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

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

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

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

Urinary cytology studied during 10 days after transurethral resection of bladder tumour and its relation to tumour recurrence

Whether or not recurrence is related to the results of urinary cytology examined within 10 days after transurethral resection of bladder tumour was studied retrospectively in 47 patients with superficial bladder tumour. Of 7 cases with positive cytology during the postoperative 10 day period, 4 cases had a later recurrence of tumour and 2 cases had a residual tumour due to incomplete resection of original tumour. By microscopic chromocystoscopy, in 11 patients concurrent urothelial atypia (carcinoma in situ or dysplasia) was found in the apparently normal mucosa. Nine of the 11 cases had a later recurrence of tumour or a residual tumour. Of in total 15 patients combined with abnormal cytology and concurrent urothelial atypia, 12 (80%) were found with recurrence of tumor cystoscopically 4 approximately 64 months (mean; 20.6 months) after TUR. This recurrence rate was significantly (p less than 0.05) higher than that (42.4%) in patients without positive cytology and concurrent urothelial atypia. These results suggest that positive urinary cytology during 10 days subsequent to TUR and/or association with concurrent urothelial atypia are indicative of later tumour recurrence, incomplete resection of tumour or presence of additional occult tumour foci.     

Ureteral carcinoma in situ after successful intravesical therapy for superficial bladder tumors: incidence, possible pathogenesis and management

A total of 66 patients with multifocal, progressive, flat carcinoma in situ of the bladder responded completely to intravesical bacillus Calmette-Guerin therapy for more than 1 year. Of the patients 19 (29 per cent) had clinical evidence of distal ureteral carcinoma in situ between 13 and 30 months (median 15 months) after bacillus Calmette-Guerin treatment. After evaluation of a positive urinary cytology study failed to reveal recurrent urothelial tumor of the bladder or prostatic urethral mucosa 6 patients underwent distal ureterectomy, 2 underwent nephroureterectomy, and 11 were managed by ureteroscopic resection and fulguration. In patients with carcinoma in situ of the bladder treated successfully with topical therapy the ureters represent a potential site of in situ carcinoma.     

Surveillance of stage O, grade I bladder cancer by cytology alone--is it acceptable?

Although the high incidence of subsequent tumors is well established there is accumulating evidence that few cases of low grade, low stage transitional cell carcinomas will progress in stage. Since the purpose of intensive endoscopic monitoring following initial tumor resection is to detect potentially lethal new tumors as soon as possible, we reviewed retrospectively the course of 36 patients with an initial grade I, stage O (Ta) transitional cell carcinoma to determine whether cytology was capable of achieving this goal. Of these patients 10 (28 per cent) had a subsequent tumor of a higher grade or stage. Cytology performed at or before recurrence was positive in 8 patients (80 per cent) and 2 (20 per cent) had grade II, noninvasive transitional cell carcinoma with negative cytology. Subsequent tumors in these 2 patients have been grade I. All 36 patients are alive. Given the patient inconvenience, expense and risk of infection of cystoscopy compared to cytology, this retrospective review suggests that when an experienced cytopathologist is available patients with grade I, noninvasive transitional cell carcinoma may be monitored primarily by urinary cytology with less frequent endoscopy. A prospective study must be performed to confirm this approach.     

Comparative histopathology and deoxyribonucleic acid flow cytometry of random mucosal biopsies in untreated bladder carcinoma

In a study of 290 patients with untreated carcinoma of the bladder, histopathological studies of random mucosal biopsies were compared with the results of deoxyribonucleic acid (DNA) flow cytometry. By histopathology the findings were classified as severe atypia corresponding to primary grade 3 carcinoma in situ, atypia not fulfilling the criteria for carcinoma in situ and no atypia. The DNA histograms were classified as diploid or aneuploid. Aneuploid cell populations in mucosal biopsies were found mainly in cases with aneuploid tumors of grade 3. Of the biopsies classified as concomitant carcinoma in situ 76% were aneuploid. In biopsies exhibiting less severe or no atypia aneuploidy was found in 41 and 10%, respectively. For these 3 morphological categories the distributions of the aneuploid cell populations were similar irrespective of the histopathological findings and they were also the same as that found in primary carcinoma in situ. We concluded that gross chromosomal aberrations may appear at an early stage of the tumor development and before changes recognizable by morphology. The similarity of the DNA profiles of the aneuploid cell populations, regardless of morphological findings, indicates that apart from gross chromosomal aberrations changes of the phenotype are necessary for the expression of morphological changes.     

The significance of random bladder biopsies in superficial bladder cancer

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

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

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

Seminal vesicle involvement by urothelial carcinoma in situ of the bladder with mucosal spread pattern: a case report

Mucosal spreading of urothelial tumors to the seminal vesicles is very rare. We experienced a case of mucosal involvement of the seminal vesicles by a bladder tumor in a 72-year-old man. The patient had a history of transurethral resection for invasive urothelial carcinoma of the bladder 8 years previously. Radical cystoprostatectomy was performed owing to recurrent and multiple urothelial carcinoma in situ. Microscopically, the urothelial carcinoma in situ was throughout the mucosa of the urinary bladder, both ureters, the prostate, and the left seminal vesicle. To date, the implication of mucosal involvement of the seminal vesicles by urothelial carcinoma is unclear. However, careful microscopic examination is needed to avoid an erroneous diagnosis.     

Significance of atypical urinary cytology in the evaluation of patients with end‐stage renal disease for kidney transplantation – a retrospective study

To determine what percentage of renal transplant candidates have atypical urinary cytology, what proportion have urothelial carcinoma and whether cystoscopy is necessary with atypical cytology. All end‐stage renal disease (ESRD) patients (703) presenting for renal transplantation at our institution were retrospectively reviewed. Individuals producing sufficient urine were screened with urine cytology and those with atypical cytology or risk factors for bladder cancer underwent cystoscopy. Four hundred and thirty patients had available urinary cytology and, of these, 151 (35%) had atypical cytology. Of patients with atypical cytology, three were identified to have urothelial carcinoma. However, three additional patients with urothelial carcinoma did not present with atypical cytology. In total, 6 of 703 (0.85%) patients had bladder cancer. All were treated with transurethral resection and eventually underwent renal transplant. One patient has had disease progression post‐transplant to distant metastases. This is the largest study to date evaluating the incidence of urothelial carcinoma in ESRD patients presenting for transplant workup. We found the incidence of bladder cancer to be higher than in the general Canadian population, however, most lesions were low grade. We found atypical cytology in transplant candidates to be a poor predictor for these low‐grade lesions and do not recommend routine cystoscopy for atypical cytology.     

Flow cytometry versus urinary cytology in the evaluation of patients with bladder cancer

We compared the roles of urinary cytology and flow cytometry in the evaluation of patients with bladder cancer in clinical practice situations at a large general hospital. Specimens included 105 bladder washings from patients being followed for urothelial carcinomas and 28 control washings from individuals undergoing cytoscopy for other reasons. Flow cytometry and cytology were performed on aliquots of the same specimen in all bladder cancer samples. When carcinoma was present at the time of specimen collection it was detected by positive cytology in 75 per cent and deoxyribonucleic acid aneuploidy in 78 per cent of the cases. Combination of flow cytometry and urinary cytology increased the diagnostic yield to 95 per cent. Flow cytometry was slightly more sensitive than urinary cytology for detection of abnormalities in specimens from noninvasive and untreated tumors but the only statistically significant difference between the 2 procedures occurred among specimens from treated invasive cancers in which flow cytometry was a less sensitive method than cytology. Abnormal deoxyribonucleic acid ploidy was documented in a few specimens from noncancer-bearing patients having diseases associated with high urothelial cell turnover rates but the concomitant urinary cytology was negative for neoplasia. When used in conjunction with urinary cytology, flow cytometry was a valuable procedure in the followup of patients with bladder cancer. The diagnostic yield with this combination was such that flow cytometry and cytology may be used to reduce the frequency of cystoscopy and biopsy during clinical management in selected situations.     

Subsequent upper urothelial cancer following bladder tumor

A total of 110 patients were treated with primary transitional cell carcinoma (TCC) of the urinary bladder from 1990 to 2000. During the follow-up period, which was for at least two years, four patients (3.6 percent) had subsequent upper urothelial cancer at an average of 61.5 months after initial treatment of the bladder tumor. Two of the four patients received transurethral resection several times, and the remaining two patients underwent radical cystectomy for the initial bladder tumor. The histopathological findings of subsequent upper urothelial cancer were almost the same as those for the initial bladder tumor. One patient had accompanying carcinoma in situ (CIS) and the other had adenocarcinoma with TCC. Since 1) high grade, 2) multiple, 3) recurrent and 4) occupational bladder tumors, 5) concomitant CIS, 6) vesicoureteral reflux and 7) tumor invasion of the intravesical ureters have been reported to be risk factors for developing subsequent upper urothelial cancer, patients with bladder tumors who have these risk factors should be followed-up closely.     

Results of 6 weekly intravesical bacillus Calmette-Guerin instillations on the treatment of superficial bladder tumors

We evaluated 104 patients with superficial bladder tumors for response to intravesical bacillus Calmett-Guerin therapy. Patients received 6 weekly intravesical bacillus Calmette-Guerin instillations and they were followed for response every 3 months with urinary cytology, cystoscopy and bladder biopsy. Patients were considered treatment failures if either the cytology studies or biopsies were positive for tumor. Of 65 patients who failed the initial treatment course 57 were given an additional 6-week course of therapy. One 6-week course of bacillus Calmette-Guerin was successful in 20 of 55 patients (36 per cent) treated for prophylaxis, 12 of 32 (37 per cent) treated for carcinoma in situ and 7 of 17 (41 per cent) treated for residual tumor. The response rate for the total patient population treated with 1, 6-week course was 37.5 per cent (39 of 104). A second 6-week course was successful in 19 of 29 patients (65 per cent) treated for prophylaxis, 11 of 18 (71 per cent) treated for carcinoma in situ and 4 of 10 (40 per cent) treated for residual tumor. The response rate for all patients receiving a second course of bacillus Calmette-Guerin was 59.6 per cent (34 of 57). Of 6 patients who refused another 6-week course of bacillus Calmette-Guerin 4 had additional recurrences and 3 of these 4 suffered invasive disease. The over-all therapeutic response rate for patients treated with either 6 or 12 weeks of therapy was 70 per cent. These results suggest that 6 weeks of intravesical bacillus Calmette-Guerin do not provide optimal therapy for superficial bladder tumors. The data further suggest that more intensive regimens may increase therapeutic efficacy.     

Percutaneous bacillus Calmette-Guerin perfusion of the upper urinary tract for carcinoma in situ

Ten pyeloureteral systems in 8 patients (mean age 74 years) with cytologically proved ureteral carcinoma in situ (1 combined with ureteral papillary tumors) were perfused with bacillus Calmette-Guerin via a percutaneous nephrostomy tube. In 4 patients cytology results remained negative after 1 treatment course during an observation time of 18 to 28 months. In 1 patient a papillary tumor persisted while cytology results became negative for carcinoma in situ. Two patients with bilateral disease had repeated perfusion of bacillus Calmette-Guerin until cytology results became negative and they remained negative during observation for 18 months in 1. The other patient had a multifocal recurrence of carcinoma in situ, combined with a stage T1, grade 3 urothelial cancer in the bladder after 12 months and a recurrence of carcinoma in situ in 1 ureter after 24 months. In 1 patient treatment was stopped prematurely after severe septicemia. Although our short-term results are promising, percutaneous perfusion of bacillus Calmette-Guerin for carcinoma in situ of the upper urinary tract should be considered as an investigational treatment modality until long-term results are available.     

The significance of atypia in fine needle aspiration cytology of the prostate

Of 411 fine needle aspirates of the prostate 208 could be matched with conventional pathological material. Cytological diagnosis had a complete sensitivity of 94 per cent, specificity 99 per cent and efficiency 74 per cent. Corresponding figures for 36 patients who underwent total prostatectomy were complete sensitivity 100 per cent, specificity 100 per cent and efficiency 78 per cent. Atypical cytology results not amounting to frank malignancy were the main reasons for reduced efficiency and, therefore, analysis of the significance of atypia was performed. In 50 aspirates from 43 patients atypia of varying degree was noted but the degree of atypia did not allow for a diagnosis of malignancy. Subsequent diagnosis of carcinoma was made by cutting needle biopsy or transurethral resection in 7 of 14 specimens (50 per cent) of severe, 3 of 9 (33 per cent) moderate, 3 of 7 (43 per cent) mild and 3 of 16 (19 per cent) reactive atypia. Thus, specific cytological diagnoses have a high degree of accuracy but atypia and attempts to categorize it did not predict accurately the final diagnosis. Pathological conditions that may account for atypia in fine needle aspiration cytology are reviewed.     

Intravesical bacillus Calmette-Guerin therapy for in situ transitional cell carcinoma involving the prostatic urethra

A total of 23 patients presenting with multifocal superficial bladder cancer and concomitant in situ transitional cell carcinoma of the prostatic urethra (mucosal in 19 and ductal in 4) underwent transurethral resection and intravesical bacillus Calmette-Guerin therapy. Median followup was 51.6 months (range 6 to 105 months). Of the 23 patients 13 (48 per cent) had a complete response with a median followup of 43.7 months without recurrence. Progression of some type (local, muscle invasion or metastasis) occurred in 10 patients (44 per cent); none occurred in the prostatic urethra. Median interval free of progression was 55.7 months; 7 of 10 patients required cystectomy for progression or refractory disease in the bladder (prostate negative for transitional cell carcinoma). A trial of complete transurethral resection plus intravesical bacillus Calmette-Guerin is a viable alternative to immediate radical cystectomy for patients with mucosal and/or ductal involvement of the prostatic urethra with in situ transitional cell carcinoma.     

Upper urinary tract tumors following bladder cancer

We treated in total 795 patients with primary transitional cell carcinoma of the urinary bladder between April, 1964 and December, 1988. Eighteen patients of them had upper urothelial cancer during the follow-up period. Thirteen of the 18 patients had received transurethral resection for the initial bladder cancer, while 3 total cystectomy and 2 segmental resection. The over-all incidence of bladder cancer patients who subsequently developed upper urinary tract tumors was 2.3 per cent. The interval between initial treatment of the bladder cancer and treatment for the upper urinary tract tumor ranged from 2 to 74 months (median 20 months). The five-year survival rate after treatment for the upper urinary tract tumor was 31.7 per cent. We conclude that the following are high risk patients for development of upper urinary tract recurrences: 1) patients with bladder cancer near orifices, 2) patients with recurrent bladder cancer under bladder preserving treatment for a long time, 3) patients with G2 multifocal bladder cancer.     

Bladder tumors: when to do and what to expect from random mucosal biopsies with reference to blood group cell surface antigens

Routine random biopsies of normal looking bladder mucosa in the evaluation of bladder tumors demonstrated a high occurrence of anomalies ranging from dysplasia to carcinoma in situ (CIS). 75 patients with a urothelial bladder tumor were submitted to 165 endoscopic procedures under anesthesia including transurethral resection of any bladder tumor and random mucosal biopsies in the 4 quadrants of the bladder. The frequency and severity of mucosal anomalies rise with the tumor grade and stage: in stage 0.Ta, the percentage of anomalies rises from 15% in grade-1 lesions to 53% in grade-3 tumors. 80% of the stage A (T1) B and C (T2, T3) tumors are associated with anomalies of the normal looking bladder mucosa characterized by CIS in 50% of the cases. These lesions which may persist in the absence of any visible tumor respond dramatically to endovesical bacillus Calmette-Guérin therapy. Simultaneous determinations of blood group antigens fail to demonstrate a clear correlation between the antigenic status of the tumor and that of random biopsies. These results may help to clarify the indications of random mucosal biopsies which should be reserved to the treatment and surveillance of grade 3-tumors, irrespective of their stage.     

A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma

PURPOSE: We determine the relative sensitivities of cytology and fluorescence in situ hybridization (FISH) for the detection of urothelial carcinoma. MATERIALS AND METHODS: A mixture of fluorescent labeled probes to the centromeres of chromosomes 3, 7 and 17, and band 9p21 (P16/CDKN2A gene) was used to assess urinary cells for chromosomal abnormalities indicative of malignancy. A total of 280 urine specimens from 265 patients, including 150 with a history of urothelial carcinoma and 115 without a history of urothelial carcinoma, were analyzed. FISH analysis was performed without prior knowledge of clinical findings, that is biopsy, cystoscopy and cytology results. A positive result was defined as 5 or more urinary cells with gains of 2 or more chromosomes. RESULTS: A total of 75 biopsies showed urothelial carcinoma at FISH analysis among the 265 patients. The sensitivity of urine cytology for pTa (36 cases), pTis (18) and pT1-pT4 (15) tumors was 47%, 78% and 60%, respectively, for an overall sensitivity of 58%. The sensitivity of FISH for pTa (37 cases), pTis (17) and pT1-pT4 (19) tumors was 65%, 100% and 95%, respectively, for an overall sensitivity of 81%. FISH was significantly more sensitive than cytology for pTis (p = 0.046), pT1-pT4 (p = 0.025), grade 3 (p = 0.003) and all tumors (p = 0.001). The specificity of cytology and FISH among patients without cystoscopic evidence of urothelial carcinoma and no history of urothelial carcinoma was 98% and 96%, respectively (p = 0.564). CONCLUSIONS: The sensitivity of FISH for the detection of urothelial carcinoma is superior to that of cytology, and the specificity of FISH and cytology for urothelial carcinoma are not significantly different. Further prospective studies are required but FISH has the potential to improve significantly the management of urothelial carcinoma.     

Monitoring intravesical bacillus Calmette-Guerin treatment of superficial bladder carcinoma by postoperative urinary cytology

We studied 51 patients with superficial bladder carcinoma who had been treated with transurethral resection of all gross tumor followed by intravesical bacillus Calmette-Guerin weekly for 6 weeks. Within 72 hours of either the first or second quarterly cystoscopic surveillance examination after bacillus Calmette-Guerin therapy, a conventional cytology study was obtained. Of these patients 8 (15.7 per cent) had positive, 9 (17.6 per cent) suspicious and 34 (66.7 per cent) negative postoperative cytology studies. Subsequent tumor recurrence was defined as a positive biopsy or visible papillary tumors on cystoscopic examination. All 8 patients with a positive postoperative cytology study had tumor recurrence at a median interval of 4 months. Of the 9 patients with a suspicious study 7 (77.8 per cent) had recurrent tumor at a median interval of 7 months and 2 (22.2 per cent) had no evidence of disease at 16 and 19 months, respectively. Of the 34 patients with a negative postoperative cytology study 13 (38.2 per cent) had tumor recurrence after a median interval of 4 months and 21 (67.8 per cent) had no evidence of disease after a median of 25 months. The tumor recurrence rate in patients with a positive or suspicious postoperative cytology study was significantly greater than that of patients with a negative study (p equals 0.001, Fisher's exact test). Postoperative cytology appears to be a significant prognostic indicator following transurethral resection and intravesical bacillus Calmette-Guerin treatment of superficial bladder carcinoma.