Fluorescence in situ hybridization for detecting transitional cell carcinoma: implications for clinical practice

OBJECTIVE: To determine the diagnostic sensitivity of genetic studies using fluorescence in situ hybridization (FISH) for detecting both new and recurrent cases of transitional cell carcinoma (TCC) in a routine clinical practice setting, as bladder cancer has a significant risk of recurrence and progression to invasive disease and thus sensitive surveillance testing is very important. PATIENTS AND METHODS: FISH was performed using the UroVysion kit (Vysis Inc., Downers Grove, IL, USA) Consecutive patients were assessed using FISH, both to evaluate those with a history of TCC or with suspicious symptoms, and the FISH results were compared with concurrent biopsy and cytological assessments. RESULTS: In all, 521 consecutive FISH tests from 300 patients were evaluated; 47% had a history of bladder cancer and 53% had suspicious symptoms. Of the 521 FISH tests, 24% were positive; concurrent cytology was available for 84% of the FISH tests, with a concordance rate of 78% (6% were positive for both and 72% were negative by both tests). For the discordant cases, FISH was positive and cytology negative in 21% of cases, and cytology was positive with a negative FISH for 1%. In all, 99 FISH tests had concurrent biopsy data. Of the 44 cases histologically positive for TCC, 32 were FISH-positive, resulting in an overall sensitivity (95% confidence interval) of 73 (60-88)%. FISH detected 95% of cases with high-grade carcinoma, while only seven of these 17 were positive by concurrent cytological assessment. FISH detected 56% and cytology detected 32% of low-grade lesions. FISH detected all nine new cases with positive histology. Overall, the specificity of FISH was 65 (53-78)%. Of 112 patients with previous TCC, 28 had a recurrence; 22 of these had positive FISH results. CONCLUSION: FISH analysis has a high sensitivity for detecting new cases of TCC, as well as recurrences. From the present data FISH is considerably more sensitive and only slightly less specific than cytology in diagnosing TCC. Therefore, we recommend FISH as a useful initial diagnostic tool in patients suspected of both new and recurrent TCC.     

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.     

Clinical evaluation of a multi-target fluorescent in situ hybridization assay for detection of bladder cancer

PURPOSE: The UroVysion fluorescence in situ hybridization assay (UroVysion Bladder Cancer Recurrence Kit, Vysis, Inc., Downers Grove, Illinois) is a multi-target assay that detects aneuploidy of chromosomes 3, 7 and 17, and loss of the 9p21 band in exfoliated cells in urine from patients with transitional cell carcinoma. We performed 2 multicenter trials. In 1 trial we compared the sensitivity of the FISH assay to the BTA Stat test (Bion Scientific, Redmond, Washington) and voided cytology in the detection of transitional cell carcinoma. In a separate study of healthy volunteers and patients with other (nontransitional cell carcinoma) conditions we determined the specificity of the FISH assay. MATERIALS AND METHODS: A total of 176 patients with transitional cell carcinoma in the previous 9 months provided voided urine before cystoscopy. Each specimen was split, preserved and shipped to a central laboratory where all 3 tests were performed. All sites were blinded to results. Sensitivity calculations were based on central pathology review of resected tissue. Specificity was determined by testing 275 volunteers who were healthy and with nontransitional cell carcinoma conditions. RESULTS: The 21 sites enrolled 176 patients with a history of transitional cell carcinoma, with 62 recurrences while undergoing surveillance. Overall sensitivities (with 95% CI) were FISH 71% (95% CI 58 to 82), BTA Stat test 50% (37 to 63) and cytology 26% (16 to 39). FISH was negative in 260 of the 275 healthy volunteers or patients with no history of transitional cell carcinoma (specificity 94.5%). CONCLUSIONS: Sensitivity of the FISH assay is superior to that of cytology and at least equivalent to the BTA Stat test in detecting recurrent transitional cell carcinoma. Its specificity approaches that of cytology. Further testing of its clinical use is warranted.     

Fluorescence In Situ Hybridisation in the Diagnosis of Upper Urinary Tract Tumours

Background

Upper urinary tract (UUT) tumours are often a diagnostic challenge. Because of delayed diagnosis at an advanced stage, prognosis is less qualitative when compared to bladder tumours. There is, therefore, a need for reliable markers to improve diagnosis.

Objective

Because of the difficulty in interpreting washing cytologies of the UUT, we evaluated the reliability of fluorescence in situ hybridisation (FISH) in the detection of upper tract urothelial cancer.

Design, setting, and participants

A prospective, multicentre cohort study was carried out on 55 consecutive patients with a suspected UUT tumour.

Measurements

Between May 2007 and May 2009, 55 consecutive patients (mean age 71.7 yr; range: 52–93) with a suspected urinary tract tumour were studied with intravenous pyelography, cytology, washing cytology, ureterorenoscopy, and endoscopic biopsies. The patients were followed for a mean observation time of 12.21 mo (range: 0.5–20; standard deviation: 6.12). A multicolour-FISH approach was performed on a liquid-based washing urinary cytology in all cases.

Results and limitations

Twenty-one out of 55 patients had a histologically proven urothelial carcinoma, of which 10 had stage pTa disease, 6 had pT1 disease, 2 had pT2 disease, 2 had pTis disease, and 1 had pTx disease (6 G1, 6 G2, and 9 G3). Three patients had a papilloma, 2 had renal cell carcinoma, 27 had a negative histologic report, and 2 had a nondiagnostic histology. In total, 68 analyses were performed. The cytology was negative or doubtful in 60 out of a total 68 specimens (88.2%) and was suspicious or positive for malignancy in 7 (10.3%) specimens. One specimen was not diagnostic. FISH was negative in 37 of 68 analyses (54.4%) and positive in the other 30 analyses (44.1%). One FISH analysis was not diagnostic as a result of insufficient cellular material. The overall sensitivity of the cytology was 20.8% and of FISH 100%. The specificity was 97.4% for cytology and 89.5% for FISH. Even though this is the largest UUT cohort studied with FISH, the sample size is relatively small.

Conclusions

The UroVysion FISH test is a reliable method in the diagnosis of UUT tumours in cases with clinical suspicion but negative or doubtful cytology and no diagnostic histology.     

The UroVysion fluorescence in situ hybridization assay is an effective tool for monitoring recurrence of bladder cancer

The newly developed UroVysion fluorescence in situ hybridization (FISH) probe was applied to urine specimens from 19 patients being monitored for recurrence of bladder cancer. The results for the multi-target DNA FISH assay were compared with independent analyses of urine cytology and flexible cystoscopy. Patients with tumors identified through the cystoscopy exam were biopsied and/or underwent surgery. In 12 patients with normal cytoscopy, cytology and FISH were also normal. Therefore, the specificity of these two tests was 100%. In 7 patients, a tumor was diagnosed by cystoscopy, and 3 of them had abnormal urine cytology while 6 of them had an abnormal result in the FISH assay. Accordingly, the sensitivity was 43% for the cytology and 87% for the FISH test. Interestingly, a pT1G3 tumor in a bladder diverticulum was not detected by cytology or the FISH test. These results agreed with a large series previously published using similar FISH probes and support the proposal for a multicenter trial to confirm the usefulness of the UroVysion probe as a screening tool to select patients for cystoscopy.     

Immunocyt test improves the diagnostic accuracy of urinary cytology: results of a French multicenter study

PURPOSE: The limitations of urinary cytology and the invasiveness of cystoscopy generate an increasing interest in noninvasive diagnostic tools for the management of transitional cell carcinoma. We assess the clinical performance of ImmunoCyt (DiagnoCure, Inc., Saint-Foy, Canada) in the detection of bladder cancer in a 10-center French trial. MATERIALS AND METHODS: From October 2000 to April 2001, 694 patients undergoing cystoscopy were prospectively included in the study. Of the patients 458 (66%) had been previously treated for superficial transitional cell carcinoma and 236 (34%) were referred for symptoms suggestive of bladder cancer. All patients underwent ImmunoCyt test and standard urinary cytology from voided urine as well as a complete evaluation including cystoscopy and transurethral resection or biopsy of suspicious lesions. Sensitivity and specificity values of urinary cytology and ImmunoCyt whether or not combined were calculated using cystoscopy as the gold standard and histopathology when available. RESULTS: A total of 85 recurrent and 58 newly diagnosed bladder tumors were diagnosed by cystoscopy and histologicaly confirmed. Overall sensitivity of urinary cytology was 17.9%, 46.3% and 63.8% respectively, for G1, G2 and G3 transitional cell carcinoma, whereas that of ImmunoCyt was 60.7%, 75.6% and 76.8%. Sensitivity of the combined tests was 66.7%, 78% and 87%, respectively. Moreover, 10 of 55 (18.2%) new pT1 and pT2 or greater tumors were diagnosed by ImmunoCyt alone. Specificity of urinary cytology was 94.5%, whereas that of ImmunoCyt was 84.2%. Specificity of the combined tests was 80.7%. Marked variations in urinary cytology sensitivity were observed among the different centers (27.3% to 66.7%), whereas combined assays (urinary cytology and ImmunoCyt) enhanced the overall sensitivity in the 80% range at most centers. CONCLUSIONS: This prospective multicenter series confirmed a marked increase in sensitivity without significant loss in specificity when including ImmunoCyt in standard urinary cytology protocol. This increased sensitivity was observed in high grade lesions (with 100% sensitivity for carcinoma in situ) as well in low grade, low stage tumors.     

Quantitative molecular urinary cytology by fluorescence in situ hybridization: a tool for tailoring surveillance of patients with superficial bladder cancer?

OBJECTIVE: To determine whether it is possible to stratify patients with superficial bladder cancer into low- and high-risk groups for tumour recurrence/progression based on the chromosomal pattern detected by fluorescence in situ hybridization (FISH) in one urine cytology specimen used for follow-up testing. PATIENTS AND METHODS: Voided urine samples from 47 consecutive patients with urinary tract neoplasms (13 with no history of urothelial malignancy and 34 under follow-up after complete transurethral resection of superficial urothelial carcinoma of the bladder) were evaluated by liquid-based cytology (ThinPrep(R), CYTYC Corp., Boxborough, MA, USA) and UroVysion FISH (Vysis-Abbott, Downers Grove, IL). RESULTS: Of the 34 patients under surveillance, the UroVysion test was negative in four, 17 had loss of 9p21 sequences either alone or combined with low-frequency trisomy/ies or tetrasomy/ies of chromosomes 3, 7 and 17 in single cells (low-risk FISH), and 13 also had complex aneusomies of the remaining chromosomes (high-risk FISH). One of the four FISH-negative neoplasms, four of the 17 low-risk FISH cases and five of the 11 informative high-risk FISH-positive patients developed recurrence. Progression occurred only in patients with high-risk FISH results, showing high-frequency complex chromosomal polysomies (four of 11). CONCLUSION: The results from this pilot study indicate that the UroVysion FISH test may help to individually assess the clinical behaviour of superficial bladder cancer, based on the chromosomal pattern of exfoliated tumour cells in follow-up urinary cytology. It might be of use to identify those patients likely to progress at earlier and curable stages of disease, and lengthen the surveillance period in those with persistent or recurrent low-risk disease.     

Surveillance of upper urinary tract transitional cell carcinoma: the role of ureteroscopy, retrograde pyelography, cytology and urinalysis

PURPOSE: A select group of patients with upper tract transitional cell carcinoma are treated with ureteroscopic resection. We determine the validity and accuracy of urinalysis, bladder cytology, upper tract biopsy/cytology and retrograde pyelography for the detection of recurrent upper tract transitional cell carcinoma compared to endoscopic findings. MATERIALS AND METHODS: Patients with ureteroscopically treated upper tract transitional cell carcinoma were followed with surveillance every 3 to 6 months. Surveillance included urinalysis with dipstick and microscopic examination, bladder cytology, retrograde pyelography read by a urologist and radiologist, and ureteropyeloscopy with cytology and biopsy of suspicious areas. Not all results were available for all surveillance procedures. Measures of sensitivity and specificity for the aforementioned surveillance procedures were determined relative to endoscopic findings that were defined as the standard. Confidence intervals were also estimated. Initially, a generalized estimation equation approach was used to take into account the clustering of repeated testing within patients. The accuracy of each procedure was also calculated. RESULTS: There were 23 patients with previously resected low grade upper tract transitional cell carcinoma who underwent a total of 88 surveillances in 30 months. A total of 56 of 88 (64%) recurrences were detected ureteroscopically, including 11 (12%) associated bladder recurrences. In patients who did not have bladder recurrences urinalysis had a sensitivity of 37.5% but specificity was 85%, while bladder cytology had a sensitivity of 50% and specificity was 100%, and retrograde pyelography read in the endoscopy room revealed a sensitivity of 71.7% and specificity of 84.7%. Ureteroscopic biopsy/cytology had a sensitivity and specificity of 93.4% and 65.2%, respectively. CONCLUSIONS: Our findings indicate that compared to ureteroscopy, urinalysis, bladder cytology, retrograde pyelography and ureteroscopic cytology/biopsy are less valid and accurate in detecting upper tract transitional cell carcinoma recurrences. Based on our data we recommend ureteroscopic evaluation as an essential procedure for the surveillance of patients treated endoscopically for upper tract transitional cell carcinoma.     

UroVysion compared with cytology and quantitative cytology in the surveillance of non-muscle-invasive bladder cancer

OBJECTIVES: The multitarget fluorescence in situ hybridization probe set Vysis UroVysion, consisting of probes for chromosomes 3, 7, and 17 and for the 9p21 band, was studied to evaluate its value in the follow-up of patients with bladder cancer. The results were compared with conventional cytology and quantitative cytology (Quanticyt). The aim of this study was to evaluate whether UroVysion is a better adjunct to urethrocystoscopy than cytology and quantitative cytology. METHODS: UroVysion, cytology, and quantitative cytology were performed on 113 voided urinary samples of 105 patients under surveillance for non-muscle-invasive bladder cancer. Before urethrocystoscopy or transurethral resection of the bladder, a voided urinary sample was obtained. Results of all tests were compared to evaluate the value of UroVysion. RESULTS: Sixty-four patients had biopsy-proven urothelial cell carcinoma. Sensitivity and specificity were, respectively, 39.1% and 89.7% for UroVysion, 40.6% and 89.7% for cytology, and 42.1% and 67.9% for quantitative cytology. When the UroVysion test and cytology were combined, sensitivity increased to 53.1%, but specificity decreased to 79.5%. Detection of Ta tumours was equal for cytology and UroVysion (26.7%), detection of T1 and T2-T4 samples by UroVysion was 60% and 50%, respectively. Detection of grade 1, 2, and 3 tumours by UroVysion was 21.4%, 36.8%, and 66.7%, respectively. In four cases the UroVysion test was positive, but no abnormalities were seen at cystoscopy. CONCLUSIONS: Our data suggest that the use of UroVysion provides no improvement over cytology or quantitative cytology in the diagnosis of recurrent non-muscle-invasive bladder tumours.     

Clinical decisions for treatment of different staged bladder cancer based on multitarget fluorescence in situ hybridization assays?

Non-invasive methods for detecting genetic alterations of bladder cancer are increasingly becoming the focus of attention as diagnostic tools. The fluorescence in situ hybridization we performed to detect genetic alterations of chromosomes 3, 7, 9p21, and 17 (UroVysion Test) showed very high sensitivity, higher even than cytology, in detecting bladder tumors of varying differentiation (pTa-pT4). The use of this test in everyday clinical urology can be a very useful decision aid in treating problem cases. A pT1G3 bladder carcinoma in the presence of multichromosomal alterations should be treated as a muscle-invasive pT2 tumor. Other superficial bladder tumors (pTaGI-III, pT1GI-II) with negative histopathology in follow-up and positive FISH analysis with the UroVysion Test should have bladder mapping performed again. Although FISH analysis is currently the most sensitive marker for bladder tumors, the elaborate handling, the cost of the DNA probes and the laboratory equipment required, limit the use of this method in the urologist’s everyday routine.     

Immunocyt: a new tool for detecting transitional cell cancer of the urinary tract

PURPOSE: The limitations of cytology and the invasiveness of cystoscopy for detecting bladder cancer generate increasing interest in noninvasive, urine bound diagnostic tools. We assessed the diagnostic value of the newly developed immunocytochemical test, Immunocyt, which detects cellular markers specific for transitional cell cancer in the voided urine of patients with bladder cancer. MATERIALS AND METHODS: Participating in our prospective study were 264 consecutive patients with a mean age of 65.9 years, including 114 in whom symptoms were suggestive of bladder cancer and 150 who were being followed after complete transurethral resection of superficial transitional cell carcinoma. Voided urine specimens were evaluated by standard cytology and the Immunocyt test, which traces the monoclonal antibodies M344, LDQ10 and 19A211 against transitional cell carcinoma in exfoliated urothelial cells. In all cases cystoscopy was subsequently performed and any suspicious lesion was evaluated by biopsy. RESULTS: Histologically proved transitional cell carcinoma was found in 79 patients. Immunocyt with cytology had 89.9% sensitivity overall (84, 88 and 96.5% in grades 1 to 3 disease, respectively). A total of 34 (43%), 3 (3.8%) and 34 (43%) cases were positive on Immunocyt only, cytology only and both evaluations, respectively. In 8 cases (10.1%) both tests were negative. Overall Immunocyt only was 86.1% sensitive (84, 84 and 89.6% in grades 1 to 3 disease, respectively) and 79.4% specific. Overall cytology only was 46.8% sensitive (4, 52 and 79.3% in grades 1 to 3 disease, respectively) and 98.2% specific. CONCLUSIONS: Immunocyt is a noninvasive, highly sensitive test for detecting transitional cell carcinoma of all grades and stages. When combined with conventional urinary cytology, it may replace cystoscopy in select patients, especially in followup protocols of low grade transitional cell carcinoma.     

Urinary level of nuclear matrix protein 22 in the diagnosis of bladder cancer: experience with 130 patients with biopsy confirmed tumor

PURPOSE: We prospectively evaluated the value of nuclear matrix protein 22 (NMP22dagger) and cytology in the diagnosis of bladder cancer. MATERIALS AND METHODS: We analyzed NMP22 in voided urine from 235 patients before cystoscopy. Of the patients 130 had transitional cell carcinoma of the bladder and subsequently underwent surgery. In a subset of 200 patients bladder washout samples for cytology were collected during cystoscopy. The cutoff for NMP22 was 10.0 units per ml. For cytology only high grade atypia was considered positive. RESULTS: Histology showed 77 superficial (pTa, pTis) and 53 invasive (pT1 or greater) tumors. Sensitivity of NMP22 was 51% and specificity was 83%. NMP22 sensitivity was 36% for superficial tumors and 73% for invasive transitional cell carcinoma. Overall sensitivity of cytology was 52% and specificity was 89%. Cytology sensitivity was 38% for superficial tumors and 83% for invasive transitional cell carcinoma. NMP22 sensitivity for grades 1, 2 and 3 tumors was 30%, 56% and 68%, respectively. Cytology sensitivity for grades 1, 2 and 3 tumors was 30%, 50% and 91%, respectively. Combined NMP22 and cytology had a sensitivity of 70%. CONCLUSIONS: NMP22 has sensitivity and specificity similar to those of cytology from bladder washout samples. Particularly in low stage and low grade tumors both tests show the same disappointing sensitivity. Because of a false-negative rate of 49%, NMP22 cannot replace cystoscopy in clinical practice, as the danger of missing NMP22 negative tumors is too high to rely on its results in an individual patient.     

Oral or intravesical bacillus Calmette-Guerin immunoprophylaxis in bladder carcinoma

A total of 71 patients with superficial transitional cell carcinoma underwent transurethral resection of bladder tumor. All patients had stage pTa or pT1 transitional cell carcinoma or carcinoma in situ without other concurrent malignancies. The patients were assigned to 3 treatment groups: control group--transurethral resection discontinued within the study, oral bacillus Calmette-Guerin (BCG) group--transurethral resection of bladder tumor plus BCG (Moreau) and intravesical BCG group--transurethral resection of bladder tumor plus BCG. Of 9 patients in the control group 8 (89%) experienced tumor recurrence during a mean followup of 20 months. Of the 28 patients in the oral BCG group 11 (39.3%) had recurrence during a mean followup of 36 months. Of the 34 patients in the intravesical group 6 (18%) had recurrence in a 24-month mean followup. The incidence of complications was higher in the intravesical (41.2%) than in the oral BCG group (28.5%). These results show that intravesical BCG is a more effective immunotherapy; however, oral BCG can be used in patients who do not accept intravesical BCG administration.     

Role of fluorescence in situ hybridization in bladder cancer surveillance of patients with negative cytology

ObjectivesThe clinical utility of urine markers in urothelial cancer (UC) surveillance is not established. We previously evaluated the use of fluorescence in situ hybridization (FISH) in managing patients with atypical cytology at risk for UC. This study evaluates its role in patients with negative cytology with a history of UC.Materials and methodsBetween June 2007 and January 2009, every patient with a history of UC who underwent cystoscopy and cytology with UroVysion test were identified. A comprehensive chart review was performed on each patient with negative cytology.ResultsThe population comprised 142 patients undergoing cancer surveillance; 111 patients with negative cystoscopy, 19 with equivocal cystoscopy, and 12 with positive cystoscopy. In patients with negative cystoscopy, there was cancer in only 1 of 111 patients. UroVysion could detect the only patient with UC with sensitivity of 100% and had a negative predictive value (NPV) of 100%. In patients with equivocal cystoscopy, it detected 2 tumors that would be missed by cytology. There were 4 false negative results (sensitivity 33.3% and NPV 66.7%). In patients with obvious lesion on cystoscopy, there were 9 false negative results (sensitivity 10% and NPV 18.2%).ConclusionsFew patients with negative cystoscopy and negative cytology have cancer. Patients with equivocal and positive cystoscopy and negative cytology frequently have cancer and the UroVysion FISH assay was not helpful in these cases. The cost-effectiveness of the FISH assay needs to be assessed prior to widespread use in patients with negative cytology.     

Value of urethral wash cytology in the retained male urethra after radical cystoprostatectomy

PURPOSE: We determined the outcome in patients who underwent urethrectomy after cystectomy followed by routine urethral wash cytology versus those not followed by urethral wash cytology who presented with bleeding or urethral discharge. We retrospectively evaluated the outcome in post-cystectomy urethrectomy cases at our institution from 1994 to 2000. MATERIALS AND METHODS: A total of 24 patients with a median age of 70.5 years underwent urethrectomy after cystectomy, including 17 due to asymptomatic, positive urethral wash cytology (group 1) and 7 who were not followed by urethral wash and presented with bleeding/urethral discharge (group 2). Median time from cystectomy to urethrectomy was 11.4 months (range 6.7 to 67.1). Median followup after cystectomy and urethrectomy was 37 and 27.7 months, respectively. RESULTS: Urethrectomy pathological evaluation showed pTis disease in cases 12 (50%), pT0 in 9 (37.5%) and pT1 in 3 (12.5%). Cystectomy pathology was organ confined (pT0, pTis and pT1-pT2b disease) in 12 cases (50%), nonorgan confined (pT3a-pT4) in 6 (25%) and pT any N1 in 5 (21%). Cystectomy pathology was unknown in 1 case. At the most recent followup there was no evidence of disease in 14 patients (58%), 5 (21%) were alive with disease, 3 (12.5%) were dead of disease, 1 (4%) was dead of other causes and disease status was unknown in 1 (4%). There was no statistical difference in survival in groups 1 and 2 when controlling for original bladder tumor stage. Cox regression analysis revealed that cystectomy pathology was the only statistically significant parameter of disease-free survival (p = 0.011), while urethrectomy pathology and followup method (urethral washing versus no washing) were not significant. There were no perioperative or postoperative complications and no patients died. CONCLUSIONS: There was no significant survival difference in patients followed and not followed with urethral washing. Longer followup and increased patient numbers are needed to determine the significance of these findings.     

Urinary cytology has a poor performance for predicting invasive or high-grade upper-tract urothelial carcinoma

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Accurate preoperative staging for upper‐tract urothelial carcinoma (UTUC) lesions is presently limited. Urinary cytology has shown promise for characterizing pathological features of bladder cancer. The role of cytology for UTUC is at present poorly defined. In this large multi‐institutional cohort of patients, urinary cytology was limited in its ability to accurately predict the grade and stage of upper‐tract lesions. Selective ureteral sampling improved the diagnostic accuracy of cytology when compared to bladder specimens. Improved preoperative surrogate markers for staging UTUC remain necessary.

OBJECTIVE

? To evaluate the diagnostic accuracy of urine cytology for detecting aggressive disease in a multi‐institutional cohort of patients undergoing extirpative surgery for upper‐tract urothelial carcinoma (UTUC).

METHODS

? We reviewed the records of 326 patients with urinary cytology data who underwent a radical nephroureterectomy or distal ureterectomy without concurrent or previous bladder cancer. ? We assessed the association of cytology (positive, negative and atypical) with final pathology. Sensitivity and positive predictive value (PPV) of a positive (± atypical) cytology for high‐grade and muscle‐invasive UTUC was calculated.

RESULTS

? On final pathology, 53% of patients had non‐muscle invasive disease (pTa, pTis, pT1) and 47% had invasive disease (≥pT2). Low‐grade and high‐grade cancers were present in 33% and 67% of patients, respectively. ? Positive, atypical and negative urine cytology was noted in 40%, 40% and 20% of cases. Positive urinary cytology had sensitivity and PPV of 56% and 54% for high‐grade and 62% and 44% for muscle‐invasive UTUC. ? Inclusion of atypical cytology with positive cytology improved the sensitivity and PPV for high‐grade (74% and 63%) and muscle‐invasive (77% and 45%) UTUC. Restricting analysis to patients with selective ureteral cytologies further improved the diagnostic accuracy when compared with bladder specimens (PPV > 85% for high‐grade and muscle‐invasive UTUC).

CONCLUSIONS

? In this cohort of patients with UTUC treated with radical surgery, urine cytology in isolation lacked performance characteristics to accurately predict muscle‐invasive or high‐grade disease. ? Improved surrogate markers for pathological grade and stage are necessary, particularly when considering endoscopic modalities for UTUC.     

The Use of Urine Cytology for Diagnosing Bladder Cancer in Spinal Cord Injured Patients

Purpose

The diagnosis of bladder cancer in spinal cord injured patients is complicated by inflammatory changes caused by long-term indwelling catheters, which make cystoscopic followup difficult. We evaluated cytology as an aid in diagnosing bladder cancer in spinal cord injured patients.

Materials and Methods

The charts of 208 spinal cord injured patients were reviewed retrospectively from January 1988 to July 1995 to define the value of cytology in the diagnosis of bladder cancer in this population. In all patients at least 1 urine cytology study was done less than 3 months before bladder biopsy. We examined 272 bladder biopsies (several patients underwent more than 1 biopsy at least 1 year apart) with 1 to 6 cytology studies done before biopsy.

Results

Cytology results were classified as negative-no malignant cells, inflammation or benign urothelial cells, reactive-atypia or atypical reactive and suspicious-atypical suspicious, keratinizing squamous metaplasia, suspicious for cancer, cancer of dysplastic. A total of 960 cytology specimens was obtained before the 272 biopsies (average 3 before each biopsy). Of 17 patients with cancer 12 had at least 1 prior suspicious urine cytology result. The sensitivity and specificity of cytology were 71 and 97%, respectively, when evaluating only patients with suspicious findings.

Conclusions

The high sensitivity and specificity of multiple cytology studies in this population suggest that cytology is a useful adjunct to improve the detection of bladder cancer in spinal cord injured patients with chronic (longer than 5 years) indwelling catheters. We recommend a minimum of yearly cytology in all high risk spinal cord injured patients with subsequent biopsies in all patients with any suspicious finding.     

Surveillance of patients with bladder carcinoma using fluorescent in-situ hybridization on bladder washings

OBJECTIVES

To compare the sensitivity and specificity of the UroVysion^TM (Abbott Laboratories Inc., Downers Grove, IL, USA) fluorescent in‐situ hybridization (FISH) assay to that of urinary cytology obtained from bladder irrigation during cystoscopic surveillance in patients with bladder carcinoma.

PATIENTS AND METHODS

The medical records were retrospectively reviewed for 41 consecutive patients screened at the authors’ institution between August 2000 and December 2006 for recurrence of pathologically confirmed bladder cancer. All 162 cytology examinations and 141 FISH assay results obtained from bladder washing were included. Recurrence was determined by cystoscopy, bladder biopsy and upper‐tract imaging. Sensitivity, specificity, positive predictive and negative predictive values were assessed using a chi‐square distribution with one degree of freedom.

RESULTS

There were 24 men and 17 women (male to female ratio 0.59), the mean (range) age was 56 (33–73) years and the mean follow‐up 30 (2–57) months. At the initial diagnosis, 35 of the 41 patients (85%) had superficial tumours (stage ≤ T1), while six (15%) had muscle‐invasive tumours (stage ≥T2). Twenty‐six (63%) had low‐grade and 15 (37%) had high‐grade tumours. In 16 of 141 (11%) of the FISH assays and 16 of 162 (10%) of the cytological samples that were collected from bladder irrigations, there were too few cells for an adequate analysis. The FISH assay correctly correlated with subsequent cystoscopy, bladder biopsy or upper‐tract imaging in 110/125 (88%) cases but not in 15/125 (12%). Cytology correctly correlated with the subsequent evaluation in 112/146 (77%) cases but did not in 34/146 (23%). When the FISH was compared with cytology in this setting, the sensitivity was 77% (30/39) vs 74% (37/50; P > 0.1), the specificity was 93% (80/86) vs 78% (75/96; P < 0.01), the positive predictive value was 83% (30/36) vs 64% (37/58; P < 0.05), and the negative predictive value was 90% (80/89) vs 85% (75/88; P > 0.1), respectively.

CONCLUSION

The UroVysion FISH assay obtained from bladder washings during cystoscopic surveillance of patients with a history of bladder cancer provides a similar specificity but greater sensitivity than that of cytology for detecting bladder cancer recurrences. Given the better specificity and similar sensitivity of UroVysion compared with urine cytology obtained from bladder washings, a reasonable approach might be to use the UroVysion assay as the primary marker for recurrence, with urine cytology used as a complementary examination.     

Percutaneous management of renal pelvic urothelial tumors: long-term followup

PURPOSE: We present the long-term outcome of percutaneous resection of renal urothelial tumor. MATERIALS AND METHODS: A total of 24 patients underwent primary percutaneous resection of renal urothelial tumor. Patients with low stage pT0-1 disease were treated primarily with percutaneous surgery. All pelvicaliceal tumors were taken for biopsy and treated with percutaneous resection. Patients with multi-segmental pelvicaliceal system involvement, stage greater than pT1, high grade histology or additional ureteral tumors were considered for nephroureterectomy. Topical chemotherapy (mitomycin C or epirubicin) was administered via nephrostomy tube or intravesical instillation after Double-J stent (Medical Engineering Corp., New York, New York) insertion. Surveillance included upper tract cytology, nephroscopy or fiberoptic ureterorenoscopy. Long-term followup was correlated with histopathology. RESULTS: Of the 24 cases 2 had squamous cell carcinoma, 5 had grade III transitional cell carcinoma, 15 had grade I to II transitional cell carcinoma and 2 had no tumor. Control was established with initial percutaneous resection in 18 (75%) cases and second look nephroscopy in 4. Early recurrences were detected by excretory urography (IVP) in 3 cases, small pelvic recurrences by IVP in 2, fiberoptic ureterorenoscopy in 2 and bladder tumors by flexible cystoscopy in 3 after 1 year. A total of 10 nephroscopies were performed in 5 cases, 24 flexible uretereorenoscopies in 9 and IVP in 6. Three synchronous, grade I bladder tumors were managed conventionally. All patients with high grade disease died of malignancy except one (with no further treatment) and 6 of the 15 patients with low grade noninvasive transitional cell carcinoma underwent nephroureterectomy during followup either due to progression of disease, concomitant tumor or complications. Two patients with solitary kidneys died of renal failure unrelated to malignancy. High grade tumors or tumors greater than T1 were treated with nephroureterectomy early during management. There was no perioperative mortality and 9 (60%) of the low grade cases the kidneys were preserved at a mean followup +/- SD of 64 +/- 15 months. All excised tracks from patients who underwent nephroureterectomy and the renal fossae were free of tumor on histopathological examination. CONCLUSIONS: Percutaneous resection of transitional cell tumor should be considered primarily in patients with early stage disease excluding tumors crossing caliceal infundibula, ureteropelvic junction tumor, tumor extending over multiple calices and synchronous ureteral tumors. The long-term outcome of low grade tumors is good and they should be managed by either form of minimally invasive surgery. Nephron sparing is possible in a large percentage of low grade disease but high grade tumors should be treated with nephroureterectomy.     

Bacillus Calmette-Guerin for superficial transitional cell carcinoma of the bladder

Pasteur strain bacillus Calmette-Guerin was used to treat superficial transitional cell carcinoma of the bladder in 28 patients. Patients selected for treatment had an incomplete resection, positive selected site biopsies and/or post-resection positive cytology findings. Complete response required negative histology and cytology findings at cystoscopic followup 4 to 8 weeks after completion of treatment. Of the patients 20 (71 per cent) demonstrated a complete response, including all 6 with carcinoma in situ. Results converted to negative in 16 of 17 patients with positive urine cytology findings and 4 with positive prostatic urethral biopsies. Of the responders 8 had received prior treatment with thiotepa. The treatment regimen of 120 mg. Pasteur strain bacillus Calmette-Guerin weekly for 6 weeks was well tolerated. It was necessary to limit the number of treatments to 5 because of local irritative effects in only 3 patients. No chronic bladder disability has been noted during followup of 3 to 30 months. This experience supports the efficacy of bacillus Calmette-Guerin as a cost-effective, well tolerated treatment modality for patients with superficial transitional cell carcinoma of the bladder.