The prognosis of superficial bladder cancer in terms of recurrence and disease progression is related to bladder tumor multiplicity and the presence of concomitant "plane” tumors such as high-grade dysplasia and carcinoma in situ. This study in 33 patients aimed to demonstrate the role of fluorescence cystoscopy in transurethral resection of superficial bladder cancer. The method is based on the detection of protoporphyrin-IX-induced fluorescence in urothelial cancer cells by topical administration of 5-aminolevulinic acid. The sensitivity and the specificity of this procedure on apparently normal mucosa in superficial bladder cancer are estimated to be 82.9% and 81.3%, respectively. Thus, fluorescence cytoscopy is a simple and reliable method for mapping the bladder mucosa, especially in the case of multifocal bladder disease, and it facilitates the screening of occult dysplasi

Forrer, M.

Graber, P.

Guillou, L.

Jichlinski, P.

Leisinger, H.

Mizeret, J.

Oswald, M.

Schmidlin, F.

Van den Bergh, H.

Wagnières, G.

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Urol Res (1997) 25 [Suppl 1]: S 3-S 6 © Springer-Verlag 1997 P. J i ch l insk i  • G. Wagnibres • M.  Forrer  • J. M izeret  L. Gu i l lou  • M.  Oswa ld .  F. Schmid l in  • P. Graber  H. Van den Bergh • H.- J .  Le is inger  Clinical assessment of fluorescence cystoscopy during transurethral bladder resection in superficial bladder cancer Abstract  The prognosis of superficial bladder cancer in terms of recurrence and disease progression is related to bladder tumor multiplicity and the presence of concomi- tant "plane" tumors such as high-grade dysplasia nd car- cinoma in situ. This study in 33 patients aimed to demon- strate the role of fluorescence cystoscopy in transurethral resection of superficial bladder cancer. The method is based on the detection of protoporphyrin-IX-induced flu-orescence in urothelial cancer cells by topical administra- tion of 5-aminolevulinic a id. The sensitivity and the spec- ificity of this procedure on apparently normal mucosa in superficial bladder cancer are estimated to be 82.9% and 81.3%, respectively. Thus, fluorescence cytoscopy is a simple and reliable method for mapping the bladder mucosa, especially in the case of multifocal bladder dis- ease, and it facilitates the screening of occult dysplasia. Key  words  Carcinoma • Transitional cell - Cystoscopy Fluorescence - 5-Aminolevulinic acid • Protoporphyrin IXIntroduction In superficial bladder transitional cell carcinoma, tumor multiplicity and concomitant urothelial atypia are indica- tors of a poor disease prognosis [1, 2]. High-grade dyspla- R Jichlinski (~) - M. Oswald • H.-J. Leisinger Department ofUrology, University Hospital, CHUV, CH-1011 Lausanne, Switzerland G. Wagni~res • M. Forrer • J. Mizeret • H. Van den Bergh Laboratory of Environmental Engineering, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland L. Guillou Institute of Pathology, University Hospital, CHUV, CH-1011 Lausanne, Switzerland F. Schmidlin • R Graber Department ofUrology, University Hospital, HCUG, CH-1205 Geneva, Switzerland sia or carcinoma in situ point to a higher isk of recurrence or progression [I, 3]. Occasionally, reddish and mossy spots of the bladder mucosa allow the localization by biopsy of these foci of dysplasia, but mostly no specific changes of the bladder wall can be recognized by white light cystoscopy [4]. Although its accuracy is highly variable, urinary blad- der cytology as a routine test in the early detection of blad- der cancer and in the patient monitoring after treatment iswell established, but does not enable concomitant urothe- lial atypia at the time of the first bladder tumor resection to be discovered. Moreover, the usefulness of random biopsies from normal-looking mucosa has recently been seriously questioned [5]. Therefore, as for epithelial can- cers of other organs such as the oesophagus or the uterine cervix, there is a need to localize urothelial atypia during the endoscopic exploration. Simple methods uch as mucosal staining with methyl- ene blue have failed due to lack of sensitivity and speci- ficity [6]. Fluorescence studies correlated with histology on cystectomy specimens after intravenous injection ofhe- matoporphyrin derivatives have demonstrated the possible role of a photodynamic method for detecting and localiz- ing dysplasia nd carcinoma in situ in bladder cancer [7]. However, the sophisticated equipment needed to obtain good images, the lack of selectivity of the photosensitizer and the risk of skin photosensitization have limited its ap- plication for clinical routine practice in urology. Recently, the high fluorescence ontrast and intensity observed when treating cutaneous in situ tumors by photodynamic therapy using the endogenous photosensitizer p otoporphyrin IX(PpIX), induced by the topical application of 5-amino- levulinic acid (ALA), has suggested the same approach to be suitable for detection and treatment of epithelial tu- mors of other organs, such as the oesophagus and the bladder [8]. The first clinical reports on the photodetection of early transitional cell carcinoma by light-induced fluo- rescence of PpIX following topical administration ofALA [9, 11] stimulated interest in this new method of mapping the bladder mucosa in search of dysplasia or carcinoma in situ. $4 By comparison to the first system of bladder wall  i l lumination with a krypton ion laser, the new light source, a xenon arc lamp, considerably simplif ies the procedure by enabling the investigator to examine the bladder wall in real time without the necessity for an aux- i l iary device. This study presents our experience with this new system and attempts to assess the accuracy of the method in the detection of high-grade dysplasia nd carci- noma in situ. Material and method Fifty milliliters of a 3% solution of ALA, buffered with 5 ml phos- phate-buffered saline (PBS) and adjusted to a pH of 5.3 with 7 ml sodium hydroxide (1 N), were instilled into the bladder through a 16-French Foley catheter about 6 h before photodetection. Patients were asked to keep the catheter closed for 4 h to optimize the exposure of the bladder wall to the photosensitizing solution. The light source was a filtered xenon arc lamp which produced either white light for conventional cystoscopy or blue light with a wavelength range of 380-450 nm to excite the sensitized bladder mu- cosa. A foot pedal was used to switch from white to blue light and vice versa when necessary. The power of the fluorescence exci- tation light at the end of the cystoscope ranged between 150 and 480 mW, giving under normal conditions of use a power density of 2 65 mW/cm . The white light, the blue excitation light and the result- ing tissue fluorescence were transmitted through the optical fiber bundle of a Storz cystoscope or resectoscope. Two optics of 0 ° and of 30 °, suitable for either a cystoscope or resectoscope sheath, were specially configured to optimize the light transmission. As the PpIX emission peak was 635 nm, a long-pass filter (X>490 nm) was adapted to the ocular piece of the cystoscope to transmit he red and cut out most of the blue-reflected xcitation light. Thus, the flu- orescent spots appeared red, whereas the non-fluorescent mucosa stayed green. The somewhat darker bladder wall vessels facilitated the positioning of the cytoscope during the operation. Starting in January t995, 33 bladder examinations were per- formed in 31 patients, 23 male patients and 8 female patients (two patients had two successive operations). Mean age was 66.1, rang- ing from 44 to 84 years. Eleven patients were operated on for the first time, 6 for the second time and 16 for the third time or more. Topical chemotherapy or immunotherapy with bacille Cal- mette-Gu6rin (BCG) was added to the previous urgical treatment in19 patients. Bladder urinary cytological examination was regularly performed when the catheter was introduced for the ALA instilla- tion. The operation always started with a careful bladder inspection under white light in order to note the presence, number and location of all the visible tumors and suspicions areas. To evaluate the sensitivity and the specificity of the method in patients with bladder tumors, a four-quadrant random biopsy of the normal bladder mucosa was performed for each patient as follows: the randomly des- ignated spot of normal mucosa under white light was excited under blue light to determine the fluorescence r sponse and then immedi- ately sampled by forceps for biopsy. A total of 132 random biopsies were obtained in this way, 51 in fluorescent areas and 81 in non- fluorescent areas. All other fluorescent areas on an apparently nor- mal or slightly irregular mucosa under white light were also biop- sled and sent for analysis. The transurethral resection of significant tumors was generally performed under fluorescence, xcept in the case of major bleeding. Papillary and nonpapillary urothelial carci- nomas were graded and staged according to the WHO 1973 classi- fied [12] and the IUCC/AJC-1992 system [13], respectively. Flat intraepithelial neoplastic lesions were graded according to the crite- ria of Nagy et al. [14], and classified as grade 1 (mild dysplasia), grade 2 (moderate dysplasia), grade 3 (marked ysplasia) and in si- tu carcinoma. Results No systemic or local side effects fol lowing ALA bladder insti l lation either before or after the photodetect ion proce- dure were noted. Except for one pTaG1 tumor, all papil-  lary tumors visible on white l ight cystoscopy were fluo- rescent. The correlations between the f luorescence find- ings and the presence or absence of cancer cells for the 132 random biopsies on apparently normal mucosa are shown in Table 1. The predict ive value of a posit ive fluo- rescence corresponding to a tumor is estimated at 66.6% (34/51), and the predict ive value of a negative f luorescence corresponding to benign tissue at 91.3 % (74/81). The sen- sitivity of this photodetect ion method in superficial blad- der cancer can be estimated at 82.9% (34/41) and the spec- if icity at 81.3% (74/91). In 22/33 patients, 66.6% of our col lective, 47 tumors were detected by the f luorescence (Table 2). Seven of these 22 patients (31.8%) had grade 3 dysplasia or carcinoma in situ (CIS). Table 3 shows the correlations between cytol- ogy, white l ight cystoscopy and f luorescence f indings for each patient. The f luorescence method detected addi- t ional urothelial atypia, invisible under white light, in 12/14 patients (85%) with mult iple tumors and in 5/12 pa- tients (41%) with a single tumor. In contrast to the f luorescence cytoscopy, urinary cytology was not real ly helpful in patients with macroscopic tumors. For patients previously operated on for a superficial bladder cancer, who presented no specific lesion on white l ight cystoscopy, f luorescence cystoscopy conf irmed the absence of neo- plastic lesions in three and detected urothelial atypia or even a small tumor in four of them. In these cases, urinary cytology could only give an indication of the presence or absence of cancerous cells, whereas f luorescence cytos- copy precisely del ineated the number of carcinomatous spots. Table 1 Correlation between fluorescence findings and histopath- ological diagnosis for the 132 random biopsies on apparently nor- mal mucosa in superficial bladder cancer Positive Negative Total histology histology Positive fluorescence 34 17 51 Negative fluorescence 7 74 81 41 91 132 Table 2 Diagnosis distribution of the 47 tumors invisible by white light cystoscopy and detected by fluorescence in 22/33 patients "Flat" intraepithelial tumors 41 Papillary tumors 6 Grade 1 dysplasia 12 pTaG1 2 Grade 2 dysplasia 15 pTaG2 3 Grade 3 dysplasia 3 pT1G3 1 Carcinoma in situ 11 Table 3 Correlation between cytology, white light cystoscopy (CUS) and fluorescence findings $5 Cytology White light CUS a Diagnosis TaG1 TaG2 T1G2 T1G3 Fluorescence CUS b Dys G1-2 Dys G3-CIS TaG2 Correct 6 x Multiple tumors 14 3 7 1 3 Correct 5 x Unique tumor 12 6 5 0 1 Correct 5 x No specific lesion 7 No tumor 9 3 0 3 2 0 1 1 2 a Except one pTaGl tumor, all papillary tumors, visible by white light cystoscopy, were fluorescent b Additional tumors invisible under white light and detected by fluorescence Discussion In the Canton of Vaud in Switzerland, the incidence of superficial bladder cancer is around 18.6/100 00 per year in male patients and 4.2/100000 per year in female pa- tients, which represents a ratio of  4:1 [15]. The individual risk of cancer progression, reflecting the natural history of the disease, varies from 4 to 45% [16]. Moreover, in the year following the first treatment, superficial bladder can- cer tends to recur in a proportion up to 70%; and 10-20% of recurrences on the site of the initial tumor grow from carcinomatous foci left during the first operation [17]. I f  the characterization of dysplastic changes in the urothe- lium is important in the evaluation of the disease progno- sis and the risk of recurrence, the surgical treatment of all exophytic and "flat" tumors during the first operation is mandatory. So far no reliable method has been available to deter- mine the cancer cells in delineating the tumor basis and screening urothelial atypia. PpIX-induced fluorescence de- tection of urothelial cancer cells by topical administration of  ALA is a simple and harmless method for this. No lo- cal or systemic reaction was noted after ALA  bladder in- stillation or illumination with the xenon blue light. The cor- relation between the fluorescence tissue response and the histopathological diagnosis on normal mucosa in superfi- cial bladder cancer establishes that a fluorescent spot cor- responds to a carcinoma in about two out of three cases and above all that a nonfluorescent spot corresponds to be- nign tissue in nine out of ten cases. Undoubtedly, fluores- cence cystoscopy aids in the biopsy of the urothelium at the right place in bladder cancer. The electrocoagulation of false-positive fluorescent areas, due to inflammatory or hyperplastic ells, does not harm the bladder with normal compliance. The sensitivity and the specificity of  the procedure on apparently normal mucosa in patients with superficial bladder cancer is estimated at 82.9% and 81.3%, respec- tively. Calculated on a per patient basis it has been esti- mated at 94.2% by the Munich group [10]. Following the same approach in our collective, bladder biopsies revealed dyspastic urothelial changes or CIS in 23 patients, among whom 22 had a positive fluorescence. Thus, our per pa- tient estimated sensitivity is near 95.6%, an equivalent value to the previous estimation. Fluorescence cystoscopy constitutes a previous aid to white light cystoscopy. It is a simple and a reliable method in mapping the mucosa in bladder cancer. It facilitates the delineation of tumors and the screening of occult dysplas- tic changes, especially in multiple papillary bladder dis- ease. In addition, it appears very useful in monitoring the patients after treatment. Subsequent studies will be needed to assess whether the optimal transurethal bladder esection obtained with fluo- rescence cytoscopy contributes to a reduction of the risk of recurrence in superficial bladder cancer. Acknowledgement This study has been supported by the Vaud-Ge- neva Foundation. References 1. Olsen PR, Wolf H, Schroeder T, Fischer A, Hojgaard K (1988) Urothelial atypia and survival rate of 500 unselected patients with primary transitional-cell tumour of the urinary bladder. Scand J Urol Nephrol 22:257 2. Witjes JA, Kiemeney LALM, Oosterhof GON, Debruyne FMJ (1992) Prognostic factors in superficial bladder cancer. Eur Urol 21:89 3. Wolf H, Hojgaard K (1983) Urothelial dysplasia concomitant with bladder turnouts as a determinant factor for future new oc- currences. Lancet 8340:134 4. Wallace DMA, Hindmarsh JR, Webb JN, Busuttil A, Hardgreave TB, Newsam JE, Chisholm GD (1979) The role of multiple mu- cosal biopsies in the management of patients with bladder can- cer. Br J Urol 51:535 5. Kiemeney LALM, Witjes JA, Heijbroek RP, Koper NR Verbeek ALM, Debruyne FMJ and the Members of the Dutch South-East Co-operative Urological Group (1994) Should random urothe- lial biopsies be taken from patients with primary superficial bladder cancer? A decision analysis. Br J Urol 73:164 6. Vicente J, Ch6chile G, Algaba F (1987) Value of in vivo muco- sa-staining test with methylene blue in the diagnosis of pretu- moral and tumoral lesions of the bladder. Eur Urol 13:15 7. Benson RC, Farrow GM, Kinsey JH, Cortese DA, Zincke H, Utz DC (1982) Detection and localization of in situ carcinoma of the bladder with hematoporphyrin derivative. Mayo Clin Proc 57:548 8. Kennedy JC, Pottier RH, Pross DC (1990) Photodynamic ther- apy with endogenous protoporphyrin IX: Basic principles and present clinical experience. J Photochem Photobiol B: Biol 6:143 9. Kriegmair M, Baumgartner R, Knuechel R, Steinbach P, Ehsan A, Lumper W, Hofstfidter F, Hofstetter A (1994) Fluorescence photodetection f neoplastic urothelial esions following intra- vesical instillation of 5-aminolevulinic a id. Urology 44:836 $6 10. Kriegmair M, Baumgartner R, Knuechel R, Stepp H, Hofstfidter F, Hofstetter A (1996) Detection of early bladder cancer by 5-ami- nolevulinic acid induced porphyrin fluorescence. J Urol 155:105 11. Jichlinski P, Forrer M, Mizeret J, Glanzmann T, Braichotte D, Wagni~res G, Zimmer G, Guillou L, Schmidlin F, Graber P, van den Bergh H, Leisinger HJ (in press) Clinical evaluation of a method for detecting superficial transitional cell carcinoma of the bladder by light induced fluorescence of protoporphyrin IXfollowing topical application of 5-aminolevulinic acid. Prelim- inary results. Lasers Surg Med (in press) 12. Mostofi FK, Sobin LH, Torloni H (1973) Histological typing of urinary bladder tumours. In: World Health Organisation (ed) International histological c assification of tumours. WHO, Ge- neva 13. UICC (1992) TNM classification f malignant tumours, 4th edn. Springer-Verlag, Berlin Heidelberg New York 14. Nagy GK, Frable WJ, Murphy WM (1982) Classification of premalignant urothelial bnormalities. A Delphi study of the Na- tional Bladder Cancer Collaborative Group A. In: Sommers SC, Rosen PP (eds) Pathology Annual, Appleton-Century-Crofts, Norwalk, p 219 15. Levi F, La Vecchia C, Randimbison L, Franceschi S (1993) In- cidence of infiltrating cancer following superficial bladder car- cinoma. Int J Cancer 55:419 16. Abel PD (1993) Follow-up of patients with "superficial" transi- tional cell carcinoma ofthe bladder: the case for a change in pol- icy. Br J Urol 72:135 17. Klein R, Loy V, Huland H (1991) Residual tumor discovered in routine second transurethral resection i  patients with stage T1 transitional cell carcinoma of the bladder. J Urol 146:316 

Clinical assessment of fluorescence cystoscopy during transurethral bladder resection in superficial bladder cancer

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Clinical assessment of fluorescence cystoscopy during transurethral bladder resection in superficial bladder cancer

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