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COX-2 EXPRESSION IN UROTHELIAL CARCINOMAS OF THE UPPER URINARY TRACT CORRELATES WITH TUMOUR PROGRESSION
Langner C.1, Hutterer G.2, Chromecki T.2, Rehak P.3, Zigeuner R.2
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814
SUBDIVISION OF STAGE PT3 IN UROTHELIAL CARCINOMA OF THE RENAL PELVIS FACILITATES DETECTION OF PATIENTS AT HIGH RISK FOR FAILURE
Langner C.1, Hutterer G.2, Chromecki T.2, Rehak P.3, Zigeuner R.2
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Medical University Graz, Institute of Pathology, Graz, Austria, 2Medical University Graz, Urology, Graz, Austria, 3Medical University Graz, Biomedical Engineering and Computing, Graz, Austria INTRODUCTION & OBJECTIVES: Cyclooxygenase-2 (COX-2) has been shown to be associated with stage, grade and progression in bladder cancer. With respect to upper tract urothelial cancer (UC), data in the literature are limited. We investigated the role of COX-2 in a large series of upper tact UCs. MATERIAL & METHODS: 268 consecutive upper urinary tract UCs (169 pelvic and 99 ureteral tumours) from 239 consecutive patients (108 females, 131 males) operated between 01/1984 and 12/2004 were chosen for analysis. For association with metastasis-free survival, all patients with non-invasive (n=41) and multiple (n=37) tumours were excluded resulting in a nal group of 190 UCs (134 pelvic, 56 ureteral tumours) from 190 patients. Tumour specimens were stained immunohistochemically with a monoclonal anti-human COX-2 antibody (DAKO, Glostrup, Denmark) using a tissue microarray technique. A distinct granular cytoplasmic staining was considered positive, and immunoreactivity was categorized as focal (<10% of tumour cells positive), moderate (10-50%) or extensive (>50%). Immunohistochemical ndings were correlated with tumour stage, grade and metastasis-free survival using the Fishers exact test, Kaplan-Meier method and Log-Rank test, respectively. For multivariate testing, a Cox proportional hazards model was used.

Medical University Graz, Institute of Pathology, Graz, Austria, 2Medical University Graz, Urology, Graz, Austria, 3Medical University Graz, Biomedical Engineering and Computing, Graz, Austria INTRODUCTION & OBJECTIVES: Urothelial carcinoma (UC) of the renal pelvis is relatively uncommon, accounting for about 5% of all urothelial tumours. Tumour stage has been documented as major prognostic factor. Stage pT3 comprises tumours invading beyond muscularis into peripelvic fat or renal parenchyma. Our study aimed to assess the potential value of a subdivision of stage pT3 in predicting patient outcome. MATERIAL & METHODS: 57 consecutive stage pT3 UCs of the renal pelvis from 57 patients (21 females, 36 males) operated between 01/1984 and 12/2004 were re-evaluated and subdivided regarding different patterns of tumour involvement as follows: (i) tumours invading renal parenchyma on a microscopic level only, (ii) tumours with macroscopic renal parenchyma invasion discerned from the gross appearance of the resection specimen, and (iii) tumours with spread into peripelvic fat. Eight tumours showing continuous tumour growth within collecting duct lumina, however, without penetration of the duct basal membrane, were analysed for comparison. Association between tumour stage and tumour grade were assessed using the Fishers exact test. Prognostic impact was analysed using the Kaplan-Meier method and the Log-Rank test. RESULTS: 13 (23%) tumours showed microscopic inltration of renal parenchyma only, whereas 33 (58%) tumours inltrated the renal parenchyma on a macroscopic level. 28 (49%) of the latter additionally invaded peripelvic fat. The remaining 11 (19%) tumours showed fat invasion without evidence of renal parenchyma inltration. Regarding the recent two-tiered WHO/ISUP grading system, 46 (81%) tumours were of high tumour grade and 11 (19%) of low tumour grade. 8/11 (73%) low grade UCs showed only microscopic renal parenchyma inltration compared with 5/46 (11%) high grade UCs (p<0.001). Metastatic disease occurred in 37/53 (70%) patients for whom follow-up data were available. Among them, 3/13 (23%) patients with tumours showing only microscopic invasion of renal parenchyma developed metastatic disease compared with 34/40 (85%) patients with tumours showing macroscopic invasion and/or spread into peripelvic fat (p<0.001). No disease progression was observed among the eight tumours showing intraductal tumour growth only. CONCLUSIONS: The stage pT3 category of pelvic UCs seems so comprise a heterogeneous sample of tumours. From a practical point of view, this category could be sub-divided by prognostic impact (similar to the recent change in the classication of bladder UCs) into two categories, with one group (pT3a) showing renal parenchyma invasion on a histological level only and the other (pT3b) revealing parenchyma invasion already at gross inspection of the resection specimen and/ or showing tumour spread into peripelvic fat. In contrast, mere intraductal involvement lacked prognostic signicance and should consequently be excluded from pT3 disease.

RESULTS: Stage pTa was present in 41 (15.3%), pT1 in 102 (38.1%), pT2 in 37 (13.8%), pT3 in 80 (29.9%) and pT4 in eight (3.0%) cases, respectively. 141 (52.6%) UCs were of low (LG) and 127 (47.4%) of high (HG) tumour grade. Expression of COX-2 was noted in 89/260 (34.2%) evaluable tumours and was focal in 54 (20.8%), moderate in 28 (10.8%), and extensive in 7 (2.7%) cases, respectively. COX-2 immunoreactivity was associated with high tumour stage (36/139 [(25.9%] pTa/pT1 vs. 53/121 [43.8%] pT2-pT4; P=0.003) and high tumour grade (25/139 [18%] LG vs. 64/121 [52.9%] HG; P<0.001). Pelvic and ureteral UCs showed comparable staining results. Metastatic disease occurred in 71/181 (39.2%) patients. 37/69 (53.6%) patients with UCs with COX-2 expression developed disease progression, compared with 34/112 (30.4%) patients with UCs without COX-2 expression (P<0.001). In multivariate analysis, however, only pT-stage >1 (P<0.001, risk ratio [RR] = 7.41, 95% condence interval [CI] = 3.34-16.42) and high tumour grade (P=0.001, RR=3.33, 95% CI 1.62-6.85) proved to be independent predictors of metastatic disease, whereas COX-2 immunoreactivity lacked independent inuence on patient outcome (p=0.16). CONCLUSIONS: Although COX-2 expression did not prove to be an independent prognostic factor in upper tract UCs, its association with high tumour stage and grade may offer additional perspectives in cancer prevention and treatment.

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THE EFFECT OF COMPETING MORTALITY ON THE RISK OF BLADDER-CANCER RECURRENCE AND BLADDER CANCERSPECIFIC SURVIVAL
Chun K.h.F.1, Briganti A.1, Shariat S.F.2, Palapattu G.S.3, Yair L.2, Craig R.3, Bastian P.3, Amiel G.4, Gupta A.2, Vazina A.4, Matt N.3, Arthur S.2, Lerner S.4, Schoenberg M.3, Karakiewicz P.I.1
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POSITIVE CYTOLOGY, BUT NEGATIVE WHITE LIGHT ENDOSCOPY: AN INDICATION FOR FLUORESCENCE CYSTOSCOPY IN BLADDER CANCER? Karl A.1, Reich O.1, Tritschler S.1, Knuechel-Clarke R.2, Hartmann A.3, Stief C.1, Zaak D.1
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University of Montreal, Cancer Prognostics and Outcomes Research Unit, Montreal, Canada, 2UT Southwestern Medical School, Department of Urology, Dallas, United States, 3Johns Hopkins University School of Medicine, Department of Urology, Baltimore, United States, 4Baylor College of Medicine, Department of Urology, Huston, United States INTRODUCTION & OBJECTIVES: One in three patients treated with cystectomy die of other causes than bladder cancer. Despite this observation, Kaplan-Meier (KM) and Cox regression models do not account for the contribution of competing causes of mortality. Instead, KM and Cox models censor those who die of other causes. Censored patients are no longer are at risk of cause-specic events: recurrence or death from bladder cancer. We hypothesized that the effect of censoring due to competing causes of mortality may signicantly underestimate renal cancer related events. We studied the effect of competing mortality on the rate of bladder cancer recurrence and on survival after cystectomy using competing risks regression in a large multi-institutional cohort. MATERIAL & METHODS: We used 750 complete observations addressing patients with exclusive transitional cell carcinoma (TCC) pathology, from a cohort of 958 patients treated with cystectomy for bladder cancer between 1984 and 2003. RESULTS: Cumulative incidence plots addressing any type of recurrence (Fig. A) and survival (Fig. B) are shown below and indicate that at respectively 5 and 10 years, 7 and 15% of patients are censored due to competing mortality and are no longer at risk of experiencing a recurrence. In survival models, at 5 and 10 years respectively, competing causes affect 10% and 20% of patients. These patients are no longer at risk of dying of bladder cancer. In multivariate competing risks regression models, which accounted for three possible outcomes (bladder cancerspecic mortality, other cause mortality and loss to f/u) lymphovascular invasion, pathologic stages T3 and T4 and presence of lymph node invasion represented signicant predictors of recurrence as well as of mortality. Age, tumour grade and number of nodes removed failed to reach multivariate predictors status (all p>0.05).

Ludwig-Maximilians-University Munich, Urology, Munich, Germany, 2RWTH University of Aachen, Pathology, Aachen, Germany, 3University of Regensburg, Pathology, Regensburg, Germany INTRODUCTION & OBJECTIVES: The cytological proof of high grade carcinoma in combination with a negative white light cystoscopy is a diagnostical and therapeutical dilemma. Nevertheless, after exclusion of upper urinary tract disease, a histological specimen is recommended in order to initiate an adequate treatment. It was the aim of the present study to evaluate the efcacy of uorescence cystoscopy (FC) in these unfavourable cases. MATERIAL & METHODS: Two hours prior to FC, 1.5 g 5-ALA dissolved in 50 ml of 5.7% sodium monohydrogen phosphate was instilled intravesically. Before FC, all patients underwent white light endoscopy and a bladder washing cytology was obtained. Suspicious sites were identied by their red uorescence contrasting against backscattered blue light and biopsies were taken in the same examination. RESULTS: In 331 patients white light cystoscopy revealed no suspicion of tumour. 63 out of 331 (19%) patients presented a cytologic specimen positive or suspicious of disease. In 51 of these patients (80.9%), the cytological ndings were veried by FC, which detected the precise site of malignancy within the bladder (17 Dys II, 20 Cis; 14 pTa-1/G1-3). In addition in 39 out of 268 patients with negative bladder washing cytology, urothelial neoplasms (14 Dys II, 5 Cis; 20 pTa-1/G1-3) were found. The sensitivity of bladder washing cytology in high grade tumours was found to be 81%.

CONCLUSIONS: Competing risks regression models indicate that between 5 and 15% of patients are removed from the analyses of either recurrence or survival after cystectomy. Removal of these patients decreases the causespecic recurrence and mortality rates and underestimates the effect of bladder cancer on recurrence and/or mortality by at least 5 to 15%.

CONCLUSIONS: Fluorescence cystoscopy proves to be an effective tool in detecting the precise site of malignancy, especially in case of positive cytology without evidence of tumour in white light cystoscopy. Therefore FC should be recommended even for these unfavourable cases.

Eur Urol Suppl 2006;5(2):226