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Keywords:

  • bladder cancer;
  • fluorescence cystoscopy;
  • cytology;
  • detection

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

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.


Abbreviations
FC

fluorescence cystoscopy

WLC

white-light cystoscopy

CIS

carcinoma in situ

ISUP

International Society of Urological Pathology

5-ALA

5-aminolaevulinic acid

HAL

hexylaminolaevulinate.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Bladder cancer is a frequent disease and represents the second most common genitourinary neoplasm [1]. Although many aspects of the management of superficial bladder cancer are now well established, significant challenges remain, which influence the outcome. Early detection and treatment of recurrent disease is required to optimize bladder preservation, reduce patient morbidity, and increase quality of life and survival [2]. The combination of cystoscopy and cytology is considered to be the reference standard in the detection and surveillance of bladder cancer [3]. However, their sensitivities and specificities are far from being satisfactory, leading to incomplete detection of primary or recurrent carcinoma, especially in case of multifocal growth [4]. In particular, flat urothelial lesions, e.g. carcinoma in situ (CIS) or urothelial dysplasias, are frequently under-diagnosed clinically. This could be an additional reason for incomplete tumour resection and for tumour recurrence and/or progression [5]. As the natural history of untreated tumours indicates a progression rate of more than half over 5 years and an even higher recurrence rate for CIS, the importance of a sensitive diagnostic procedure and treatment of CIS is obvious. Furthermore, the risk of incomplete removal of tumour tissue during transurethral resection of the bladder is significant, either by overlooking flat dysplastic lesions extending from the resected tumour area, or by missing small papillary satellite tumours [6].

The limitations of cytology and standard cystoscopy became evident in studies comparing standard white-light cystoscopy (WLC) with fluorescence cystoscopy (FC), often referred to as ‘photodynamic diagnosis’, which showed increased detection and decreased recurrence rates after fluorescence-guided transurethral resection [7–12]. The aim of the presented study was to evaluate the role of FC in patients with positive bladder-wash cytology but entirely negative WLC.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

From January 1996 to December 2006, 348 patients (96 women and 252 men, mean 63.5 years, range 17–89) had WLC for suspected or surveillance of TCC of the urinary bladder, with no evidence of macroscopic tumour lesions. Of these 348 patients, 120 presented with suspected primary bladder cancer (gross haematuria, microhaematuria, etc.) and 228 for surveillance due to a history of TCC of the urinary bladder.

For FC, 5-aminolaevulinic acid (5-ALA) or hexylaminolaevulinate (HAL) was used. At 2.5 h before cystoscopy, 1.5 g 5-ALA (Medac GmbH, Wedel, Germany) dissolved in 50 mL 5.7% sodium monohydrogen phosphate buffer was instilled intravesically in every patient, using a 14 F catheter. After this instillation patients were instructed to move around to guarantee contact of the substance with the entire lumen of the bladder. Patients were also instructed to avoid urinating for the 2.5 h. Shortly after approval of HAL in Germany (Hexvix®, PhotoCure, Oslo, Norway), this new agent was used exclusively instead of 5-ALA in our hospital. In 15 of 348 patients, who met the inclusion criteria, HAL was used for diagnosis; 8 mmol of HAL was dissolved in 50 mL PBS and instilled intravesically 1 h before cystoscopy. Patients received the same instructions for HAL as given for 5-ALA. In all cases the solution was prepared shortly before the instillation; the catheter was removed immediately after the instillation.

The excitation light source used (D-Light®, K. Storz, Tuttlingen, Germany) consists of a short-arc xenon lamp equipped with a dielectric short-pass filter (445 nm). An observation filter (long pass, 450 nm) is integrated into the eyepiece. For documentation, colour-sensitive endoscopic cameras were used. The endoscopic procedure started with a careful inspection of the whole bladder exclusively in white-light mode. Then a washing cytological specimen was obtained using 0.9% saline. Subsequently FC was used, in the blue-light mode (Figs 1,2). All fluorescing lesions were documented using specially designed forms and subsequently compared with the previous WLC findings. Resection specimens and/or cold-cup biopsies were taken from those fluorescing areas that appeared normal under WLC. Occasionally biopsies were also taken in areas that were not macroscopically suspicious, even if fluorescing sites were detected within the bladder. All procedures were carried out video-endoscopically. The histological and cytological diagnoses were assessed at the Pathological Institute of Aachen and Regensburg, Germany.

image

Figure 1. CIS visualised by WLC is barely visible.

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image

Figure 2. Fluorescing CIS when using FC.

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RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Of 348 patients with no evidence of tumour on WLC, 77 (22.2%) had a clear positive cytological finding. In 63 of these 77 patients (82%) the positive cytological finding was verified by FC, which detected the precise site of the malignant or premalignant lesions within the bladder (Table 1); 18 moderate dysplasias, 27 CIS, 12 Ta-1/G1-2 and six pTa-1/G1-3 were diagnosed, using the WHO/International Society of Urologic Pathology (ISUP) classification of 1999 [13], that being the system at the start of the study. Fourteen remaining patients with positive cytological findings had no positive fluorescence on FC, and no positive histological features were found in the random biopsies taken. In all of these patients neoplastic disease of the upper urinary tract was excluded by retrograde pyelography and ureterorenoscopy. With additional surveillance (median 8.5 months), neoplastic disease was detected by FC-guided biopsies in eight of these 14 patients. The remaining six patients showed no tumour in the follow up visits (median follow-up 24 months).

Table 1.  Histological results in relation to cytology and FC according to the WHO/ISUP classification of 1999 [13]
Tumour lesions detected by FC onlyCytology, n
PositiveNegative
N77271
Dysplasia II18 15
CIS27  6
Ta-1/G1-212 21
Ta-1/G3 6  1

Despite negative cytological findings in 271 patients, moderate dysplasia, CIS, Ta-1/G1-2 or Ta-1/G3 were diagnosed by FC only in 15, six, 21 and one, respectively (Table 1). FC and cytology were both negative in 228 patients and both positive in 63, with 14 FC negative/cytology positive and 23 both negative. No major adverse events from using 5-ALA or HAL were reported for the whole period of the analysis.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

It is well known that urinary cytology has good sensitivity for G3 (89.9%) and G2 (64.0%) tumours, combined with a high specificity (>90%) [14]. Considering this, every positive cytological finding must be evaluated until the malignant lesion has been detected or another explanation for positive cytology has been found.

Every positive urinary cytology finding must be assessed by cystoscopy of the bladder and the upper urinary tract. As CIS is often located in the normal-appearing bladder mucosa and therefore can be easily missed during conventional endoscopy, the situation can be significantly improved with the use of photosensitizers, e.g. 5-ALA or HAL, which can be safely administered intravesically [15,16]. In one of the first studies of FC of the bladder, this procedure had a sensitivity of 97% and a specificity of 65%[17]. Meanwhile, several trials compared the efficacy of FC using HAL, with WLC [16,18]; Jichlinski et al.[19] reported a sensitivity of 96% for HAL and 73% for WLC.

As FC was a highly sensitive and cost-effective tool [20] in the diagnosis of urothelial tumours, we analysed our data, focusing on cases with positive bladder-wash cytology but negative WLC. Currently the taking of random biopsies is recommended by different guidelines if the cytological findings are positive in combination with negative WLC. The current question is how the result of random biopsies should be interpreted and what risks are taken in this procedure? May et al.[21] took multiple random biopsies in 1033 patients with suspected urothelial carcinoma; in 12.4% the histology showed malignant tissue. Altogether, due to the random biopsy results, the therapy was changed in 6.8% of patients. By contrast, a report from the European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Cooperative Group showed that routine random biopsies will not significantly influence the management of patients [22]. Therefore the benefit of random biopsies should at least be questioned, as the detection rate is low, the urothelium is traumatized and there is a possible risk of tumour-cell seeding [23]. FC, as a risk-free and cost-effective diagnostic procedure, could help, especially in these cases, to avoid unnecessary biopsies by indicating the precise sites of malignancy.

In the present study FC had a high sensitivity for detecting malignant and premalignant lesions, which lead to the immediate detection and verification of the positive cytological findings in 63 of 77 patient (82%).

All lesions assessed in this study were categorised using the WHO/ISUP classification of 1999 [13], as the data were assessed starting in 1996. Using this classification 33 high-grade lesions were detected (27 CIS, six Ta-1G3). The number of high grade lesions would presumably not have changed significantly had the samples been re-evaluated using the current WHO/ISUP classification of 2004 [24]. The importance of detecting and locating such highly aggressive tumours is obvious. By contrast with the cited studies on random biopsies [21,22], FC provides high sensitivity for these malignant lesions.

Even when the cytological findings were negative, malignant and premalignant urothelial lesions (15 dysplasias II, six CIS, 21 pTa-1/G1-2, one pTa-1G3, WHO/ISUP 1999) were detected in 43 of 271 patients (15.9%) by FC. This is remarkable, as the presumed high sensitivity of cytology in G3 tumours was found to be lower (81%) in the present study than published previously [25]. It is possible that FC enables the detection of high-grade flat lesions at such an early stage, in which cells are potentially ‘not yet detectable’ by urine cytology, as they could be still connected tightly to the bladder mucosa and therefore do not appear in the urine. Further studies are needed to confirm this hypothesis. However, the higher detection rate of FC in cytologically negative patients can be explained by the relatively low sensitivity of cytology in well-differentiated tumours (21 Ta-1/G1-2).

Analysing the 14 patients who were diagnosed as positive by urine cytology but were negative on FC, random biopsies and examination of the upper urinary tract did not verify any tumorous lesions. With additional surveillance (median 8.5 months), neoplastic disease was detected by FC-guided biopsies in eight of these 14 patients. In the other six patients no tumour was detected during the follow-up (median 24 months).

The detection of a tumour after a median of 8.5 months could be explained by an initial overlooking of a small tumour lesion even on FC. Also, a failure to instil the photosensitizing agent is possible, if the retention time for the substance was insufficient for an accurate diagnosis (possible reasons include patient’s incontinence, urge symptoms, etc.). These factors could lead to a false-negative finding on FC.

The negative follow-up of the remaining six patients could be explained by the lack of specificity of cytology itself, resulting in false-positive cytology. Although it seems very unlikely, a tumour could also have been overlooked even after several examinations.

A possible difference in the sensitivity or specificity of 5-ALA and HAL could not be examined in this study, as only 15 patients met the inclusion criteria of the study since HAL was used in our clinic, too few to allow any statistical analysis of this factor.

The presented study has some limitations. A weakness of this analysis is use of the former WHO/ISUP classification of 1999. A comparison with other studies would have been easier if the current classification could have been used. A further limitation is the retrospective approach and the relatively few patients who met the inclusion criteria. Furthermore, several groups recommend random biopsies when flat lesions are suspected. We did not take random biopsies in these cases, so we do not have full information on fluorescence-negative, inconspicuous sites of the bladder. Further prospective studies would be of interest to confirm the present data and to understand more about the timing of tumour cells in urine in relation to FC.

In conclusion, the present study showed that FC is beneficial in detecting malignant and premalignant lesions in patients with positive urine cytology but negative WLC. The identification of the exact site of a malignant lesion by FC enables a more accurate diagnosis with no delays.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Alexander Karl and Dirk Zaak have acted as investigators on a study supported by and have received a lecture honorarium from Photocure (Oslo, Norway). They have also received lecture honoraria from GE Medical health care and medac GmBH.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES
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