Combining imaging and ureteroscopy variables in a preoperative multivariable model for prediction of muscle-invasive and non-organ confined disease in patients with upper tract urothelial carcinoma

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Improved patient selection for conservative management, neoadjuvant chemotherapy, and/or extended lymphadenectomy is urgently needed. We developed a highly accurate preoperative model to predict muscle‐invasive and non‐organ‐confined upper tract urothelial carcinoma based on standard imaging and ureteroscopy features.

OBJECTIVE

? To create a preoperative multivariable model to identify patients at risk of muscle‐invasive (pT2+) upper tract urothelial carcinoma (UTUC) and/or non‐organ confined (pT3+ or N+) UTUC (NOC‐UTUC) who potentially could benefit from radical nephroureterectomy (RNU), neoadjuvant chemotherapy and/or an extended lymph node dissection.

PATIENTS AND METHODS

? We retrospectively analysed data from 324 consecutive patients treated with RNU between 1995 and 2008 at a tertiary cancer centre. ? Patients with muscle‐invasive bladder cancer were excluded, resulting in 274 patients for analysis. ? Logistic regression models were used to predict pT2+ and NOC‐UTUC. Pre‐specified predictors included local invasion (i.e. parenchymal, renal sinus fat, or periureteric) on imaging, hydronephrosis on imaging, high‐grade tumours on ureteroscopy, and tumour location on ureteroscopy. ? Predictive accuracy was measured by the area under the curve (AUC).

RESULTS

? The median follow‐up for patients without disease recurrence or death was 4.2 years. ? Overall, 49% of the patients had pT2+, and 30% had NOC‐UTUC at the time of RNU. ? In the multivariable analysis, only local invasion on imaging and ureteroscopy high grade were significantly associated with pathological stage. ? AUC to predict pT2+ and NOC‐UTUC were 0.71 and 0.70, respectively.

CONCLUSIONS

? We designed a preoperative prediction model for pT2+ and NOC‐UTUC, based on readily available imaging and ureteroscopic grade. ? Further research is needed to determine whether use of this prediction model to select patients for conservative management vs RNU, neoadjuvant chemotherapy, and/or extended lymphadenectomy will improve patient outcomes.     

The clinical utility of atypical cytology is significantly increased in both screening and monitoring for bladder cancer when indexed with nuclear matrix protein-22

OBJECTIVES

To assess atypical cytology as a positive bladder tumour marker and to determine if indexing atypical cytology to nuclear matrix protein‐22 (NMP22) can decrease the false‐positive results or increase the positive predictive value (PPV).

PATIENTS AND METHODS

In all, 197 patients at risk of bladder cancer were identified as having atypical urine cytology; 126 were incident (screening) cases and 71 were prevalent (monitoring) cases of bladder cancer. All patients with atypical cytology were evaluated using office cystoscopy. All cancers were confirmed histologically and patients had a negative upper tract study within a 1‐year interval. The atypical cytology was then indexed with NMP22 values in an effort to decrease the false‐positive results.

RESULTS

Atypical cytology detected 17 cancers in the 126 patients who were screened, giving a PPV of 13% (17/126). When stratified by NMP22, using a threshold of >10 U/mL, the PPV increased to 71% (15/21). In the 71 patients who were being monitored, atypical cytology detected 43 cancers, for a PPV of 61% (43/71). When stratified by NMP22 using a threshold of >6 U/mL, the PPV increased to 92% (35/38).

CONCLUSIONS

The clinical utility of atypical cytology was significantly increased in both screening and monitoring for bladder cancer when indexed with NMP22 levels.     

Epstein–Barr virus DNA load in tumour tissues correlates with poor differentiation status in non‐muscle invasive urothelial carcinomas

What’s known on the subject? and What does the study add? Epstein‐Barr virus (EBV) could be detected in bladder cancer. In our paper, we showed that DNA of EBV could be detected more in the high grade urothelial carcinoma. In superficial bladder cancer, although high grade tumour associated with higher EBV titers, the recurrence free survival was not compromised by high EBV DNA load.

OBJECTIVE

To detect the correlation between the clinical staging, grading and genomic Epstein–Barr virus (EBV) viral numbers in tumour tissues of urothelial carcinoma patients.

PATIENTS AND METHODS

From June 2004 to May 2008, 60 urothelial carcinoma patients (50 cases of bladder carcinoma and 10 of upper tract urothelial carcinoma (UTUC) were enrolled in the study. Eight patients who underwent transurethral resection of prostate for prostate hyperplasia and two patients receiving nephrectomy for non‐function kidney were used as normal controls. The EBV viral copy numbers in genomic DNA were evaluated using a real‐time PCR‐based study. The BamHI W region of the Namalwa cell line was constructed to the plasmid clone and was used as standard curve for absolute quantitative PCR (Q‐PCR).

RESULTS

Epstein–Barr virus DNA was detected in 56% (28/50) and 60% (6/10) of the bladder and UTUC patients, respectively. The EBV DNA could not be detected in the normal control group. By pooling the UTUC and bladder patients in stage Ta,T1, the high copy number in fixed genomic DNA amount (100 ng/20 µL) was correlated with the high grading in stage Ta,T1 urothelial carcinoma (P= 0.014). The overall grading was not statistically associated with EBV copy number (P= 0.25). Although the copy numbers between paired tumour and normal tissues were not statistically different (P= 0.169), there were more copies of EBV in the normal tissues adjacent to the tumours than in those free from urothelial carcinoma. There was no significant difference between recurrence of non‐muscle invasive bladder cancer and the presence of EBV (P > 0.05).

CONCLUSIONS

Epstein–Barr virus DNA could be detected in the genome of the urothelial carcinoma specimens. The poor differentiation status was correlated with the high load of the EBV genome in non‐muscle invasive urothelial carcinoma. However, recurrence‐free survival was not greater in EBV‐positive patients than in EBV‐negative patients.     

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.     

Urinary cytology and nuclear matrix protein 22 in the detection of bladder cancer recurrence other than transitional cell carcinoma

OBJECTIVE

To assess the value of nuclear matrix protein‐22 (NMP22), compared with urinary cytology, in predicting the recurrence of bladder cancer that is not transitional cell carcinoma (non‐TCC).

PATIENTS AND METHODS

We tested the sensitivity, specificity and the predictive accuracy of NMP22 in the context of non‐TCC bladder cancer recurrence, and compared it to the performance of urinary cytology. The study group comprised 2687 patients with history of non‐muscle‐invasive bladder cancer from 10 centres across four continents.

RESULTS

The mean patient age was 64.8 years and 75.4% were men; of all patients, 513 (19.1%) had positive urinary cytology, 906 (33.7%) had a positive NMP22 test (≥10 units/mL) and 80 (3.0%) had non‐TCC recurrence. Most of these, i.e. 60 (75%), were stage ≥T2. The sensitivity and specificity of urinary cytology were, respectively, 20.0% and 94.8%, vs 77.5% and 81.8% for NMP22 of ≥10 units/mL. The predictive accuracy of urinary cytology was 57.5%, vs 87.1% for NMP22 ≥ 10 units/mL. A combined model that included dichotomized NMP22 and urinary cytology was 85.3% accurate.

CONCLUSION

The ability of a NMP22 level of ≥10 units/mL to predict non‐TCC recurrence was better than that of urinary cytology, suggesting that NMP22 might have a role in the surveillance of patients at risk of non‐TCC recurrence.     

Prognostic indicators for upper tract urothelial carcinoma after radical nephroureterectomy: the impact of lymphovascular invasion

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? In an array of urological and non‐urological malignancies, lymphovascular invasion (LVI) is a pathological feature known to be associated with adverse outcomes for recurrence and survival. For some cancers, LVI has therefore been incorporated into American Joint Committee on Cancer TNM staging algorithms. This study presents an analysis of the impact of LVI in upper urinary tract urothelial carcinoma (UTUC) treated at our institution over a 20‐year period. In addition to known associations with features of aggressive disease and overall survival, we were able to show that LVI‐positive status upsets the TNM staging for UTUC. Namely, patients with superficial stage and LVI‐positive disease have overall survival outcomes similar to those of patients with muscle‐invasive LVI‐negative carcinoma. Such evidence may support the addition of LVI to future TNM staging algorithms for UTUC.

OBJECTIVE

• ? To assess the impact of lymphovascular invasion (LVI) on the prognosis of patients with upper urinary tract urothelial cell carcinoma (UTUC) treated with radical nephroureterectomy (RNU).

PATIENTS AND METHODS

• ? The Columbia University Medical Center Urologic Oncology database was queried and 211 patients undergoing RNU for UTUC between 1990 and 2010 were identified.
• ? These cases were retrospectively reviewed, and the prognostic significance of relevant clinical and pathological variables was analysed using log‐rank tests and Cox proportional hazards regression models.
• ? Actuarial survival curves were calculated using the Kaplan–Meier method.

RESULTS

• ? LVI was observed in 68 patients (32.2%).
• ? The proportion of LVI increased with advancing stage, high grade, positive margin status, concomitant carcinoma in situ, and lymph node metastases. The 5‐ and 10‐year overall survival rates were 74.7% and 53.1% in the absence of LVI, and 35.7% and 28.6% in the presence of LVI, respectively.
• ? In multivariate analysis, age, race and LVI were independent predictors of overall survival.

CONCLUSIONS

• ? The presence of LVI on pathological review of RNU specimens was associated with worse overall survival in patients with UTUC.
• ? LVI status should be included in the pathological report for RNU specimens to help guide postoperative therapeutic options.
• ? With confirmation from large international studies, inclusion of LVI in the tumour‐node‐metastasis staging system for UTUC should be considered.

     

The role of haematuria in bladder cancer screening among men with former occupational exposure to aromatic amines

Study Type – Diagnostic (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? Microscopic haematuria (µH) is frequently detected in elderly adults. The American Urological Association recommends the follow‐up of subjects with µH on bladder cancer. Whereas gross haematuria is considered an important sign of the presence of bladder cancer, the disease‐predictive value of µH is less clear. No association of µH with the development of bladder tumours in a prospective screening cohort of chemical workers was observed. The positive predictive value of µH for bladder cancer was as low as 1.2%. Haematuria interfered with NMP22 but not with cytology and UroVysion^TM test results.

OBJECTIVE

? To assess the positive predictive value (PPV) of microhaematuria (µH) and gross haematuria (GH) in bladder cancer screening and the influence of haematuria on tumour tests in a prospective study.

PATIENTS AND METHODS

? From September 2003 to January 2010, 1323 men took part in an annual voluntary bladder cancer screening programme for chemical workers with former exposure to aromatic amines. ? In 5315 urine samples haematuria was determined with a dipstick, followed by a microscopic blood cell count in the sediment. Haematuria was categorized into traces, µH and GH. ? Urinary leukocytes and other factors were investigated as potential predictors of haematuria using a generalized estimating equation model for repeated urinalysis. The risk of haematuria for positive tumour tests was analysed correspondingly. ? The bladder cancer risk was estimated for the highest degree of haematuria occurring during the study with Poisson regression.

RESULTS

? As of July 2010, 15 bladder tumours were detected in 14 participants. ? GH was found in four out of nine high‐grade tumours and associated with a rate ratio of 3.82, 95% confidence interval (CI) 0.50–29.15 for the development of bladder lesions. ? The PPV of GH was 11.4%, but only 1.2% for µH. µH occurred in 18.8% of urine samples and was not associated with bladder cancer [rate ratio (RR) 0.72, 95% CI 0.11–4.78]. ? Abundant urinary leukocytes were associated with µH [odds ratio (OR) 8.34, 95% CI 2.26–30.69] and even stronger with GH (OR 22.25, 95% CI 6.42–77.06). ? Haematuria and leukocytes influenced NMP22 positivity (µH: OR 1.63, 95% CI 1.06–2.51, abundant leukocytes: OR 8.90, 95% CI 1.58–50.16), but not test results for urine cytology and UroVysion^TM.

CONCLUSION

? While the PPV of µH for bladder cancer was low, there was a strong influence of haematuria and leukocytes on the protein‐based tumour test NMP22®. ? Erythrocytes and leukocytes should be determined at least semi‐quantitatively for the interpretation of positive NMP22 test results. ? In addition, a panel of tumour tests that includes methods not affected by the presence of erythrocytes or leukocytes such as cytology and UroVysion^TM would improve bladder cancer screening.     

The fate of an unsatisfactory urine cytology test among patients with urothelial carcinoma

OBJECTIVE

To determine the outcome of patients with a urinary cytology test that is unsatisfactory (UUCyt) for evaluation (<50 urothelial cells) to guide the clinical decision‐making process, as currently there are no guidelines to aid in interpreting this result and directing further investigations.

PATIENTS AND METHODS

We retrospectively reviewed 142 patients, with 265 instances of UUCyt, in our bladder cancer database and by chart review. The cytology, cystoscopy and pathology results in the subsequent 12 months after a UUCyt result were reviewed, and the incidence of new and recurrent genitourinary tract cancers was calculated.

RESULTS

All patients had a previous history of, or developed, urothelial carcinoma during the follow‐up. There were 41 instances (16.3%) in which bladder cancer was evident at the time of the UUCyt and 29% of these tumours were high‐grade. There were another 44 instances (17.5%) in which new or recurrent bladder cancer developed in the subsequent year after a UUCyt test, and many (38.6%) of these tumours were high‐grade.

CONCLUSION

The incidence of urothelial carcinoma after a UUCyt was high (33.9%) with a substantial number of high‐grade (34%) tumours, implying that a UUCyt result cannot be interpreted as negative for malignancy. Therefore, in these cases, the urologist must depend on cystoscopy to make a diagnosis.     

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.     

Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: a 15‐year comprehensive review of 160 consecutive patients

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Upper urinary tract urothelial carcinomas (UTUC) have historically been treated with radical, extirpative surgery, primarily nephroureterectomy with bladder‐cuff excision. In general, there has been growing interest in renal preservation, as evidenced by the broadening application of nephron‐sparing surgery for renal parenchymal tumours. Beyond imperative reasons such as tumour in a solitary kidney, bilateral disease, or comorbidities preventing radical surgery, there is a growing role for endoscopic management of upper tract tumours. The aim has been to obtain similar oncological results to those of extirpative surgery, while preserving long‐term renal function. Properly selecting patients for these therapies, designing specific treatments based on a complex presentation, and general information with regard to outcomes and risks for patient counselling have been based historically on results from relatively small series without long‐term follow‐up. This study reflects all patients with UTUC treated by a single tertiary referral surgeon, accrued prospectively over 15 years using the same surgical techniques and treatment algorithms throughout the entire study period, with 10‐year survival data. The consecutively accrued nature and size of the study groups, uniformity in treatments, statistical review and long‐term follow‐up provide baseline oncological data that could help frame future study.

OBJECTIVE

• ? To present long‐term oncological outcomes of all patients treated surgically for upper urinary tract urothelial carcinoma (UTUC) over a 15‐year period.

PATIENTS AND METHODS

• ? All patients (N= 160) treated from January 1996 to August 2011 were prospectively studied and placed into three distinct groups after initial diagnostic ureteroscopy (URS): Group 1: low grade lesions treated with URS (n= 66); Group 2: high grade lesions palliatively treated with URS (n= 16); and Group 3: extirpative surgery (nephroureterectomy [NU]; n= 80).
• ? Statistical analysis was performed using Kaplan–Meier methodology to calculate overall (OS), cancer‐specific (CSS) and metastasis‐free survival (MFS).

RESULTS

• ? The median patient age at presentation was 73 years, and the mean (range) follow‐up time was 38.2 (1–185) months. At initial diagnostic URS, 71 (44.4%) patients presented with high grade and 89 (55.6%) patients presented with low grade disease.
• ? The 2‐, 5‐ and 10‐year CSS rates were 98, 87 and 81% for patients with low grade disease, and 97, 87 and 78% for patients treated with URS (Group 1), not significantly different from those patients with low grade disease treated with NU (Group 3), (P= 0.54).
• ? Of the patients treated with URS for low grade disease, 10 (15.2%) progressed to high grade disease at a mean time of 38.5 months.
• ? Patients with high grade disease treated with NU had a 2‐, 5‐, and 10‐year CSS of 70, 53 and 38%, with a MFS of 55, 45 and 35%.
• ? Median survival of patients with high grade disease treated with palliative URS was 29.2 months with a 2‐year OS of 54%.
• ? On multivariate analysis only high grade lesion on initial presentation was found to be a significant factor (P < 0.001; hazard ratio = 7.27).

CONCLUSIONS

• ? Grade is the most significant predictor of OS and CSS in those with UTUC, regardless of treatment method.
• ? Ureteroscopic and extirpative therapy are acceptable options for those with low grade disease showing excellent long‐term CSS.
• ? Extirpative therapy was found to result in relatively poor long‐term CSS in patients with high grade disease, underscoring the need for adjuvant or neoadjuvant therapies.

     

Impact of risk factors on the performance of the nuclear matrix protein 22 point-of-care test for bladder cancer detection

OBJECTIVES

To evaluate the impact of different risk factors and symptoms on the performance characteristics of the nuclear matrix protein 22 (NMP22) BladderChek® test (Matritech Inc., Newton, MA, USA) for the detection of bladder cancer, as this is a point‐of‐care assay that measures NMPs in voided urine.

PATIENTS AND METHODS

In all, 23 academic, private practice and veterans’ facilities in 10 states prospectively enrolled consecutive patients from September 2001 to May 2002. Participants included 1328 patients at elevated risk of bladder cancer from factors such as a history of smoking or symptoms including haematuria and/or dysuria. Patients at risk of malignancy of the urinary tract provided a voided urine sample for analysis of NMP22 protein and cytology before cystoscopy.

RESULTS

Of the 1328 patients: no urinary disease, benign disease and malignancy were found in 545 (41%), 704 (53%) and 79 (6%) patients, respectively. Overall, the positive predictive value (PPV) for detection of bladder cancer was 20.3% (45/222) and negative predictive value (NPV) was 96.9% (1072/1106). The PPV was higher in men (24.0%) than women (13.2%). In men, the PPV increased with smoking (35.4%), gross haematuria (51.2%) and a combination of both factors (70.6%). The impact on the PPV of smoking (9.7%) and gross haematuria (28.6%) was less dramatic in women. The PPV increased from 16.8% in patients aged <65 years to 23.5% in those aged >65 years. The NPV remained almost always >95% except in men with gross haematuria where it decreased to 77% in smokers and 94% in non‐smokers.

CONCLUSION

The PPV of the BladderChek test improves in patients at higher risk of bladder cancer reaching 77% in men presenting with gross haematuria who are aged >65 years and smoke. The NPV is highest in women aged <65 years, up to 100%.     

The risk profiles of three clinical types of carcinoma in situ of the bladder

Study Type – Therapy (individual cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Although it has been reported that patients with primary carcinoma in situ of the bladder (CIS) have a better prognosis than patients with concomitant or secondary CIS, the risk profiles of these three clinical types of CIS have not yet been fully clarified. The current study was performed to give further insight into the risk profiles of these three clinical types of CIS. In clinical practice it would be helpful to be able to discriminate ‘high‐risk’ from ‘low‐risk’ CIS before the start of intravesical therapy and as such to tailor the treatment and follow‐up to this risk‐profile.

OBJECTIVE

? To further clarify the risk profiles of three clinical types of carcinoma in situ (CIS) of the bladder.

MATERIALS AND METHODS

? Population‐based data from the Comprehensive Cancer Centre Middle Netherlands, as part of the nationwide Netherlands Cancer Registry, were used for patients presenting with CIS in the period from 1987 to 2009. ? Patients with muscle‐invasive bladder cancer on primary diagnosis were excluded. The patients were divided into three groups according to their ‘clinical type’, being primary, concomitant or secondary CIS.

RESULTS

? Overall, 90 patients with CIS were identified with a mean age of 63.4 years, predominantly men (91.1%). Primary CIS (P‐CIS) was found in 43 patients (47.8%), concomitant CIS (C‐CIS) in 21 patients (23.3%) and secondary CIS (S‐CIS) in 26 patients (28.9%). Mean follow up was 81.3 months (range 8–222 months). Recurrence of disease was observed in 68.9% of patients, with significantly more recurrences in the S‐CIS group (88.5%). ? Progression to muscle‐invasive disease was seen in 17 patients (18.9%): eight patients (18.7%) with P‐CIS, four (19.0%) with C‐CIS and five (19.2%) with S‐CIS. Overall, 29 patients underwent a cystectomy, equally distributed over the three groups. The duration of bladder preservation was worse in the C‐CIS group but did not differ significantly between the groups. ? Overall survival at 5 years was 79.6% for the total group, with poorer results for the C‐CIS group, although the difference was not significant.

CONCLUSIONS

? Carcinoma in situ is clearly an entity that requires meticulous treatment and thorough follow up because of its high recurrence rate (68.9%) and high rate of progression to muscle‐invasive bladder cancer (18.9%). ? The C‐CIS group appears to have a poorer prognosis with a shorter duration of bladder preservation and a worse overall survival.     

Using urine microscopy and cytology for early detection of bladder cancer in male patients with lower urinary tract symptoms

Objectives

Irritative urinary symptoms and micro-hematuria are the common findings in bladder cancer patients. In this study, we investigated the use of urine microscopy and cytological examination for early detection of bladder cancer in patients with lower urinary tract symptoms (LUTS).

Methods

Male patients presented with LUTS to urology clinic were enrolled. Voiding symptoms were evaluated with international prostate symptoms score, and urine samples were collected for microscopy and cytological examination. Cystoscopy was performed in patients with microscopic hematuria, suspicious/malignant cells in urine or at the time of transurethral resection of prostate. Subjects, who had no indication and did not receive cystoscopy, were followed up in clinic for progress of symptoms, including gross hematuria and occurrence of bladder cancer.

Results

Nine hundred and eighty-eight patients were enrolled during the period of 2005?C2007. Fifty-two (5.26%) urine samples were documented as atypical, and 936 (94.7%) were negative. There was no suspicious or malignant cytology result in this series. Micro-hematuria was noticed in six patients (0.61%). The mean follow-up time was 29.1 ± 12.5 months. One (0.10%) patient had bladder cancer 44 months after the first visit in the cohort, who had micro-hematuria, atypical urine cytology, but normal cystoscopy before diagnosis.

Conclusion

The prevalence rate of bladder cancer in male patients with LUTS is low. This study adds to information that microscopy and cytological examination are not useful to detect bladder cancer. Due to the economic concerns and burden of unnecessary investigations, the routine use of these tests is in doubt.     

Predictors of locally advanced and metastatic disease in patients with small renal masses

What's known on the subject? and What does the study add? According to current treatment guidelines, magnetic resonance imaging (MRI) or computed tomography (CT) can be used to assist in staging bladder cancer patients being considered for radical surgery. In this article, we review the evidence supporting the use of MRI for bladder cancer staging. The ability of MRI to differentiate non‐muscle invasive from muscle‐invasive bladder cancer, to differentiate organ‐confined from non‐organ‐confined bladder cancer, and to identify lymph node metastases is described in detail. Additionally, the role of MRI as a biomarker of chemotherapeutic response in bladder cancer is reviewed and summarized.

OBJECTIVES

• ? A Pubmed/MEDLINE search was conducted to identify original articles, review articles, and editorials regarding the use of MR in bladder cancer.

RESULTS

• ? To date, sample sizes and study designs are insufficient to clearly establish the role of MR in bladder cancer management, and to this end, well designed prospective trials are needed.

     

Elective endoscopic management of transitional cell carcinoma first diagnosed in the upper urinary tract

OBJECTIVE

To report our experience using ureteroscopic or percutaneous management of upper urinary tract (UUT) transitional cell carcinoma (TCC) in patients with no history of bladder TCC.

PATIENTS AND METHODS

Between 1983 and 2004 we identified 22 patients who underwent endoscopic management of TCC first diagnosed in the UUT and in the setting of a normal contralateral kidney. We performed a retrospective chart review and conducted outcome analyses.

RESULTS

The median (range) age at diagnosis was 64 (37–86) years and the median tumour size was 0.8 (0.3–2.6) cm. The tumour grade was 1, 2, or diagnosed as visual low grade in two (9%), seven (32%), and 13 (59%) patients, respectively; no patient had grade 3 TCC at diagnosis. Tumour stage was Ta or visual Ta in all patients. The median follow‐up was 4.9 (0.4–17) years during which 11 (50%) patients developed 21 UUT recurrences and 10 (45%) patients developed bladder TCC. At last follow‐up, seven (32%) patients required a nephroureterectomy for recurrent TCC and two (9%) patients died from TCC. Among 13 patients with a diagnosis based on visual inspection only, three recurred with grade 3 invasive TCC during follow‐up. No patient with pathological confirmation of low‐grade/stage TCC recurred with high‐grade or invasive TCC.

CONCLUSIONS

Recurrence is common after endoscopic management of UUT‐TCC, underscoring the need for strict surveillance. Patients diagnosed visually, without adequate tissue for pathological examination, can recur with high‐grade invasive TCC. No patient with pathological confirmation of low‐grade TCC developed progressive disease during follow‐up.     

Upper urinary tract urothelial carcinoma with loco-regional nodal metastases: insights from the Upper Tract Urothelial Carcinoma Collaboration

Study Type – Therapy (multi‐insititutional cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Neoadjuvant chemotherapy offers survival benefits for patients with urothelial carcinoma of the bladder. However, it is still underutilized in the ‘biologically similar’ upper tract urothelial carcinoma. Systemic chemotherapy in a neoadjuvant setting is a more attractive option, as loss of renal function after nephrectomy can complicate the administration of adjuvant chemotherapy. We found that preoperative systemic therapy followed by aggressive surgical debulking is a promising treatment strategy for upper tract urothelial carcinoma patients with known or at risk of loco‐regional nodal metastasis.

OBJECTIVE

? To describe a multicentre experience with preoperative platinum‐based chemotherapy before radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) with loco‐regional nodal metastases.

PATIENTS AND METHODS

? We identified 313 patients from the UTUC Collaboration (over 1200 patients), who underwent RNU with concomitant retroperitoneal lymph node dissection between 1990 and 2007 and met the inclusion criteria for one of three groups. ? Group 1 comprised patients who received chemotherapy before RNU because of biopsy‐proven loco‐regional nodal metastases. ? Group 2 consisted of patients who underwent primary RNU and were found to have metastatic nodal disease on final pathological review (node‐positive). ? Group 3 comprised a comparative cohort of patients treated with primary RNU for invasive or locally advanced (pT2/pT4) node‐negative (N0) UTUC.

RESULTS

? Groups 1, 2 and 3 included 18, 120 and 175 patients, respectively. The 5‐year disease‐free survival rates were 49%, 30% and 64%, whereas the 5‐year cancer‐specific survival rates were 44%, 36% and 69% in groups 1, 2 and 3, respectively. ? In group 1, on final pathological evaluation, nine patients were pN0, six patients were pT0 and five patients had pT0N0 disease. Kaplan–Meier survival analyses showed similar recurrence and survival rates in group 1 compared with group 3 (P= 0.14 and P= 0.06, respectively). ? Meanwhile, group 2 had significantly lower disease‐free and cancer‐specific survival rates compared with group 3 (P < 0.001 and P < 0.001, respectively) and compared with group 1 (P= 0.04 and P= 0.06, respectively).

CONCLUSIONS

? Preoperative chemotherapy followed by aggressive surgical consolidation may yield favourable oncological outcomes in patients with UTUC with loco‐regional nodal metastases. ? These data support further evaluation of neoadjuvant systemic therapy in patients at risk for locally advanced UTUC.     

Long-term follow-up of T1 high-grade bladder cancer after intravesical bacille Calmette-Guérin treatment

Study Type – Therapy (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? High‐grade non muscle invasive bladder cancer is a very aggressive disease, potentially lethal if not managed adequately, because of the ability of these tumours to invade surrounding tissues and become metastatic. Treatment with intravesical BCG has been shown to delay progression to muscle invasive or/and metastatic disease, preserve the bladder, and decrease the risk of death from bladder cancer. However, most studies have analyzed patients with short follow‐up, and long‐term data about the real efficacy of BCG to prevent tumour recurrence, progression and impact mortality are lacking. This study has analyzed a large series of patients with high‐grade non muscle invasive bladder cancer treated with intravesical BCG in two University Institutions (Toronto and Rotterdam), with a central pathology review by a very experienced uro‐pathologist. It provides further insight into the long‐term risks of progression of patients harbouring high‐grade T1 bladder cancer treated with BCG, demonstrating that about 30% of patients are at risk of progression and that late progressions even more than 3 years after the initial resection and BCG treatment are rare but not exceptional.

OBJECTIVE

To report the long‐term results of bacille Calmette‐Guérin (BCG) intravesical therapy in relation to disease progression and recurrence in primary T1 high‐grade (HG) bladder cancer (BC) confirmed by central pathological review.

PATIENTS AND METHODS

In all, 136 patients from two university centres (Rotterdam, n= 49; Toronto, n= 87) were diagnosed with primary T1HG BC. One experienced uro‐pathologist reviewed all slides, ensuring all cases were indeed HG and that muscle was present in all specimens. Patients were treated with BCG induction (six instillations) after transurethral resection (TUR) of the tumour and followed with cystoscopy and urinary cytology. Predictors for recurrence, progression and survival were assessed with multivariable Cox regression models.

RESULTS

Mean (range) follow‐up was 6.5 (0.3–21.6) years. There were no significant differences for recurrence (P= 0.52), progression (P= 0.35) and disease‐specific survival (DSS) (P= 0.69) between the two centres. Among the cohort, 47 patients (35%) recurred and 42 (30.9%) progressed with a median time to progression of 2.1 years; 16 (38%) of these progressions occurred ≥3 years after the initial BCG course; 22 (16%) patients who progressed died from BC. Overall, 96 (71%) patients had no evidence of disease at the last follow‐up. Carcinoma in situ was the only independent predictor for recurrence in multivariate analysis (P= 0.011). No independent predictors were found for progression.

CONCLUSIONS

Conservative treatment with BCG is a valid option in primary T1HG BC. Nevertheless, the aggressive nature of T1HG BC is evident in the fact that 30% progressed, with a high proportion of these progression events occurring ≥3 years after BCG. Caution should be exercised when relying on the long‐term effects of BCG, and close follow‐up of these patients should not be neglected.     

Long‐term endoscopic management of upper tract urothelial carcinoma: 20‐year single‐centre experience

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Endoscopic management of small, low‐grade, non‐invasive upper tract urothelial cell carcinoma (UTUC) is a management option for selected groups of patients. However, the long‐term survival outcomes of endoscopically‐managed UTUC are uncertain because only four institutions have reported outcomes of more than 40 patients beyond 50 months of follow‐up. Moreover, there is significant variance in the degree of underlying UTUC pathology verification in some of these reports, which precludes an analysis of disease‐specific survival outcomes. The present study represents one of the largest endoscopically managed series of patients with UTUC, with a long‐term follow‐up. The degree of verification of underlying UTUC pathology is one of the highest, which allows a grade‐stratified analysis of different outcomes, including upper‐tract recurrence‐free survival, intravesical recurrence‐free survival, renal unit survival and disease‐specific survival. These outcomes provide further evidence suggesting that endoscopic management of highly selected, low‐grade UTUC can provide effective oncological control, as well as renal preservation, in experienced centres.

OBJECTIVE

• ? To report the long‐term outcomes of patients with upper tract urothelial cell carcinoma (UTUC) who were treated endoscopically (either via ureteroscopic ablation or percutaneous resection) at a single institution over a 20‐year period.

PATIENTS AND METHODS

• ? Departmental operation records were reviewed to identify patients who underwent endoscopic management of UTUC as their primary treatment.
• ? Outcomes were obtained via retrospective analysis of notes, electronic records and registry data.
• ? Survival outcomes, including overall survival (OS), UTUC‐specific survival (disease‐specific survival; DSS), upper‐tract recurrence‐free survival, intravesical recurrence‐free survival, renal unit survival and progression‐free survival, were estimated using Kaplan–Meier methods and grade‐stratified differences were analyzed using the log‐rank test.

RESULTS

• ? Between January 1991 and April 2011, 73 patients underwent endoscopic management of UTUC with a median age at diagnosis of 67.7 years.
• ? All patients underwent ureteroscopy and biopsy‐confirmation of pathology was obtained in 81% (n= 59) of the patients. In total, 14% (n= 10) of the patients underwent percutaneous resection.
• ? Median (range; mean) follow‐up was 54 (1–223; 62.8) months.
• ? Upper tract recurrence occurred in 68% (n= 50). Eventually, 19% (n= 14) of the patients proceeded to nephroureterectomy.
• ? The estimated OS and DSS were 69.7% and 88.9%, respectively, at 5 years, and 40.3% and 77.4%, respectively, at 10 years. The estimated mean and median OS times were 119 months and 107 months, respectively. The estimated mean DSS time was 190 months.

CONCLUSIONS

• ? The present study represents one of the largest reported series of endoscopically‐managed UTUC, with high pathological verification and long‐term follow‐up.
• ? Upper‐tract recurrence is common, which mandates regular ureteroscopic surveillance.
• ? However, in selected patients, this approach has a favourable DSS, with a relatively low nephroureterectomy rate, and therefore provides oncological control and renal preservation in patients more likely to die eventually from other causes.

     

Evaluation of diagnostic strategies for bladder cancer using computed tomography (CT) urography, flexible cystoscopy and voided urine cytology: results for 778 patients from a hospital haematuria clinic

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Haematuria clinics with same day imaging and flexible cystoscopy are an efficient way for investigating patients with haematuria. The principal role of haematuria clinics with reference to bladder cancer is to determine which patients are ‘normal’ and may be discharged, and which patients are abnormal and should undergo rigid cystoscopy. It is well recognised that CT urography offers a thorough evaluation of the upper urinary tract for stones, renal masses and urothelial neoplasms but the role of CT urography for diagnosing bladder cancer is less certain. The aim of the present study was to evaluate the diagnostic accuracy of CT urography in patients with visible haematuria aged >40 years and to determine if CT urography has a role for diagnosing bladder cancer. This study shows that the optimum diagnostic strategy for investigating patients with visible haematuria aged >40 years with infection excluded is a combined strategy using CT urography and flexible cystoscopy. Patients positive for bladder cancer on CT urography should be referred directly for rigid cystoscopy and so avoid flexible cystoscopy. The number of flexible cystoscopies required therefore may be reduced by 17%. The present study also shows that the diagnostic accuracy of voided urine cytology is too low to justify its continuing use in a haematuria clinic using CT urography and flexible cystoscopy.

OBJECTIVES

• ? To evaluate and compare the diagnostic accuracy of computed tomography (CT) urography with flexible cystoscopy and voided urine cytology for diagnosing bladder cancer.
• ? To evaluate diagnostic strategies using CT urography as: (i) an additional test or (ii) a replacement test or (iii) a triage test for diagnosing bladder cancer in patients referred to a hospital haematuria rapid diagnosis clinic.

PATIENTS AND METHODS

• ? The clinical cohort consisted of a consecutive series of 778 patients referred to a hospital haematuria rapid diagnosis clinic from 1 March 2004 to 17 December 2007. Criteria for referral were at least one episode of macroscopic haematuria, age >40 years and urinary tract infection excluded. Of the 778 patients, there were 747 with technically adequate CT urography and flexible cystoscopy examinations for analysis.
• ? On the same day, patients underwent examination by a clinical nurse specialist followed by voided urine cytology, CT urography and flexible cystoscopy. Voided urine cytology was scored using a 5‐point system. CT urography was reported immediately by a uroradiologist and flexible cystoscopy performed by a urologist. Both examinations were scored using a 3‐point system: 1, normal; 2, equivocal; and 3, positive for bladder cancer.
• ? The reference standard consisted of review of the hospital imaging and histopathology databases in December 2009 for all patients and reports from the medical notes for those referred for rigid cystoscopy. Follow‐up was for 21–66 months.

RESULTS

• ? The prevalence of bladder cancer in the clinical cohort was 20% (156/778). For the diagnostic strategy using CT urography as an additional test for diagnosing bladder cancer, when scores of 1 were classified as negative and scores of 2 and 3 as positive, sensitivity was 1.0 (95% confidence interval [CI] 0.98–1.00), specificity was 0.94 (95% CI 0.91–0.95), the positive predictive value (PPV) was 0.80 (95% CI 0.73–0.85) and the negative predictive value (NPV) was 1.0 (95% CI 0.99–1.00).
• ? For the diagnostic strategy using CT urography as a replacement test for flexible cystoscopy for diagnosing bladder cancer, when scores of 1 were classified as negative and scores of 2 and 3 as positive, sensitivity was 0.95 (95% CI 0.90–0.97), specificity was 0.83 (95% CI 0.80–0.86), the PPV was 0.58 (95% CI 0.52–0.64), and the NPV was 0.98 (95% CI 0.97–0.99). Similarly using flexible cystoscopy for diagnosing bladder cancer, if scores of 1 were classified as negative and scores of 2 and 3 as positive, sensitivity was 0.98 (95% CI 0.94– 0.99), specificity was 0.94 (95% CI 0.92–0.96), the PPV was 0.80 (95% CI 0.73–0.85) and the NPV was 0.99 (95% CI 0.99–1.0).
• ? For the diagnostic strategy using CT urography and flexible cystoscopy as a triage test for rigid cystoscopy and follow‐up (option 1), patients with a positive CT urography score are referred directly for rigid cystoscopy, and patients with an equivocal or normal score were referred for flexible cystoscopy. Sensitivity was 1.0 (95% CI 0.98–1.0), specificity was 0.94 (95% CI 0.91–0.95), the PPV was 0.80 (95% CI 0.73–0.85), and the NPV was 1.0 (95% CI 0.99–1.0).
• ? For the diagnostic strategy using CT urography and flexible cystoscopy as a triage test for rigid cystoscopy and follow‐up (option 2), patients with a positive CT urography score are referred directly for rigid cystoscopy, patients with an equivocal score are referred for flexible cystoscopy and patients with a normal score undergo clinical follow‐up. Sensitivity was 0.95 (95% CI 0.90–0.97), specificity was 0.98 (95% CI 0.97–0.99), the PPV was 0.93 (95% CI 0.87–0.96), and the NPV was 0.99 (95% CI 0.97–0.99).
• ? For voided urine cytology, if scores of 0–3 were classified as negative and 4–5 as positive for bladder cancer, sensitivity was 0.38 (95% CI 0.31–0.45), specificity was 0.98 (95% CI 0.97–0.99), the PPV was 0.82 (95% CI 0.72–0.88) and the NPV was 0.84 (95% CI 0.81–0.87).

CONCLUSIONS

• ? There is a clear advantage for the diagnostic strategy using CT urography and flexible cystoscopy as a triage test for rigid cystoscopy and follow‐up (option 1), in which patients with a positive CT urography score for bladder cancer are directly referred for rigid cystoscopy, but all other patients undergo flexible cystoscopy.
• ? Diagnostic accuracy is the same as for the additional test strategy with the advantage of a 17% reduction of the number of flexible cystoscopies performed.
• ? The sensitivity of voided urine cytology is too low to justify its continuing use in a hospital haematuria rapid diagnosis clinic using CT urography and flexible cystoscopy.

     

Significance of Ureteroscopic Biopsy Grade in Patients with Upper Tract Urothelial Carcinoma

Background

The objective of this study was to assess the significance of the ureteroscopic biopsy grade for patients with upper tract urothelial carcinoma (UTUC).

Patients and Methods

This study included 40 patients who were diagnosed with a single focus of UTUC by ureteroscopic biopsy and subsequently underwent nephroureterectomy. The significance of the biopsy grade as a predictive factor for pathological outcomes of nephroureterectomy was retrospectively analyzed.

Results

Of these 40 patients, 19 (47.5%) and 21 (52.5%) were diagnosed with low and high grade UTUC, respectively. The ureteroscopic biopsy grade matched the pathological grade of surgically resected specimens in 35 of the 40 cases (87.5%), and there was a significant correlation between the biopsy and pathological grades (p < 0.001). Furthermore, the biopsy grade was also shown to be closely associated with the pathological stage (p < 0.001); that is, only 1 of the 19 patients (5.3%) with biopsy low grade UTUC were pathologically diagnosed as having muscle invasive disease, while 17 of the 21 patients (81.0%) with biopsy high grade UTUC appeared to show tumor invasion into muscle or deeper.

Conclusions

The grade of UTUC on ureteroscopic biopsy could provide accurate diagnostic information on the final pathology of nephroureterectomy specimens.Key Words: Upper tract urothelial carcinoma, Ureteroscopic biopsy, Urinary cytology