Hypericin-based fluorescence diagnosis of bladder carcinoma

OBJECTIVE: To determine the use of hypericin instillation for the fluorescent detection of papillary bladder cancer and carcinoma in situ. PATIENTS AND METHODS: Eighty-seven patients with papillary bladder cancer and/or carcinoma in situ received instillations with 40 mL of an 8 micromol/L hypericin solution for at least 2 h. Fluorescent excitation with blue light was effective for up to 16 h, and biopsies were examined by fluorescence microscopy. RESULTS: There were no side-effects reported, no photobleaching and all papillary lesions fluoresced red. The sensitivity and specificity for detecting carcinoma in situ was 94% and 95%, respectively. An interval of 4 months is recommended after BCG instillations before using this test. Fluorescence microscopy showed that hypericin was selectively localized in the epithelium. CONCLUSIONS: Hypericin-induced fluorescence has a high sensitivity and specificity for detecting bladder cancer. After 4 months there are few false-positive results in patients treated with BCG.     

Fluorescence detection of bladder cancer: a review

An effective therapeutic outcome in the treatment of bladder cancer is largely defined by its early detection. In this context, big expectations have been placed on the fluorescence-guided diagnosis of bladder cancer. This paper reviews the applications of endo- and exogenous fluorescence for early diagnosis of in situ carcinoma of the bladder. Despite certain advantages of autofluorescence, exogenous fluorescence, based on the intravesical instillation of fluorophores with the following visible light excitation, has been shown to be more effective in terms of sensitivity and specificity for detecting carcinoma in situ. The equipment consists of a slightly modified light source in order to choose between white (conventional endoscopy) or blue light (fluorescence endoscopy) excitation, and specific lenses, in order to enhance maximally the contrast between normal (blue) autofluorescence and red fluorescence from malignancies. Among exogenous fluorophores, a particular emphasis will be put on the 5-aminolevulinic acid (ALA), its ester derivative (h-ALA) and hypericin. These dyes demonstrated an excellent sensitivity above 90% and specificity ranging from 70% to 90%.     

Treatment of carcinoma in situ of the urethra with intraurethral instillations of bacillus Calmette-Guérin. Case report and review of literature.

We present the case of a 60-year-old man with carcinoma in situ of the urethra after previous successful radiotherapy of an invasive bladder tumor. Intraurethral instillations with bacillus Calmette-Guérin were given. In spite of initial success, recurrences developed after two courses of 12 intraurethral instillations, and radical surgery was performed. The use of bacillus Calmette-Guérin is reviewed with regard to the locations of superficial transitional cell carcinoma outside the bladder cavity.     

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.     

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.     

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).     

Fluorescence guided optical coherence tomography for the diagnosis of early bladder cancer in a rat model

PURPOSE: We describe the technique of fluorescence image guided optical coherence tomography (FG-OCT). We examined its ability to enhance specificity and sensitivity for the noninvasive diagnosis of early bladder cancer. MATERIALS AND METHODS: Transitional cell carcinoma was developed in 54 Fisher 344 female rats by intravesical methyl-nitroso-urea instillations. Two or three rats were diagnosed sequentially by 5-ALA (5-aminolevulinic acid hydrochloride) induced fluorescence imaging, cross-sectional OCT and histological microscopy weekly during weeks 11 to 33 following initial methyl-nitroso-urea instillation to track the course of carcinogenesis. RESULTS: The specificity of fluorescence detection was significantly enhanced by FG-OCT (53% and 93%, respectively, p <0.0001). The sensitivity of fluorescence detection and FG-OCT was 79% and 100%, respectively. CONCLUSIONS: FG-OCT cystoscopy has the potential to diagnose early bladder cancer with high sensitivity and specificity with drastically decreased imaging time compared to that of white light guided OCT cystoscopy.     

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34例报告)

目的　探讨 5 氨基乙酰丙酸 (5 ALA)诱导荧光光动力学诊断对膀胱肿瘤早期诊断的价值。　方法　 34例血尿患者行 5 ALA诱导荧光染色膀胱镜检及活组织检查 :以 5 ALA缓冲液灌注膀胱 ,2～ 3h后 ,用D LIGHT系统进行荧光膀胱镜检 ,对荧光阳性区域及白光下肉眼观有异常但荧光阴性的区域进行活检。活检结束后行经尿道电切术 (TUR)。　结果　 31例呈荧光阳性 ,其中 2 6例为尿路上皮癌 ,5例为良性病变 ;3例呈荧光阴性 ,其中腺性膀胱炎 2例 ,出血性膀胱炎 1例。 11例移行细胞癌患者于癌旁或远处发现普通膀胱镜下无法识别的微小荧光阳性区域 ,经活检均证实有肿瘤存在 ,其中 2例为原位癌。 6 1处活检结果经统计分析 ,该诊断方法对膀胱肿瘤的灵敏度为 97.6 %(4 1/ 4 2 ) ,特异性为 4 7.4 % (9/ 19)。　结论　 5 ALA诱导荧光光动力学诊断对膀胱肿瘤诊断有较高价值 ,能发现早期肿瘤 ,同时可彻底进行电切除。     

Recent developments in fluorescence cystoscopy: do novel agents bring a benefit?

PURPOSE OF REVIEW: In flat bladder cancer and carcinoma in situ, and in multifocal papillary cancer, some smaller lesions may be overlooked at cystoscopy. For 10 years fluorescence cystoscopy has been promoted to solve these problems without wider acceptance. New fluorophobes now promise better clinical applicability. RECENT FINDINGS: In prospective multicenter studies fluorescence cystoscopy shows significant improvement in the detection of flat bladder cancer and carcinoma in situ. It also permits more reliable identification of all neoplastic lesions with multifocal tumors, hence more precise removal and as a consequence lower recurrence rates. SUMMARY: New agents bring a significant benefit. Hexyl-aminolevulinate offers more rapid urothelial accumulation, better fluorescence contrast and less photobleaching than previously used fluorophobes. It is simple to use in everyday practice and has a favorable toxicity profile.     

Fluorescence cystoscopy in the management of bladder cancer: a help for the urologist!

As a disease characterized by a nature polymorphic and fluctuant in its evolution, superficial transitional cell carcinoma of the bladder remains a perpetual therapeutic challenge, and raises a great interest in the development of new diagnostic and surveillance techniques. This paper reviews 10 years of experience of fluorescence cystoscopy, a simple technique perfectly adapted to the current endoscopic equipment. Its principle is to enhance the visual contrast between benign and malignant cells. Three photosensitizing agents are available, two prodrugs: delta-aminolevulinic acid or hexaminolevulinate, and a natural substance: hypericin. With a detection rate of over 90% for carcinoma in situ and a real potential for detecting small tumors overlooked by standard cystoscopy, fluorescence cystoscopy may be clearly recommended in clinical practice. This technique favors a standardization of superficial bladder cancer endoscopic management and is susceptible to have a real impact on the disease recurrence and progression rate.     

Photodynamic diagnosis in urology: state-of-the-art

OBJECTIVES: To provide an overview on the methodology and clinical relevance of fluorescence diagnosis with exogenous fluorochromes or fluorochrome prodrugs in urology. METHODS: The methodology is summarised on the basis of our experience and the relevant literature. Clinical results and perspectives are reported and concluded after we scanned and evaluated sources from PubMed. Search items were "aminolev*" or "hypericin" or "photodyn*" or "porphyrin" or "fluorescence" or "autofluorescence" and "bladder" or "prostate" or "kidney" or "peni*" or "condylo*". Some literature was also obtained from journals not indexed. RESULTS: A large number of clinical trials have shown that photodynamic diagnosis (PDD) improves the ability to detect inconspicuous urothelial carcinoma of the bladder. Fluorescence diagnosis has recently been approved in Europe for the detection of bladder cancer after instillation of a hexaminolevulinate (Hexvix) solution. PDD is recommended by the European Association of Urology for the diagnosis of carcinoma in situ of the bladder. To date, the major weakness of PDD for the detection of bladder cancer is its relatively low specificity. Initial results with PDD for the detection of penile carcinoma, prostate cancer, kidney tumours, and urethral condylomata are promising. CONCLUSIONS: To determine the actual impact of PDD on recurrence and progression rates of bladder cancer, further long-term observational studies are necessary. These studies also will clarify whether PDD is cost efficient.     

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 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.     

Fluorescence cystoscopy and bladder surveillance

PURPOSE OF REVIEW: Update on new developments in the field of fluorescence cystoscopy. RECENT FINDINGS: New agents are being studied to improve the accuracy of fluorescence cystoscopy. Hexyl-5-aminolevulinic acid is an ester form of 5-aminolevulinic acid with improved uptake by tumor cells. It has been shown to have higher specificity than 5-aminolevulinic acid and can possibly play a complementary role to standard cystoscopy. Hypericin is a promising new agent that has excellent sensitivity and specificity. The use of confocal microscopy to examine fluorescent tissue may help improve the accuracy. SUMMARY: The addition of newer agents to the armamentarium of fluorescence cystoscopy has great potential with promising results in improving the diagnostic accuracy of bladder cancer and in particular carcinoma in situ. These agents need to be studied in large randomized trials to prove that using these agents can facilitate early diagnosis and improved prognosis in patients with bladder cancer.     

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).     

A case of transitional cell carcinoma with squamous differentiation which developed squamous cell carcinoma in situ in the clinical course

In August 2000, a 62-year-old woman presented to another municipal hospital with macroscopic Transurethral resection of bladder tumor (TUR-Bt) was performed. The pathological hematuria. diagnosis was transitional cell carcinoma (TCC), G2 > squamous cell carcinoma (SCC). TUR-Bt repeated in July 2003 indicated recurrence. The pathological diagnosis was TCC, G2. She was referred to our hospital in August 2003 because she desired bladder preservation. After cystoscopy and random biopsy, pathological diagnosis was TCC with squamous differentiation, G1-G2, pTis. She received 7 weekly intravesical bacillus Calmette-Guerin (BCG) instillations. In April 2004, TUR-Bt was repeated and multiple recurrences were found. The pathological diagnosis was TCC with squamous differentiation, G1-G2, pTa. She received 10 weekly intravesical Pirarubicin hydrochroride instillations. In August cystoscopy and random biopsy were performed for evaluation of the intavesical instillation treatment. Pathological diagnosis was atypical squamous cells. In November, cystoscopy revealed recurrence of a bladder tumor. After admission, a small papillary tumor and multiple flat lesion biopsies demonstrated SCC without obvious invasion. The patient underwent cystectomy. There were widespread areas of full thickness squamous atypia. Most of the bladder did not show appearance of typical TCC, but the final pathological diagnosis was TCC because the case developed from TCC and could not be diagnosed as pure SCC. The diagnosis of SCC in situ of bladder is difficult, and this may contribute to its rarity.     

Flat carcinoma in Situ of bladder.

36 patients with flat carcinoma in situ of the bladder have been reviewed. Those with widespread disease usually presented with dysuria or obstructive outflow tract symptoms and radical surgery appeared to give better results than radiotherapy. However, when the lesion was confined to small areas of the bladder mucosa, haematuria or pain were the main presenting symptoms and a conservative approach seemed justified. It is suggested that the term flat carcinoma in situ be used for this lesion whose behavior differs significantly from that of the commoner papillary or invasive tumours. The pathological appearances are to be reported elsewhere in full.     

The ablative effect of quarter dose bacillus Calmette-Guerin on a papillary marker lesion of the bladder

PURPOSE: Low dose bacillus Calmette-Guerin (BCG) for stage TaT1 transitional cell carcinoma of the bladder has been given in various studies with the aim of decreasing side effects while maintaining the same efficacy as full dose bacillus Calmette-Guerin. However, its application in clinical practice remains controversial. We examined the ablative activity and incidence of side effects of intravesical quarter dose BCG given for a papillary marker lesion of the bladder. MATERIALS AND METHODS: Included in our study were 44 patients with primary or recurrent, multiple but no more than 10 lesions of stage pTaT1, grades 1 to 2 transitional cell carcinoma of the bladder. Intravesical treatment begun 14 days after the complete transurethral resection of all visible tumors except 1 marker lesion no larger than 1 cm. consisted of instillations of 30 mg. Connaught strain BCG diluted in 50 ml. saline once weekly for 6 consecutive weeks. Two weeks after the last instillation any residual tumor was completely resected. In cases of complete disappearance of the marker lesion deep biopsy of the tumor area was done. Urine cytology was also performed. RESULTS: There was a complete response in 27 of the 44 patients (61%), no response in 12 (27%) and progression to carcinoma in situ in 1 (2%), while the response was not evaluable in 4. Local side effects included dysuria in 54% of cases and macroscopic hematuria in 39%. Neither BCG induced infection nor BCG sepsis was observed. CONCLUSIONS: Quarter dose BCG has a clear ablative effect on superficial bladder cancer with a 61% response rate. Phase III trials are now required to compare its efficacy and toxicity to those of full dose BCG.