%) received cell-salvaged blood and 313 (82.8%) did not. The two groups had similar baseline characteristics. There were no differences between the two groups when compared by pathologic stage. The median follow-up for patients who did and did not receive cell-salvaged blood was 19.1 and 20.7 months, respectively (P = 0.464). The 3-year disease-specific survival rate for the two groups was 72.2% and 73.0%, respectively (P = 0.90)., Conclusions: Intraoperative cell salvage is a safe blood management strategy for patients undergoing RC. There is no increased risk of metastatic disease or death for those who receive cell-salvaged blood. Concerns about spreading tumors cells by IOCS during RC would seem unwarranted. However, only a prospective, multicenter, randomized trial would provide the most valid assessment of the safety of IOCS.

Muscle-invasive urothelial (transitional cell) carcinoma is a potentially lethal condition for which an attempt at curative surgery is required. Clinical staging does not allow for accurate determination of eventual pathologic status. Muscle-invasive urothelial carcinoma is a highly progressive disease, and initiation of definitive therapy within 3 months of diagnosis is worthwhile. Age is not a contraindication for aggressive surgical care, and surgical candidates should be evaluated in the context of overall medical comorbidity. In those patients who undergo surgery, clinical pathways may streamline care. Radical cystectomy remains the "gold standard" of therapy, providing 5-year survival rates of 75% to 80% in patients with organ-confined disease, yet organ-sparing procedures demonstrate clinical effectiveness as well. Cystectomy should be undertaken with the intent of performing complete pelvic lymph node dissection and attaining surgically negative margins. In younger female patients, the preservation of reproductive organs may be achieved in many cases. Prostate- and seminal vesicle-preserving cystectomy has been performed, yet the long-term safety and efficacy of such a procedure remains to be determined. Laparoscopic and robotic cystectomy procedures continue to be explored by several investigators. The role of "radical transurethral resection" in muscle-invasive disease is limited to a small cohort of patients, and, when it is performed, cystectomy may be required to consolidate therapy. Postoperative follow-up after cystectomy should occur over short intervals during the first 2 years and can be extended, but not discontinued, beyond that time. Currently, no tumor markers have been prospectively validated to help guide clinical decision making, and prospective trials incorporating marker data should be encouraged.

Purpose: Intravesical therapy is an integral part of treatment in patients with superficial urothelial carcinoma of the bladder. The American Urological Association and European Association of Urology guidelines on bladder cancer incorporate it for the treatment of superficial bladder cancer. Given the extensive use of intravesical immunotherapy and chemotherapy, it is essential for the practicing urologist to be aware of the local and systemic side effects of these therapies., Materials and Methods: We reviewed the literature on intravesical immunotherapy and chemotherapy with particular emphasis on side effects, complications and their management. A Medline search of the English language literature for the last 25 years was done on Entrez PubMed and all relevant articles were studied in full. All side effects and complications were studied and their management was reviewed., Results: Intravesical therapy for transitional cell carcinoma of the bladder is generally safe. There is a high incidence of local, usually self-limiting, relatively minor side effects and infrequent, potentially severe local and systemic side effects. Most side effects are avoidable., Conclusions: Although intravesical therapy is generally safe, local and systemic side effects occur and it is important to be aware of them. Identifying complications early, preventing them when possible and managing them efficiently are critical. Most complications are preventable. Knowing the risks and benefits of chemotherapeutic and immunotherapeutic agents may decrease the short-term and long-term toxicity of these agents. Adherence to guidelines may prevent inappropriate use, which can lead to unnecessary complications, resulting in bladder dysfunction and even cystectomy.

Objectives: To critically evaluate the survival of patients with high-grade Ta or T1 urothelial cancer (UC) or carcinoma in situ of the bladder who have received bacillus Calmette-Guérin (BCG) and who have undergone radical cystectomy., Methods: We retrospectively reviewed our single-surgeon database of those patients who underwent cystectomy and previously received BCG. We evaluated the baseline characteristics, pathologic outcomes, and survival data., Results: Of 313 patients who underwent cystectomy between January 1992 and March 2004, 90 (29%) received BCG before bladder removal. The mean time from the first BCG course to the date of cystectomy was 27.9 months. The mean duration of follow-up from cystectomy was 32.1 months. The risk of progression to muscle invasion for those who underwent cystectomy less than or more than 1 year from the time of their first BCG dose was 59% and 36%, respectively (P = 0.05). The disease-specific survival rate was 81% versus 80% for those who underwent early versus delayed cystectomy (P = 0.9)., Conclusions: Patients with high-grade UC are at risk of dying from this cancer, even if they ultimately undergo cystectomy. Patients who receive BCG should be appropriately counseled that they remain at risk for disease progression and death from UC. It is difficult to ascertain the proper time to proceed with cystectomy if an initial bladder conservation approach is used.

Objectives: To evaluate the incidence of bacille Calmette-Guérin (BCG)-contracted bladders and attempt to ascertain the potential risk factors for this severe complication. BCG is the most effective intravesical agent for the treatment of high-grade, noninvasive transitional cell carcinoma (TCC) of the bladder. Widely used by urologists for the management of superficial TCC, adverse effects are not uncommon. These adverse effects are most commonly limited to irritative voiding symptoms, hematuria, and fever; however, severe adverse effects may occur., Methods: We retrospectively reviewed two cystectomy databases (University of Southern California/Norris Cancer Center and University of Miami Miller School of Medicine) and identified patients who underwent cystectomy and orthotopic neobladder reconstruction for BCG-induced bladder contracture., Results: We identified 1 case each in the two institutions' cystectomy databases of severely contracted bladders. The overall incidence of this complication leading to cystectomy was 0.05% and 0.3% at each institution. Both patients were salvaged with cystoprostatectomy and orthotopic reconstruction with an ileal neobladder. Neither patient had residual cancer at pathologic analysis of the cystectomy specimen, and both patients' severe lower urinary tract symptoms were alleviated postoperatively., Conclusions: A contracted bladder due to extravasation of BCG, although rare, is a serious complication. Cystoprostatectomy with orthotopic neobladder reconstruction may be the optimal solution to alleviate severe lower urinary tract symptoms and remove the risk of subsequent urothelial malignancy.

Objectives: To review our cystoprostatectomy (CP) database to determine the urethral recurrence rate. Urethral recurrence after CP has been reported to occur in up to 10% of patients. Recent data have suggested a much lower incidence. This has important implications when considering the type of urinary diversion and postoperative monitoring., Methods: We retrospectively analyzed our single-surgeon, consecutive CP series and determined the urethral recurrence rate and prognostic factors for recurrence. Urethrectomy was performed at CP if the prostatic apical margin was positive for carcinoma. All patients were followed up quarterly for 2 years and then semiannually. Urethral wash cytology was obtained if the patient had an ileal conduit. Cytology and cystoscopy were performed if they had an orthotopic neobladder., Results: A total of 226 men had undergone radical CP. The mean age for all patients was 69 years. Eight (3.5%) had undergone urethrectomy at CP. The mean follow-up was 42 months for the remaining 218 patients, of whom 108 had an orthotopic neobladder and 110 had supravesical diversion. Of the 218 patients, 8 (3.7%) developed urethral recurrence, 7 (6.4%) in the 110 who had undergone supravesical diversion and 1 in the 108 (0.9%) who had an orthotopic neobladder. Seven patients underwent urethrectomy for the recurrence and had no evidence of disease at last follow-up. One patient died of metastatic transitional cell carcinoma at 61 months., Conclusions: In our series, the risk of urethral recurrence after radical CP was low. The risk was substantially lower for patients who had an orthotopic neobladder. Our results show that urethrectomy at CP is rarely necessary because the proximal urethral margin is usually free of cancer. An orthotopic neobladder can therefore be safely considered in most patients. Delayed urethrectomy can be safely performed in those few patients with isolated urethral recurrence without compromising their survival.

Objective: To review the incidence, pattern and outcome of upper tract transitional cell carcinoma (TCC) after radical cystectomy for carcinoma of the bladder, and identify risk factors for its development., Patients and Methods: The records of 235 consecutive patients who had a radical cystectomy and urinary diversion for TCC at the authors' institution by one surgeon between January 1992 and August 2003 were retrospectively reviewed., Results: Five (2%) of 235 patients developed an upper tract urothelial tumour. The mean follow-up for all patients was 42 months, and was 52.2 months for those with an upper tract tumour. Four of the five patients presented with haematuria and one was diagnosed on routine follow-up intravenous urography. The mean time to the diagnosis of an upper tract tumour was 39.6 months. Of the potential risk factors, only the presence of TCC of the prostatic urethra had a statistically significant association with eventual upper tract tumour (P < 0.01). At the last follow-up, four patients died from urothelial cancer and one was disease-free., Conclusions: The incidence of upper tract tumour after cystectomy for TCC is low; most patients present with symptoms (haematuria) and have advanced disease at diagnosis. Patients with prostatic urethral involvement at cystectomy are at greater risk of developing upper tract tumour.

Purpose: The majority of patients with stage Ta or T1 bladder cancer will have a subsequent tumor. Many of these patients invariably undergo multiple transurethral resections to manage small subsequent tumors or recurrences. We report our experience monitoring patients whose subsequent tumors appear to be small, low grade and papillary., Materials and Methods: A total of 32 patients with small, papillary, low grade appearing tumors and a history of Ta or T1 transitional cell carcinoma were monitored. The decision to delay resection or fulguration and observe these tumors was based on bladder cancer history, endoscopic appearance of the tumor and presence or lack of symptoms. All patients had a previous Ta tumor, and the tumor being observed was always papillary and appeared to be low grade. The decision to resect the tumor(s) was based on change in appearance (size or configuration) at followup endoscopy or hematuria. Patient records were reviewed, and bladder cancer history and tumor observation periods were recorded. Several patients underwent a number of observation periods. Tumor grade and stage before the observation interval were compared to the pathology of the observed tumor(s) after eventual resection. Tumor growth rate was calculated based on estimated tumor size documented at each interval., Results: Mean patient age was 72 years (range 39 to 88). Mean time since diagnosis of bladder cancer (initial urothelial tumor event) was 71 months (range 12 to 139). Mean number of subsequent tumor episodes or recurrences per patient was 3.8 (range 1 to 10). Mean number of transurethral resections was 3.8. Mean tumor-free interval before development of a subsequent tumor or mean time to recurrence was 13.4 months based on 104 tumor episodes. Not all tumor recurrences were observed. Mean number of tumor observation periods per patient was 1.8 (range 1 to 5) with a mean duration of 10.09 months per period based on 56 observation intervals. Mean time since the beginning of the initial observation period was 38 months (range 6 to 126). Mean tumor growth rate for 37 tumors was 1.77 mm per month (range 0 to 5.8). Only 3 of 45 (6.7%) patients had tumor progression from a pre-observation, low grade, noninvasive (TaG1 to 2) to a high grade Ta or T1 tumor. In the 3 observation periods in which the patient's most recent tumor was T1, 2 (67%) patients had TaG1 on resection after observation. Every patient with a T1 tumor before observation of a small new tumor had a history of a Ta tumor. No disease progressed to muscle invasion., Conclusions: Small, recurrent, low grade appearing bladder tumors are slow growing and pose minimal risk. Therefore, as an alternative to in office fulguration to minimize morbidity and cost associated with repeat transurethral resection it may not be necessary to remove these tumors promptly at new tumor occurrence or recurrence.

Purpose: Transitional cell carcinoma involving the lamina propria (stage T1) is associated with a high recurrence and progression rate with implications for patient survival and quality of life. A better understanding of the natural history of and treatment alternatives for this tumor may improve the outcome in patients with this stage of bladder cancer., Materials and Methods: Literature of the last decade was comprehensively reviewed in regard to clinical and pathological diagnosis, adjuvant treatments, prognosis, and the role and timing of cystectomy. The information was gathered from MEDLINE, current urology journals, abstracts from recent urological meetings and personal experience., Results: High grade and the depth of lamina propria invasion are important prognostic factors. Early diagnosis and accurate pathological assessment are essential for determining the most adequate treatment pathway. Initial treatment consists of complete transurethral resection and adjuvant treatment with intravesical instillation of bacillus Calmette-Guerin (BCG). Immediate postoperative instillation of mitomycin C decreases the risk of recurrence possibly related to tumor implantation. Intravesical treatment does not substantially decrease the chance of progression. Lack of a complete response to BCG at 3 to 6 months, high grade, the depth of lamina propria invasion, the association of carcinoma in situ and prostate mucosa or duct involvement represent significant predictors for progression. Cystectomy should be suggested for recurrent stage T1 tumor after BCG, new onset or persistent carcinoma in situ, tumor located at a difficult site for resection, prostatic duct or stromal involvement and muscle invasion., Conclusions: High grade stage T1 transitional cell carcinoma is a highly malignant tumor. Complete resection followed by immediate mitomycin C instillation and 6 weekly BCG instillations results in an acceptably low recurrence and progression rate. Rigorous long-term surveillance and continuous reconsideration of radical cystectomy in concordance with the evolution of the disease are essential.

The heterogeneity of bladder cancer concerning progress of recurrence is an essential characteristic of this disease. Hyaluronic acid (HA) and its degrading enzyme hyaluronidase (HAase) are intricately associated with bladder cancer angiogenesis and metastasis. Tumor-associated HA and HAase are secreted in urine. In 513 urine specimens (261 bladder cancer patients, 252 patients without bladder cancer) and 83 bladder tissue specimens (71 bladder tumors, 12 normal bladder tissues), the accuracy of HA and HAase as tumor markers was studied. Elevated urinary HA levels (> or = 500 ng/ml), indicating a positive HA test, suggest the presence of bladder cancer regardless of tumor grade. Elevated urinary HAase levels (> or = 10 mU/mg) indicate high-grade (G2/G3) bladder cancer. The combined HA-HAase urine test showed 91% sensitivity and 84% specificity to detect bladder cancer. The HA-HAase test is equally sensitive for monitoring tumor recurrence. Immunohistochemistry (IHC) staining of HA and HAase in the G1 and G2/G3 bladder cancer specimens was significantly (p < 0.001) higher than in normal bladder tissue. HA and HAase appear to be useful markers in the diagnosis of bladder cancer. When compared with other noninvasive tests, the HA-HAase urine test may be less expensive and more accurate.

Purpose: We reviewed our radical cystectomy series to determine whether the majority of patients present with muscle invasive bladder cancer., Materials and Methods: The records of 184 radical cystectomies performed by 1 surgeon from 1992 to 1999 were reviewed, and all slides of presenting pathology were reviewed by 1 pathologist. The pathological stage of the tumor at presentation was noted in each case, and the number of muscle invasive tumors at presentation was compared to 2 earlier series., Results: Radical cystectomy was performed for muscle invasive transitional cell carcinoma of the bladder in 176 cases and for other histology in 8. There were 101 (57.3%) patients with muscle invasive cancer at presentation compared to 84% and 91% in the 2 earlier series, respectively, which was a statistically significant decrease (p <0. 0001) in the number of de novo muscle invasive bladder cancers. Women were more likely to be diagnosed with muscle invasion primarily than men (85.2% and 50.7%, respectively), and younger patients (younger than 50 years) were more likely to present with superficial bladder cancer compared to those older than 50 years who were more likely to present with de novo muscle invasive bladder cancer., Conclusions: Analysis of our data supports the findings of the earlier series that the majority of patients present with muscle invasive bladder cancer. However, there is a significant decrease in the percentage of tumors invading the muscularis propria at presentation. Although this observation is encouraging, we emphasize that it is not as dramatic as the stage migration associated with prostate cancer, which may be largely attributed to the widespread use of prostate specific antigen for early detection. Therefore, we support the suggestion that therapeutic gains might follow from improved education regarding the signs and symptoms associated with bladder cancer, with enhanced focus on women and consideration of screening methods for those at high risk for bladder cancer.

Purpose: Specific patterns of progression and frequent recurrence of bladder tumors determine the choice of treatment, frequency of surveillance, quality of life, and ultimately, patient prognosis. The prognosis would be improved if an accurate noninvasive test was available for diagnosis. Identification of markers that function in bladder cancer progression would be helpful in designing such diagnostic tests. The glycosaminoglycan, hyaluronic acid (HA), promotes tumor metastasis. Hyaluronidase (HAase), an endoglycosidase, degrades HA into small fragments that promote angiogenesis. We have previously shown that both HA and HAase are associated with bladder cancer and may function in bladder tumor angiogenesis. In this study we examined whether urinary HA and HAase levels serve as bladder cancer markers., Materials and Methods: Among the 513 urine specimens analyzed, 261 were from transitional cell carcinoma (TCC) patients, 9 from patients with non-TCC tumors, and 243 from controls (normals, patients with other genitourinary (GU) conditions or a history of bladder cancer (HxBCa)). The urinary HA and HAase levels were measured by two ELISA-like assays that utilize a biotinylated HA binding protein for detection. These levels were normalized to total urinary protein and were expressed as ng./mg. (HA test) and mU/mg. (HAase test), respectively., Results: The urinary HA levels were elevated (2.5 to 6.5 fold) in bladder cancer patients (1173.7+/-173.4; n = 261) as compared with normals (246.1+/-38.5; n = 41); GU patients (306.6+/-32.2; n = 133), and patients with a HxBCa (351.1+/-49.1; n = 69) (p <0.001). The urinary HAase levels were elevated (3 to 7 fold) in G2/G3 bladder cancer patients (26.2+/-3.2) as compared with normals (4.5+/-0.9) and patients with either GU conditions (5.8+/-1.3), HxBCa (8.2+/-2.6) or G1 tumors (9.7+/-2.5) (p <0.001). The HA test showed 83.1% sensitivity, 90.1% specificity and 86.5% accuracy in detecting bladder cancer, regardless of the tumor grade. The HAase test showed 81.5% sensitivity, 83.8% specificity and 82.9% accuracy to detect G2/G3 patients. Combining the inferences of the HA and HAase tests (HA-HAase test) resulted in detection of bladder cancer, regardless of tumor grade and stage, with higher sensitivity (91.2%) and accuracy (88.3%), and comparable specificity (84.4%)., Conclusion: Our results show that the HA-HAase urine test is a noninvasive, highly sensitive and specific method for detecting bladder cancer and evaluating its grade.

Purpose: Patients with transitional cell carcinoma of the bladder are at risk for concurrent or subsequent cancer of the upper tract. Traditionally disease is monitored by radiography (excretory or retrograde urography). Some elect to sample the upper tract by obtaining urine for cytology. Are the results meaningful when performed in a patient with bladder cancer?, Materials and Methods: We evaluated 27 consecutive patients with transitional cell cancer of the bladder (grade 1 to 3, Ta to T2) with bladder wash for cytology and cystoscopy as well as resection of visible tumor. A 5F ureteral catheter was positioned at each ureteral orifice, flushed with saline and passed into each renal pelvis. Urine was collected for cytology., Results: Of 19 patients (68%) with high grade (grade 3) bladder cancer 13 had a positive bladder wash, including 6 (32%) with tumor cells detected in the urine from the upper tract. Of 8 patients (38%) with low grade (grade 1 to 2) transitional cell cancer 3 had a positive bladder wash and 2 (25%) had a positive upper tract cytology. All patients had a normal upper tract by excretory or retrograde urography. Ureteroscopy was not performed., Conclusions: Given the normal appearance of the upper urinary tract, it is highly unlikely that most, if any, of these patients with bladder cancer have tumor in the upper tract despite tumor cells in urine obtained by retrograde catheterization. Thus, upper tract sampling by a retrograde technique lacks specificity for localizing transitional cell cancer to the upper tract when performed in a patient with bladder cancer.

Objectives: To assess how the community urologist employs intravesical therapy in patients with transitional cell carcinoma (TCC) of the bladder because most data on intravesical therapy reflect the experience of major referral centers., Methods: The medical records of 234 consecutive patients with TCC were reviewed. Sixty-nine patients received intravesical treatment before referral. The initial pathologic findings, the indication for treatment (eg, grade and stage, initial versus recurrent tumor), the schedule of intravesical therapy, and the drug selected for each course of treatment were assessed., Results: A total of 1 39 courses of intravesical treatment were given to 69 patients; thus, the avarage number of courses was 2.02 per patient. The drug used was bacillus Calmette-Guerin (BCG) in 81 (58%), mitomycin C in 34 (24%), thiotepa in 16 (12%), Adriamycin in 4 (3%), and unknown in 4 (3%). Intravesical treatment was given after transurethral resection of the initial tumor in 33 patients; the initial pathologic finding was high grade (ie, grade 3 or carcinoma in situ) and/or Stage T1 in 22, TaG1-G2 in 9, and unknown in 2. One course of treatment was administered to 34 patients (49%) and two or more courses to 35 patients (51%). Eleven patients with TaG 1 -2 tumors were treated repetitively despite failure, with an average of 3.5 courses per patient; the drug used was BCG in 44%. Nineteen percent of patients received maintenance therapy. Intravesical therapy had to be discontinued in 10 patients because of side effects; 8 patients (12%) developed small contracted bladders and severe irritative symptoms, 3 required cystectomy despite the lack of bladder cancer., Conclusions: Intravesical therapy in community practice conforms with the generally accepted indications for high-grade and T1 disease. However, the use of BCG for low-grade TCC appears to be quite common. Repeated courses may result in significant side effects. We emphasize that excessive treatment should be avoided for low-grade, Ta lesions and BCG reserved for patients with TaG3, carcinoma in situ, or T1 TCC.

The ideal treatment for T1 G3 transitional cell carcinoma (TCC) of the urinary bladder remains controversial. Therapeutic options after the initial transurethral (TUR) resection are observation, intravesical therapy, a repeat resection, radiation therapy, and cystectomy. Because more than half of patients with T1 G3 TCC of the urinary bladder do not progress, initial cystectomy can represent overtreatment. However, observation alone following TUR for T1 G3 TCC of the urinary bladder is associated with a progression rate of 48%. Intravesical immunotherapy has been shown to decrease recurrence and progression in high-grade Ta carcinoma in situ and T1 bladder cancer. When patients with T1 G3 tumors are well selected, intravesical therapy following the initial TUR can significantly improve survival and quality of life. Persistence or recurrence of high-grade tumor mandates consideration of cystectomy.

Benign fibroepithelial polyps of the renal pelvis are extremely rare, with only 23 cases previously reported. The diagnosis is usually made following nephrectomy or nephroureterectomy for an assumed malignancy. This case involves a 66-year-old woman referred with presumed biopsy-proven transitional cell carcinoma of the renal pelvis. Radiographic findings were suggestive of a benign lesion. Pyelotomy and frozen section confirmed these suspicions. The polyp was excised and the kidney spared. The diagnosis and management of fibroepithelial polyps are discussed and the literature reviewed.

Hyaluronic acid (HA), a glycosaminoglycan, is known to promote tumor cell adhesion and migration, and its small fragments stimulate angiogenesis. We compared levels of HA in the urine of normal individuals and patients with bladder cancer or other genitourinary conditions, using a sensitive ELISA-like assay. Among the 144 specimens analyzed, the urinary HA levels of bladder cancer patients with G1 (255 +/- 41.7 ng/mg), G2 (291.8 +/- 68.3 ng/mg) and G3 (428.4 +/- 67 ng/mg) tumors are 4-9-fold elevated as compared to those of normal individuals (44.7 +/- 6.2 ng/mg) and patients with other genitourinary conditions (69.5 +/- 6.8 ng/mg; P < 0.001). Urinary HA measurement by the ELISA-like assay shows a sensitivity of 91.9% and specificity of 92.8% to detect bladder cancer. Thus, urinary HA measurement is a simple, noninvasive yet highly sensitive and specific method for bladder cancer detection. The increase in urinary HA concentration is a direct correlate of the elevated tumor-associated HA levels, because the HA levels are also elevated (3-5-fold) in bladder tumor tissues (P < 0.001). The profiles of urinary HA species of normal individuals and bladder cancer patients are different. Although only the intermediate-size HA species are found in the urine of normal and low-grade bladder tumor patients, the urine of high-grade bladder cancer patients contains both the high molecular mass and the small angiogenic HA fragments. These urinary HA fragments stimulate a mitogenic response (2.4-fold) in primary human microvessel endothelial cells, suggesting that the small HA fragments may regulate tumor angiogenesis by modulating endothelial cell functions.

Successful management of transitional-cell carcinoma of the urinary bladder is greatly dependent upon regular surveillance and early detection of persistent or recurrent carcinoma. The development of a highly sensitive urinary test for the detection of transitional-cell carcinoma of the bladder could have a dramatic impact on our ability to diagnose and monitor bladder cancer patients as well as influence the treatment outcome. The urinary level of the nuclear matrix protein, NMP22, has been found to be elevated in patients with urothelial malignancy. This has prompted the development of an immunoassay to quantitate urinary NMP22 and use it as a cancer-specific marker. We provide a summary of the studies completed with the immunoassay for urinary NMP22 as an indicator for the presence of transitional-cell carcinoma and compare the results with those obtained using other screening modalities.

Purpose: The purpose of this trial was to evaluate an immunoassay for urinary nuclear matrix protein, NMP22, as an indicator for transitional cell carcinoma of the urinary tract., Materials and Methods: Three groups of subjects participated in this trial of NMP22: 1-175 with transitional cell carcinoma, 2-117 with benign urinary tract conditions and 3-375 healthy volunteers. Each subject provided a single (3 voids) urine sample for analysis at the time of study entry. Each sample was assayed for the level of NMP22., Results: In normal healthy volunteers and in subjects with benign conditions median NMP22 levels were 2.9 and 3.3 units per ml., respectively. Median urinary NMP22 levels in patients with transitional cell carcinoma were significantly greater than in comparison subjects. Patients with active transitional cell carcinoma had significantly greater median urinary NMP22 levels than those with no evidence of disease (6.04 versus 4.11 units per ml., p = 0.027, 1-tailed Mann-Whitney U test). We noted no effect of tumor grade, extent of disease or exposure to intravesical therapy on urinary NMP22 levels., Conclusions: NMP22 is a promising urinary tumor marker for monitoring transitional cell carcinoma. Nuclear matrix proteins are a new class of tumor markers that represent the basis for the development of assays with increased efficacy for the detection and treatment of cancer.

Purpose: We evaluated the ability of an immunoassay for nuclear matrix protein 22 (NMP22 test kit) to predict the subsequent disease status of patients with transitional cell carcinoma of the urinary tract at approximately 10 days after transurethral resection of bladder tumor., Materials and Methods: A total of 90 patients with transitional cell carcinoma provided voided urine samples at least 5 days postoperatively. NMP22 was determined using a commercial test kit. At initial cystoscopic examination 3 to 6 months later the disease status was recorded, and the NMP22 values before and after transurethral resection of bladder tumor were compared., Results: Of 125 followup cystoscopic examinations (60 patients had 1, 26 had 2, 3 had 3 and 1 had 4 recurrences) transitional cell carcinoma was pathologically confirmed in 33. No malignancy was present at 79 examinations (if tumor was seen endoscopically, pathological evaluation indicated atypia, dysplasia or no abnormality). NMP22 values in these 2 populations were significantly different (malignancy median 20.81 units per ml. and no malignancy median 5.72 units per ml., Mann-Whitney U test for differences between 2 medians p = 0.00005). Of the 33 recurrences 23 (70%) had NMP22 values greater than the reference range (10 units per ml.). Additionally, NMP22 identified all 6 subjects (100%) who had invasive disease 3 to 6 months later. Of 72 patients with NMP22 less than 10 units per ml. 62 (86%) had no malignancy at subsequent cystoscopy., Conclusions: NMP22 was highly predictive of tumor status at followup cystoscopy. This quantitative, noninvasive assay, with high negative predictive value (86%) and sensitivity to detect malignancy (100% for invasive disease and 70% overall), may be a helpful adjunct to cytology and endoscopy for monitoring disease status after endoscopic tumor resection.

Relatively few data are available on UT TCC following cystectomy. In most circumstances nephroureterectomy is the treatment of choice. The risk of bilateral disease is small (2% to 4%); however, in patients with bilateral UT TCC, a solitary kidney, or poor renal function and low-stage, low-grade TCC, renal preservation by local resection and/or topical therapy may be effective. In high-grade or high-stage disease, whenever feasible nephroureterectomy should be performed.

Background: Radical cystectomy continues to be one of the primary modalities of treatment for locally advanced bladder cancer. However, long-term survival after cystectomy has improved only marginally in the last decade, and still, nearly half of the patients die from the disease within 5 years. Adjuvant treatments such as radiation therapy and chemotherapy have been used, but a clear advantage has not been demonstrated., Methods: The authors reviewed 130 patients who underwent radical cystectomy by the same surgeon as treatment for transitional cell carcinoma of the bladder. Morbidity, postoperative mortality, overall survival time, and accuracy of clinical staging as well as the effect of perioperative chemotherapy were evaluated., Results: The overall actuarial survival rate at 2, 5, and 10 years was 80%, 53%, and 45%, respectively. The survival rate based on T-classification at 5 years was 82%, 65%, and 28% for less than pT2, pT2, and greater than pT2, respectively. Regional lymph node status had a significant effect on survival. The 5-year survival rate for all patients with negative nodes was 65%, whereas patients with positive nodes had a 18% 5-year survival rate. The overall clinical staging error was 61.5%, with 41.5% of the cancers understaged. Of the patients with cTis, 60% were found to be of greater extent than pT1 tumors. No apparent survival advantage was noted for those patients who received perioperative chemotherapy when compared with patients who were followed conservatively or received chemotherapy upon relapse. These results, however, are not conclusive because this was an observation study and the number of patients was limited., Conclusions: Only a modest improvement in survival time after radical cystectomy has been observed in the last decade, despite the use of adjuvant treatments such as radiation and chemotherapy. The pathologic (pT) classification is the most accurate prognostic indicator. Clinical errors in classification are common and impair the evaluation of neoadjuvant treatments. A high incidence of invasive tumors of greater extent than pT1 was found among patients with clinical cTis; this supports an aggressive approach when these patients do not respond promptly to intravesical chemotherapy. Prospective randomized studies are needed to evaluate objectively the benefit of perioperative adjuvant treatment in locally advanced transitional cell carcinoma of the bladder.

Endoscopic evaluation and transurethral resection are the most important steps in the management of patients with bladder cancer. While multifocality is primarily a prognostic factor with respect to tumor recurrence, tumor grade and depth of invasion are prognostic regarding progression in stage. Transurethral resection biopsies of the prostate should always been obtained in patients with high grade tumors. Follow-up of patients should be individualized: patients with risk for progression, but not necessarily for recurrence, should be followed more closely than patients with low-grade tumors and low risk for progression. In this setting cytology is especially helpful because most high-grade tumors will be detected by cytology. Intravesical therapy is indicated in patients with high-grade tumors, carcinoma in-situ and multiple low grade tumors. While there is a growing body of evidence that BCG is superior to intravesical chemotherapy, one also has to take into account the more frequent and more serious side effects of BCG when compared with mitomycin C or thiotepa.

More than 90 percent of bladder cancers are transitional cell carcinoma (TCC). Superficial TCC is defined as a transitional cell tumor that is confined to the mucosa (Stages Ta or carcinoma in situ) or that has invaded the lamina propria (Stage T1). When treating patients with superficial bladder cancer, urologists are faced with a number of important tasks. First, the initial tumor or tumors must be removed. Second, the other parts of the urothelium must be assessed for the presence of premalignant or malignant abnormalities. Third, the depth and extent of invasion (i.e., tumor stage) must be determined. Fourth, the clinician must decide whether additional treatment (e.g., intravesical chemotherapy or immunotherapy, cystectomy, or radiotherapy) is indicated. Finally, the patient must be monitored for the development of subsequent tumors. This article provides an overview of the management of superficial bladder cancer.

Accompanying the advances in surgical techniques and new intravesical and systemic therapeutic agents for the treatment of individuals with bladder cancer has been the development of greatly improved instrumentation for viewing the interior of the urinary tract and removing neoplasms. Fiberoptic lenses can now be combined with a video system, which enables the urologist to examine the lower urinary tract, not only more easily but with greater magnification. Training is obviously accelerated with the use of video endoscopy. The system also provides the opportunity for documentation and transmittal of the operative findings using either still or motion photography. The endoscopic procedure should be carried out in an orderly fashion. Sufficient lenses and cautery loops must be available to visualize the entire lower urinary tract and to biopsy or resect any abnormality and ensure hemostasis. The urologist should work closely with the pathologist to obtain sufficient cytologic and pathologic material to be confident of the presence or absence of tumor.

Intraluminal hyperthermia is potentially useful in the management of superficial bladder cancer. The potential inhibitory effect of hyperthermia on various human bladder cancer cell lines, normal human bladder cells and the murine MBT-2 bladder cancer cell line has been studied in vitro. These cell lines were exposed for one hour to 43 +/- 0.5C and compared to controls. Cell survival was assessed comparing the cell growth curve and colony formation. The human transitional cell carcinoma (TCC) cell lines vary in their sensitivity to heat. MGH-U1 was the most heat sensitive cell line. The human A-1698, CUB-2, UM-UC-3 and the murine MBT-2 lines were heat insensitive. We conclude that the cytocidal effect of hyperthermia in bladder transitional cell carcinoma is variable. Further experiments using the combination of hyperthermia and intravesical anticancer agents are in progress.

We reviewed the clinical courses of 86 men after radical cystoprostatectomy for transitional cell carcinoma of the bladder to determine who were at highest risk for urethral recurrence. We assessed patients for prostatic involvement as well as tumor extent in the bladder and distal ureters. Of the 30 patients with tumor in the prostate 11 (37%) suffered urethral recurrences. Of the 56 patients with all other types of tumor involvement patterns exclusive of disease in the prostate only 2 (4%) had recurrence. We recommend rigorous screening for transitional cell carcinoma of the prostate before cystectomy. Prophylactic urethrectomy is indicated for patients with prostatic involvement, while those without such involvement may be considered at low risk for urethral recurrence.

Intravesical bacillus Calmette-Guerin is effective in the treatment and prophylaxis of superficial urothelial cancer of the bladder. There have been few reports of its efficacy and toxicity when instilled into the upper urinary tract. We elected to use intracavitary bacillus Calmette-Guerin in a patient with recurrent high grade transitional cell carcinoma in the renal pelvis of a solitary autotransplanted kidney. The patient required hospitalization and triple-drug therapy after 5 instillations. She was free of tumor 1 year after bacillus Calmette-Guerin instillations.

Methotrexate (MTX) has activity in transitional cell carcinoma (TCC) in man and some have suggested an advantage of high-dose methotrexate versus the standard dose in controlling tumor growth and prolonging survival. MBT-2, a poorly differentiated TCC induced by the carcinogen FANFT, is both grossly and histologically similar to human TCC and has been used as an animal model. One hundred twenty C3H/HE female mice were injected in the hind limb with 7.5 X 10(4) MBT-2 tumor cells. When palpable tumors developed in all animals, therapy was initiated. Animals were randomized into a control group and nine treatment groups as follows: cisplatin (DDP), MTX32 mg, MTX50 mg, MTX80 mg, DDP + MTX32, MTX50 + Leucovorin, MTX80 + Leucovorin, DDP + MTX50 + Leucovorin, DDP + MTX80 + Leucovorin. The combination of MTX50 mg with Leucovorin + DDP and DDP alone were the two most effective regimens in controlling tumor growth and prolonging survival. No statistically significant difference was observed between the group treated by high-dose MTX alone and those treated by low-dose MTX. No toxicity was observed even when high doses of MTX were used.

The approach that I have followed for patients with recurrent superficial transitional cell carcinoma of the urinary bladder has generally been to perform a thorough endoscopic evaluation of the bladder with appropriate evaluation of the prostatic urethra as well as the upper urinary tract, and if it is felt that the neoplasm is confined to the bladder (and possibly the mucosa of the prostatic urethra), then all obvious tumor should be resected and a three-month trial of intravesical therapy instituted. Based upon the results presented, the response at the first three-month evaluation has major prognostic importance. Those patients who had no evidence of tumor at this first three-month evaluation were less likely to have a subsequent cystectomy or die of bladder cancer than those who had evidence of persistent tumor. Among the 80 patients who received a treatment course of MMC, 13% of the complete responders compared to 34% of those who failed had a subsequent cystectomy, and among the 55 patients who received BCG, 6% of the complete responders compared to 25% of the failures had a subsequent cystectomy during the follow up interval. Indeed, part of this difference can be explained by the gradual adherence to the philosophy that if there is persistent high grade tumor or a high grade tumor develops following an adequate treatment course of MMC or BCG, cystectomy is indicated in order to avoid the development of a tumor which invades into the muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied 36 patients with stages O and A (Tis, Ta and T1) bladder cancer who had received 8 weekly doses of 30 or 40 mg. mitomycin C as definitive therapy. Of this group 16 had failed thiotepa therapy and 13 had grade III tumors (6 multifocal carcinoma in situ). The complete response rate at 12 weeks was 45 per cent (negative biopsy and cytology), while an additional 33 per cent had a partial response. Response did not correlate with tumor grade or stage. Patients who had failed thiotepa therapy were less likely to have a complete response, although the over-all response rate was identical to patients who had either not received prior chemotherapy or were not clear thiotepa failures. Followup of these patients indicates that the complete responders were benefited by this regimen since the subsequent recurrence rate was reduced when compared prior to initiation of mitomycin C. Most of these patients received monthly maintenance therapy.

The nature and severity of side effects accompanying intravesical chemotherapy with mitomycin C were studied in 29 patients. No patient experienced systemic toxicity. Local side effects developed in 7 patients (24 per cent), and consisted of moderate cystitis in 3 and drug-related palmar desquamation, with or without generalized rash, in 4. Based on skin tests 3 of these patients were believed to have a contact dermatitis. The fourth patient had a generalized rash, in addition to palmar desquamation, that appeared after subsequent instillations of mitomycin C and the drug had to be discontinued. Careful cleansing of the hands and perineum on the day of treatment can prevent most skin reactions.