Value of urine cytology versus bladder washing in bladder cancer.

A prospective study compared the diagnostic outcome of paired urine cytology and bladder washings in 26 patients as well as the diagnostic accuracy of cytologic reading of voided urine in 43 patients, all with documented bladder cancer. We demonstrate the superiority of bladder washing over voided urine cytology and recommend its routine use in spite of the additional cost and patient discomfort.     

Value of bladder washing cytology in the diagnosis and follow-up of bladder tumors

It is reported on the accuracy of the cytological examination of freshly voided urine of 247 patients with 318 urothelial bladder tumors, and the results are compared with the evaluation of bladder washing cytology in 82 patients with 105 bladder tumors. If voided urine is used for examination, there is no evidence in tumors with 0 and 1 grade of malignancy, whereas the bladder washing cytology of grade 1 tumors shows a correlation for the histological findings in 26.3%. In tumors with malignant grades GII and GIII, the bladder washing cytology shows a significantly higher accuracy (81.4%) than in examination of voided urine (67.2%). In both methods the accuracy of cytology rises with infiltration and differentiation grades of the tumor.     

Value and limitations of urinary cytology in the diagnosis of bladder tumors]

There were studied 222 patients with bladder tumors, 64 with operated transitional cell carcinoma and 166 with non-malignant diseases from cytologic and histologic point of view. Each patient was investigated by urinary cytology, endoscopy, and during the intervention biopsies were taken, which helped us to establish the histological form, the degree of differentiation and "T" element, using TNM system. All smears were stained by blue polychrome-tannin Dragan method and correlated with histological results which allowed us to appreciate cytodiagnostic as real positives, false negatives, real negatives and false positives. We signalled out some morphological aspects of malignant cells revealed by blue polychrome-tannin Dragan stain, which identified malignant elements in 87% tumors of the bladder G1, in 91.5% in G2 and 93.5% in G3; results were enhanced using washings of the bladder. There was some causes for false negatives results: a calcified tumor in its surface, tumors developed in vesical diverticulum, a limited exfoliation and a wrong interpretation of exfoliated cells. In patients transurethrally operated for tumors of the bladder the urinary cytology identified malignant elements in 22 of them; four presented tumors in the moment of endoscopic examination and 18 were considered as "apparently false-positive"; eleven of them developed tumors in the next 6-24 months from the intervention. In patients with non-malignant diseases false positives results were related specially to urinary lithiasis and chronic renal failure. Results of initial and survey cytodiagnosis allowed us to increase the period between traditional cystoscopies.     

Comparison of the Bard Trak test with voided urine cytology in the diagnosis and follow-up of bladder tumors

OBJECTIVES: To compare the results of the BTA Trak test with voided urine cytology (VUC) in the diagnosis and follow-up of bladder tumors. PATIENTS AND METHODS: Urine samples were obtained from 53 patients with bladder tumor (77 samples) and 53 patients treated for bladder tumor with no evidence of disease on the basis of cystoscopic evaluation (88 samples). Urine samples were collected prior to cystoscopy. The BTA assay was performed by the BTA Trak test according to the manufacturer's recommendations. A value >14 U/ml was considered abnormal. RESULTS: There was a statistically significant increase in median BTA value with increasing stage of tumor: 11.9, 57.9 and 391.0 U/ml respectively for stages pTa, pT1 and pT2/3 (p<0.0001, Kruskal-Wallis test). There was also a correlation between increasing grade and median BTA values measured at 6.9, 13.1 and 235.0 U/ml in grades 1, 2 and 3 tumors respectively (p<0.0001, Kruskall-Wallis test). The overall sensitivity of the BTA Trak test was 58.4% compared to 46.7% for VUC, a difference of 11.7%, which was statistically significant (McNemar test, p<0.005). The sensitivity of both tests combined was 63.6%. The specificity of the VUC (94.3%) was significantly higher than that of the BTA Traktrade mark (75.0%) (p<0.005, McNemar test). The accuracy of the Bard Trak test (67.3%) was similar to that of VUC (66.9%). CONCLUSION: The BTA Trak test is more sensitive than urinary cytology in the detection of bladder tumors but the improvement involved is insufficient to consider decreasing the frequency of endoscopic examinations in the follow-up of superficial bladder tumor.     

Detection of interleukin 2 in the urine of patients with superficial bladder tumors after treatment with intravesical BCG

Adjuvant intravesical BCG therapy is an effective means of treating superficial bladder tumors. The mechanism by which BCG mediates antitumor activity is not known; however, clinical and animal studies suggest that immunological responsiveness to BCG antigens correlates with antitumor activity. In this report the detection of interleukin 2 (IL-2, a lymphokine produced in response to BCG) in urine specimens of patients treated with intravesical BCG is reported. Patients with superficial transitional cell carcinoma of the bladder received intravesical BCG once each week for six weeks. No intradermal injections were administered. Urine specimens were obtained prior to BCG instillation and four, eight and 24 hours afterwards. The specimens were dialysed, concentrated five-fold and assayed for the presence of IL-2 in a biological assay using an IL-2 dependent cultured T-cell line. IL-2 was detected in urine but not serum after intravesical BCG instillation. IL-2 was characterized by absorption against an IL-2-dependent T cell line and neutralization by monoclonal anti-IL-2 antibodies. No IL-2 was detected in specimens obtained prior to BCG instillation or from donors with no detectable bladder pathology. One of 10 urine specimens from patients with urinary tract infections had detectable IL-2 levels. IL-2 production generally peaked during the fourth to sixth intravesical BCG treatment. Production was short-term in that IL-2 levels peaked four to eight hours after BCG instillation and were rarely (six of 54 specimens) observed 24 hours after instillation. Mean IL-2 levels were higher in patients who were rendered tumor free after BCG therapy but statistical significance was not achieved. Ten of 12 patients (83%) who responded to BCG therapy had urine IL-2 levels greater than or equal to 1.6 units/ml. at least once during the six week treatment period while two of six (33%) patients not responding to therapy had similar urine IL-2 levels. These results show that intravesical BCG therapy induces the production of lymphokines including IL-2. The presence of BCG-induced lymphokines may be associated with anti-tumor activity.     

Comparative evaluation of the nuclear matrix protein,fibronectin, urinary bladder cancer antigen and voided urine cytology in the detection of bladder tumors

PURPOSE: We evaluate the diagnostic efficacy of nuclear matrix protein-22 (NMP22, Matritech, Newton, Massachusetts), fibronectin and urinary bladder cancer antigen (UBC, IDL Biotech, Borlange, Sweden) compared with voided urine cytology in the detection of bladder cancer. MATERIALS AND METHODS: A total of 168 patients provided a single voided urine sample for NMP22, fibronectin an ideal monoclonal for urinary bladder cancer and cytology before cystoscopy. Cystoscopy was done for all patients as the reference standard for identification of bladder cancer. Biopsy of any suspicious lesion was performed for histopathological examination. Of the 168 cases 100 were histologically diagnosed as bladder cancer, whereas the remaining 68 had benign urological disorders. A group of 47 healthy volunteers were also enrolled in this study. Voided urine was evaluated by NMP22, fibronectin and UBC, and their values were expressed relative to mg. creatinine. RESULTS: The optimal threshold values for NMP22, fibronectin and UBC were calculated by receiver operator characteristics curves as 27 units per mg. creatinine, 198 mg./mg. creatinine and 13 ng./mg. creatinine, respectively. The levels and positive rates of the 3 parameters were significantly higher in the malignant group compared to either the benign group or normal controls. Of the entire group NMP22, fibronectin and UBC were positive in 93.2%, 91% and 68.2%, respectively in bladder cancer cases with positive cytology. Moreover, these positive rates were significantly higher in bilharzial bladder cancer cases (58.8%, 67.5%, 58.8%, respectively) compared to nonbilharzial cases (35.6%, 36.3%, 31.1%). Overall sensitivity and specificity were 85% and 91.3% for NMP22, 83% and 82.6% for fibronectin, 67% and 80.8% for UBC and 44% and 100% for voided urine cytology. Combined sensitivity of voided urine cytology with the 3 biomarkers together was higher than either combined sensitivity of voided urine cytology with 1 of the biomarkers or than that of the biomarker alone. CONCLUSIONS: Our data indicate that NMP22 and fibronectin had superior sensitivities compared to UBC and voided urine cytology, while NMP22 and voided urine cytology had the highest specificities. The combined use of markers increased the sensitivity of cytology from 44% to 95.3%. The higher sensitivities of markers in bilharzial than nonbilharzial bladder cancer highlight their clinical use in screening patients with urinary bilharziasis.     

Eosinophil cationic protein in urine in patients with urinary bladder tumors

Summary Measurement of eosinophil cationic protein (ECP) in urine constitutes a new biochemical method for assessment of local eosinophil activity in the bladder. ECP in urine was measured in 18 patients previously treated for various types of urinary bladder tumors and a comparable control group of 18 normals. The median concentration of ECP in urine from the patients was 46.5 arb. U/l versus 24.5 arb. U/l from normals. This difference was statistically highly significant (p<0.01). This study suggests that eosinophils are involved in the host tumor relationship in patients with urothelial neoplasia. Measurement of ECP in urine may imply a new concept for assessment of urothelial tumors.     

Epidermal growth factor in urine from patients with urinary bladder tumors

Epidermal growth factor (EGF) concentration and 24-hour excretion in urine were measured with a radioimmunoassay in 18 patients previously treated for various types of urinary bladder tumors and a comparable control group of 18 normals. The median concentration of EGF in urine from the patients was 1.50 nmol/l and from normals 3.03 nmol/l. The median 24-hour excretion of EGF in urine from the patients was 1.96 nmol and from normals 3.33 nmol. These differences between patients and normals were statistically significant (p less than 0.05 and p less than 0.005) although there was an overlap in individual values of EGF concentration and excretion in urine from patients and normals. This study suggests that urothelial neoplasia is related to a low concentration and excretion of EGF.     

Clinicopathological study of urinary bladder tumors. Clinical evaluation of immunohistochemistry in urine cytology

We report on the immunohistochemical detection of carcinoembryonic antigen in the urine cytology of 5 patients with urinary bladder tumors classified as low, moderate, and high grade. Immunohistochemically carcinoembryonic antigens were detected in urine cytology in the case of moderate and high grade tumors, but not, low grade tumors. Carcinoembryonic antigen positivity in urine cytology correlated with the histological grade of a bladder tumor. Carcinoembryonic antigen in urine cytology seemed to be a potentially good marker to distinguish between high grade and low grade tumors.     

Clinical evaluation of the BTA trak assay and comparison to voided urine cytology and the bard BTA test in patients with recurrent bladder tumors

Objectives

To assess the clinical performance of the BTA TRAK assay and to compare it with that of voided urine cytology (VUC) and the Bard BTA test (BTA) in the detection of recurrent bladder cancer (BC).

Methods

The study was performed on randomly selected archival voided urine samples for many of which VUC and/or BTA information was available. Sensitivity was determined in samples from patients with histologically confirmed recurrent BC. Specificity was determined in samples from healthy volunteers, patients with three categories of current medical conditions, and patients with a history of BC but no current evidence of disease.

Results

The TRAK assay was positive in 156 of 216 samples for patients diagnosed with BC, for an overall sensitivity of 72%. Mean values increased with progressing grade and stage of disease. In the comparison between TRAK and VUC, the overall sensitivities were 68% and 25%, respectively (P < 0.001 ). For Stages Ta and T1 and for all tumor grades, the sensitivity of the TRAK assay was significantly greater than that of VUC (P < 0.001 ). TRAK sensitivity was also significantly better than that of BTA (73% versus 58%, P = 0.005). The specificity of the TRAK assay ranged from 75% in samples from patients with genitourinary disease to 97% in healthy volunteers.

Conclusions

The TRAK assay is superior to VUC and the original BTA test in the detection of BC. The results of the study indicate that the TRAK assay may be a useful adjunct to cystoscopy in the management of patients with recurrent BC.     

Clinical significance of immediate urine cytology after transurethral resection of bladder tumor in patients with non‐muscle invasive bladder cancer

Objectives: To assess the clinical significance of immediate urine cytology (IUC) after transurethral resection of bladder tumor (TURBT) for non‐muscle invasive bladder cancer (NMIBC). Methods: We reviewed the records of 174 patients who underwent IUC after TURBT for NMIBC. IUC was obtained just before Foley catheter removal after TURBT. The relationship between IUC and tumor stage, grade, size and multiplicity, as well as preoperative urine cytology and immediate intravesical epirubicin therapy, were assessed. The relationship between a positive IUC and cancer recurrence was also assessed. Multivariate Cox proportional hazards regression analysis was carried out, including IUC, tumor stage, tumor grade, tumor size, tumor multiplicity, preoperative urine cytology and immediate intravesical epirubicin therapy. Results: IUC was positive in 76 patients (43.7%) and negative in 98 patients (56.3%). In the positive IUC group, tumor stage and grade were higher (P = 0.001, <0.001), tumor size was larger (P = 0.001), tumor multiplicity was higher (P = 0.002) and positive preoperative cytology was more likely (P = 0.006) than in the negative IUC group. In the positive IUC group, the cancer recurrence rate was 72.3% and that of the negative IUC group was 30.6% (P < 0.001). In a multivariate Cox proportional hazards regression analysis, positive IUC (HR 1.83, P = 0.019), tumor size (HR 1.72, P = 0.045), tumor multiplicity (HR 3.63, P = 0.015), preoperative urine cytology (HR 1.23, P = 0.043) and immediate intravesical epirubicin therapy (HR 0.171, P = 0.001) were independent prognostic factors for cancer recurrence. Conclusion: These data suggest that IUC after TURBT for NMIBC can be an independent prognostic factor to predict cancer recurrence.     

Bladder tumors: superiority of urinary cytology after bladder lavage

Sixty two endoscopic examinations were performed on fifty five patients for the followup of bladder tumors. The results of urinary cytological examinations performed on voided specimens of urine, on specimens collected after introduction of the endoscope, and specimens obtained by bladder washing with saline, were compared with the results of histological examinations of the tumors, and mucosal biopsies. The results show a definite superiority of bladder washing over the other methods: the rate of non-diagnostic procedures falls from 17 to 1.5%, the detection of grade III tumors or carcinomas in situ improves from 55 to 75% and from 33 to 88% respectively. Bladder washing cytology is thus a useful adjunct to voided urinary cytology.     

Exfoliative urine cytology in the treatment of bladder cancer

Urine cytology in addition to cystoscopy and transurethral resection is an integral part in diagnostic and follow-up of transitional carcinomas. The WHO-Classification of 2004 distinguishes between low grade and high grade tumours. Cytological diagnosis had to be adjusted to this new classification. Above all cytology has to detect high grade lesions in a reliable manner. The sensitivity for these lesions ranges between 85?C95%. Well differentiated transitional cell carcinomas show marginal nuclear alterations compared to normal urothelial cells. Therefore the cytological low grade diagnosis is needless. Well differentiated papillary tumours can be detected with conventional cystoscopy in nearly 100 percent of all cases. This subtype of urothelial carcinomas is characterized by a very low rate of tumour progression despite a relevant rate of tumour recurrence. A negative cytology result combined with a cystoscopically proven papillary bladder tumour implies low grade disease with low risk of tumour progression.     

A comparative study of the sensitivity of bladder washing flow cytometry, voided urine cytology and bladder washing cytology in the detection of bladder carcinoma

In order to evaluate flow cytometric deoxyribonucleic acid measurement (FCM) of bladder washing in the diagnosis of bladder carcinoma, the sensitivity of voided urine cytology, bladder washing cytology and bladder washing FCM was tested in 76 samples from 56 patients with histologically proven bladder carcinomas. The positive rates were 43.2% and 75.7% in bladder washing cytology and bladder washing FCM, respectively. On the other hand, 36.5% and 57.1% positive rates for once- and three-times-voided urine cytology, respectively, were obtained. Bladder washing cytology and bladder washing FCM were positive in 20% and 70% patients with a histological diagnosis of atypia or dysplasia, respectively. The sensitivity of bladder washing FCM according to the tumor grade was 33.3%, 81.9% and 88.9% for grade-1 (G-1), G-2 and G-3 tumors, respectively. The sensitivity of bladder washing cytology according to the tumor grade was 0, 40.9% and 77.8% for G-1, G-2 and G-3 tumors, respectively. The sensitivity of three-times-voided urine cytology was 25.0%, 55.6% and 83.3% for G-1, G-2 and G-3 bladder tumors, respectively, and it was superior to that of single bladder washing cytology. These results indicate that FCM is more sensitive than voided urine cytology and/or bladder washing cytology in patients with bladder carcinoma. FCM may indicate urothelial neoplasia before it is apparent on urine cytology, especially against a background of inflammation. Therefore, FCM is valuable for case finding in suspect populations or for follow-up cases with diagnosed bladder cancer.     

Short-term culture of exfoliated cells from the urine of patients with bladder tumors

Summary This report concerns the short-term culture of urothelial cells from the urine sediment of over 100 patients with bladder tumors. Primary cell outgrowth was obtained in approximately 60% of the cultures initiated. Culture outcome was not related to tumor grade, patient age, or volume of the urine sample. Around 85% of the proliferating cultures were successfully transferred into multi-compartment chamber/slides. These results suggest that the culture system may be a useful tool for the study of urothelial cells using patient material obtained by non-invasive means.     

Comparative evaluation of the BTAstat test, NMP22, and voided urine cytology in the detection of primary and recurrent bladder tumors

OBJECTIVES: This prospective study was undertaken to evaluate the diagnostic efficacy of the BTAstat test and nuclear matrix protein (NMP22) compared with voided urine cytology (VUC) in the detection of primary and recurrent bladder cancer. METHODS: A total of 147 patients provided a single voided urine sample for the BTAstat test, NMP22, and cytology prior to cystoscopy. Eighty-five of them had no bladder cancer history, whereas the remaining 62 were monitored for superficial bladder cancer. A group of 21 healthy age-matched volunteers were also enrolled in the study. RESULTS: Bladder cancer was confirmed histologically in 99 patients, of which 62 had primary tumors and 37 had recurrent ones. The overall sensitivity and specificity were 71.7% and 56.5% for the BTAstat test, 62.6% and 73. 9% for NMP22, and 38.4% and 94.2% for VUC. The optimal threshold value for NMP22 calculated with receiver operating characteristics curve, was 8 U/mL. BTAstat test was significantly more sensitive than VUC in detecting bladder cancer in all stage and grade subgroups, except GIII. On the contrary, NMP22 was significantly more sensitive than VUC only in stage Ta, grade I and II patients. BTAstat test had higher but not significantly different sensitivity than NMP22. CONCLUSIONS: Our data indicate a superiority of both BTAstat test and NMP22 over VUC in the detection of bladder cancer. Comparing BTAstat test with NMP22, the former proved to be more sensitive, whereas the latter was more specific. Ruling out diseases with potential interference can increase the overall specificity of both tests. False-positive results of either test in patients followed up for bladder cancer seem to correspond to future recurrences.     

Urinary cytology and bladder biopsy in patients with bladder cancer

Two hundred fifty patients with bladder tumor were evaluated over a three-year period. Cystoscopy, cytology, and random bladder and tumor biopsy were part of the workup. The follow-up of these patients resulted in a total of 509 cystoscopies, 772 specimens of bladder washings and urinary cytologies, and 503 tumor or selected mucosal biopsies. The value of cytologic study of bladder washings and cystoscopic urine samples as well as the importance of selected site mucosal biopsies in detecting "field changes" in the bladder epithelium associated with bladder tumors are discussed.