Value of multicolour fluorescence in situ hybridisation (UroVysion) in the differential diagnosis of flat urothelial lesions.

AIMS: During the past 10 years, multitarget fluorescence in situ hybridisation has been established as a valuable adjunct in the cytological diagnosis of precancerous and malignant lesions of the urinary tract. The aim of the present study was to define its value in detecting chromosomal imbalances in patients with various flat urothelial lesions in routine paraffin-embedded bladder biopsy samples. In addition, the HER2 gene amplification and HER2 expression pattern were examined, since alterations of the HER2 expression patterns have been demonstrated in invasive bladder cancer. METHODS: 29 samples of normal urothelium and 86 flat urothelial lesions (hyperplasia, reactive atypia, dysplasia and carcinoma in situ (CIS)) from 73 patients were analysed patients using tissue microarrays and centromeric probes for chromosomes 3, 7 and 17, and gene-specific probes for 9p21/P16 and HER2 (UroVysion, PathVysion). The expression of HER2 was studied by immunohistochemistry. RESULTS: Polysomy of at least one of the chromosomes was found in about half of the dysplastic cells, and in more than 90% of cells in CIS or cells in invasive bladder tumours. Polysomic cells were found in only 17% of urothelial hyperplasia, reactive atypia and normal urothelium of healthy patients, whereas about 30% of non-neoplastic lesions in patients with concomitant urothelial carcinoma showed polysomy of at least one chromosome. These alterations indicate a field effect and are associated with synchronous development of dysplastic lesions of a higher grade. Deletion of the P16 locus was most frequently observed in aneuploid lesions, whereas overexpression of HER2 was found in 10-20% of invasive urothelial carcinomas, and only occasionally in CIS (5%). An altered HER2 expression pattern was present in non-neoplastic lesions (25%). CONCLUSIONS: UroVysion fluorescence in situ hybridisation is a valuable tool for the detection of genetically unstable flat urothelial lesions, and can help to resolve difficult cases, particularly the differential diagnosis of reactive atypia and dysplasia.

[Reducing the risk of superficial bladder cancer recurrence with 5-aminolevulinic acid-induced fluorescence diagnosis. Results of a 5-year study]. / Senkung des Rezidivrisikos oberflächlicher Harnblasenkarzinome mittels 5-Aminolävulinsäure-induzierter Fluoreszenzdiagnostik. Resultate einer 5-Jahres-Studie.

A prospective monocentre randomized parallel-group Phase III trial was performed to investigate whether primary transurethral resection (TUR) with 5-aminolevulinic acid induced Fluorescence diagnosis (FD) allows for a more thorough TUR of superficial Bladder Carcinoma compared to conventional white light (WL). Evaluation of residual tumor rate and recurrence free survival were defined as the two primary study endpoints. The residual tumor rate was 25.2% in the WL arm (n=103) vs. 4.5% in the (n=88) FD arm (p<0.0001). Median follow up of the patients in the WL arm was 42 months (range 25-61) compared to 43 (range 24-61) in the FD arm. Recurrence free survival in the fluorescence diagnosis group was 90.9%, 90.9% und 85 % after 12, 24 and 48 months compared with 78.6%, 69.9% und 60.7 %, respectively, in the white light group (p=0.0005). This superiority proved to be independent of risk group. The adjusted hazard ratio of fluorescence diagnosis versus white light transurethral resection was 0.29 (95% CI: [0.15; 0.56]). ALA induced FD is statistically significantly superior to conventional WL TUR with respect to both residual tumor rate and recurrence-free survival. The differences in RFS imply that FD offers a clinically relevant procedure to reduce the number of tumor recurrences.

Do patients profit from 5-aminolevulinic acid-induced fluorescence diagnosis in transurethral resection of bladder carcinoma?

OBJECTIVES: To evaluate in a prospective study the influence of fluorescence diagnosis (FD) controlled transurethral resection of bladder tumors on therapeutic consequences. The aim was to determine in how many patients FD led to a change in treatment strategy compared with conventional white light (WL) cystoscopy. METHODS: A total of 279 patients with suspected bladder tumors underwent transurethral resection using FD in addition to WL cystoscopy. The number of additional tumor-positive patients, staging change, number of multilocular tumors exclusively detected by FD, and resulting therapeutic consequences compared with the results after WL cystoscopy were investigated. In addition a biopsy-based evaluation was performed. RESULTS: Tumor or dysplasia II degrees (moderate dysplasia) was detected in 177 patients. In 168 patients, tumor was detected by WL cystoscopy, and in 9 (5.1%) of the patients, tumor was completely overlooked by WL cystoscopy and diagnosed exclusively by FD (n = 3 TaG1-G2, n = 2 carcinoma in situ, n = 1 greater than T1, and n = 3 dysplasia II degrees ). Multilocular tumor involvement was detected in 10 cases using FD, and a change in the stage by detection of coexisting dysplasia II degrees and carcinoma in situ occurred in 8 patients. In 27 patients (15.3%), additional information was obtained by exclusive detection of tumors by FD. This resulted in a change in the treatment strategy for 16 patients (9%). CONCLUSIONS: FD leads to an improvement in the diagnosis of bladder carcinoma. It allows the early selection of the best treatment option and thus has a potentially positive effect on the prognosis of the affected patients.

No generalized skin phototoxicity after intravesical application of 5-aminolevulinic acid for fluorescence diagnosis of superficial bladder cancer.

INTRODUCTION: A prospective monocenter open study was carried out to evaluate if generalized phototoxic skin reactions occur after intravesical application of 5-aminolevulinic acid (ALA) for fluorescence diagnosis of superficial bladder carcinomas. PATIENTS AND METHODS: On 21 patients, skin phototoxicity was determined prior to as well as 4, 8 and 28 h after intravesical instillation of a 3% ALA solution by exposing small skin areas to a progressively graded series of defined UVA-light doses (n = 9; 5-80 J/cm(2)). RESULTS: Prior to ALA instillation, erythema or pigmentation as signs of cutaneous phototoxicity occurred at an UVA-light dose of 28 +/- 1.5 J/cm(2) (mean +/- SEM). A reduction of the minimal phototoxic dose (MPD) was not detected 4 (28 +/- 1.9 J/cm(2)), 8 (28 +/- 1.6 J/cm(2)) and 28 h (28 +/- 1.5 J/cm(2)) after ALA instillation. Consequently phototoxic reactions were not observed. CONCLUSIONS: A reduction of MPD for UVA was not detected. Therefore, it is not necessary to protect the skin of patients from ambient or daylight after intravesical instillation of ALA for fluorescence diagnosis.

Correlation of persistent stress urinary incontinence with quality of life after suspension procedures: is continence the only decisive postoperative criterion of success?

OBJECTIVES: To determine objective continence rates and to include in the evaluation subjective assessment of continence and quality of life by the affected patients and correlate these with the objective continence rates in a retrospective study. METHODS: One hundred thirty-three female patients in our clinic underwent suspension procedures for stress urinary incontinence, 68 undergoing a Burch colposuspension and 65 a Raz bladder neck suspension. The continence rate was evaluated by questionnaire and compared with patients' postoperative self-assessment of continence and pre- and postoperative quality of life assessments. RESULTS: For the 105 women returning evaluable questionnaires (57 Burch and 48 Raz procedure), the continence rate was 69.5% (75.4% in the Burch group, 60.4% in the Raz group). Mild incontinence requiring 1 to 2 sanitary pads daily was found in 19.3% of the Burch group and 31.3% of the Raz group. Moderate incontinence requiring 3 to 5 pads daily was found in 5.3% of the Burch and 8.3% of the Raz group. No patients had severe incontinence (more than 5 pads daily). Both groups showed statistically significant improvement in postoperative quality of life. Despite persistent incontinence, the satisfaction rate was comparable to that of continent patients. CONCLUSIONS: The results show that in addition to objective parameters, subjective assessment of quality of life is a factor that should be included in the postoperative evaluation of surgical results.

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.

5-aminolevulinic acid-induced fluorescence endoscopy applied at secondary transurethral resection after conventional resection of primary superficial bladder tumors.

OBJECTIVES: A prospective investigation was carried out to evaluate the use of 5-aminolevulinic acid (5-ALA)-induced fluorescence diagnosis with secondary transurethral resection (TUR). METHODS: Fifty patients underwent secondary TUR of the former resection area 6 weeks after conventional TUR for superficial bladder carcinoma. 5-ALA-induced fluorescence diagnosis was used in addition to standard white light endoscopy. All former resection areas were biopsied regardless of fluorescence findings. In addition, specific red fluorescent areas were resected, as were suspicious areas seen at white light endoscopy. RESULTS: One hundred thirty areas or tumors were resected. The sensitivity of fluorescence cystoscopy was 77.8% (95% confidence interval 52.4% to 93.6%). Residual tumors were found in the area of the former resection in 7 (14%) of 50 patients; 4 of these 7 were fluorescence negative and 3 were fluorescence positive. In an additional 7 patients (14%), exclusively fluorescing tumors not visible under white light could be detected outside the areas of former resection (n = 5, Stage pTaG1/2; n = 1, Stage pT1G1/2; n = 1, carcinoma in situ). CONCLUSIONS: Despite high sensitivity, fluorescence diagnosis at this early stage of control does not allow us to evaluate sufficiently the granulation tissue of necrotic areas after TUR without biopsy. The main advantage of the 5-ALA-induced fluorescence endoscopy is in the evaluation of untreated urothelium because of the easier detection of tumors not visible by conventional endoscopy.