Prospective registration of all patients in a geographical region with newly diagnosed bladder carcinomas during a two-year period.

OBJECTIVE: To report the age, stage and grade of all patients with newly diagnosed bladder carcinoma in a well-defined geographical region and to compare this cohort with previous reports which come mainly from large referral centres. MATERIAL AND METHODS: All newly diagnosed bladder carcinoma patients (n = 701) in Western Sweden were prospectively registered during a 2-year period (1987-88). The histopathological material was re-examined by a reference pathologist. All the original clinical records were reviewed by one urologist 5-7 years after diagnosis. Demographic data, tumor grade, stage, multiplicity, presence of carcinoma in situ and lymphatic invasion are presented. RESULTS: The mean age at diagnosis was 70.5 years. Grade and stage increase with age. The proportion of non-invasive tumors (55%) is higher than in any previous Scandinavian report. The age-standardized incidence in bladder carcinoma among men in the largest city (Göteborg) is 55% higher than in the rest of the region (p<0.0001). Deviations between the primary pathologist and the reviewer with regard to tumor grade were particularly seen in tumors of grades I and II. CONCLUSIONS: Differences in mean age, stage and grade distribution were found between the present report, which included all patients with newly diagnosed bladder carcinoma in a geographical area, and other reports, which mainly comprised patients from large treatment centres. These differences can probably and mainly be explained by selection factors such as various degrees of inclusion of low-grade papillary tumors.

Recurrence and progression in low grade papillary urothelial tumors.

PURPOSE: We report long-term followup data on patients with World Health Organization (WHO) grade I bladder tumors, and determine whether histopathological subgrouping as papillary neoplasm of low malignant potential and low grade papillary carcinoma is of clinical value. MATERIALS AND METHODS: All 680 patients in western Sweden with first diagnosis of bladder carcinoma in 1987 to 1988 were registered and followed for at least 5 years. Of the tumors 255 (37.5%) were stage Ta, WHO grade I. Tumors were further classified as papillary neoplasm of low malignant potential in 95 patients and low grade papillary carcinoma in 160 according to WHO and the International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the bladder. RESULTS: Mean age of patients at first diagnosis of low grade papillary carcinoma was 69.2 years, which was 4.6 years higher than those with papillary neoplasm of low malignant potential (p<0.005). During a mean observation time of 60 months our 255 patients underwent 577 operations for recurrences and had 1,858 negative cystoscopies. The risk of recurrence was significantly lower in patients with papillary neoplasm of low malignant potential compared to those with low grade papillary carcinoma (35 versus 71%, p<0.001). The risk of recurrence was higher in patients with multiple tumors at first diagnosis as well as those with recurrence at the first followup after 3 to 4 months. Stage progressed in 6 patients (2.4%), all with low grade papillary carcinoma at diagnosis. CONCLUSIONS: More than 90% of patients with stage Ta, WHO grade I have a benign form of bladder neoplasm, and few have truly malignant tumors. Future research should focus on reducing the number of recurrences and followup cystoscopies, and finding methods to identify malignant tumors so that pertinent treatment can be instituted. Subgrouping of WHO grade I bladder tumors as papillary neoplasm of low malignant potential and low grade papillary carcinoma seems to add valuable prognostic information.

Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder.

OBJECTIVE: To compare the efficacy and tolerability of tolterodine with that of oxybutynin in patients with an overactive bladder. PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled, parallel group, multinational phase-III study was conducted in urology and gynaecology clinics in the UK, Republic of Ireland and Sweden. The study enrolled 293 patients with urodynamically confirmed bladder overactivity, increased frequency of micturition (> or = micturitions/24 h) and symptoms of urgency and/or urge incontinence (> or = 1 episode/24 h). Patients received either tolterodine (2 mg twice daily) or oxybutynin (5 mg three times daily) or placebo. Doses could be reduced, to prevent withdrawal, to 1 mg or 2.5 mg, respectively. The main outcome measures were the mean change from baseline in frequency of micturition/24 h, the number of incontinent episodes/24 h and volume voided per micturition. RESULTS: After 12 weeks' treatment, the mean frequency of micturition decreased by 21% and 19.5% in those receiving tolterodine (n = 118) and oxybutynin (n = 118), respectively, and by 10.5% in those on placebo (n = 57). Among those with urge incontinence at baseline (75% of patients), the mean number of incontinent episodes decreased by 47%, 71% and 19%, respectively, in those receiving tolterodine, oxybutynin and placebo. The effect of tolterodine and oxybutynin on these two micturition variables was statistically equivalent. There was also a comparable increase in mean volume voided per micturition in the tolterodine (27%) and oxybutynin groups (31%), compared with 7% in the placebo group. Dry mouth was the most common adverse event and was reported with greater frequency and intensity among patients receiving oxybutynin than among those receiving either tolterodine or placebo. In the oxybutynin group, more patients also withdrew because of adverse events and a greater proportion required dose reduction as a result of adverse events. Despite dose reduction, the frequency of adverse events and the intensity of dry mouth remained higher among those receiving oxybutynin (2.5 mg three times daily) than in patients who remained on tolterodine 2 mg twice daily. CONCLUSION: Tolterodine 2 mg twice daily is effective and well tolerated in the treatment of bladder overactivity. Tolterodine was better tolerated than oxybutynin, particularly with respect to the frequency and intensity of dry mouth, but had comparable clinical efficacy. The superior tolerability of tolterodine therefore allows more patients to remain on effective therapy than the current most commonly prescribed agent for the treatment of the overactive bladder.

Long-term followup of a bladder carcinoma cohort: routine followup urography is not necessary.

PURPOSE: We evaluate whether routine excretory urography is needed in the long-term followup of patients with bladder carcinoma. MATERIALS AND METHODS: A total of 680 patients with an initial diagnosis of bladder carcinoma from 1987 to 1988 in western Sweden were prospectively registered and followed for at least 5 years. All carcinomas of the kidney, renal pelvis and ureter, and all surgically treated cases of ureteral stricture were registered. RESULTS: During followup renal pelvic or ureteral carcinoma developed in 16 patients, renal cell carcinoma was diagnosed in 2 and 6 underwent surgery for benign obstruction of the distal ureter. CONCLUSIONS: The low annual incidence of malignant upper urinary tract and renal tumors as well as ureteral strictures supports our opinion that routine imaging of the upper urinary tract is not indicated during followup of patients with bladder carcinoma. We recommend urography at initial diagnosis of bladder carcinoma, when tumor progression occurs and when symptoms or signs raise suspicion of upper urinary tract disease.

Long-term followup of all patients with muscle invasive (stages T2, T3 and T4) bladder carcinoma in a geographical region.

PURPOSE: We studied the relationship between long-term survival and treatment of stages T2, T3 and T4 bladder carcinoma in an unselected patient population. MATERIALS AND METHODS: A total of 680 patients with the initial diagnosis of bladder carcinoma in 1987 to 1988 in Western Sweden was prospectively registered and followed until 1994. Of these patients 107 had stage T2 to T3 and 41 had stage T4 disease. RESULTS: Of the patients with stage T2 to T3 disease 30 (mean age 66) underwent radical cystectomy, 33 (mean age 75) full dose radiotherapy and 44 (mean age 81) nonradical therapy (mainly transurethral resection of the bladder). The 5-year crude survival rates were 33, 15 and 14%, respectively. Of the patients with stage T4 disease 6 (mean age 61) underwent radical cystectomy, 9 (mean age 73) full dose radiotherapy and 26 (mean age 81) nonradical therapy (mainly transurethral resection of the bladder). All except 1 patient died of disease within 4 years. CONCLUSIONS: More than 60% of the patients in the cohort were considered unsuitable for radical cystectomy and their survival was poor, whether treated with full dose radiotherapy or transurethral resection of the bladder alone.

The importance of the depth of invasion in stage T1 bladder carcinoma: a prospective cohort study.

PURPOSE: We studied the depth of invasion in the lamina propria in all patients with primary stage T1 bladder cancer in a geographical region and related the findings to the long-term prognosis. MATERIALS AND METHODS: All 121 primary stage T1 tumors diagnosed in western Sweden between 1987 and 1988 were analyzed with respect to the depth of invasion in relation to the lamina muscularis mucosae. All clinical records were reviewed in 1994 and 1995. RESULTS: More than 90% of the histopathological specimens could be separated into superficially (pT1a) or deeply (pT1b) invasive stage T1 tumors. Grade 3 tumors were significantly more common among patients with stage pT1b disease (79 versus 40%, p < 0.001). Patients with stage pT1b grade 3 cancer had a higher progression rate (58 versus 36%, p > 0.05) and an almost doubled risk of dying of bladder carcinoma compared to those with stage pT1a grade 3 disease (45 versus 23%, p > 0.05). Carcinoma in situ at the primary operation was associated with an impaired prognosis in patients with grade 3 tumors regardless of the depth of invasion in the lamina propria. CONCLUSIONS: The prognosis is poor in patients with deep lamina propria invasion (stage pT1b) treated with transurethral resection alone. Patients treated with radical cystectomy had excellent survival regardless of the depth of invasion in the lamina propria. Radiotherapy was associated with poor survival.

The relationship among multiple recurrences, progression and prognosis of patients with stages Ta and T1 transitional cell cancer of the bladder followed for at least 20 years.

A retrospective study was done on 176 patients with primary stages Ta and T1 bladder cancer treated between 1963 and 1972. One patient was lost to followup after 6 years, while the remainder were followed to death or for at least 20 years. In 1993, 13 patients had no evidence of disease, 39 died of bladder cancer and 123 died of intercurrent disease. Of 77 patients with a primary noninfiltrating tumor and 99 with a primary lamina propria invasive tumor 9 (11%) and 30 (30%), respectively, died of bladder cancer. Recurrences were noted on 10 or more cystoscopic studies in 16 patients and 10 died of bladder cancer 3.5 to 19 years after the primary transurethral resection. A total of 14 patients received repeated thiotepa instillations, all continued to have recurrences and 10 subsequently died of bladder cancer. Only 1 upper tract tumor was diagnosed on routine followup excretory urography. Invasive transitional cell carcinoma of the bladder developed in only 1 of 59 patients who had been tumor-free for 5 years. The results indicate that patients with recurrences on 10 or more cystoscopic studies will continue to have recurrences until death or cystectomy. Recurrence more than 4 years after the primary tumor operation is another ominous sign. Repeated thiotepa instillations did not influence the course of the disease in patients with a history of multiple recurrences. Followup cystoscopy may be discontinued 5 to 10 years after the last recurrence, at least in patients with a solitary low grade primary tumor. Routine followup urographic studies are neither cost-effective, clinically indicated nor justified in patients with superficial bladder cancer.

Epirubicin and medroxyprogesterone acetate versus estramustine phosphate in hormone-resistant prostatic cancer: a prospective randomized study.

The effect of a medroxyprogesterone acetate (MPA) plus epirubicin combination versus estramustine phosphate was evaluated in 149 prospectively randomized patients with hormone-resistant prostatic cancer. The estimated probability of being free from progression after 1 year was 17% for the patients treated with estramustine and 29% for the MPA-epirubicin group. There is a significant difference between the two groups regarding risk of progression (p = 0.013). However, no difference in survival was recorded (p > 0.30) with about 60% of the patients dead during the first year in both groups. Progression was highly correlated to sedimentation rate (p < 0.001) and to performance index (p = 0.002). Heart failure occurred in a substantial number of patients in both groups which must be considered before starting therapy.

Experiences with doxo/epirubicin and medroxyprogesterone acetate (MPA) in prostatic cancer.

Maximal androgen blockade (MAB) has been reported to prolong the time to progression and the duration of survival in metastatic prostatic cancer. The addition of epirubicin to MAB in such patients seems to improve the therapeutic results further. The beneficial effect of combining castration with epirubicin in metastatic cases appears questionable. In comparing the time to progression in patients treated with MAB +/- epirubicin versus castration +/- epirubicin or estramustine, many studies reveal similar figures. Whether the results after treatment are actually improved remains controversial. In hormone-refractory cases, medroxyprogesterone acetate (MPA) alone seems superior to estramustine or prednisolone treatment. Combining MPA and epirubicin improves the results, but even if the improvement is of clinical value, it is nonetheless of limited magnitude.

Carcinoma of the ureter: a clinicopathologic study of 49 cases.

We reviewed 49 patients with urothelial tumors of the ureter: 33 male and 16 female patients with a mean age of 64.8 and 66.3 years, respectively. Median followup was 83 months. Gross hematuria was present in 29 patients and a silent kidney was found in 21. The majority of the tumors were in the distal ureter and approximately 50 per cent of the patients had synchronous or asynchronous urothelial tumors. The majority of the patients had low grade, low stage tumors (75 per cent). A total of 21 patients underwent local resection and none died of tumor. Only 1 of these 21 patients had an ipsilateral recurrence. Nephroureterectomy was performed in 24 patients and 5 of them died of ureteral tumor, including 4 in whom periureteral tumor growth initially was recorded. The prognosis of patients with papillomas or grades 1 to 3, stages Pa to P1 ureteral tumors was excellent and a conservative approach is recommended for these patients. Abuse of combination analgesics containing phenacetin, phenazone and caffeine may be a risk factor for development of ureteral tumors.

Scanning electron microscopic findings in interstitial cystitis.

Scanning electron microscopy (SEM) was performed on transurethral resection biopsies from 13 patients with classic interstitial cystitis. Biopsies from 9 patients with stress incontinence served as controls. The SEM appearance of the bladder surface in interstitial cystitis varied considerably, exhibiting small round and large polygonal cells. The proportion of cells displaying round uniform and pleomorphic microvilli was high and sometimes dominated the area examined. SEM characteristics earlier assigned to bladder tumours were detected in patients with interstitial cystitis and, at a lower frequency, also in control patients. The mucin layer covering the urothelial cells seemed reduced in interstitial cystitis compared with control specimens. Surface characteristics specific for interstitial cystitis were, however, not detected by SEM.

The influence of antipyrene on N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced urinary tract carcinogenesis.

Human over-use of analgesics containing phenacetin, antipyrene (phenazone) and caffeine has been associated with the development of both renal pelvic and bladder tumors. In Sprague-Dawley rats antipyrene has been shown to be a weak complete urinary tract carcinogen. The present study was designed to evaluate the promoting capacity of antipyrene in N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-induced urinary tract carcinogenesis. One hundred and eighty male Sprague-Dawley rats were divided into groups of 30 and were treated with the following chemicals in the diet: group 1 received a control diet without chemicals; group 2 was treated with 0.2% FANFT in the diet for five weeks followed by control diet; group 3 received 0.2% FANFT for five weeks followed by 0.535% antipyrene in the diet; group 4 was treated with 0.535% antipyrene; group 5 was treated with 0.102% caffeine; and group 6 was treated with 0.535% antipyrene and 0.102% caffeine in the diet. Ten of 27 rats in group 3 (37%) developed urinary tract tumors (P greater than 0.001, five of which were renal pelvic tumors and five were bladder tumors. The majority of the tumors were well differentiated non-invasive urothelial carcinomas. None of the rats in other groups developed urinary tract tumors. In addition, renal papillary necrosis (RPN) was found in 33% of the rats in group 3, 50% in group 4, and 10% in group 6. The present study clearly shows that antipyrene acts as a promoter of FANFT-induced urinary tract carcinogenesis and that it is nephrotoxic to the renal papilla resulting in renal papillary necrosis.

The influence of urinary tract infection on the incidence of urinary tract tumors in N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide induced carcinogenesis in male Sprague-Dawley rats.

Epidemiological studies have demonstrated an association between urinary tract infection and the development of bladder cancer. The present study aimed at evaluating the influence of urinary tract infection in male Sprague-Dawley rats exposed to a sub-carcinogenic dose of N-[4-(nitro-2-furyl)-thiazolyl]formamide (FANFT). A single injection of Escherichia coli into the bladder resulted in a persistent upper urinary tract infection in a high percentage of the rats. Thirty-two percent of the rats exposed to FANFT and E. coli infection developed urinary tract tumors, all but one occurring in the renal pelvis. Urinary tract tumors were not found in rats treated with FANFT or E. coli alone. The present results support that inflammation resulting from infection is actively involved in urinary tract tumorigenesis and may support the epidemiological studies showing an association between infection and human urinary tract cancer. The formation of dimethylnitrosamine or other nitroso compounds from nitrates in the urine or increased cell proliferation due to chronic inflammation or both may be important pathogenetic factors in tumor development.

Enhancement of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced carcinogenesis by urinary tract infection in rats.

Epidemiological studies suggest that urinary tract infection is an important risk factor in the development of bladder cancer. Chronic urinary tract infection in rats is associated with urothelial hyperplasia and papillomatosis. In the Sprague-Dawley strain, exposure to the 5-nitrofuran, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), is associated in particular with the development of renal pelvic tumors. The present study was designed to evaluate whether chronic urinary tract infection could enhance tumor development in FANFT-induced urinary tract carcinogenesis. One hundred forty-four female Sprague-Dawley rats were divided into the following groups. Group 1 received 0.2% FANFT in the diet for 7 wk followed by control diet. Group 2 received 0.2% FANFT in the diet for 7 wk followed by control diet. One wk after completion of FANFT administration, the suspension of 0.5 ml of Escherichia coli (06K13H1) was injected into the bladder through the urethra. Group 3 received 0.2% FANFT in the diet for 7 wk followed by control diet. One wk after completion of FANFT administration, a suspension of heat-killed E. coli (06K13H1) was injected into the bladder through the urethra. Group 4 received a suspension of 0.5 ml of E. coli (06K13H1) through the urethra and received control diet throughout the experiment. Group 5 was fed control diet only. The experiment continued for 104 wk. A significantly higher number of urinary tract tumors, particularly of the renal pelvis, was recorded in Group 2 compared to Groups 1, 3, 4, and 5. The majority of the rats in Groups 2 and 4 had morphological signs of urinary tract infections, particularly pyelitis and/or pyelonephritis. Thus, a single injection of E. coli (06K13H1) into the bladder results in an enhancement of FANFT-induced urinary tract carcinogenesis in the Sprague-Dawley rat, especially for renal pelvic tumors. The formation of dimethylnitrosamine or other nitroso compounds from nitrates in the urine or increased cell proliferation due to chronic inflammation or both may be important pathogenetic factors in the tumor development.

Scanning electron microscopy of upper urinary tract tumors.

Scanning electron microscopy (SEM) was performed on specimens from 16 patients with low-grade tumors, and 4 patients with benign lesions of the upper urinary tract. Pleomorphic microvilli could be seen at a low frequency on the majority of the tumor specimens as well as on surface cells of specimens from patients with inverted papilloma, fibroepithelial polyp, and hydronephrosis. The SEM appearance of the lining cells was similar whether the specimen was obtained from a patient with a tumor, or an inflammatory or proliferative lesion. Furthermore, pleomorphic microvilli were observed in five histologically normal bladders in which the covering cells had been rubbed off with a cold loop of a resectoscope. Pleomorphic microvilli are thus not morphologic markers of preneoplastic hyperplasia or tumor. It is likely that their presence merely reflects an increased rate of detachment of superficial epithelial cells which are replaced by cells from the deeper part of the epithelium. The demonstration of pleomorphic microvilli is therefore of questionable value in the preoperative diagnosis of tumors of the upper urinary tract and, consequently, their significance must be re-evaluated.

Scanning electron microscopy of polypoid cystitis--a reversible lesion of the human bladder.

Scanning electron microscopy was performed on forceps biopsies from 13 patients with catheter-associated polypoid cystitis. Pleomorphic microvilli, which varied considerably in appearance, were found on surface cells of all cases with polypoid cystitis. Practically all of the characteristics of pleomorphic microvilli assigned earlier to bladder tumor cells in humans were identified on specimens from patients with polypoid cystitis. Pleomorphic microvilli were not observed in the bladder biopsies from control patients. The appearance of pleomorphic microvilli was consistent with reversible lesions of the human bladder and they are not specific markers of pre-neoplastic hyperplasia or malignancy.

Primary adenocarcinoma of the urinary bladder. A clinicopathologic and prognostic study.

The study is a clinicopathologic report on 64 patients with primary adenocarcinoma of the urinary bladder and urachus, with particular reference to important prognostic and therapeutic factors. All tumors exhibited adenocarcinomatous features in at least two thirds of the examined tumor area. Pure forms of the different histological patterns were seen in 50% of the cases and in the remaining tumors a mixture was recorded. Poorly differentiated tumors were found in 41 cases. All tumors were invasive and in 40 cases the tumors penetrated through the bladder wall. The pattern and frequency of metastasis was similar to that of conventional bladder tumors of high stage. The prognosis for patients with primary adenocarcinoma of the bladder was poor and the 5-year survival rate in this study was 18%. Important prognostic factors were tumor stage, size and grade and treatment. The location of the tumor seemed less important and tumors located in the dome or anterior wall did not indicate a poorer prognosis. The adenocarcinomas of the urinary bladder were predominantly solitary tumors. They were poorly differentiated, deeply invasive large tumors associated with an exceedingly poor prognosis. Partial bladder resection appears to be adequate therapy only in patients with moderately well differentiated small tumors. In other cases more radical therapy must be considered.

The influence of phenacetin or mechanical perforation on the development of renal pelvic and urinary bladder tumors in FANFT-induced urinary tract carcinogenesis.

The influence of 0.535% phenacetin in the diet or mechanical perforation of the renal pelvis and urinary bladder of male Sprague-Dawley rats in FANFT-induced urinary tract carcinogenesis was studied. The 151 rats were divided into 5 experimental and one control group. The rats were followed for up to 80 weeks. FANFT administered at 0.2% in the diet for 11 weeks resulted in a high incidence of urinary tract tumors particularly of the renal pelvis. Similar results were obtained by administration of 0.2% FANFT for 6 weeks followed by 0.535% phenacetin while FANFT for 6 weeks preceded or followed by mechanical perforation of the renal pelvis resulted in a significantly lower incidence of renal pelvic tumors. Phenacetin appeared to enhance the development of renal pelvic tumors in FANFT-induced urinary tract carcinogenesis. In contrast no effect of phenacetin on the urinary bladder could be detected.

The combined effect of mechanical trauma and phenacetin or sodium saccharin on the rat urinary bladder.

The effect of 0.535% phenacetin or 5% sodium saccharin administered in the diet on proliferating urothelium in 160 Sprague-Dawley rats was studied by light microscopy and scanning electron microscopy. Reparative urothelial proliferation was induced by perforating the urinary bladder with a 23 gauge needle. The rats were then treated with phenacetin or sodium saccharin for up to 70 weeks. Non-perforated rats treated with phenacetin or sodium saccharin developed a slowly increasing urothelial hyperplasia detectable by light microscopy and SEM examination. When the rats were subjected to perforation of the bladder followed by phenacetin or sodium saccharin there was a significant increase in the incidence and severity of the hyperplastic lesions compared to rats treated with phenacetin or sodium saccharin alone. Although pleomorphic microvilli were detected on the luminal surface of the bladder in 30 of 160 rats, only 2 rats developed bladder tumors. Among female rats pleomorphic microvilli, although initially frequently present, seemed to disappear. The presence of pleomorphic microvilli therefore seems also to be consistent with a reversible hyperplasia.

The reversibility of catheter-associated polypoid cystitis.

Cystoscopic and histologic evidence of polypoid cystitis was recorded in 20 hospitalized patients with indwelling urethral catheters followed by cystoscopy, biopsies and repeated urine samples before and after catheter removal. The majority of the lesions were located in the posterior wall or dome. The lesions disappeared after removal of the catheter in 13 of the 15 patients followed for up to 28 weeks despite persistent bacteriuria. Polypoid cystitis still remained 28 weeks after catheter removal in 1 patient. The lesion is important as a differential diagnosis to bladder tumor. The importance of adequate biopsies is emphasized.