BJUI. The value of bladder mapping and prostatic urethra biopsies for detection of carcinoma in situ (CIS)

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1 BJUI BJU INTERNATIONAL The value of bladder mapping and prostatic urethra biopsies for detection of carcinoma in situ (CIS) Sigurdur Gudj ó nsson *, Mats Bl ä ckberg, Gunilla Chebil, Staffan Jahnson, Hans Olsson, P ä r-ola Bendahl, Wiking M å nsson * and Fredrik Liedberg * *Department of Urology, Skane University Hospital, Malmö, Departments of Urology and Pathology, Helsingborg County Hospital, Helsingborg, Division of Urology, Department of Clinical and Experimental Medicine Link ö ping University Hospital, Linköping, Department of Oncology, Clinical Sciences, Lund University, Lund, Department of Pathology, Linköping University Hospital, Linköping, and Department of Urology, Växjö County Hospital, Växjö, Sweden Accepted for publication 4 August 2011 Study Type Diagnostic (case series) Level of Evidence 4 OBJECTIVES To assess the value of bladder mapping and prostatic urethra biopsies for detection of urothelial carcinoma in situ (CIS). CIS of the urinary bladder is a flat high-grade lesion of the mucosa associated with a significant risk of progression to muscle-invasive disease. CIS is difficult to identify on cystoscopy, and definite diagnosis requires histopathology. Traditionally, if CIS is suspected, multiple cold-cup biopsies are taken from the bladder mucosa, and resection biopsies are obtained from the prostatic urethra in males. This approach is often called bladder mapping (BMAP). The accuracy of BMAP as a diagnostic tool is not known. PATIENTS AND METHODS Male patients with bladder cancer scheduled for cystectomy underwent cold-cup bladder biopsies (sidewalls, posterior wall, dome, trigone), and What s known on the subject? and What does the study add? It is well known that CIS is a major risk factor for muscle-invasive bladder cancer and that this entity can be difficult to diagnose. Taking cold-cup mapping biopsies from different areas of the bladder (BMAP) is commonly used in patients at risk of harbouring CIS. The diagnostic accuracy of this approach has not been assessed until now. By using the CIS found in the cystoprostatectomy specimen as an indicator of the true occurrence of CIS and comparing that with the findings of BMAP, it is clear that the sensitivity of BMAP to detect CIS when present is low and that negative findings should be considered unreliable. resection biopsies were taken from the prostatic urethra. After cystectomy, the surgical specimen was investigated in a standardised manner and subsequently compared with the BMAP biopsies for the presence of CIS. RESULTS The histopathology reports of 162 patients were analysed. CIS was detected in 46% of the cystoprostatectomy specimens, and multiple ( 2) CIS lesions were found in 30%. BMAP (cold-cup bladder biopsies + resection biopsies from the prostatic urethra) provided sensitivity of 51% for any CIS, and 55% for multiple CIS lesions. The cold-cup biopsies for CIS in the bladder mucosa showed sensitivity and specificity of 46% and 89%, respectively. CONCLUSION Traditional cold-cup biopsies are unreliable for detecting CIS in bladder mucosa and negative findings must be interpreted with caution. KEYWORDS bladder cancer, carcinoma in situ (CIS), bladder mapping, biopsies, prostatic urethra INTRODUCTION Most patients with bladder malignancies are found to have non-muscle-invasive bladder cancer (NMIBC) at diagnosis. The risk of progression to muscle-invasive bladder cancer (MIBC) within 5 years of diagnosis varies from 0.8% to 45%, depending on the patient s risk profile [1 ]. It has been suggested that patients with NMIBC who are at high risk of progression and later develop MIBC have a worse prognosis than those presenting with MIBC [2,3 ]. Carcinoma in situ (CIS) of the bladder mucosa is known to be the strongest risk factor for progression from NMIBC to MIBC, as well as a risk factor for recurrence of NMIBC [ 1 ]. Consequently, it is essential to be able to 2011 BJU INTERNATIONAL 110, E41 E45 doi: /j x x E41

2 GUDJÓNSSON ET AL. TABLE 1 Exclusion criteria FIG. 1. Sectioning of specimen. Reasons for exclusion N BMAP not done 124 PDD used for BMAP 2 Neoadjuvant therapy 16 Non-urothelial tumour detect CIS in patients with NMIBC, when present. Diagnosis of CIS is based on histological examination of bladder tissue. The CIS lesion is flat and therefore difficult to identify by traditional cystoscopy [4 ]. CIS is usually discovered in conjunction with a high-grade exophytic bladder cancer but it can be the only manifestation of malignancy in the urothelium (i.e. primary CIS). Suspicion of CIS is sometimes due to positive urinary cytology, and further diagnostic evaluation comprises upper urinary tract imaging and collection of biopsies from the bladder mucosa. Cold-cup biopsies are taken from suspicious- and normal-looking areas of the mucosa, including the sidewalls, trigone, posterior wall, and dome of the bladder. Routine evaluation of a patient with positive but unassigned cytology also includes taking resection biopsies from the prostatic urethra in men and from the bladder neck in women. This diagnostic approach is often referred to as bladder mapping (BMAP). Although this has been a common practice for many years, the sensitivity of BMAP for bladder CIS is unknown and has not been properly assessed. The aim of the current study was to evaluate the reliability of BMAP for diagnosis of CIS as compared with the true occurrence of CIS in the cystoprostatectomy specimen. PATIENTS AND METHODS The present study was prospective in design. In a consecutive manner, 308 men scheduled for cystoprostatectomy at three urological centres from April 2000 to December 2009 were considered for inclusion. Before analysing the material, we excluded all patients who had non-urothelial bladder cancer on the final pathology report or were receiving neoadjuvant chemotherapy (20 patients). We also excluded all patients not subjected to BMAP as planned in the protocol (mostly referral cases), as well as two patients in whom photodynamic diagnosis (PDD) was used at BMAP ( Table 1 ). Thus, 162 patients remained for analysis. The BMAP consisted of cold-cup biopsies taken from the left, right, and posterior walls, the trigone, and the dome of the bladder. If suspicious mucosal areas were seen in these locations, the biopsies were taken from those areas. Otherwise, biopsies were taken from normal-looking mucosa. Depending on the size and location of the individual bladder tumours that were found, all planned biopsies could not be taken in all patients. Also, resection biopsies were performed from the bladder neck down to the level of the verumontanum at the 5 and 7 o clock positions as viewed through the cystoscope [5 ] ; this was usually done during the resection of the culprit tumour, although in some cases (mainly in referral patients) it was carried out afterwards as a separate procedure. Each biopsy was marked and fixed separately in formaldehyde, and sent to an uropathologist for analysis. Results were recorded regarding the presence of atypia, dysplasia, and CIS, and the quality of individual biopsies. Based on the pathology report, the overall quality of the biopsies from each patient was designated as poor, good or intermediate according to the following criteria: poor indicated that more than half of the collected specimens showed severe artefacts or were denuded of epithelium and hence could not be assessed; good meant that all biopsies had assessable mucosa without artefacts; intermediate 7 1 Dome 2 Posterior wall 3 Anterior wall 4 Left side wall 5 Right side wall 6 Trigone 7 Left ureter 8 Right ureter 9 Tumour including at least one whole mount section 10 Prostate and prostatic urethra sagittal whole mount section including bladder neck 11 Perivesical fat signified all other cases. Histological diagnosis of CIS was made according to the 1999, WHO/the International Society of Urologic Pathology consensus classification of urothelial neoplasms [6 ]. All histological material was evaluated by experienced uropathologists (G.C. and H.O.). The cystoprostatectomy specimen was filled with formaldehyde via a Foley catheter, immersed in formaldehyde, and then transferred to the uropathologist. The specimen was sampled in a standardized manner taking sections from the tumour and from all other suspicious areas of the bladder. Multiple sections were also taken from other parts of the bladder, distal ureters, and prostatic urethra; this was done according to a predetermined protocol ( Fig. 1 ). The bladder neck, prostate and prostatatic urethra were cut into 4 5 mm sagittal sections for whole-mount processing. We evaluated the sensitivity and specificity of BMAP, as a tool for diagnosing focal and multifocal CIS in the cystoprostatectomy specimen. We also investigated the association between the number and quality of bladder biopsies and diagnostic reliability of BMAP. Associations in two by two tables were evaluated with Fisher s exact test whereas associations in ordered two by two tables were analysed using a chi-squared test for trend. All tests are two-sided and the significance level was set to E BJU INTERNATIONAL

3 BLADDER MAPPING AND PROSTATIC URETHRA BIOPSIES FOR DETECTION OF CIS TABLE 2 Patient characteristics Variable Value Number of eligible patients 162 Median age, years 68 Gender All male History of BCG treatment, n (%) 21 (13) Median (range) nodes removed 28 (1 67) Nodal status, n (%) N0 113 (70) N1 24 (15) N 24 (15) N3 1 (1) Pathological T stage, n (%) T0 15 (9) Tis 14 (9) Ta 9 (6) T1 15 (9) T2 38 (23) T3 51 (31) T4 20 (12) RESULTS The median (range) age of the patients was 68 (40 84) years and other characteristics are listed in Table 2. A median (mean; range) of 4 (4.1; 1 6) cold-cup biopsies were taken from the bladder mucosa and a median of two resection biopsies were taken from the prostatic urethra. The overall quality of the biopsies was good in 70% of cases and poor in 5%. According to the final pathology report, CIS was detected in 46% (74/162) of the cystoprostatectomy specimens and multifocal CIS in 30% (49/162). In 41% (66/162) of the cases CIS was found in the bladder mucosa and in 17% (27/162) the prostatic urethra was involved ( Table 3 ). By comparison, CIS was discovered in 33% (53/162) of the men by BMAP biopsies. The bladder biopsies revealed CIS in 26% (42/162) of the patients, whereas 9% (15/162) had CIS-positive biopsies from the prostatic urethra. Comparing the findings of BMAP to those of the cystoprostatectomy specimen, the sensitivity and specificity for detecting CIS were 51% (38/74) and 83% (73/88), respectively (Table 4 ). The sensitivity of BMAP for any focus of CIS in patients with confirmed multifocal CIS in the TABLE 3 CIS-detection rate in relation to site and diagnostic method used BMAP, n /N (%) Cystoprostatectomy, n /N (%) CIS in bladder mucosa 42/162 (26) 66/162 (41) CIS in prostatic urethra or ducts 15/162 (9) 27/162 (17) Any CIS detected 53/162 (33) 74/162 (46) Multifocal CIS 24/162 (15) 49/162 (30) Sensitivity, n /N (%) Specificity, n /N (%) Any CIS 38/74 (51) 73/88 (83) Multifocal CIS 27/49 (55) 107/113 (95) CIS in bladder mucosa 30/66 (46) 85/96 (89) cystoprostatectomy specimen was 55% (27/49). The sensitivity of bladder biopsies (excluding information on the prostatic urethra) in diagnosing bladder CIS was only 46% (30/66) with a specificity of 89% (85/96). There was no association between the number ( P = 0.83) or quality ( P = 0.32) of the biopsies taken and the probability of finding CIS in the final specimen. There was some degree of atypia or dysplasia in BMAP in 25% (40/162) of the patients, but this was not significantly associated with the presence of CIS in the cystoprostatectomy specimen ( P = 0.11). In 39 patients (24%), one or more of the BMAP bladder biopsies were denuded (i.e. no epithelial layer seen in histology), but this was not associated with presence of CIS in the bladder mucosa ( P = 0.64). DISCUSSION CIS is a flat, high-grade, non-invasive urothelial carcinoma, which, if left untreated, has a 50% progression rate to MIBC [7 ], making it a significant risk factor for death from bladder cancer. Treatment with serial BCG instillations can achieve a complete response rate of 70 80% [8 10 ], and therefore, even though 10 20% of the responders will eventually progress/recur and become cystectomy candidates, it is important to make a timely diagnosis and initiate treatment when CIS is present. The traditional diagnostic tools for CIS are urinary cytology, cystoscopy and cold-cup biopsies from the mucosa. Cytology is TABLE 4 Sensitivity and specificity of BMAP in detecting CIS considered to be highly sensitive for detecting shed high-grade cancer cells, but more importantly it is known to be very specific [11 ]. Consequently, a positive cytology finding should prompt the clinician to search for CIS. In some cases, CIS can be suspected when velvety erythematous areas are seen on cystoscopy. As CIS can often be found in normal-looking mucosa, the traditional approach has involved taking cold-cup biopsies to screen for CIS, and this procedure is frequently called BMAP. However, deciding when to take biopsies from apparently normal bladder mucosa is a matter of debate [ 12 ]. The yield is low in patients harbouring small, solitary papillary tumours with unsuspicious cytology [13,14 ], whereas CIS can be found concomitantly in up to 59% of patients with high-risk tumours and positive cytology [15 ]. For patients with NMIBC, it has been shown that the prognosis is worse in those who have both papillary tumour and CIS compared with those with papillary tumour alone [ 1 ], and there is also a suggestion that the detection of CIS by random biopsies influences therapy recommendations and disease-specific survival [16 ]. Patients with low-grade papillary tumours and CIS should be given BCG instead of intravesical chemotherapy and early cystectomy should be considered in cases of T1 tumours with concomitant CIS [17,18 ]. Therefore, it is crucial to diagnose CIS when present. In other clinical situations, it is important to exclude concomitant CIS. For instance, CIS detected in prostatic urethral biopsies is associated with an increased risk of urethral 2011 BJU INTERNATIONAL E43

4 GUDJÓNSSON ET AL. recurrence [19 ], and it can therefore be considered a relative contraindication for bladder substitution at the time of cystectomy. Also, the absence of multifocal CIS is considered to be a prerequisite for bladder-sparing treatment of solitary MIBC [20 ]. The current European Association of Urology (EAU) guidelines recommend biopsies be taken from normal-looking bladder mucosa only in patients with positive cytology or when an exophytic tumour has a nonpapillary appearance, because the yield is considered to be too low under other circumstances. The EAU stipulates that biopsies of the prostatic urethra should be considered when a tumour is located on the trigone or bladder neck, and when there is a bladder CIS or multiple tumours, and also in cases when cytology is positive and there is no evidence of tumour in the bladder, or when there are visible abnormalities of the prostatic urethra [21 ]. Little is known about the diagnostic accuracy of BMAP biopsies. The present study was performed specifically to address this. The present results indicate that conventional BMAP will reveal CIS in only about half of the patients who actually have this form of cancer. Even in patients with multifocal CIS, we found that BMAP had a sensitivity of only 55%. In CIS, the adherence of the transitional cell layer to the underlying lamina propria is decreased. Therefore, it is advisable to question the reliability of negative BMAP when one or more biopsies are described as denuded. Of the patients assessed in the present study, 24% had one or more denuded BMAP biopsies from the bladder but we found no association between denuded BMAP biopsies and the occurrence of CIS in the final specimen. The present observation that number of biopsies taken was not correlated with diagnostic accuracy, argues against the notion that increasing the number of biopsies can significantly improve the sensitivity of the test. Although it might be more interesting to assess the reliability of BMAP for diagnosing CIS in patients with NMIBC rather than MIBC, this cannot be done in the same fashion because patients with NMIBC are not routinely considered candidates for cystectomy. On the other hand, the higher incidence of concomitant CIS in patients with MIBC makes this an interesting patient group to study. The cystoprostatectomy specimens in the present study were subjected to very careful pathological examination for CIS, but we must nonetheless assume that some CIS cases were missed, as only parts of the normal mucosa were sampled. This assumption is supported by the falsepositive cases in the present study ( Table 4 ). Thus, of the 96 patients that had no bladder CIS in the final pathology report, 11 had CIS in the BMAP biopsies, reflecting a limited sensitivity of standard sectioning for CIS detection in cystectomy specimens. Moreover, an earlier histopathology study has reported the presence of CIS in >60% of cystectomy specimens. This figure is higher than the 41% found by using the present protocol, possibly due to the different number of sections examined, as sections were taken from each specimen in that study [22 ]. Accordingly, it is likely that CIS lesions will be missed unless all of the mucosa is investigated. This means that, even though the sensitivity of BMAP was found to be low in the present investigation, it was probably overestimated. An important limitation of the present study is that we lack information on which individual cold-cup biopsies were taken from somewhat suspicious mucosa and which from totally normal-looking mucosa. We are therefore unable to draw conclusions about the value of sampling entirely normallooking mucosa which has been questioned [12 ]. However, the sampling method used represents traditional approach for identifying CIS in suspected cases and each patient is his own control, which provides access to the true occurrence of CIS in the pathology specimen, with the restrictions mentioned above. Previously, one study has been published using similar methods to ours, showing the accuracy of random biopsies to be 77% in 53 cases. However, that study was retrospective and the protocol used for sectioning of the cystectomy specimen was not described [23 ]. The poor performance of BMAP underlines the need for more reliable tools to assess the CIS status in high-risk cases, which can have a marked impact on treatment choice and patient outcome. Several randomised studies have in recent years shown that PDD is superior to white light for cystoscopic detection of tumour tissue, and, most importantly, it facilitates identification of CIS. In a multicentre study, PDD detected 18 cases of CIS that were missed by white-light cystoscopy and BMAP. PDD identified 28% more CIS than white-light cystoscopy [24 ]. Similarly, other investigations have indicated that 24 32% more CIS lesions are detected when using PDD [25 27 ]. The present study was initiated before the start of the PDD era and at some centres, the use of random biopsies to screen for CIS has already been abandoned and replaced with PDD-guided biopsies based on the results of the above-mentioned studies. Still, to our knowledge, PDD-guided biopsies have thus far only been compared with random BMAP biopsies of the bladder, because the prostatic urethra cannot be examined by the PDD technique. Thus, the real sensitivity of PDD in detecting CIS is not known, and further studies are needed to elucidate the diagnostic performance of PDD in the same way as BMAP was examined in the present investigation. Although the present results indicate that traditional BMAP biopsies have limited sensitivity for CIS, we still encourage urologists to continue to perform BMAP as recommended in the EAU Guidelines. In centres were PDD is not available, BMAP remains the best approach to diagnose this cancer form. However, we have to keep in mind that negative biopsies do not exclude the presence of CIS, and only positive findings can be considered reliable. In conclusion, as the presence of CIS is highly relevant for treatment decisions, it has been customary to take several biopsies from normal- and suspicions-looking mucosa in patients judged to be at increased risk of harbouring CIS. According to the present results the sensitivity of such biopsies is limited, and negative findings must be interpreted with caution. A study comparing the outcome of PDD-guided biopsies with the presence of CIS in cystectomy specimens is warranted. CONFLICT OF INTEREST None declared. E BJU INTERNATIONAL

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