A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study

PURPOSE: We compared hexaminolevulinate (Hexvix) fluorescence cystoscopy with white light cystoscopy for detecting carcinoma in situ. MATERIALS AND METHODS: In this multicenter study 298 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM hexaminolevulinate for 1 hour. Cystoscopy was then performed, first using standard white light and then hexaminolevulinate fluorescence cystoscopy. Lesions or suspicious areas identified under the 2 illumination conditions were mapped and biopsied for histological examination. In addition, 1 directed biopsy was obtained from an area appearing to be normal. RESULTS: Of 196 evaluable patients 29.6% (58 of 196) had carcinoma in situ, including 18 with carcinoma in situ alone, and 35 with carcinoma in situ and concomitant papillary disease, which was only detected on random biopsy in 5. Of the 18 patients with no concomitant papillary disease carcinoma in situ was detected only by hexaminolevulinate fluorescence in 4 and only by white light in 4. In the group with concomitant papillary disease carcinoma in situ was found only by hexaminolevulinate fluorescence in 5 patients and only by white light in 3. The proportion of patients in whom 1 or more carcinoma in situ lesions were found only by hexaminolevulinate cystoscopy was greater than the hypothesized 5% (p=0.0022). Overall more carcinoma in situ lesions were found by hexaminolevulinate than by white light cystoscopy in 22 of 58 patients (41.5%), while the converse occurred in 8 of 58 (15.1%). Biopsy results confirmed cystoscopy findings. Of a total of 113 carcinoma in situ lesions in 58 patients 104 (92%) were detected by hexaminolevulinate cystoscopy and 77 (68%) were detected by white light cystoscopy, while 5 were detected only on directed visually normal mucosal biopsy. Hexaminolevulinate instillation was well tolerated with no local or systemic side effects. CONCLUSIONS: In patients with bladder cancer hexaminolevulinate fluorescence cystoscopy with blue light can diagnose carcinoma in situ that may be missed with white light cystoscopy. Hexaminolevulinate fluorescence cystoscopy can be used in conjunction with white light cystoscopy to aid in the diagnosis of this form of bladder cancer.     

Clinical results of the transurethreal resection and evaluation of superficial bladder carcinomas by means of fluorescence diagnosis after intravesical instillation of 5-aminolevulinic acid

BACKGROUND AND OBJECTIVE: The high recurrence rate of superficial bladder carcinomas requires new approaches in diagnosis and therapy. Particularly, an improvement in detection, resulting in better resection of flat lesions, which are poorly or not detectable under white light, is necessary. The effectiveness of fluorescence diagnosis for detection and transurethral resection of bladder carcinomas was investigated in a prospective study. MATERIALS AND METHODS: From 120 patients, 347 biopsies were taken or tumors resected with the aid of fluorescence from 5-aminolevulinic acid. Urothelial carcinomas and dysplasias were detected in 124 cases. RESULTS: Of the lesions, 119 were fluorescence positive (N = 74 pTaG1/2; N = 9 pT1G1/2; N = 11 pT1G3; N = 7 carcinoma in situ; N = 6 p > T1; N = 12 dysplasia II), and 5 were falsely negative (N = 3 pTaG1/2; N = 1 pT1G1/2; N = 1 dysplasia II). The sensitivity of the fluorescence diagnosis (96.0%) was significantly higher than the 67.5% sensitivity of white-light cystoscopy (P < 0.0001). Taking the data for primary or recurrent tumor resection and secondary resection separately, the sensitivity was 100% and 80%, respectively, and was significantly higher than that of white-light cystoscopy, which was 80.8% and 20 %, respectively (P < 0.0001 and P < 0.0008). The lower sensitivity of fluorescence diagnosis in secondary transurethral resection is attributed to the higher rate of false-negative findings in areas of former resection. CONCLUSIONS: The high rate of false-positive findings limits the correct interpretation of fluorescence findings. In spite of this, fluorescence diagnosis is superior to white-light cystoscopy in every case. By means of better detection of urothelial neoplasias and dysplasias, as well as more thorough and extensive resection under fluorescence control, it should be possible to reduce the recurrence rate of superficial bladder carcinomas.     

Detection of bladder dysplasia using 5-aminolaevulinic acid-induced porphyrin fluorescence

OBJECTIVE: To report results of a clinical investigation on the detection of bladder dysplasia and in situ carcinoma by using fluorescence induced by 5-aminolaevulinic acid (ALA). PATIENTS AND METHODS: The study included 50 patients with a primary bladder lesion, who had a bladder instillation of 50 mL of 3% ALA solution >or= 1 h before transurethral resection of the tumour. Random biopsies were taken using white-light cystoscopy, then using blue light to induce fluorescence; positive zones were noted and biopsied. The primary lesion was then resected. The frequency of dysplasia detected by ALA-induced fluorescence was evaluated, as was the risk of recurrence with a follow-up of >or= 2 years. RESULTS: In all patients the tumours were positive; in 21 fluorescence distant from the tumour was detected. The pathological report of the biopsies showed 11 cases of dysplasia, six of carcinoma in situ and four of inflammatory lesions. In 29 patients there was no fluorescence and quadrant biopsies were normal in all but three with moderate dysplasia. Within the minimum follow-up patients with bladder dysplasia detected by ALA-induced fluorescence had a higher risk of recurrence. CONCLUSION: ALA-induced fluorescence of the bladder significantly enhanced the detection of dysplasia and in situ carcinoma. However, this technique requires further investigation using well-characterized instrumentation and study protocols to determine any effect on treatment choice.     

Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study

PURPOSE: We determined if improved tumor detection using hexaminolevulinate (HAL) fluorescence cystoscopy could lead to improved treatment in patients with bladder cancer. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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).     

Diagnostic efficacy of fluorescence cystoscopy for detection of urothelial neoplasms.

BACKGROUND AND PURPOSE: A major problem diagnosing bladder cancer using conventional white-light cystoscopy is that flat and tiny papillary neoplasms can be overlooked. Fluorescence cystoscopy is based on the detection of protoporphyrin IX (PpIX)-induced fluorescence in urothelial neoplasms through the topical administration of 5-aminolevulinic acid (ALA). The diagnostic efficacy of fluorescence cystoscopy in urothelial neoplasms was evaluated in this study. The focus of this investigation was to ascertain whether fluorescence cystoscopy could make a major contribution to staging and improving the choice of adjuvant therapy after transurethral resection. PATIENTS AND METHODS: A series of 62 patients with suspected bladder cancer were investigated by fluorescence cystoscopy. An intravesical instillation of ALA was conducted 2 hours prior to fluorescence. A total of 274 tissue samples were obtained from the fluorescing and nonfluorescing areas of the bladder. RESULTS: The sensitivity and negative predictive value of fluorescence cystoscopy were 98.0% and 94.7%, respectively, but the specificity was low (42.9%). Among a total of 148 lesions of urothelial neoplasm, 58 foci (dysplasia in 5, carcinoma in situ in 19, stage Ta in 15, T1 in 15, above T2 in 4) that were invisible under white-light cystoscopy were detected by fluorescence cystoscopy. The final histopathologic status was changed in 45% of patients (28/62) according to this technique. Among these patients, eight (13%) needed additional therapy, including a radical cystectomy in one patient and intravesical therapy in 10. CONCLUSIONS: The ALA-based fluorescence cystoscopy technique is a safe and simple procedure that enhances the detection of flat and papillary urothelial neoplasms. Moreover, it will be able to provide useful information that will enable proper staging and appropriate further treatment.     

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.     

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.     

Hexaminolevulinate-Guided Fluorescence Cystoscopy in the Diagnosis and Follow-Up of Patients with Non–Muscle-Invasive Bladder Cancer: Review of the Evidence and Recommendations

Context

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.

Objective

Our aim was to define specific indications for hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and management of non–muscle-invasive bladder cancer (NMIBC).

Evidence acquisition

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.

Evidence synthesis

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.

Conclusions

Evidence is available to support the use of hexaminolevulinate-guided fluorescence cystoscopy in a range of indications, as endorsed by an expert panel.     

Significance of fluorescence cystoscopy for diagnosis of superficial bladder cancer after intravesical instillation of delta aminolevulinic acid.

OBJECTIVES: Most lesions of superficial bladder cancer may be easily missed during conventional white light cystoscopy. The aim of this work was to evaluate the efficiency of endoscopic fluorescence diagnosis of superficial malignant bladder tumours following intravesical instillation of delta-aminoleviulenic acid. PATIENTS AND METHODS: 30 patients of suspected or previously diagnosed bladder cancer were subject of evaluation. All patients received 50 ml of a 3% delta-ALA solution intravesically, 2-3 h prior to diagnostic cystoscopy. Fluorescence excitation intraoperatively was achieved by a violet-blue light from a xenon light source. RESULTS: A clear strong red fluorescence colour was observed emitting from all malignant vesical lesions. A diagnostic sensitivity of 98% and specificity of 65% has been determined for this novel diagnostic modality. CONCLUSION: Fluorescence cystoscopy using delta-ALA is a reliable procedure that can be offered to all patients with suspected bladder cancer lesions.     

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.     

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.     

Flexible Cystoscopy Assisted by Hexaminolevulinate Induced Fluorescence: A New Approach for Bladder Cancer Detection and Surveillance?

OBJECTIVE: The aim of this study was the assessment of flexible cystoscopy assisted by hexaminolevulinate (HAL) fluorescence. METHODS: This study was a prospective controlled, within-patient comparison of flexible HAL cystoscopy with standard flexible cystoscopy, HAL rigid and standard white light rigid cystoscopy. Eligible patients received an intravesical instillation of 50 ml hexylaminolevulinate 8 mM solution. First flexible than rigid cystoscopy was performed in each patient using a Combilight PDD system (Richard Wolf, Germany), which provided standard white light and blue light at 375 to 440 nm, with mapping of all lesions detected. All tumors and suspicious areas identified under white light and by red fluorescence with flexible or rigid cystoscopy were then resected by TUR or biopsied. The specimen was assessed by an independent blinded pathologist. RESULTS: In the 45 patients studied 41 (91%) patients had exophytic tumors, of which 39 (95.1%) were detected by HAL flexible cystoscopy and 40 (97.5%) by HAL rigid cystoscopy. 17 (37.8%) patients had concomitant or carcinoma in situ only, which was identified by HAL flexible cystoscopy in 14 (82.3%), by HAL rigid cystoscopy in 15 (88.2%), by flexible standard in 11 (64.7%) and by standard white light rigid cystoscopy in 13 (76.7%) patients. CONCLUSION: HAL fluorescence flexible cystoscopy compared to HAL rigid cystoscopy showed almost equivalent results in detecting papillary and flat lesions in bladder cancer patients. Both procedures were superior to standard white light flexible cystoscopy.     

Fluorescence detection of bladder tumors with 5-amino-levulinic acid

BACKGROUND: Preliminary data suggest that photodiagnosis by fluorescence detection of protoporphyrin IX, a biosynthetic product of the photosensitizer 5-amino-levulinic acid (ALA), is superior to conventional cystoscopy in bladder tumor detection. PATIENTS AND METHODS: We instilled 1.5 g of ALA into the bladders of 52 patients with suspect bladder lesions 1 to 4 hours prior to transurethral resection or biopsy. Red fluorescence was induced by violet-blue light (wavelength 380-450 nm). RESULTS: In 13 patients (25%), significant tumors were detected by fluorescence that were missed on conventional cystoscopy. In the present series, ALA photodetection had a sensitivity of 94.6% (compared with 76% for cystoscopy) and a specificity of 43%. CONCLUSION: Fluorescence diagnosis with ALA may become a standard procedure for bladder tumor detection and resection, especially in endoscopically difficult situations (carcinoma in situ, multifocal tumors, multiple prior resections, or previous drug instillation therapy).     

5-氨基乙酰丙酸诱导荧光膀胱镜在膀胱肿瘤诊断中的应用（附31例报告）

目的：研究5-氨基乙酰丙酸（5-ALA）诱导荧光光动力学对膀胱肿瘤的早期诊断价值。方法：对血尿患者行5-ALA诱导荧光膀胱镜检查及活组织检查,以5-ALA膀胱灌注,2h后采用D-light光源系统进行膀胱镜检,对荧光阳性区域及白光下肉眼可见异常但荧光阴性区域进行活检,活检后行经尿道膀胱肿瘤电切术。结果：31例患者中有4例荧光阴性且普通光肉眼观阴性者未活检。余27例患者共取活检96处,其中荧光阳性区域取活检89处（包括普通光肉眼观阴性区域35处）,切缘取活检7处。病理检查结果显示：尿路上皮癌65处,阳性率为73．03％（65／89）,非肿瘤性病变24例,假阳性率为27％（24／89）,切缘活检7处为阴性。荧光下阳性而白光下阴性的肿瘤位点11处,切缘活检7处均为阴性。结论：5-ALA诱导荧光光动力学诊断对膀胱肿瘤有较高价值,能发现早期肿瘤,同时进行电切将更彻底。     

Clinical experience with intravesical instillations of 5-aminolevulinic acid (5-ALA) for the photodynamic diagnosis using fluorescence cystoscopy for bladder cancer

PURPOSE: To report our clinical experience with intravesical instillations of 5-aminolevulinic acid (5-ALA) for the photodynamic diagnosis of bladder cancer and to assess any side-effects of the diagnostic method. MATERIALS AND METHODS: Photodynamic diagnosis was performed in 18 patients of which 14 were men and 4 women with a median age of 71 years (range 44-84), 7 were primary cases and 11 were recurrent cases with bladder cancer. Two to two and half hours prior to endoscopy 1.5 g 5-ALA dissolved in 50 ml of 8.4% sodium hydrogen carbonate (NaHCO3) solution was instilled intravesically. For fluorescence excitation a blue light source (D-LIGHT System, Karl Storz Endoscopy Japan K. K.) was used. Under white and fluorescence light guidance, tumor locations were recorded, cold cup biopsies were taken and tumors were resected. The levels in images of the 5-aminolevulinic acid-induced fluorescence were compared with the pathological results. The area under the receiver operative characteristic (ROC) curve (AUC) in blue light endoscopy was also compared with that in white light endoscopy. RESULTS: Among the 129 specimens obtained by transurethral biopsy 45 were obtained from polypoid lesion and 84 from non-polypoid lesion, and among the 76 malignant diseases 36 were obtained from polypoid lesion and 40 from non-polypoid lesion (including 19 carcinoma in situ), and 21 patients with dysplasia were detected pathologically, with a sensitivity of 89.5% and specificity of 58.5% with a predictive accuracy of 77.0%. The AUC in blue light endoscopy was more than that in white light endoscopy in not only all cases (p = 0.010) but also in cases with non-polypoid lesion (p = 0.007) and recurrent cases (p = 0.002). Duration of 5-ALA instillation with a median time of 80 (range 30-150) min. did not seem to affect the accuracy of photodynamic diagnosis. Procedures were well tolerated by all patients with mild bladder irritability but no systemic side effect. CONCLUSION: Photodynamic diagnosis with intravesically applied 5-ALA is more effective than observation by conventional cystoscopy in detecting bladder cancer without additional risk or complication, and is expected to become a golden standard in the detection program.     

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.     

Fluorescence detection of flat bladder carcinoma in situ after intravesical instillation of hypericin

PURPOSE: We determined the sensitivity and specificity of detecting flat bladder carcinoma in situ through fluorescent detection after intravesical hypericin instillations. MATERIALS AND METHODS: The study included 40 patients, of whom 26 presented with macroscopic visible tumor, 9 had a positive cytology without visible tumor and 5 underwent cystoscopy after bacillus Calmette-Guerin instillations (4) or radiotherapy (1). We instilled 40 ml. of a 8 microM. solution of hypericin intravesically for at least 2 hours. Fluorescence excitation with blue light was effective up to 16 hours after termination of the instillation. RESULTS: All visible papillary tumors showed red fluorescence. In addition, 134 flat fluorescent areas were detected. Analysis of 281 biopsies from flat bladder wall indicated 93% sensitivity and 98.5% specificity for detecting carcinoma in situ. Visible lesions resulting from radiotherapy, chemotherapy or immunotherapy did not show any fluorescent signs and, therefore, did not induce false-positive readings. There were no signs of photobleaching during inspection and resection. CONCLUSIONS: We report a simple yet comprehensive endoscopic method for early detection of bladder cancer, including carcinoma in situ. Hypericin induced fluorescence has a high sensitivity and specificity for detection of bladder transitional cell carcinoma, papillary and flat carcinoma in situ. When carcinoma in situ is suspected, this technique is highly recommended.     

窄光成像膀胱镜在膀胱肿瘤诊断中的应用

目的 探讨窄光成像诱导光动力学检查对膀胱肿瘤早期诊断的应用价值. 方法 应用高清窄光成像膀胱镜系统对28例血尿患者进行膀胱镜检,术中分别对普通光下及窄光下的可疑部位膀胱黏膜组织活检,普通光组取样35处,窄光组取样79处(含普通光35处,普通光镜下疑似者窄光均显示镜下疑似,不重复取样)送病理检查.比较窄光取样组和普通光取样组肿瘤检出敏感性.结果 窄光取样组活检病理报告尿路上皮癌32处(21例),其中原位癌11处,腺性膀胱炎5处(2例),良性病变(炎性病变)3处(2例),正常黏膜4处(3例).普通光取样组尿路上皮癌17处(15例),腺性膀胱炎2处(1例),无原位癌.活检病理阳性32处,窄光组病理阳性32处,肿瘤检出率100%(32/32);普通光组病理阳性17处.肿瘤检出率53%(17/32);膀胱肿瘤及原位癌检出率2组比较差异有统计学意义(P<0.01).共取样79处,其中窄光组阳性32处,敏感性41%(32/79);普通光组阳性17处,敏感性22%(17/79),2组肿瘤取样敏感性比较差异有统计学意义(P<0.01). 结论 窄光成像膀胱镜能提高对膀胱肿瘤特别是原位癌的诊断敏感性,降低术中残存率,减少膀胱肿瘤复发危险性.     

Role of 5-aminolevulinic acid in the diagnosis and treatment of superficial bladder cancer: improvement in diagnostic sensitivity

Objectives. To use 5-aminolevulinic acid (5-ALA) in diagnostic cystoscopy and during transurethral resection of the bladder (TURB) to treat transitional cell carcinoma. The efficacy of this new technique was compared with standard cystoscopy.Methods. The 5-ALA, instilled in the bladder 2 hours before cystoscopy, makes the pathologic tissue fluorescent when illuminated with blue light (375 to 400 nm). This allows a better recognition of the neoplastic forms for both diagnostic and therapeutic purposes during TURB. This method has been used since May 1997 on 49 patients in whom bladder tumor was diagnosed either immediately or during postchemotherapy follow-up.Results. One hundred seventy-nine biopsies were taken of fluorescent and nonfluorescent areas (3.5 per patient) to check the effectiveness of the new method compared with standard cystoscopy. A good correlation was found between 5-ALA cystoscopy and the histopathologic diagnosis, with a good sensitivity (87%). The 5-ALA cystoscopy allowed the diagnosis of a tumor in 24 patients with negative standard cystoscopic findings. Furthermore, 5-ALA cystoscopy detected 7 cases of carcinoma in situ. Neither local nor systemic (because of endovesical instillation) side effects were noted.Conclusions. We believe that 5-ALA could be routinely used in the diagnosis of superficial bladder tumors, as it was shown to improve the diagnostic sensitivity for carcinoma in situ and to reduce the risk of recurrence related to missed cancerous lesions or incomplete TURB.     

Is photodynamic diagnosis using hypericin better than white‐light cystoscopy for detecting superficial bladder carcinoma?

OBJECTIVE: To review the initial clinical results of photodynamic diagnosis (PDD) using hypericin (a new photosensitizer for PDD that helps to label flat urothelial tumours to facilitate biopsy) for the early detection of superficial bladder carcinoma, as flat noninvasive tumours of the bladder may be missed during conventional white-light cystoscopy (WLC) if there is bladder overdistension or ongoing cystitis. PATIENT AND METHODS: Between 1 January 2001 and 30 October 2004, 41 consecutive patients (mean age 66.1 years, sd 9.1, range 46-81) had transurethral resection for bladder cancer. Hypericin was introduced intravesically for 2 h before cystoscopy. Immediately after WLC, fluorescence cystoscopy (FC) was used at the same location and the same bladder site inspected using violet light. FC findings, e.g. positive or negative red fluorescence, were documented for each specific bladder site examined, and the exact location sampled for biopsy. RESULTS: The mean (sd, range) bladder capacity of the patients was 431 (86, 300-650) mL. In all, 179 biopsies were taken from the 41 patients; urothelial cancers were found in 41% (74) and 80% (33) had macroscopically visible bladder tumours; 40% (71) of the biopsies were positive under FC and 86% (61) of the 71 FC-positive biopsies showed cancer on histology. Twenty-five biopsies (14%) were positive on FC but not WLC. PDD testing with hypericin had a sensitivity of 82% (61/74) and specificity of 91% (95/105), vs WLC, at 62% (46/74) and 98% (103/105), respectively. The PDD test had a positive predictive value of 86% (61/71) and a negative predictive value of 88% (95/108), vs 96% (46/48) and 79% (103/131), respectively for WLC. There were no reports of significant complications after the procedure. CONCLUSION: PDD using hypericin shows promise, as it has a higher sensitivity but equivalent specificity than WLC. It can be used to detect flat lesions not seen on WLC. PDD testing is also well tolerated with minimal side-effects.