Hexaminolevulinate photodynamic diagnosis in non-muscle invasive bladder cancer: experience of the BLUE group

ObjectivesPhotodynamic diagnosis (PDD) with hexaminolevulinate has been recently used to improve detection of non-muscle invasive bladder cancer. Our main purpose was to quantify the benefit of PDD vs. conventional white light cystoscopy (WL) in our area.Material and methodsFluorescence-guided cystoscopy using hexaminolevulinate was performed at the time of the transurethral resection (TUR) in 305 patients from 7 Spanish hospitals. All lesions found with WL and PDD were numbered and recorded in an online database. Each lesion was sent separately for pathology analysis. Random biopsies were also obtained in 148 patients.ResultsA total of 1659 lesions were biopsied: 522 were identified with PDD and WL, 237 only with PDD, 19 only with WL and 881 random biopsies. Of the 600 tumors, PDD detected 563, WL 441 and random biopsies 29 (20 CIS). The mean overdetection rate for PDD over WL was 31.9% for all types of lesions, but it was 209% for carcinoma in situ (CIS). Sensitivity was 93.8% for PDD and 78.2% for WL. Specificity was 81.5% for PDD and 90.5% for WL. In 23% of patients, PDD detected at least one additional neoplastic lesion compared to WL.ConclusionsHexaminolevulinate fluorescence cystoscopy improves detection and resection of non-muscle invasive bladder cancer, especially of CIS. Sensitivity of PDD is higher than WL, but specificity is lower. In our study, random biopsies were able to detect some CIS not visible under PDD.     

Hexaminolevulinate-guided transurethral resection of non-muscle-invasive bladder cancer does not reduce the recurrence rates after a 2-year follow-up: a prospective randomized trial

Purpose

To assess the impact of hexaminolevulinate (HAL) on the long-term recurrence rate of NMIBC.

Methods

A total of 130 patients with bladder tumour were randomized into two groups. The patients in one group had a HAL instillation before surgery, and they first had a white-light and after that a blue-light cystoscopy (BL group) and resection. The second group had only white-light cystoscopy (WL group) and resection. They have been followed up with cystoscopy every 3 months for a period of up to 40 months.

Results

The recurrence-free period was not significantly different between the two groups (BL and WL groups) (long-rank test p = 0.202). The use of HAL helped detect four flat lesions and 28 papillary lesions with cancer that would have been missed under WL only, on 16 out of the 54 patients (29.6 % CI 95 % 11.1–33.3). The use of HAL changed the proposed postoperative treatment and follow-up for one out of the five patients.

Conclusions

Although the use of HAL cystoscopy identified at least one cancer lesion more than WL cystoscopy on one out of the three patients, the recurrence-free period was not significantly different.     

Fluorescence Cystoscopy with High-Resolution Optical Coherence Tomography Imaging as an Adjunct Reduces False-Positive Findings in the Diagnosis of Urothelial Carcinoma of the Bladder

Background

The advantage of photodynamic diagnosis in detecting urothelial cell carcinoma (UCC) of the bladder has been demonstrated clearly, but it comes at the price of a higher false-positive rate. Optical coherence tomography (OCT) is a noninvasive, real-time, microstructural imaging modality that uses near-infrared light for a point analysis of the bladder-wall microstructure.

Objective

To evaluate whether adding targeted OCT analysis of lesions that are suspicious at white-light (WL) and hexaminolevulinate (HAL) fluorescence cystoscopy improves diagnostic accuracy in the detection of UCC.

Design, setting, and participants

In this prospective single-center study with same-patient comparison, patients with suspected UCC first received an intravesical instillation of HAL. Cystoscopy was performed in WL, followed by blue-light inspection and OCT scanning.

Intervention

Suspicious lesions identified by WL or HAL were evaluated by OCT and were subsequently resected or biopsied.

Measurements

We measured changes in sensitivity and specificity in detecting UCC using WL, HAL, and targeted OCT.

Results and limitations

In 66 patients studied, 232 lesions were detected, were scanned by OCT, and were subsequently resected or biopsied. Additionally, 132 areas of normal-appearing urothelium were investigated by all three methods and biopsied. On a per-lesion basis, sensitivity and specificity were respectively 69.3% and 83.7% for WL, 97.5% and 78.6% for HAL, and 97.5% and 97.9% for HAL combined with OCT. Overall, UCC was diagnosed in 58 patients (87.9%), with a per-patient sensitivity of 89.7% for WL and 100% for both HAL alone and HAL with targeted OCT. Per-patient specificity for HAL alone and targeted HAL was 62.5% and 87.5%, respectively. The limitation of OCT results from poor visualization of flat lesions in WL, making scanning a time-consuming procedure.

Conclusions

Combining fluorescence cystoscopy with targeted OCT increases the specificity of fluorescence cystoscopy significantly, with no added morbidity, and reduces the need for unnecessary (false-positive) biopsies.     

Safety of repeat blue light cystoscopy with hexaminolevulinate (HAL) in the management of bladder cancer: Results from a phase III,comparative, multi-center study

PurposeThe therapeutic benefit of intravesical instillation of hexaminolevulinate (HAL) at the time of transurethral resection of bladder tumor (TURBT) has been demonstrated in multiple studies. The purpose of this study was to prospectively assess the safety of repeated administration of HAL from a phase III pre-trial planned analysis.Materials and methodsAll patients evaluated in the study received at least 1 dose of HAL at the time of office cystoscopy, and a subset of these patients (n = 103, 33.2%) received a second dose a few weeks later at the time of TURBT. Adverse events (AEs) were recorded, and the safety of repeat use of HAL was determined by comparing the proportion of patients with AEs considered causally related to HAL in the surveillance examination compared to the OR examination. Association between categorical variables was tested using Fisher's Exact Test, and a P < 0.05 was considered statistically significant.ResultsHAL-related AEs were experienced by 6 patients (2.2%) during surveillance cystoscopy and 3 patients (3.4%) following TURBT (P = 0.76); 181 patients (59.5%) had prior exposure to HAL before enrolling in the study with no difference in the number of AEs when comparing prior exposure to HAL to no prior exposure (P = 0.76). Of the patients who previously received intravesical therapy, 8 (2.9%) had at least 1 AE during surveillance compared to 3 (9.7%) who had no prior intravesical therapy (P = 0.09).ConclusionsRepeat use of HAL is safe even when administered within a few weeks of receiving a dose of intravesical therapy.     

Urinary cytology for the detection of urothelial carcinoma of the bladder—a flawed adjunct to cystoscopy?

ObjectivesTo test the sensitivity of urinary cytology at a tertiary academic institution and to assess the impact of pathologist' experience on detection of urothelial carcinoma of the bladder (UCB).Materials and methodsBetween April 1999 and September 2008, 8,574 cytology specimens were evaluated. There were 882 consecutive patients (612 males, 270 females) who underwent bladder biopsy or transurethral resection of bladder tumor for UCB. Sensitivity rates of prior urinary cytology were determined. We tested the influence of experience of pathologist on sensitivity.ResultsUrinary cytology detected 237 out of 503 UCB (overall sensitivity 47.1%). Cytology after bladder washing resulted in higher sensitivity than in voided urine (50.4% vs. 36.2%; P = 0.008). Sensitivity rates significantly increased by UCB stage; 30.6% in pTa (n = 245), 60.5% in patients with any form of CIS (n = 119), 62.9% in pT1 (n = 89), and 69.6% in ≥pT2 (n = 46; P < 0.001). Similarly, higher sensitivity was observed with increasing grade, ranging from 16.7% in low (n = 108) to 62.2% in high grade tumors (n = 283; P < 0.001). No statistically significant difference between more and less experienced investigators was observed.ConclusionsSensitivity rates of urinary cytology at our institution are not superior to those reported in the literature. Cytology missed many high grade cancers, pointing to inherent methodological limitations of urinary cytology. A higher experience level of the pathologist was not significantly associated with higher sensitivity rates. Urinary cytology represents a flawed adjunct to cystoscopy with limited potential of improvement even in the hands of experienced pathologists.     

Transurethral Resection of Non–Muscle-Invasive Bladder Transitional Cell Cancers With or Without 5-Aminolevulinic Acid Under Visible and Fluorescent Light: Results of a Prospective,Randomised, Multicentre Study

Background

Fluorescent light (FL)–guided cystoscopy induced by 5-aminolevulinic acid (5-ALA) has been reported to detect more tumours compared with standard white-light (WL) cystoscopy. Most reports are from single centres with relatively few patients.

Objective

To evaluate whether 5-ALA–induced FL and WL cystoscopy at transurethral resection (TUR) is superior compared with standard procedures under WL only with respect to tumour recurrence and progression in patients with non–muscle-invasive bladder cancer.

Design, setting, and participants

This randomised, multicentre, observer- and pathologist-blinded, prospective phase 3 clinical trial enrolled 300 patients, and of those patients, 153 were randomised to FL cystoscopy and 147 were randomised to standard WL cystoscopy.

Intervention

All patients were first inspected under WL and all lesions were recorded. Patients randomised to FL underwent a second inspection. TUR was carried out in both groups.

Measurements

Control cystoscopy under WL was performed in all patients every 3 mo during the first year after randomisation and biannually thereafter.

Results and limitations

At the first TUR, the mean number of resection specimens per patient was 2.5 (FL: 2.5; WL: 2.4; p = 0.37) and the resulting mean number of resected tumours was 1.7 with FL and 1.8 with WL (p = 0.85). More patients were diagnosed with carcinoma in situ (CIS) in the WL group (13%) than in the FL group (4.2%). Within-patient comparison of FL patients only showed that FL detected more lesions than WL. Tumour lesions solely detected by FL cystoscopy that would not otherwise be detected by WL cystoscopy included 52% dysplasia, 33% CIS, 18% papillary neoplasms, 13% pT1, and 7% pTa. Outcome at 12 mo did not show any difference between groups with regard to recurrence-free and progression-free survival rates.

Conclusions

In this prospective, randomised, multi-institutional study, we found no clinical advantage of FL cystoscopy compared with WL cystoscopy and TUR.     

Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy

PURPOSE: In this European multicenter study we compared hexaminolevulinate (HAL) fluorescence cystoscopy and standard white light cystoscopy for the detection of carcinoma in situ (CIS) in patients suspected of having high risk bladder cancer. MATERIALS AND METHODS: This study was a prospective controlled, within-patient comparison of standard and HAL fluorescence cystoscopy. Eligible patients received an intravesical instillation of 50 ml HAL 8 mM solution. Cystoscopy was performed using a D light system, which provided white and blue light at 375 to 440 nm. The bladder wall was inspected and mapped, first under white light, followed by blue light. All tumors and suspicious areas identified under white light and by red fluorescence were resected or biopsied. Histological findings were assessed by an independent central pathologist blinded to the identity of the biopsies. RESULTS: Of 211 evaluable patients 83 (39%) had CIS, of whom 18 (22%) were detected by HAL cystoscopy only, 62 (75%) were detected by standard and HAL cystoscopy, 2 (2%) were detected by standard cystoscopy only and 1 (1%) was detected by nonguided biopsy. Therefore, HAL cystoscopy identified 28% more patients with CIS than standard cystoscopy. The side effects of HAL instillation were negligible and no unexpected events were reported. CONCLUSIONS: HAL fluorescence cystoscopy improves the detection of bladder CIS significantly, which has consequences for clinical management and may improve the patient prognosis. The procedure is easily implemented as an adjunct to standard cystoscopy and it adds no significant risk of complications.     

Photodynamic Diagnosis of Non–muscle-invasive Bladder Cancer with Hexaminolevulinate Cystoscopy: A Meta-analysis of Detection and Recurrence Based on Raw Data

Background

Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence.

Objective

To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence.

Design, setting, and participants

This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non–muscle-invasive bladder cancer (NMIBC).

Intervention

A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy.

Outcome measurements and statistical analysis

We studied the detection of NMIBC (intention to treat [ITT]: n = 831; six studies) and recurrence (per protocol: n = 634; three studies) up to 1 yr. DerSimonian and Laird's random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection.

Results and limitations

BL cystoscopy detected significantly more Ta tumours (14.7%; p < 0.001; odds ratio [OR]: 4.898; 95% CI, 1.937–12.390) and CIS lesions (40.8%; p < 0.001; OR: 12.372; 95% CI, 6.343–24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p < 0.001), significant also in patients with primary (20.7%; p < 0.001) and recurrent cancer (27.7%; p < 0.001), and in patients at high risk (27.0%; p < 0.001) and intermediate risk (35.7%; p = 0.004). In 26.7% of patients, CIS was detected only by BL (p < 0.001) and was also significant in patients with primary (28.0%; p < 0.001) and recurrent cancer (25.0%; p < 0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p = 0.006; RR: 0.761 [0.627–0.924]), and lower in patients with T1 or CIS (p = 0.052; RR: 0.696 [0.482–1.003]), Ta (p = 0.040; RR: 0.804 [0.653–0.991]), and in high-risk (p = 0.050) and low-risk (p = 0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used.

Conclusions

This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9–12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.     

The bladder epicheck test and cytology in the follow-up of patients with non-muscle-invasive high grade bladder carcinoma.

BackgroundThe management of non-muscle invasive bladder carcinoma (NMIBC) after transurethral resection of a bladder tumor consists of adjuvant intravesical therapy and strict and long surveillance with urine cytology and cystoscopy. The Bladder EpiCheck test (Nucleix Ltd) (BE) is a newly developed urinary markers based on DNA methylation changes in a panel of 15 genomic biomarkers, with a promising performance in term of non-invasive NMIBC detection.MethodsIn this study we prospectively enrolled 151 consecutive patients with high grade NMIBC, treated with intravesical BCG and mitomycin C therapy and evaluated during the follow-up by voided urine cytology and white-light cystoscopy, according to the European Association of Urology Guidelines. The Bladder EpiCheck test was performed at the same time of urine cytology in voided specimen. In all cases with positive cytology the diagnosis was confirmed by histology and a diagnosis was made according to the 2017 tumor, node, metastasis (TNM) classification and graded using both the 1973 and the 2004 World Health Organization (WHO) classifications.ResultsAt three months of follow-up, we reported similar overall specificity rates for BE and urine cytology (85,1% vs 86,3%). In the group of patients with carcinoma in situ (CIS), we found the same specificity for BE and urine cytology (81,4%), while in the groups of patients with papillary high grade NMIBC, the specificity of BE was higher compared to cytology (96,3% vs 90,4%). The sensitivity of BE was always higher compared to cytology during all the follow-up both for papillary NMIBC and CIS.ConclusionIn the early follow-up of NMIBC the EpiCheck test might replace urinary cytology.     

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

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

Evaluating the need for transurethral bladder biopsy at first follow up after intravesical BCG therapy for superficial bladder cancer: Preliminary data

IntroductionPatients with high-risk superficial transitional cell carcinoma (TCC) of the bladder have a lifelong risk of progression and require particular attention. Intravesical Bacillus Calmette-Guerin (BCG) is recommended as a first-choice adjuvant treatment to reduce the risk of progression of high-grade tumors and carcinoma in situ (CIS).ObjectivesTo evaluate the need for routine transurethral bladder biopsy from the site of previously resected tumor three months following intravesical BCG therapy, even if the urine cytology and cystoscopy were both negative.Subjects and methodsA prospective study was carried out on 45 patients of both genders presenting with superficial bladder cancer. All patients received a six-week course of intravesical BCG. The mean age of the patients was 59 (range 33–80) years. Three months following resection, urine cytology was negative in all patients. Cystoscopy was then performed and although it was negative for any suspicious lesions, a routine biopsy from the previous resection site was taken.ResultsThe indication for BCG instillation was T1G1 in 20 patients (44%), T1G2 in 12 patients (27%) and TaG2 in eight patients (18%). Three patients (7%) had a positive bladder biopsy for malignancy at follow-up despite the negative cystoscopy and cytology. There were no statistically significant differences between patients with positive and those with negative biopsies with regard to the stage and grade of the tumor before resection or the number of resected lesions. The original pathology of the three positive patients was T1G1 (two patients) and T1G2 (one patient). The pathology after BCG treatment was the same as before instillation, T1G1 (two patients) and T1G2 (one patient).ConclusionUntil more studies on larger numbers of patients are done, a routine biopsy from the site of previously resected tumor at the time of check cystoscopy may improve the detection of tumor recurrence.     

Evaluation of tissue and urinary survivin expression in non-muscle-invasive bladder cancer

IntroductionApproximately 70% of bladder cancers are non-muscle-invasive (NMIBC), and respond well to endoscopic transurethral resection. However, 70% of these patients experience tumor recurrence. As the tendency for local recurrence and/or progression extends over the lifetime, patients with superficial bladder cancer must undergo life-long surveillance. Combination of cystoscopy and urine cytology is considered the “gold standard” for this surveillance. However, they suffer from drawbacks where cystoscopy is an invasive procedure and urine cytology shows limited ability to detect low grade bladder tumors. Therefore, new non-invasive tests with high sensitivity and specificity that are easy to perform are needed not only for initial diagnosis but also in surveillance for recurrent tumors.ObjectiveTo investigate the magnitude investigate the magnitude of survivin expression in non-muscle-invasive bladder cancer and its possible value as a non invasive diagnostic tool.Patients and methodsFrom March 2010 to October 2010, 68 patients with known history of NMIBC who were scheduled for follow-up cystoscopy in the department of Urology, Alexandria University were included in this study prospectively. All patients underwent cystoscopy under general anaesthesia, and those who were found to have a definite or suspicious lesion(s) in the bladder underwent complete TURBT. Survivin expression was determined in urine and in bladder cancer tissue both by Western blotting and by ELISA.ResultsThe study included 68 patients. Tumor recurrence was detected in 38 patients, of whom, 24 had low grade recurrence. The urinary concentration of survivin was significantly higher in the recurrence group by both detection methods (U = 141, P = 0.018 and χ² = 10.46, P = 0.001 for ELISA and WB respectively). Survivin by ELISA showed higher sensitivity and specificity (84.4% and 100%) than that by WB (55.3% and 93.3%). In tumor tissue, by both methods, survivin was detected in higher levels than in urine but there was no significant correlation between urinary and tissue levels neither in the whole recurrence group nor in the low grade subgroup.ConclusionUrinary survivin is a useful marker for non-invasive detection of non-muscle-invasive bladder cancer recurrence. Its detection is better using ELISA technique than WB and there is no correlation between its expression in tissue and urine.     

Positive urine cytology but negative white‐light cystoscopy: an indication for fluorescence cystoscopy?

OBJECTIVE

To evaluate the possible benefit of fluorescence cystoscopy (FC) in detecting cytologically ‘confirmed’ lesions when assessing urothelial carcinoma of the bladder, as negative white‐light cystoscopy in cases of a positive cytological finding represents a diagnostic dilemma.

PATIENTS AND METHODS

From January 1996 to December 2006, 348 patients, who had cystoscopy for surveillance or due to suspicion of urothelial carcinoma, presented with an entirely negative white‐light cystoscopy at our hospital. However, 77 of the 348 patients (22.2%) were diagnosed with a positive cytological finding. All patients had white‐light cystoscopy first and a bladder‐wash cytological specimen was obtained, then FC, followed by cold‐cup biopsies and/or transurethral resection of the bladder tumour.

RESULTS

In the 77 patients with a positive cytological specimen FC enabled the detection of the precise site of malignancy within the bladder in 63 (82%). As malignant or premalignant lesions, there were 18 moderate dysplasias, 27 carcinoma in situ (CIS), and 18 pTa‐1/G1‐3 tumours. Moreover using FC, malignant or premalignant lesions were detected in 43 of 271 patients (15.9%) who had a negative cytological specimen (15 moderate dysplasias, six CIS, 22 pTa‐1/G1‐3).

CONCLUSION

This study shows that FC is beneficial in the detection of malignant and premalignant lesions, if there is negative white‐light cystoscopy but positive urine cytology. The immediate identification of the exact site of a malignant lesion during FC enables the physician to diagnose and treat these patients more accurately and with no delay.     

A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer

PURPOSE: We compared hexaminolevulinate fluorescence cystoscopy with white light cystoscopy for detecting Ta and T1 papillary lesions in patients with bladder cancer. MATERIALS AND METHODS: A total of 311 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM HAL for 1 hour. The bladder was inspected using white light cystoscopy, followed by blue light (fluorescence) cystoscopy. Papillary lesions were mapped and resected for histological examination. RESULTS: Noninvasive pTa tumors were found in 108 of 196 evaluable patients (55.1%). In 31 patients (29%) at least 1 more tumor was detected by HAL than by white light cystoscopy (p<0.05). Six of these patients had no lesions detected by white light, 12 had 1 lesion detected by white light and more than 1 by HAL, and 13 had multiple Ta lesions detected by the 2 methods. Conversely at least 1 more tumor was detected by white light cystoscopy than by HAL cystoscopy in 10 patients (9%, 95% CI 5-16). Tumors invading the lamina propria (T1) were found in 20 patients (10.2%). At least 1 additional T1 tumor was detected by HAL but not by white light cystoscopy in 3 of these patients (15%), while at least 1 more T1 tumor was detected by white light cystoscopy than by HAL cystoscopy in 1 patient (5%, 95% CI 0-25). Detection rates for Ta tumors were 95% for HAL cystoscopy and 83% for white light cystoscopy (p=0.0001). Detection rates were 95% and 86%, respectively, for T1 tumors (p=0.3). HAL instillation was well tolerated with few local or systemic side effects. CONCLUSIONS: HAL fluorescence cystoscopy detected at least 1 more Ta and T1 papillary tumor than white light cystoscopy in approximately a third of the patients with such tumors. Whether this would translate to improved patient outcomes has yet to be determined.     

Photodynamic Diagnosis in Non-Muscle-Invasive Bladder Cancer

ObjectiveThis paper reviews the development and clinical validation of photodynamic diagnosis (PDD) of bladder cancer.MethodsThe authors reviewed the literature on the development of PDD, in particular the evidence for the clinical efficacy of hexaminolevulinate PDD in the diagnosis of bladder cancer.ResultsAfter initial work on ultraviolet cystoscopy following oral tetracycline, the focus of PDD research shifted to the use of synthetic porphyrins. First, the prodrug delta-aminolevulinic acid (ALA) was shown to cause a transient but significant accumulation of protoporphyrin IX (PpIX) in malignant or premalignant bladder tissue. Excitation by blue light leads to PpIX fluorescence (red), which distinguishes tumour from normal tissue (blue). Hexaminolevulinate (HAL, Hexvix), an ester of ALA, was then developed and has greater bioavailability and stability than the parent compound. It has been approved for clinical use in the diagnosis of bladder cancer. Clinical studies have shown that HAL PDD detects tumours, including carcinoma in situ (CIS), that are missed by conventional white-light cystoscopy.ConclusionsHAL PDD is a valuable aid to the detection of bladder tumours, including CIS.     

Hexylaminolaevulinate ‘blue light’ fluorescence cystoscopy in the investigation of clinically unconfirmed positive urine cytology

OBJECTIVE

To investigate the value of photodynamic diagnosis (PDD) using hexylaminolaevulinate (Hexvix®, PhotoCure, Oslo, Norway) in the investigation of patients with positive urine cytology who have no evidence of disease after standard initial investigations.

PATIENTS AND METHODS

Twenty‐three patients referred with positive urine cytology but no current histological evidence of cancer were investigated between April 2005 and January 2007 with PDD, using Hexvix and the d ‐light system (Karl Storz, Tuttlingen, Germany) to detect fluorescence. The bladder was mapped initially under white light and then under ‘blue‐light’. Biopsies were taken from abnormal urothelium detected by white light, fluorescence, or both. All cytological specimens were reviewed by a reference cytopathologist unaware of the result of the PDD.

RESULTS

Twenty‐five PDD‐assisted cystoscopies were carried out on 23 patients (20 men/3 women; median age 64 years, range 24–80 years). Of the 23 patients, 17 (74%) were previously untreated for transitional cell carcinoma (TCC), whilst six were under surveillance for previous TCC. Nineteen of the 23 (83%) cytology specimens were confirmed as suspicious or positive by the reference pathologist. TCC of the bladder or preneoplastic lesions were diagnosed in six patients, i.e. six (26%) of those investigated and six of 19 (32%) with confirmed positive cytology. Four of the six were under surveillance for previous bladder tumour. Additional pathology was detected by fluorescence in five of the six patients, including two carcinoma in situ (CIS), one CIS + G3pT1 tumour, and two dysplasia. Diagnoses in PDD‐negative cases included one upper tract TCC and four patients with stones. In addition, one patient had CIS diagnosed on both white light and PDD 6 months later.

CONCLUSION

Additional pathology was detected by HAL fluorescence cystoscopy in 32% of patients with confirmed positive urinary cytology. PDD is a key step in the management of patients with positive urinary cytology and no evidence of disease on conventional tests.     

Prospective Validation of Clinical Usefulness of a Novel mRNA-based Urine Test (Xpert® Bladder Cancer Monitor) for surveillance in Non Muscle Invasive Bladder Cancer

ObjectivesTo assess the clinical performance characteristics of Xpert Monitor test for recurrence detection during surveillance of patients with non muscle invasive bladder cancer (NMIBC).Patients and methodsPatient with previous history of NMIBC were included in the study. Voided urine specimens were collected for Xpert monitor analysis and cytology. Office cystoscopy was performed for all study participants with in patient biopsy specimen retrieval for positive or suspicious cases. Test characteristics were calculated based on cystoscopy/biopsy results and compared between Xpert and cytology.ResultsBetween March 2018 and May 2019, 181 patients including 168 (92.8%) males fulfilled the study criteria with median age 61 years, Primary tumors were low, intermediate, high risk in 2.8%, 22.7% and 74.5% of patients respectively. Biopsy proven recurrence was detected in 19 patients (10.4%). Xpert Monitor had a sensitivity of 73.7% with a negative predictive value (NPV) of 96.3%. Xpert Monitor was positive in all cases with high grade tumors (9 patients). Urine cytology showed sensitivity of 47% and an NPV of 93.2%. During follow up surveillance, out of 162 cystoscopy negative patients (CNP), 9.3% developed recurrence within 8 months. Xpert Monitor was found to be an independent predictor of early recurrence in CNP (HR=2.8, 95%CI=1.1-7.2, p=0.01).ConclusionsXpert Monitor urine test has a superior diagnostic performance for recurrence detection in NMIBC patients compared to urine cytology. It might be a helpful tool not only for excluding bladder cancer recurrence in those patients, but also for prediction of possible future early recurrence.     

Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille Calmette‐Guérin

Study Type – Diagnosis (case series) Level of Evidence 4

OBJECTIVE

To determine if hexylaminolaevulinate fluorescence cystoscopy (HAL‐FC) has the potential to improve the diagnosis of bladder cancer in patients who have been treated with bacille Calmette‐Guérin (BCG).

PATIENTS AND METHODS

Patients scheduled for rigid cystoscopy after BCG therapy were recruited prospectively between April 2005 and February 2006. Patients received HAL (Hexvix^TM, PhotoCure ASA, Oslo, Norway) and the D‐light system (Storz, Tuttlingen, Germany) was used to detect fluorescence. The bladder was mapped and biopsies taken under white light and then using HAL‐FC. The main outcome was the frequency and nature of additional pathology detected by HAL‐FC. Twenty‐seven patients (21 men and six women; median age 70 years, range 49–82) underwent 32 HAL‐FC.

RESULTS

Recurrent bladder cancer was detected in 11 of the 32 (34%) examinations. HAL‐FC detected additional pathology in five of the 27 (19%) patients. In two of these cases the additional pathology was clinically significant (one pT4G3 intraprostatic transitional cell carcinoma and one intravesical pT1G2 + carcinoma in situ), whereas in three cases the pathology was hyperplasia/dysplasia. Overall, the false‐positive biopsy rate with HAL‐FC was 63%. In the presence of positive voided urine cytology six of eight patients had recurrent bladder tumour and the false‐positive biopsy rate was only 34%. Urine cytology was positive in four of five of the patients in whom additional pathology was detected by HAL‐FC.

CONCLUSIONS

Clinically significant occult pathology can be detected using HAL‐FC after BCG therapy, but in <10% of cases. The rate of false‐positive biopsies is high but in our hands appears to be lower than with white‐light guided biopsies after BCG. Our pragmatic approach is to use HAL‐FC after BCG when clinical suspicion is high, and when the preoperative voided urine cytology is positive.     

Hexyl aminolevulinate fluorescence cystoscopy: new diagnostic tool for photodiagnosis of superficial bladder cancer--a multicenter study

PURPOSE: We examined the sensitivity and specificity of Hexvix (PhotoCure ASA, Oslo, Norway) hexyl aminolevulinate (HAL) fluorescence cystoscopy in patients with superficial bladder cancer. MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.