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La neoplasia uroteliale occulta
Abstract
The occult urothelial cancerTransitional cell carcinoma (TCC) is the tumor that most frequently affects the urinary tract. The most common location is at the level of the bladder; the diagnosis is based, as per the follow-up, on urine cytology, endoscopic, and radiological examinations. Urine cytologic study is an important noninvasive tool used in the diagnosis and follow-up of patients with TCC. A positive urine cytologic study result is highly predictive of the presence of TCC, even in the presence of normal cystoscopy results because malignant cells may appear in the urine long before any cystoscopically visible lesion becomes apparent. A positive urinary cytology, in the absence of clinical or endoscopic evidence of a TCC, can identify an occult urothelial cancer, located in any site of the urinary tract (upper urinary tract, bladder, prostatic urethra). Actually, in literature there is no consensus on the identification and evaluation of occult urothelial cancer, whose diagnosis is still based on urine cytology. In order to improve the accuracy of urinary cytology, numerous molecular markers have been identified; however, the real clinical application remains unclear. Photodynamic diagnosis and narrow band imaging (NBI) technology increase the diagnostic accuracy of cystoscopy in the presence of lesions not easily detectable. The aim of this review is to analyze the current diagnostic standards and the new diagnostic tools in the presence of suspect occult urothelial cancer.
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The aim of this study was to assess the test performance and clinical effectiveness of photodynamic diagnosis (PDD) compared with white light cystoscopy (WLC) in people suspected of new or recurrent bladder cancer.
A systematic review was conducted of randomized controlled trials (RCTs), nonrandomized comparative studies, or diagnostic cross-sectional studies comparing PDD with WLC. Fifteen electronic databases and Web sites were searched (last searches April 2008). For clinical effectiveness, only RCTs were considered.
Twenty-seven studies (2,949 participants) assessed test performance. PDD had higher sensitivity than WLC (92 percent, 95 percent confidence interval [CI], 80-100 percent versus 71 percent, 95 percent CI, 49-93 percent) but lower specificity (57 percent, 95 percent CI, 36-79 percent versus 72 percent, 95 percent CI, 47-96 percent). For detecting higher risk tumors, median range sensitivity of PDD (89 percent [6-100 percent]) was higher than WLC (56 percent [0-100 percent]) whereas for lower risk tumors it was broadly similar (92 percent [20-95 percent] versus 95 percent [8-100 percent]). Four RCTs (709 participants) using 5-aminolaevulinic acid (5-ALA) as the photosensitising agent reported clinical effectiveness. Using PDD at transurethral resection of bladder tumor (TURBT) resulted in fewer residual tumors at check cystoscopy (relative risk [RR], 0.37, 95 percent CI, 0.20-0.69) and longer recurrence-free survival (RR, 1.37, 95 percent CI, 1.18-1.59), compared with WLC.
PDD detects more bladder tumors than WLC, including more high-risk tumors. Based on four RCTs reporting clinical effectiveness, 5-aminolaevulinic acid-mediated PDD at TURBT facilitates a more complete resection and prolongs recurrence-free survival.
To assess the clinical effectiveness and cost-effectiveness of photodynamic diagnosis (PDD) compared with white light cystoscopy (WLC), and urine biomarkers [fluorescence in situ hybridisation (FISH), ImmunoCyt, NMP22] and cytology for the detection and follow-up of bladder cancer.
Major electronic databases including MEDLINE, MEDLINE In-Process, EMBASE, BIOSIS, Science Citation Index, Health Management Information Consortium and the Cochrane Controlled Trials Register were searched until April 2008.
A systematic review of the literature was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of alternative diagnostic and follow-up strategies for the diagnosis and management of patients with bladder cancer.
In total, 27 studies reported PDD test performance. In pooled estimates [95% confidence interval (CI)] for patient-level analysis, PDD had higher sensitivity than WLC [92% (80% to 100%) versus 71% (49% to 93%)] but lower specificity [57% (36% to 79%) versus 72% (47% to 96%)]. Similar results were found for biopsy-level analysis. The median sensitivities (range) of PDD and WLC for detecting lower risk, less aggressive tumours were similar for patient-level detection [92% (20% to 95%) versus 95% (8% to 100%)], but sensitivity was higher for PDD than for WLC for biopsy-level detection [96% (88% to 100%) versus 88% (74% to 100%)]. For more aggressive, higher-risk tumours the median sensitivity of PDD for both patient-level [89% (6% to 100%)] and biopsy-level [99% (54% to 100%)] detection was higher than those of WLC [56% (0% to 100%) and 67% (0% to 100%) respectively]. Four RCTs comparing PDD with WLC reported effectiveness outcomes. PDD use at transurethral resection of bladder tumour resulted in fewer residual tumours at check cystoscopy [relative risk, RR, 0.37 (95% CI 0.20 to 0.69)] and longer recurrence-free survival [RR 1.37 (95% CI 1.18 to 1.59)] compared with WLC. In 71 studies reporting the performance of biomarkers and cytology in detecting bladder cancer, sensitivity (95% CI) was highest for ImmunoCyt [84% (77% to 91%)] and lowest for cytology [44% (38% to 51%)], whereas specificity was highest for cytology [96% (94% to 98%)] and lowest for ImmunoCyt [75% (68% to 83%)]. In the cost-effectiveness analysis the most effective strategy in terms of true positive cases (44) and life-years (11.66) [flexible cystoscopy (CSC) and ImmunoCyt followed by PDD in initial diagnosis and CSC followed by WLC in follow-up] had an incremental cost per life-year of over 270,000 pounds. The least effective strategy [cytology followed by WLC in initial diagnosis (average cost over 20 years 1403 pounds, average life expectancy 11.59)] was most likely to be considered cost-effective when society's willingness to pay was less than 20,000 pounds per life-year. No strategy was cost-effective more than 50% of the time, but four of the eight strategies in the probabilistic sensitivity analysis (three involving a biomarker or PDD) were each associated with a 20% chance of being considered cost-effective. In sensitivity analyses the results were most sensitive to the pretest probability of disease (5% in the base case).
The advantages of PDD's higher sensitivity in detecting bladder cancer have to be weighed against the disadvantages of a higher false-positive rate. Taking into account the assumptions made in the model, strategies involving biomarkers and/or PDD provide additional benefits at a cost that society might be willing to pay. Strategies replacing WLC with PDD provide more life-years but it is unclear whether they are worth the extra cost.
New developments in optical diagnostics have a potential for less invasive and improved detection of bladder cancer.
To provide an overview of the technology and diagnostic yield of recently developed optical diagnostics for bladder cancer and to outline their potential future applications.
A PubMed literature search was performed, and papers on Raman spectroscopy (RS), optical coherence tomography (OCT), photodynamic diagnosis (PDD) and narrow-band imaging (NBI) regarding bladder cancer were reviewed. Technology, clinical evidence, and future applications of the techniques are discussed.
With RS, the molecular components of tissue can be measured objectively in qualitative and quantitative ways. The first studies demonstrating human in vivo applicability are still awaited. OCT produces high-resolution, cross-sectional images of tissue, comparable with histopathology, and provides information about depth of tumour growth. The first in vivo studies of OCT demonstrated promising diagnostic accuracy. RS and OCT are not suitable for scanning the entire bladder. PDD is a technique using fluorescence to indicate pathologic tissue. Several studies have shown that PDD increases the detection rate of bladder tumours and improves resection, resulting in fewer early recurrences. The relatively low specificity of PDD remains a problem. NBI enhances contrast of mucosal surface and microvascular structures. The NBI technique has clear advantages over PDD, and the two studies published to date have shown promising preliminary results. PDD and NBI do not contribute to histopathologic diagnosis.
RS and OCT aim at providing a real-time, minimally invasive, objective prediction of histopathologic diagnosis, while PDD and NBI aim at improving visualisation of bladder tumours. For RS, OCT, and NBI, more research has to be conducted before these techniques can be implemented in the management of bladder cancer. All techniques might be of value in specific clinical scenarios.
This study was performed to examine the usefulness of medical endoscopic imaging utilizing narrow-band illumination. The contrast between the vascular pattern and the adjacent mucosa of the underside of the human tongue was measured using five narrow-band illuminations and three broadband illuminations. The results demonstrate that the pathological features of a vascular pattern are dependent on the center wavelength and the bandwidth of illumination. By utilizing narrow-band illumination of 415+/-30 nm, the contrast of the capillary pattern in the superficial layer was markedly improved. This is an important benefit that is difficult to obtain with ordinary broadband illumination. The appearances of capillary patterns on color images were evaluated for three sets of filters. The narrow, band imaging (NBI) filter set (415+/-30 nm, 445+/-30 nm, 500+/-30 nm) was selected to achieve the preferred appearance of the vascular patterns for clinical tests. The results of clinical tests in colonoscopy and esophagoscopy indicated that NBI will be useful as a supporting method for observation of the endoscopic findings of early cancer.
A newly developed narrow-band imaging (NBI) technique, in which modified optical filters were used in the light source of a video endoscope system, was applied during colonoscopy in a clinical setting. This pilot study evaluated the clinical feasibility of the NBI system for evaluating colorectal lesions.
A total of 43 colorectal lesions in 34 patients were included in the study. The quality of visualization of colorectal lesions and the accuracy of differentiation between neoplastic and non-neoplastic lesions using the NBI system were evaluated in comparison with results from conventional colonoscopy and with chromoendoscopy.
For pit pattern delineation, NBI was superior to conventional endoscopy (P < 0.001), but inferior to chromoendoscopy (P < 0.05). NBI achieved better visualization of the mucosal vascular network and of the hue of lesions than conventional endoscopy (P < 0.05). However there was no significant difference between NBI and chromoendoscopy in differentiating neoplastic from non-neoplastic lesions (both techniques had a sensitivity of 100 % and a specificity 75 %). This was better than the results of conventional colonoscopy (sensitivity 83 %, specificity 44 %; P < 0.05 for specificity).
These results suggest that in the examination of colonic lesions the NBI system provides imaging features additional to those of both conventional endoscopy and chromoendoscopy. For distinguishing neoplasms from non-neoplastic lesions, NBI was equivalent to chromoendoscopy.
To determine the most effective diagnostic strategy for the investigation of microscopic and macroscopic haematuria in adults.
Electronic databases from inception to October 2003, updated in August 2004.
A systematic review was undertaken according to published guidelines. Decision analytic modelling was undertaken, based on the findings of the review, expert opinion and additional information from the literature, to assess the relative cost-effectiveness of plausible alternative tests that are part of diagnostic algorithms for haematuria.
A total of 118 studies met the inclusion criteria. No studies that evaluated the effectiveness of diagnostic algorithms for haematuria or the effectiveness of screening for haematuria or investigating its underlying cause were identified. Eighteen out of 19 identified studies evaluated dipstick tests and data from these suggested that these are moderately useful in establishing the presence of, but cannot be used to rule out, haematuria. Six studies using haematuria as a test for the presence of a disease indicated that the detection of microhaematuria cannot alone be considered a useful test either to rule in or rule out the presence of a significant underlying pathology (urinary calculi or bladder cancer). Forty-eight of 80 studies addressed methods to localise the source of bleeding (renal or lower urinary tract). The methods and thresholds described in these studies varied greatly, precluding any estimate of a 'best performance' threshold that could be applied across patient groups. However, studies of red blood cell morphology that used a cut-off value of 80% dysmorphic cells for glomerular disease reported consistently high specificities (potentially useful in ruling in a renal cause for haematuria). The reported sensitivities were generally low. Twenty-eight studies included data on the accuracy of laboratory tests (tumour markers, cytology) for the diagnosis of bladder cancer. The majority of tumour marker studies evaluated nuclear matrix protein 22 or bladder tumour antigen. The sensitivity and specificity ranges suggested that neither of these would be useful either for diagnosing bladder cancer or for ruling out patients for further investigation (cystoscopy). However, the evidence remains sparse and the diagnostic accuracy estimates varied widely between studies. Fifteen studies evaluating urine cytology as a test for urinary tract malignancies were heterogeneous and poorly reported. The calculated specificity values were generally high, suggesting some possible utility in confirming malignancy. However, the evidence suggests that urine cytology has no application in ruling out malignancy or excluding patients from further investigation. Fifteen studies evaluated imaging techniques [computed tomography (CT), intravenous urography (IVU) or ultrasound scanning (US)] to detect the underlying cause of haematuria. The target condition and the reference standard varied greatly between these studies. The diagnostic accuracy data for several individual studies appeared promising but meaningful comparison of the available imaging technologies was impossible. Eight studies met the inclusion criteria but addressed different parts of the diagnostic chain (e.g. screening programmes, laboratory investigations, full urological work-up). No single study addressed the complete diagnostic process. The review also highlighted a number of methodological limitations of these studies, including their lack of generalisability to the UK context. Separate decision analytic models were therefore developed to progress estimation of the optimal strategy for the diagnostic management of haematuria. The economic model for the detection of microhaematuria found that immediate microscopy following a positive dipstick test would improve diagnostic efficiency as it eliminates the high number of false positives produced by dipstick testing. Strategies that use routine microscopy may be associated with high numbers of false results, but evidence was lacking regarding the accuracy of routine microscopy and estimates were adopted for the model. The model for imaging the upper urinary tract showed that US detects more tumours than IVU at one-third of the cost, and is also associated with fewer false results. For any cause of haematuria, CT was shown to have a mean incremental cost-effectiveness ratio of pounds sterling 9939 in comparison with the next best option, US. When US is followed up with CT for negative results with persistent haematuria, it dominates the initial use of CT alone, with a saving of pounds sterling 235,000 for the evaluation of 1000 patients. The model for investigation of the lower urinary tract showed that for low-risk patients the use of immediate cystoscopy could be avoided if cystoscopy were used for follow-up patients with a negative initial test using tumour markers and/or cytology, resulting in a saving of pounds sterling 483,000 for the evaluation of 1000 patients. The clinical and economic impact on delayed detection of both upper and lower urinary tract tumours through the use of follow-up testing should be evaluated in future studies.
There are insufficient data currently available to derive an evidence-based algorithm of the diagnostic pathway for haematuria. A hypothetical algorithm based on the opinion and practice of clinical experts in the review team, other published algorithms and the results of economic modelling is presented in this report. This algorithm is presented, for comparative purposes, alongside current US and UK guidelines. The ideas contained in these algorithms and the specific questions outlined should form the basis of future research. Quality assessment of the diagnostic accuracy studies included in this review highlighted several areas of deficiency.
A 62 year old man with longstanding ulcerative colitis and previous endoscopic excision of two dysplasia associated lesions or masses (DALMs) was admitted to our endoscopy unit for evaluation and resection of other possible DALMs. He had previously been offered and refused colectomy because of comorbidity from Parkinson's disease. He had multiple polypoid and sessile lesions which were assessed using a third generation prototype narrow band imaging (NBI) colonoscope with magnification. Selected lesions were either biopsied or resected with a combination of endoscopic submucosal dissection and endoscopic mucosal resection techniques. We correlated the pit pattern and vascular pattern intensity seen with magnification NBI with histology of both inflammatory and dysplastic lesions. Dysplastic areas showed Kudo pit patterns II, IIIL, and IV and high vascular pattern intensity. Non-dysplastic and dysplastic areas of recurrence immediately adjacent to the scar from a previous endoscopic mucosal resection site were also assessed. This is the first case report where NBI has been shown to help in DALM detection and to distinguish dysplastic from non-dysplastic mucosa in ulcerative colitis.
Urothelial carcinoma in situ (CIS) has a high propensity for progression. It is usually reported within the heterogeneous context of non-muscle-invasive bladder cancer (NMIBC) but warrants special consideration.
To review the contemporary literature on the diagnosis and management of CIS.
A systematic search using broad terms to capture the diagnosis and treatment of CIS was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria. Full-text original articles, reviews, and editorials from 1966 to 2014 in English were included. References from selected articles, relevant guidelines, and conference abstracts were searched. Abstracts were excluded.
A total of 1887 articles were identified, of which 120 were used in this review. Most reports were retrospective and heterogeneous in caseload. There is a lack of standardised classification of CIS. Many studies consider CIS in the context of NMIBC without a clear separation of the subset with CIS. Recent prospective phase 2 and 3 studies have improved the evidence base.
We are beginning to understand that CIS has a spectrum of biologic potential. Bacillus Calmette-Guérin immunotherapy appears superior to other intravesical agents and may alter the natural history of CIS. New imaging modalities, agents, and treatment strategies have emerged in recent years with the aim of better identification of CIS, more bladder-preserving treatments, and prevention of surgical overtreatment.
Improvements in imaging techniques combined with new bladder-preserving treatments will continue to have an impact on the outcomes of bladder carcinoma in situ.
Copyright © 2014. Published by Elsevier B.V.
Primary detection and follow-up of patients with non–muscle-invasive (NMI) bladder cancer (BC) is done by urethro-cystoscopy (UCS) and, in most cases, cytology. Many urine-based tests have been developed, and in general, these tests have a higher sensitivity than cytology but a lower specificity. In this review, we assessed the value of urine tests for screening, primary detection, and surveillance of NMIBC. Considering the frequency of UCS for follow-up, having markers for recurrent BC would be especially useful. Therefore, we updated our systematic review to include five commonly studied urine markers (BTA stat, NMP22, uCyt+/Immunocyt, FISH UroVysion, and microsatellite analysis) and cytology for surveillance. The sensitivity and/or specificity of cytology and these five markers were more than 5% lower for patients under surveillance compared to the numbers reported in other reviews, confirming that the performance of urine markers and cytology is lower for the detection of recurrent BC than is UCS. Recent data from the first randomized trial to investigate the possibility of lowering UCS frequency with urinary microsatellite analysis showed substantial underestimation of sensitivity and specificity if the urologist was not aware of the urine test outcome. These results question but do not replace UCS as the gold standard for NMIBC surveillance. In conclusion, cytology is still important as an adjunct for the evaluation of patients with hematuria and the surveillance of patients with high-risk NMIBC. Urine markers other than cytology may play a role in future screening studies and the follow-up of patients with low-grade (G1–2) NMIBC.
To evaluate multidetector computed tomography urography (MDCTU) for diagnosing upper urinary tract (UUT) urothelial tumour by comparison with retrograde ureteropyelography (RUP).
MDCTU and RUP were used in a selected series of adult patients presenting with haematuria. Entry criteria were based on findings on intravenous urography and were chosen to ensure a high prevalence of UUT urothelial tumour to allow a valid retrospective comparison of the diagnostic techniques. MDCTU and RUP studies were scored for the presence and absence of UUT urothelial tumour by two radiologists, retrospectively and independently, and while unaware of the demographic and clinical information. The reference standards were the histopathology and clinical follow-up.
MDCTU and RUP were used in 106 patients over a 24-month period. RUP was attempted in 151 of 212 UUTs; the corresponding MDCTU for each UUT was reviewed. MDCTU was a true-positive (TP) for urothelial tumour in 31, true-negative (TN) in 111, false-positive (FP) in eight and false-negative (FN) in one UUT, giving a sensitivity of 0.97, a specificity of 0.93, a positive predictive value (PPV) of 0.79 and a negative PV (NPV) of 0.99. RUP was technically successful and diagnostic in 96% of the UUTs (143/151). For diagnosing urothelial tumour, RUP was TP in 26, TN in 112, FP in four and FN in one UUT, giving a sensitivity of 0.97, specificity of 0.93, a PPV of 0.79 and NPV of 0.99.
This study validates quantitatively the use of MDCTU for diagnosing UUT urothelial tumour.
• To assess the cost-effectiveness of using cytological evaluation, NMP22 BladderChek®, and fluorescence in situ hybridization (FISH) UroVysion® in addition to cystoscopy in patients with a history of bladder cancer undergoing surveillance for recurrence.
• In all, 200 consecutive patients with a history of bladder cancer not invading the muscle were prospectively enrolled at The University of Texas MD Anderson Cancer Center. • Five surveillance strategies were compared: (i) cystoscopy alone; (ii) cystoscopy and NMP22; (iii) cystoscopy and FISH; (iv) cystoscopy and cytology; and (v) cystoscopy and positive NMP22 confirmed by positive FISH. • The cost per cancer detected was calculated. • For patients with an initial positive test and negative cystoscopy, tumour detected at first follow-up was assumed to be too small to be visualized at the initial assessment and the biomarker was credited with early detection.
• Cancer was detected in 13 patients at study entry. • Detection rates for the five surveillance strategies were: (i) 52%, (ii) 56%, (iii) 72%, (iv) 60%, and (v) 56%. • The costs per tumour detected (at the time of initial marker analysis) were (i) $7692; (ii) $12,000; (iii) $26,462; (iv) $11,846; and (v) $10,292. • When early detection of biomarkers was factored in, the CPTD became: (i) $7692; (ii) $11,143; (iii) $19,111; (iv) $10,267; and (v) $9557. • There were 12 new cancers detected at first follow-up (median time, 4.1 months). None of the tumours detected by biomarkers but not by cystoscopy were invasive.
• Cystoscopy alone remains the most cost-effective strategy to detect recurrence of bladder cancer not invading the muscle. • The addition of urinary markers adds to cost, without improved detection of invasive disease.
Compared with standard white-light cystoscopy, photodynamic diagnosis with blue light and the photosensitiser hexaminolevulinate has been shown to improve the visualisation of bladder tumours, reduce residual tumour rates by at least 20%, and improve recurrence-free survival. There is currently no overall European consensus outlining specifically where hexaminolevulinate is or is not indicated.
Our aim was to define specific indications for hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and management of non-muscle-invasive bladder cancer (NMIBC).
A European expert panel was convened to review the evidence for hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and management of NMIBC (identified through a PubMed MESH search) and available guidelines from across Europe. On the basis of this information and drawing on the extensive clinical experience of the panel, specific indications for the technique were then identified through discussion.
The panel recommends that hexaminolevulinate-guided fluorescence cystoscopy be used to aid diagnosis at initial transurethral resection following suspicion of bladder cancer and in patients with positive urine cytology but negative white-light cystoscopy for the assessment of tumour recurrences in patients not previously assessed with hexaminolevulinate, in the initial follow-up of patients with carcinoma in situ (CIS) or multifocal tumours, and as a teaching tool. The panel does not currently recommend the use of hexaminolevulinate-guided fluorescence cystoscopy in patients for whom cystectomy is indicated or for use in the outpatient setting with flexible cystoscopy.
Evidence is available to support the use of hexaminolevulinate-guided fluorescence cystoscopy in a range of indications, as endorsed by an expert panel.
The clinical benefit of photodynamic diagnosis (PDD) with 5-aminolevulinic acid or hexaminolevulinate in addition to white-light cystoscopy (WLC) in bladder cancer has been discussed controversially.
To assess in a systematic review the effect of PDD in addition to WLC on (1) the diagnosis and (2) the therapeutic outcome of primary or recurrent non-muscle-invasive bladder cancer investigated by cystoscopy or transurethral resection.
An electronic database search of Medline, Embase, the Cochrane Library, and CancerLit was undertaken, plus hand searching of relevant congress abstracts and urologic journals. Trials were included if they prospectively compared WLC with PDD in bladder cancer. The review process followed the guidelines of the Cochrane Collaboration. Two reviewers evaluated independently both trial eligibility and methodological quality and data extraction.
The primary end point of diagnostic accuracy was additional detection rate. The primary end points of therapeutic outcome were residual tumour at second resection and recurrence-free survival (RFS). Seventeen trials were identified. Twelve diagnostic trials used WLC and PDD with the same patients. Seven reported results for the subgroup of patients with carcinoma in situ (CIS). Five randomised trials studied therapeutic outcome. The results were combined in random effects meta-analyses if end points, designs, and populations were comparable. Twenty percent (95% confidence interval [CI], 8-35) more tumour-positive patients were detected with PDD in all patients with non-muscle-invasive tumours and 39% (CI, 23-57) more when only CIS was analysed. Heterogeneity was present among diagnostic studies even when the subgroup of patients with CIS was investigated. Residual tumour was significantly less often found after PDD (odds ratio: 0.28; 95% CI, 0.15-0.52; p<0.0001). RFS was higher at 12 and 24 mo in the PDD groups than in the WLC-only groups. The combined p value of log-rank tests of RFS was statistically significant (0.00002).
PDD detects more bladder tumour-positive patients, especially more with CIS, than WLC. More patients have a complete resection and a longer RFS when diagnosed with PDD.
To compare the outcomes of 5-aminolaevulinic acid (ALA) vs hexaminolaevulinate (HEX) vs white light (WL) transurethral resection of bladder tumors (TURB) to assess transferability of ALA findings to HEX. Extending WL-TURB with photodynamic diagnostic improves outcome. Two fluorescent agents have been commonly used for this. Although numerous and specific data exist on the older substance ALA, considerably less are available on hex, the only agent approved however. To date no such report has been published.
By random generator, each 200 patients with non-muscle-invasive bladder cancer having undergone TURB with WL, ALA or HEX were selected from our institutional data bank. Residual tumor in control TURB (RT) and recurrence-free survival (RFS) were assessed.
Complete follow-up data were available on 142 WL, 139 ALA, and 135 HEX patients. Median duration of follow-up was 24 months. RT was 33% in WL, 15% in ALA, and 9% in hex, respectively. RFS at 3 years was 67% in WL, 80% in ALA, and 82% in hex, respectively. RT was significantly reduced in ALA and HEX vs WL (P < .001) and RFS prolonged (P < .01). There were no significant differences between ALA and HEX in RT and RFS, respectively (RT: P = .37; RFS: P = .72).
In the present retrospective series, ALA and HEX were found to be significantly superior to WL. No differences between ALA and HEX were demonstrated. Even from a careful perspective both fluorescent agents seem to be comparable. Thus, ALA-based findings seem to be transferable on the approved agent HEX.
Photodynamic diagnosis (PDD) is a technique that enhances the detection of occult bladder tumors during cystoscopy using a fluorescent dye.
To study the differential effects of bacillus Calmette-Guérin (BCG) and mitomycin C (MMC) intravesical therapy on the false-positive rate of PDD of bladder cancer.
This study included 552 procedures and 1874 biopsies.
Tumors were resected and biopsies were taken from suspicious areas, under guidance of white-light endoscopy and 5-ALA (5-aminolevulinic acid)-induced fluorescence cystoscopy.
The influence of intravesical BCG immunotherapy and intravesical MMC chemotherapy on pyuria, inflammation, and PDD specificity was examined in univariate analyses.
BCG significantly results in inflammation (odds ratio [OR]: 1.53, p=0.002), leukocyturia (OR: 1.84, p=0.034), and false positives in PDD (OR: 1.49, p=0.001). However, a single BCG instillation within 3 mo before PDD is most likely not associated with increased false-positive rates (OR: 0.35, p=0.26). Leukocyturia normalizes within 6 wk after the last BCG instillation, but PDD specificity is reduced up to 3 mo.
BCG is an important predictor for false positives in PDD (5-ALA). More than one BCG instillation within 3 mo before fluorescence cystoscopy decreases the specificity of PDD.
Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b.
To evaluate whether narrow-band imaging cystoscopy (NBIC) can identify bladder tumour suspected on follow-up white-light cystoscopy (WLC) after intravesical bacille Calmette-Guérin (BCG) therapy, as BCG causes an intense reaction in the bladder, appearing as red lesions on WLC, which might be residual tumour or BCG-induced inflammation.
Sixty-one patients with high-risk non-muscle-invasive bladder tumours were evaluated 3 months after starting induction BCG therapy. All patients had abnormal erythematous lesions on WLC, suspected to be residual carcinoma in situ. After WLC, they were evaluated by NBIC, urine cytology and biopsy, followed by transurethral resection of all visible lesions.
Of the 61 patients, 22 (36%) had residual tumour. NBIC correctly identified tumour in 21 patients, but another 10 had unnecessary biopsy (NBIC positive, negative biopsy). Only one of 30 patients who had negative NBIC findings had tumour. NBIC outperformed urine cytology in detecting residual tumour after BCG therapy.
NBIC appears to better identify patients who have suspected residual tumour on follow-up WLC at 3 months after BCG therapy.
To determine if narrow-band imaging (NBI) can be used to detect high-grade cancerous lesions missed with the white light at the time of a second transurethral resection (TUR) of high-grade non-muscle-invasive bladder cancer (NMIBC).
Consecutive patients with newly diagnosed high-grade NMIBC were enrolled in a prospective observational study. Patients with incomplete resection or absence of muscle tissue in the specimen were excluded. About 1 month after the first TUR, NBI cold-cup biopsies were taken from areas suspicious for urothelial cancer at the end of an extensive white-light second TUR protocol including: (i) resection of the scar of the primary tumour; (ii) resection of any overt or suspected urothelial lesions; and (iii) six random cold-cup biopsies of healthy mucosa.
In 2008, 47 consecutive patients were recruited after giving written consent (median age 62 years, range 49-83, 39 men and eight women). Nine patients (19%) had macroscopic or microscopic high-grade NMI urothelial cancer, whereas one was reassessed as having muscle-invasive disease at the white-light second TUR plus the six random biopsies. NBI biopsies were taken in 40 of the 47 patients and detected six more patients with high-grade cancerous tissue (13%). In all 16 of the 47 patients (34%) were found to have residual/recurrent cancer using our extensive protocol of second TUR followed by NBI biopsies.
Adding NBI biopsies at the end of an extensive second TUR protocol in patients with newly diagnosed high-grade NMIBC can lead to the identification of patients with otherwise missed high-grade residual/recurrent urothelial carcinoma.
To evaluate the efficacy of transurethral prostatectomy (TURP) followed by bacillus Calmette-Guérin (BCG) immunotherapy in patients with prostatic urothelial carcinoma (PUC) and compare the results of studies using combined TURP and BCG with studies in which TURP was not performed.
Patients with bladder cancer and PUC were treated with TURP followed by six weekly intravesical instillations of BCG. Response was determined and monitored by periodic bladder and prostatic urethra biopsies and urinary cytology. Also, the outcome of previous series using similar methodology was compared with the outcome of studies in which TURP was not performed.
In all, 20 patients with PUC were treated with TURP followed by intravesical instillations of BCG. The median follow-up was 52.5 months. All patients had an initial complete response (CR). The prostatic urethra 5-year recurrence-free survival rate was 90%. However, bladder and prostatic urethra 5-year recurrence-free survival rate was only 30%. Five patients (25%) died from urothelial carcinoma (UC) after a median period of 58.5 months (two from bladder cancer metastases and three from upper tract metastases). The long-term prostatic urethra CR rate in studies using TURP before immunotherapy was significantly higher than the CR rate in studies using immunotherapy alone (P < 0.001). However, there was no difference when bladder and prostatic urethra CR rates were considered together (P = 0.54).
In patients with PUC, TURP before BCG immunotherapy eliminates PUC in most cases, and is probably the preferred treatment for this disease. The risk of UC-specific mortality in these patients is high.
The prostates of 36 patients who were treated with intravesical bacillus Calmette-Guerin were evaluated by digital rectal examination and transrectal ultrasonography. When abnormal palpatory and/or ultrasonographic findings were detected, core needle biopsies from the suspicious areas were performed. Of the 36 patients 20 underwent biopsies of the prostate. Pathological findings revealed typical granulomas in 8 patients (3 caseating and 5 noncaseating multifocal granulomas). Nonspecific chronic prostatitis was noted in 4 patients and benign prostatic hyperplasia was noted in 8. The number of bacillus Calmette-Guerin instillations ranged from 6 to 19. The interval from initiation of therapy to biopsy ranged from 1.5 to 14.5 months. Caseating granulomas were found during the early course of bacillus Calmette-Guerin instillations (1.5 to 3.0 months), whereas noncaseating granulomas were detected at later stages (4 to 14.5 months). These findings present a high incidence of granuloma formation in patients treated with intravesical bacillus Calmette-Guerin. The duration of therapy is a determinant factor in the induction of granuloma type.
Twenty-three men who underwent radical cystoprostatectomy between March 1, 1983, and October 1, 1986, were found to have not only multifocal carcinoma in situ (CIS) of the bladder but also transitional cell carcinoma (TCC) of the prostatic ducts. In 18 patients TCC was limited to the epithelium lining the prostatic ducts (CIS of prostatic ducts), but in 5 patients TCC also invaded the prostatic stroma (invasive TCC of prostatic ducts). During follow-up (mean, 26 months), in 2 of the 18 patients (11%) with CIS of the prostatic ducts metastases developed. By comparison, metastatic TCC developed in 5 of 5 patients (100%) who had invasion into the prostatic stroma. Evidence indicates that patients with multifocal CIS of the bladder should be evaluated very closely for the presence of TCC of the prostatic ducts. When TCC is present in the ducts, radical cystoprostatectomy is necessary to control this lesion before it progresses to invasion. When invasion has occurred, however, radical cystoprostatectomy alone is not sufficient therapy. Since metastatic TCC develops in 100 percent of these patients, we believe that chemotherapy (either adjuvant or neoadjuvant) should be used in addition to radical cystoprostatectomy.
Concomitant urothelial atypia (grade II atypia or carcinoma in situ) is predictive of new tumor growth after transurethral tumor resection. Concomitant urothelial atypia can be demonstrated by pre-selected site mucosal biopsies. However, a number of patients have new tumors despite normal pre-selected site biopsies. To investigate whether urinary cytology is a better indicator for concomitant urothelial atypia than pre-selected site biopsies, we studied in bladder tumor patients the correlation between the findings of pre-selected site biopsies (8 per patient) at tumor resection and urinary cytology (2 per patient) after successful resection. Concomitant urothelial atypia was demonstrated by biopsies in 52 per cent of the patients, of whom 60 per cent had grade II atypia and 40 per cent had carcinoma in situ. All patients with concomitant carcinoma in situ in biopsies had positive cytology findings. Of the patients with concomitant grade II atypia in biopsies 15 per cent had negative cytology studies. In 48 per cent of the patients no urothelial atypia in pre-selected site biopsies was demonstrable. However, cytology was positive, that is neoplastic cells were present, in 64 per cent of these specimens (19 patients). Of the 19 patients 16 currently have had demonstrable urothelial atypia in pre-selected site mucosal biopsies at a later occasion. We conclude that urinary cytology seems to be a better indicator for the presence of concomitant urothelial atypia than pre-selected site mucosal biopsies and, therefore, it can be used as a screening procedure for patients without demonstrable concomitant carcinoma in situ at tumor resection.
A total of 66 patients with multifocal, progressive, flat carcinoma in situ of the bladder responded completely to intravesical bacillus Calmette-Guerin therapy for more than 1 year. Of the patients 19 (29 per cent) had clinical evidence of distal ureteral carcinoma in situ between 13 and 30 months (median 15 months) after bacillus Calmette-Guerin treatment. After evaluation of a positive urinary cytology study failed to reveal recurrent urothelial tumor of the bladder or prostatic urethral mucosa 6 patients underwent distal ureterectomy, 2 underwent nephroureterectomy, and 11 were managed by ureteroscopic resection and fulguration. In patients with carcinoma in situ of the bladder treated successfully with topical therapy the ureters represent a potential site of in situ carcinoma.
We studied 51 patients with superficial bladder carcinoma who had been treated with transurethral resection of all gross tumor followed by intravesical bacillus Calmette-Guerin weekly for 6 weeks. Within 72 hours of either the first or second quarterly cystoscopic surveillance examination after bacillus Calmette-Guerin therapy, a conventional cytology study was obtained. Of these patients 8 (15.7 per cent) had positive, 9 (17.6 per cent) suspicious and 34 (66.7 per cent) negative postoperative cytology studies. Subsequent tumor recurrence was defined as a positive biopsy or visible papillary tumors on cystoscopic examination. All 8 patients with a positive postoperative cytology study had tumor recurrence at a median interval of 4 months. Of the 9 patients with a suspicious study 7 (77.8 per cent) had recurrent tumor at a median interval of 7 months and 2 (22.2 per cent) had no evidence of disease at 16 and 19 months, respectively. Of the 34 patients with a negative postoperative cytology study 13 (38.2 per cent) had tumor recurrence after a median interval of 4 months and 21 (67.8 per cent) had no evidence of disease after a median of 25 months. The tumor recurrence rate in patients with a positive or suspicious postoperative cytology study was significantly greater than that of patients with a negative study (p equals 0.001, Fisher's exact test). Postoperative cytology appears to be a significant prognostic indicator following transurethral resection and intravesical bacillus Calmette-Guerin treatment of superficial bladder carcinoma.
Fifty-one patients with predominantly superficial bladder tumours underwent prospective cytological examination at predetermined intervals following surgery in order to evaluate the prognostic reliability of bladder irrigation cytology. The results suggest that positive cytology 3 days after radical transurethral resection is a reliable indicator of incomplete resection or additional occult tumour foci. The implications for post-operative management and follow-up are discussed.
Lavage cytology was done in 101 patients with radiological filling defects in the ureter and renal pelvis. This simple and inexpensive technique is valuable in the preoperative diagnosis of tumors of the ureter and renal pelvis. In our series it was possible to recognize clearly 29 of 36 such tumors (80.5 per cent) through preoperative lavage cytology. No falsely positive diagnoses were made. Lavage cytology failed in 6 patients with hypernephroma. The diagnostic reliability of lavage cytology with urothelial tumors is far greater than that of exfoliative urine cytology and reaches almost equally good results as brush biopsy.
An aggressive evaluation of extravesical sites of disease in patients with clinically unconfirmed positive urinary cytology findings is indicated only in previously untreated asymptomatic or symptomatic patients (group 1) and in those with a complete response to intravesical therapy who are without evidence of disease for 1 year (group 4). Patients who have positive urinary cytology findings immediately after complete transurethral resection of bladder tumors or intravesical therapy will almost always have recurrent bladder transitional cell carcinoma and do not require aggressive extravesical evaluation initially. Transurethral resection prostate biopsy between the 5 and 7 o'clock positions along the entire length of the prostatic urethra is the technique of choice for detecting transitional cell carcinoma of the prostate, since other less invasive techniques frequently underestimate the extent of disease. In the absence of radiographic disease, bilateral ureteral lavage cytology is the technique of choice to identify the upper tract as the source of a positive urinary cytology result. Rigid and flexible ureteropyeloscopy should be performed only in the presence of radiographic or cytological evidence of upper tract transitional cell carcinoma, or in patients with a history of upper tract disease who have suspected relapse on the basis of a positive urinary cytology result.
The distribution of any involved prostatic urethra, ducts and acini by urothelial carcinoma was studied to determine an adequate sampling method for detecting prostatic involvement using the maps of 38 cystoprostatectomy specimens. A total of 31 patients had prostatic duct and acini involvement, while 7 had prostatic urethral involvement alone. However, the distribution of the involved prostatic urethra, ducts and acini varied. In 29 of the 31 patients (93.5%) with prostatic duct and acini involvement, urethral carcinoma in situ and/or superficial gland involvement (an involvement of the afferent ducts within a few millimeters of the urethral mucosa) at the 5 and/or 7 o'clock position of the verumontanum portion was identified. In 7 patients with prostatic urethral involvement alone 2 had carcinoma foci at the 5 and/or 7 o'clock position of the verumontanum portion. Furthermore, the frequency of deeper gland involvement (an involvement of true prostatic acini except for superficial glands) was higher in patients with superficial gland involvement at the 5 and/or 7 o'clock position of the verumontanum portion (57.7%) than in patients without such involvement (20.0%). Therefore, this study emphasizes that a transurethral resection biopsy containing prostatic tissue at the 5 and/or 7 o'clock position of the verumontanum portion substantially improves the detection of prostatic duct and acini involvement in bladder cancer patients. Moreover, if the prostatic superficial glands are involved at the 5 and/or 7 o'clock position of the verumontanum portion, the potential involvement of the deeper glands should also be suspected.
To determine the clinical utility of urine-based bladder tumor markers (UBBTMs) and cytology in the treatment of patients with transitional cell carcinoma on the basis of their statistical performance.
A comprehensive literature review was performed using Medline (1966 to current) and other search engines. Data regarding the statistical performance of UBBTMs were double extracted and rectified. Studies addressing comparable patient populations were combined and hierarchical Bayesian meta-analyses performed to calculate the sensitivity and specificity of commonly used UBBTMs, as well as urinary cytology. Patient populations were stratified by tumor stage and grade when data were presented in an extractable fashion.
The literature review yielded 54 publications, 338 distinct patient groups (controls, screening population, patients with cancer, strata based on grade and stage) and more than 10,000 patients. The number of groups varied from 1 to 18, and the number of patients ranged from less than 100 to more than 1500 for the various markers. All UBBTMs have better sensitivity compared with cytology, especially for low-grade/stage disease, but do not match cytology regarding specificity. In patients with grade 1 and 2 tumors, several UBBTMs are significantly superior statistically in terms of sensitivity compared with cytology. The sensitivity for transitional cell carcinoma in situ (Tis) is surprisingly poor for all UBBTMs.
UBBTMs can be used for follow-up of low-grade/stage tumors but should not replace cystoscopy. All UBBTMs have better sensitivity than cytology and could potentially replace routine cytology during patient follow-up.
We examined the sensitivity and specificity of Hexvix (PhotoCure ASA, Oslo, Norway) hexyl aminolevulinate (HAL) fluorescence cystoscopy in patients with superficial bladder cancer.
A total of 52 patients (38 men and 14 women) with a mean age of 72 years were investigated. HAL hydrochloride (100 mg dissolved in 50 ml phosphate buffer solution) (8 mM) was instilled into the bladder 1 hour prior to the endoscopic procedure. Cystoscopy was performed with the Storz D-light (Karl Storz, Tuttlingen, Germany) system, allowing inspection of the bladder wall under white and blue light (380 to 450 nm).
A total of 422 biopsies obtained in fluorescing (165) and nonfluorescing (257) areas, including 5 random biopsies per patient, were analyzed to provide the best reference for the calculation of sensitivity and specificity. There were a total of 143 histologically verified tumors in 45 patients, including carcinoma in situ (CIS), Ta or T1 lesions. A total of 43 patients were diagnosed by fluorescence cystoscopy compared with 33 diagnosed by white light for 96% and 73% per-patient sensitivity, respectively. HAL cystoscopy was found particularly useful for finding CIS tumors. Of 13 patients with CIS tumors all except 1 were diagnosed or confirmed by HAL cystoscopy. HAL cystoscopy was well tolerated with no definite drug related adverse events reported, including effects on standard blood parameters.
HAL fluorescence cystoscopy is a new, sensitive, promising diagnostic procedure that showed improved detection of bladder tumors, in particular CIS. The procedure is well tolerated and can easily be implemented in current clinical practice.
A combination of methods is used for diagnosis of bladder cancer because no single procedure detects all malignancies. Urine tests are frequently part of an evaluation, but have either been nonspecific for cancer or required specialized analysis at a laboratory.
To investigate whether a point-of-care proteomic test that measures the nuclear matrix protein NMP22 in voided urine could enhance detection of malignancy in patients with risk factors or symptoms of bladder cancer.
Twenty-three academic, private practice, and veterans' facilities in 10 states prospectively enrolled consecutive patients from September 2001 to May 2002. Participants included 1331 patients at elevated risk for bladder cancer due to factors such as history of smoking or symptoms including hematuria and dysuria. Patients at risk for malignancy of the urinary tract provided a voided urine sample for analysis of NMP22 protein and cytology prior to cystoscopy.
The diagnosis of bladder cancer, based on cystoscopy with biopsy, was accepted as the reference standard. The performance of the NMP22 test was compared with voided urine cytology as an aid to cancer detection. Testing for the NMP22 tumor marker was conducted in a blinded manner.
Bladder cancer was diagnosed in 79 patients. The NMP22 assay was positive in 44 of 79 patients with cancer (sensitivity, 55.7%; 95% confidence interval [CI], 44.1%-66.7%), whereas cytology test results were positive in 12 of 76 patients (sensitivity, 15.8%; 95% CI, 7.6%-24.0%). The specificity of the NMP22 assay was 85.7% (95% CI, 83.8%-87.6%) compared with 99.2% (95% CI, 98.7%-99.7%) for cytology. The proteomic marker detected 4 cancers that were not visualized during initial endoscopy, including 3 that were muscle invasive and 1 carcinoma in situ.
The noninvasive point-of-care assay for elevated urinary NMP22 protein can increase the accuracy of cystoscopy, with test results available during the patient visit.
Introduction:
The follow-up of patients with urothelial cell carcinoma (UCC) of the bladder is done by cystoscopy and, in most cases, cytology. The last decade, many urine-based tests for UCC have been developed and tested in different populations. For the urological practice, considering the amount of follow-up cystoscopies, especially urine markers for recurrent disease would be useful. Therefore, we reviewed the literature on these markers for recurrent UCC and compared our findings with recent review-articles.
Methods:
We performed a PubMed search. In case of primary and recurrent disease, the study was included if the patients under surveillance were reported separately. Patients with no evidence of disease at surveillance cystoscopy were considered to determine specificity. A marker was included if at least 2 studies from 2 different institutions/authors were available.
Results:
The literature review yielded 64 articles. We found 18 markers (BTAstat, BTAtrak, NMP22, FDP, ImmunoCyt, Cytometry, Quanticyt, Hb-dipstick, LewisX, FISH, Telomerase, Microsatellite, CYFRA21-1, UBC, Cytokeratin20, BTA, TPS, Cytology) that met our criteria. BTAstat, NMP22, ImmunoCyt and cytology were evaluated in more than 750 patients. Telomerase, Cytokeratin20 and Hb-dipstick were tested in less than 250 patients. The highest median sensitivities were reported for CYFRA21-1 (85%), Cytokeratin20 (85%) and Microsatellite analysis (82%). The highest specificities were reported for Cytology (94%), BTA (92%) and Microsatellite analysis (89%). In comparison with recent reviews, median sensitivity was>or=5% lower for the surveillance group in 13/18 urine-based tests while specificity remained relatively constant between different patient groups.
Conclusions:
To our knowledge, this is the first review that assesses sensitivity and specificity of urine markers solely for UCC surveillance. In our view, Microsatellite analysis, ImmunoCyt, NMP22, CYFRA21-1, LewisX and FISH are the most promising markers for surveillance at this time. Nevertheless, clinical evidence is insufficient to warrant the substitution of the cystoscopic follow-up scheme by any of the currently available urine marker tests. Future studies may test some of the most sensitive and specific assays to reduce the cystoscopy frequency. However, our results show that initiators of these studies should anticipate a lower sensitivity than reported in the current literature.
Bladder cancer is a frequent disease and represents the second most common genitourinary neoplasm. Although many aspects of the management of superficial bladder cancer are now well established, significant challenges remain, which influences patient outcome. Early detection and treatment of recurrent disease is required to optimize bladder preservation, reduce patient morbidity, and increase quality of life and survival. Fluorescence endoscopy, often referred to as 'photodynamic diagnosis' (PDD), with intravesical application of photosensitizing agents, has been developed to enhance the early detection of bladder cancer. There is growing evidence that PDD using 5-aminolaevulinic acid (ALA), hexyl-ALA ester or hypericin enhances the detection of bladder cancer, particularly of high-grade flat lesions. Furthermore, transurethral resection of bladder tumour under fluorescence guidance reduces the risk of recurrent tumours. However, the impact on the progression of disease remains unclear and must be investigated in prospective randomized trials.
We determined if improved tumor detection using hexaminolevulinate (HAL) fluorescence cystoscopy could lead to improved treatment in patients with bladder cancer.
A total of 146 patients with known or suspected bladder cancer were assessed in this open, comparative, within patient, controlled phase III study. Patients received intravesical HAL for 1 hour and were assessed with standard white light cystoscopy and blue light fluorescence cystoscopy. All lesions were mapped onto a bladder chart and biopsies were taken from suspicious areas for assessment by an independent pathologist. An independent urologist blinded to the detection method used recommended treatment plans based on biopsy results and medical history according to European Association of Urology bladder cancer guidelines. Any differences in recommended treatment plans arising from the 2 cystoscopy methods were recorded.
HAL imaging improved overall tumor detection. Of all tumors 96% were detected with HAL imaging compared with 77% using standard cystoscopy. This difference was particularly noticeable for dysplasia (93% vs 48%), carcinoma in situ (95% vs 68%) and superficial papillary tumors (96% vs 85%). As a result of improved detection, additional postoperative procedures were recommended in 15 patients (10%) and more extensive treatment was done intraoperatively in a further 10. Overall 17% of patients received more appropriate treatment at the time of the study following blue light fluorescence cystoscopy, that is 22% or 1 of 5 if patients without tumors were excluded.
HAL imaging is more effective than standard white light cystoscopy for detecting bladder tumors and lesions. This leads to improved treatment in a significant number of patients (p <0.0001).
This is the first of 2 articles that summarize the findings of the International Consensus Panel on cytology and bladder tumor markers. The objectives of our panel were to reach a consensus on the areas where markers are needed, to define the attributes of an ideal tumor marker, and to identify which marker(s) would be suitable for diagnosis and/or surveillance of bladder cancer. Our panel consisted of urologists and researchers from Europe, Asia, and the United States who reviewed original articles, reviews, and book chapters on individual bladder tumor markers published in the English language mainly using the PubMed search engine. Panel members also met during 3 international meetings to write recommendations regarding bladder tumor markers. The panel found that the most practical use of noninvasive tests is to monitor bladder cancer recurrence, thereby reducing the number of surveillance cystoscopies performed each year. Markers also may be useful in the screening of high-risk individuals for early detection of bladder cancer. However, more prospective studies are needed to strengthen this argument. Case-control and cohort studies show that several markers have a higher sensitivity to detect bladder cancer. However, cytology is the superior marker in terms of specificity, although some markers in limited numbers of studies have shown specificity equivalent to that of cytology. Our panel believes that several bladder tumor markers are more accurate in detecting bladder cancer than prostate-specific antigen (PSA) is in detecting prostate cancer. However, bladder tumor markers are held to a higher standard than PSA. Therefore, use of bladder tumor markers in the management of patients with bladder cancer will require the willingness of both urologists and clinicians to accept them.
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.
Discrimination between malignant and nonmalignant conditions remains the key problem in assessing microhaematuria. This prospective study investigated the role of immunocytology in the evaluation of patients with microhaematuria.
uCyt+ is a commercially available immunocytologic assay based on microscopic detection of tumour-associated antigens on the membrane of urothelial cells by immunofluorescence. Between October 2000 and August 2005, 189 consecutive patients with newly diagnosed painless microhaematuria without prior transitional cell carcinoma were included. All urine samples were examined cytologically and immunocytologically. Of the 189 samples, 178 (94%) were assessable.
Clinical assessment by physical examination, laboratory tests, endoscopy, and imaging modalities found bladder cancer in 8 patients (4%). Further diagnoses were benign prostatic hyperplasia (54 cases, 29%), cystitis (including interstitial cystitis; 20 cases, 11%), urolithiasis (18 cases, 9%), tumours of other origin (6 cases, 2%), and "further conditions" (26 cases, 13%). In 57 patients (30%) the reasons for haematuria were not disclosed. Immunocytology was positive in 7 of 8 bladder tumours (87%) and negative in 154 of 170 patients with haematuria for other reasons (91%).
The high sensitivity and good specificity of immunocytology in the diagnosis of bladder cancer was confirmed in this population with a low disease prevalence. Only one tumour of low malignant potential was missed by immunocytology. If assessment of these patients would have been based only on immunocytology, 154 costly and invasive diagnostic procedures could have been avoided, with only 16 of 170 individuals (9%) undergoing these examinations unnecessarily. The findings justify a prospective investigation of this issue.
We determined the usefulness of computerized tomographic urography for the initial evaluation of patients with hematuria as an alternative to excretory urography.
A total of 259 patients (140 men and 119 women), age range 20 to 100 (mean 59.4) years, underwent computerized tomographic urography for the evaluation of hematuria and were available for followup. A cohort of 253 patients (153 men, 100 women), age range 21 to 92 (mean 57.6) years, underwent conventional excretory urography and were evaluated for comparison.
A source of hematuria was identified in 107 patients (41.3%) in the computerized tomographic urography cohort and in 103 patients (40.7%) in the excretory urography cohort. Computerized tomographic urography alone identified a source of hematuria in 25.5% of these patients with the most commonly diagnosed lesions being renal calculi (18.9%), ureteral calculi (2.7%) and renal pelvic masses (2.3%) in the upper tract (0.94 sensitivity), and bladder masses (8.1%), prostatic abnormalities (5.4%) and inflammatory disorders (3.5%) in the lower tract (0.40 sensitivity, 0.99 specificity). The overall detection rate (19.5%), most commonly diagnosed lesions, and lower urinary tract sensitivity and specificity were similar in the excretory urography cohort. However, excretory urography exhibited a markedly lower sensitivity in detecting upper tract lesions (0.50).
Computerized tomographic urography exhibited a significantly higher sensitivity than conventional excretory urography in detecting upper tract pathology (94.1% vs 50%). However, sensitivity for detecting lower tract lesions was low (40% or less), suggesting that computerized tomographic urography offers a comprehensive alternative to excretory urography but does not obviate the need for adjunctive cystourethroscopy for accurate evaluation of the lower urinary tract.
This study was conducted to explore the diagnosis and management of urothelial carcinoma of the prostate in superficial disease and carcinoma in situ, stromal invasion, primary urothelial carcinoma, and urethral recurrence after radical surgery. A consensus conference convened by the World Health Organization (WHO) and the Société Internationale d'Urologie (SIU) reviewed the diagnosis and management of urothelial carcinoma of the bladder. English-language literature about urothelial carcinoma of the prostate was identified and reviewed. Evidence-based recommendations for the diagnosis and management of urothelial carcinoma were made. Many recommendations were level 3 or 4 citations involving the diagnosis and management of superficial urothelial carcinoma; a few were level 2 citations. Level 1 citations related only to chemotherapy and radiotherapy in patients with stromal invasion, although these were not related specifically to invasive prostatic involvement. More than 130 reviewed citations are summarized in this review. Published reports on the diagnosis and treatment of superficial urothelial disease of the prostate primarily consist of short case series from individual centers. Prospective and multicenter trials are needed to identify the real incidence and the best management of these patients. In invasive disease of the prostate, the only large series were designed to investigate invasive bladder cancer.
Photodynamic diagnosis (PDD) using 5-aminolevulinic acid has proved to be a procedure with an outstanding sensitivity for the detection of transitional cell carcinoma of the bladder, in particular in the detection of flat urothelial lesions. We report on our clinical results with 875 patients (1713 PDD procedures) between March 1995 and March 2002.
A total of 1713 PDD procedures were done in 875 patients. Fluorescence imaging was performed 2 to 3 hours after instillation of 50 mL of a 3% solution of 5-aminolevulinic acid into the bladder by an incoherent light source. In total, specimens from 4630 lesions (2.7 lesions/PDD) were taken.
In 34.8% of all biopsies, the histologic finding was malignant; 23.7% of these biopsies had been taken only because of positive fluorescence. In 28.5% of the positive biopsies, flat lesions had been identified. Also, 43.4% of carcinoma in situ and 30.7% of dysplasia II degrees were detected only by positive fluorescence. Of all tumor lesions, 92.0% were detected by PDD compared with 76.3% detected by white light endoscopy.
PDD has proved to be an effective detection device for superficial bladder cancer.
To investigate whether narrow-band imaging (NBI) flexible cystoscopy improves the detection rate of urothelial carcinomas (UCs) of the bladder. NBI is an optical image enhancement technology in which the narrow bandwidth of light is strongly absorbed by haemoglobin and penetrates only the surface of tissue, increasing the visibility of capillaries and other delicate tissue surface structures by enhancing contrast between the two.
Between November 2005 and May 2007 at the Queen Elizabeth Hospital, Birmingham, NBI flexible cystoscopy was performed on 29 patients with known recurrences of UC of the bladder after initial conventional white-light imaging (WLI) flexible cystoscopy with the same instrument (Olympus Lucera sequential RGB endoscopy system).
Subjectively, NBI provided a much clearer view of bladder UCs and in particular their delicate capillary architecture. Objectively, NBI detected 15 additional UCs in 12 of 29 patients (41%), as compared with WLI. The mean (sd) difference was 0.52 (0.74) UCs per patient (P < 0.001, Wilcoxon signed-rank test).
Even in the few patients studied there is strong evidence that NBI differs from WLI in the number of UCs it detects, with a significantly increased detection rate. We feel that further evaluation of NBI flexible cystoscopy in more patients will show this technique to be highly valuable in the detection of both new and recurrent bladder UCs, and this work is continuing in our unit.
Many markers for the detection of bladder cancers have been tested. Almost all urinary markers reported are better than cytology with regard to sensitivity, but they score lower in specificity. The purpose of this review is to highlight the most important urinary biomarkers studied and reported recently.
Literature on bladder cancer markers has been reviewed regularly in the last few years. In the current review we have tried to summarise the most recent literature of urinary markers.
The results of this review show that the first-generation urinary markers did not add much to urinary cytology. The current generation of markers is promising but larger clinical trails are needed. The future of marker development is bright with new techniques emerging, but the perfect marker is still to be found.
Currently, no single marker can yet guide us in surveillance and lower the frequency of urethrocystoscopy.