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462Polyomavirus infection as an early marker for bladder transitional cell carcinoma
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462 FOR
THE E F F E C T OF S Q U A M O U S AND/OR G L A N D U L A R DIFFERENT I A T I O N ON R E C U R R E N C E , P R O G R E S S I O N AND SURVIVAL IN U R O T H E L I A L C A R C I N O M A OF B L A D D E R
P O L Y O M A V I R U S I N F E C T I O N AS AN E A R L Y BLADDER TRANSITIONAL C E L L C A R C I N O M A
Parlaktas B.S. Erdemir F., Uluocak N., Gokce O., Tunc M.
Omodeo-Zorini E. t, Cacciotti R ~, Sogni F.2, Kocj ancic E. 2, Frea B. 2, Monga G. ~, Gaudino G.1 Gontero E 2
Gaziosmanpasa University, Urology, Tokat, Turkey I N T R O D U C T I O N & OBJECTIVES: It has been debated that urothelial carcinoma of bladder with squamous and/or glandular differentiation behaves more aggressively than conventional urothelial carcinoma. The effects of this differentiation on recurrence, progression and survival rate were evaluated and discussed with the relevant literature in this study. M A T E R I A L & M E T H O D S : Between February 1998 and January 2003, 223 patients, who had been treated with tTansurethral resection, were evaluated retrospectjvely. All the patients had histologically proven urothelial carcinoma of bladder and were divided into two groups according to histologic features of bladder tumour as; Groupl: tumour patients with squamous and/or glandular differentiation, Group II: patients without these findings. The data about stage distribution, survival rate, recurrence and progression between these two groups were compared. RESULTS: Within the total 223 transurethrally resected bladder tumours, histologically 189 (84.75 %) were conventional urothelial carcinoma and 34 (15.25 %) were tumours with squamous and/or glandular differentiation. The mean age of the patient at referral was 64.45±12.7 (36-8 lyears. Survival rates within a period of 46.234-14.8 (12-67) months were 76.47% (26/34) for Group I and 89.9% (170/189) for Group II (p=0.027). The stage distribution as pTa, pT1 and _>pT2 was 2 (5.9%), 18 (52.9%) and 14 (41.2%) in Group I and 101 (53.4%), 51 (27%) and 37 (19.6%) in group II respectively (p=0.001). There was a statistically significant tendency towards higher stage at presentation in Gro W I and the grade distribution was significantly higher in Group I than Group II (p<0.001). Recurrence and progression rates in the group with squamous and/or glandular differentiation (Group I) were 70% (14/20) and 35% (n:7/20) but for Group II they were 42.02% (n:65/152) and 9.21% (n:14/152). The difference between these values were statistically significant (p=0.022 and p=0.013). CONCLUSIONS: There was a significant difference between bladder tumours with squamous and/or glandular differentiation and conventional mmours without this differentiation with regard to clinical stage and grade at presentation, tumour recurrence and progression rates. This suggests the more aggressive behaviour of bladder mmours with squamous and/or glandular differentiation.
MARKER
1University of Piemonte Orientale Novara, Medical Sciences, Novara, Italy, 2University of Piemonte Orientale Novara, Urology, Novara, Italy I N T R O D U C T I O N & OBJECTIVES: Polyomavirus BKV, JCV and SV40 have been reported to latently infect several human tissues. Primary or induced immunodeficiency may reactivate these viruses, for which an oncogenic role has been suggested. While BK and JCV have been detected in both normal and neoplastic urothelium, to our knowledge SW40 has not been assessed yet in human bladder tissues. Aim of this work is to verify the prevalence of BKV, JCV and SV40 in Transitional Cell Carcinoma (TCC) of the bladder and to elucidate their possible role in development and progression of this neoplasm. M A T E R I A L & METHODS: Nineteen patients with primary or recurrent TCC underwent TURB of the tumour site. A cold biopsy was obtained from normal looking mucosa. Tissue samples were examined for viral genome DNA amplification by PCR, using virus specific primers. Viral protein expression was determined by Immunohistochemistry. Eight bladder specimens from patients undergoing TURP for benign prostatic hyperplasia (BPH) served as controls in the same determinations. Sera from neoplastic and control patients were also analysed. Disease grading and staging were performed by histological examination. Overall data were evaluated by non-parametric statistical analysis according to the Fisher's method. RESULTS: All bladder tissues from BPH control patients were negative for all three virus genomes. The prevalence of one or more viruses in the case patients was 42% in tumour samples and 68% in macroscopically normal mucosa respectively. Within mmoural tissues, viruses appeared more represented in primary and/or superficial TCCs compared with recurrent and/or invasive TCCs. CONCLUSIONS: These preliminary data show a strong association between bladder cancer and the presence of one or more PV family viruses. The finding of a higher prevalence of viruses in normally looking mucosa from BC patients as well as in primary or superficial turnouts seems to suggest a potential involvement of PV viruses in the early steps of bladder carcinogenesis.
463
464
THE DIAGNOSTIC AND P R O G N O S T I C VALUE OF IMMUNH1STOC H E M I C A L D E M O N S T R A T I O N OF T H E G A M M A 2 C H A I N OF LAMININ-5 IN URINARY B L A D D E R U R O T H E L I A L C A R C I N O M A
N O V E L B L A D D E R C A N C E R M O D E L IN R A B B I T FACILITATES E N D O S C O P I C DIAGNOSIS AND T R E A T M E N T : A P R E L I M I N A R Y REPORT
Wunderlich H ? , Hindermann W, 2, Berndt A. 2, Schubert j.1, Reichelt 0. I, Kosmehl U. 3
Mian B. ~,Agartan C. i, Whitbeck C. t, Levin R.2, Nazeer T.3
1Klinikum der Friedrich-Schiller-Universidit, Dept. of Urology, Jena, Germany, 2Friedrich-Schiller-University, Dept. of Pathology, Jena, Germany, 3Helios-Clinic, Dept. of Pathology, Erfurt, Germany I N T R O D U C T I O N & OBJECTIVES: Nearly 20-40% of the patients with noninvasive urothelial bladder cancer develop muscle-invasion or metastatic spread that indicates the existence of transitional cell carcinoma with variable biological characteristics and prognosis. The change into the invasive stage goes in line with a dramatically worsening of patients' outcome, because invasive bladder cancer is very aggressive and has a very poor prognosis. The study was aimed to evaluate invasion associated changes of the epithelial adhesion complex in urothelial carcinoma (UC)'monitored by immunohistochemical demonstration of the gamma-2 chain of laminin-5 (Ln-5 g2 chain). M A T E R I A L & M E T H O D S : A semiquantitative immunohistochemical analysis of 100 routinely processed paraffin embedded samples (non-invasive and invasive UC) was performed to correlate UC phenotype and patients outcome, using the antibody D4B5 specffic for the Ln-5 g2 chain. The mean follow-up period was 44.8 months (ranged from 0.1 to 157.2 months). RESULTS: An increased risk of death is associated with an increased Ln-5 loss from basement membrane (BM) (p=0.001), an increase of stroma deposition (p-0.001) as well as an increase of cellular retention of Ln-5 protein (p=0.001) (Kruskal-Wallis-test). In addition to mmour stage the cellular retention of Ln-5 is the most important prognostic parameter as shown in multivariate analysis. CONCLUSIONS: From our results we conclude that an enhanced loss of Ln-5 g2 chain from the BM, extracellular deposition and cellular retention significantly represent invasiveness of UC. The reorganization of the Ln-5 g2 chain as a hallmark of invasion in UC may be used as an additional diagnostic tool for the crucial decision between invasive and non-invasive urothelial carcinomas.
European Urology Supplements 4 (2005) No. 3, pp. 118
tAlbany Medical College, Urology, Albany, United States, 2Albany College of Pharmacy, Urology, Albany, United States, 3Albany College of Pharmacy, Pathology, Albany, United States INTRODUCTION & OBJECTIVES: Most bladder cancers are superficial at diagnosis, and require multiple endoscopic evaluations and interventions. While animal models of advanced bladder cancer are available, there are no reliable bladder cancer models that allow us to diagnose, or treat the cancers in a manner similar to the clinical practice. Our previous studies demonstrated that acute bladder overdistention results in the overexpressiun of bFGF, VEGF, HIF-1 alpha, as well as c-myc and ras family of oncogenes. Similar changes are also noted in bladder cancer of various grades and stages. We hypothesized that exposure of the rabbit urothelium, while it is undergoing the above-stated cellular and molecular changes, to a carcinogen will convert the rabbit urothelium to a malignant phenotype. We also sought to determine the feasibility of multiple endoscopic maulpulations of the rabbit bladder, similar to that required in humans. MATERIAL & METHODS: Eight adult male NZW rabbits were anaesthetized and the bladder was distended for 30 minutes following which nitrosomethylurea 2.5-5 mg in 25 ml of normal saline was instilled into the bladder, once/week for up to 8 weeks. A paediatric cystoscope was used prior to each instillation to inspect the urothelium and obtain biopsies from abnormal appearing areas. The control group included two rabbits without distention or instillation. The animals were sacrificed at the end of the study and full thickness bladder walls were sectioned and formalin-fixed for pathologic evaluation. The specimens were reviewed by a pathologist and a urologist, who were blinded to the origin of tissue samples. RESULTS: We found that the rabbits did not experience any significant untoward effects from multiple cystoscopies or biopsies. At 4 weeks, the urotheliurn appeared to develop lesions that cystoscopically appeared similar to human papillary TCC. In most of the animals, the biopsies revealed presence ofpre-malignant and early malignant lesions such as papillary hyperplasia, intestinal metaplasia, squamous metaplasia and low-grade dysplasia. The full thickness bladder wall specimens revealed presence of mild to marked papillary hyperplasia, focal to diffuse atypia, and low-grade dysplasia in all animals. CONCLUSIONS: The findings of this preliminary study suggest that exposing the urothelium to a carcinogen at a time when it is undergoing specific cellular and molecular changes, can result in a malignant phenotype. This model allows us to perform serial cystoseopic examinations to assess disease progression or response to therapy, without sacrificing the animals. In order to develop a more reliable and reproducible range of mmours, further experiments with modifications in the overdistention/instillation schedules, or carcinogen doses are currently ongoing.
462 FOR
THE E F F E C T OF S Q U A M O U S AND/OR G L A N D U L A R DIFFERENT I A T I O N ON R E C U R R E N C E , P R O G R E S S I O N AND SURVIVAL IN U R O T H E L I A L C A R C I N O M A OF B L A D D E R
P O L Y O M A V I R U S I N F E C T I O N AS AN E A R L Y BLADDER TRANSITIONAL C E L L C A R C I N O M A
Parlaktas B.S. Erdemir F., Uluocak N., Gokce O., Tunc M.
Omodeo-Zorini E. t, Cacciotti R ~, Sogni F.2, Kocj ancic E. 2, Frea B. 2, Monga G. ~, Gaudino G.1 Gontero E 2
Gaziosmanpasa University, Urology, Tokat, Turkey I N T R O D U C T I O N & OBJECTIVES: It has been debated that urothelial carcinoma of bladder with squamous and/or glandular differentiation behaves more aggressively than conventional urothelial carcinoma. The effects of this differentiation on recurrence, progression and survival rate were evaluated and discussed with the relevant literature in this study. M A T E R I A L & M E T H O D S : Between February 1998 and January 2003, 223 patients, who had been treated with tTansurethral resection, were evaluated retrospectjvely. All the patients had histologically proven urothelial carcinoma of bladder and were divided into two groups according to histologic features of bladder tumour as; Groupl: tumour patients with squamous and/or glandular differentiation, Group II: patients without these findings. The data about stage distribution, survival rate, recurrence and progression between these two groups were compared. RESULTS: Within the total 223 transurethrally resected bladder tumours, histologically 189 (84.75 %) were conventional urothelial carcinoma and 34 (15.25 %) were tumours with squamous and/or glandular differentiation. The mean age of the patient at referral was 64.45±12.7 (36-8 lyears. Survival rates within a period of 46.234-14.8 (12-67) months were 76.47% (26/34) for Group I and 89.9% (170/189) for Group II (p=0.027). The stage distribution as pTa, pT1 and _>pT2 was 2 (5.9%), 18 (52.9%) and 14 (41.2%) in Group I and 101 (53.4%), 51 (27%) and 37 (19.6%) in group II respectively (p=0.001). There was a statistically significant tendency towards higher stage at presentation in Gro W I and the grade distribution was significantly higher in Group I than Group II (p<0.001). Recurrence and progression rates in the group with squamous and/or glandular differentiation (Group I) were 70% (14/20) and 35% (n:7/20) but for Group II they were 42.02% (n:65/152) and 9.21% (n:14/152). The difference between these values were statistically significant (p=0.022 and p=0.013). CONCLUSIONS: There was a significant difference between bladder tumours with squamous and/or glandular differentiation and conventional mmours without this differentiation with regard to clinical stage and grade at presentation, tumour recurrence and progression rates. This suggests the more aggressive behaviour of bladder mmours with squamous and/or glandular differentiation.
MARKER
1University of Piemonte Orientale Novara, Medical Sciences, Novara, Italy, 2University of Piemonte Orientale Novara, Urology, Novara, Italy I N T R O D U C T I O N & OBJECTIVES: Polyomavirus BKV, JCV and SV40 have been reported to latently infect several human tissues. Primary or induced immunodeficiency may reactivate these viruses, for which an oncogenic role has been suggested. While BK and JCV have been detected in both normal and neoplastic urothelium, to our knowledge SW40 has not been assessed yet in human bladder tissues. Aim of this work is to verify the prevalence of BKV, JCV and SV40 in Transitional Cell Carcinoma (TCC) of the bladder and to elucidate their possible role in development and progression of this neoplasm. M A T E R I A L & METHODS: Nineteen patients with primary or recurrent TCC underwent TURB of the tumour site. A cold biopsy was obtained from normal looking mucosa. Tissue samples were examined for viral genome DNA amplification by PCR, using virus specific primers. Viral protein expression was determined by Immunohistochemistry. Eight bladder specimens from patients undergoing TURP for benign prostatic hyperplasia (BPH) served as controls in the same determinations. Sera from neoplastic and control patients were also analysed. Disease grading and staging were performed by histological examination. Overall data were evaluated by non-parametric statistical analysis according to the Fisher's method. RESULTS: All bladder tissues from BPH control patients were negative for all three virus genomes. The prevalence of one or more viruses in the case patients was 42% in tumour samples and 68% in macroscopically normal mucosa respectively. Within mmoural tissues, viruses appeared more represented in primary and/or superficial TCCs compared with recurrent and/or invasive TCCs. CONCLUSIONS: These preliminary data show a strong association between bladder cancer and the presence of one or more PV family viruses. The finding of a higher prevalence of viruses in normally looking mucosa from BC patients as well as in primary or superficial turnouts seems to suggest a potential involvement of PV viruses in the early steps of bladder carcinogenesis.
463
464
THE DIAGNOSTIC AND P R O G N O S T I C VALUE OF IMMUNH1STOC H E M I C A L D E M O N S T R A T I O N OF T H E G A M M A 2 C H A I N OF LAMININ-5 IN URINARY B L A D D E R U R O T H E L I A L C A R C I N O M A
N O V E L B L A D D E R C A N C E R M O D E L IN R A B B I T FACILITATES E N D O S C O P I C DIAGNOSIS AND T R E A T M E N T : A P R E L I M I N A R Y REPORT
Wunderlich H ? , Hindermann W, 2, Berndt A. 2, Schubert j.1, Reichelt 0. I, Kosmehl U. 3
Mian B. ~,Agartan C. i, Whitbeck C. t, Levin R.2, Nazeer T.3
1Klinikum der Friedrich-Schiller-Universidit, Dept. of Urology, Jena, Germany, 2Friedrich-Schiller-University, Dept. of Pathology, Jena, Germany, 3Helios-Clinic, Dept. of Pathology, Erfurt, Germany I N T R O D U C T I O N & OBJECTIVES: Nearly 20-40% of the patients with noninvasive urothelial bladder cancer develop muscle-invasion or metastatic spread that indicates the existence of transitional cell carcinoma with variable biological characteristics and prognosis. The change into the invasive stage goes in line with a dramatically worsening of patients' outcome, because invasive bladder cancer is very aggressive and has a very poor prognosis. The study was aimed to evaluate invasion associated changes of the epithelial adhesion complex in urothelial carcinoma (UC)'monitored by immunohistochemical demonstration of the gamma-2 chain of laminin-5 (Ln-5 g2 chain). M A T E R I A L & M E T H O D S : A semiquantitative immunohistochemical analysis of 100 routinely processed paraffin embedded samples (non-invasive and invasive UC) was performed to correlate UC phenotype and patients outcome, using the antibody D4B5 specffic for the Ln-5 g2 chain. The mean follow-up period was 44.8 months (ranged from 0.1 to 157.2 months). RESULTS: An increased risk of death is associated with an increased Ln-5 loss from basement membrane (BM) (p=0.001), an increase of stroma deposition (p-0.001) as well as an increase of cellular retention of Ln-5 protein (p=0.001) (Kruskal-Wallis-test). In addition to mmour stage the cellular retention of Ln-5 is the most important prognostic parameter as shown in multivariate analysis. CONCLUSIONS: From our results we conclude that an enhanced loss of Ln-5 g2 chain from the BM, extracellular deposition and cellular retention significantly represent invasiveness of UC. The reorganization of the Ln-5 g2 chain as a hallmark of invasion in UC may be used as an additional diagnostic tool for the crucial decision between invasive and non-invasive urothelial carcinomas.
European Urology Supplements 4 (2005) No. 3, pp. 118
tAlbany Medical College, Urology, Albany, United States, 2Albany College of Pharmacy, Urology, Albany, United States, 3Albany College of Pharmacy, Pathology, Albany, United States INTRODUCTION & OBJECTIVES: Most bladder cancers are superficial at diagnosis, and require multiple endoscopic evaluations and interventions. While animal models of advanced bladder cancer are available, there are no reliable bladder cancer models that allow us to diagnose, or treat the cancers in a manner similar to the clinical practice. Our previous studies demonstrated that acute bladder overdistention results in the overexpressiun of bFGF, VEGF, HIF-1 alpha, as well as c-myc and ras family of oncogenes. Similar changes are also noted in bladder cancer of various grades and stages. We hypothesized that exposure of the rabbit urothelium, while it is undergoing the above-stated cellular and molecular changes, to a carcinogen will convert the rabbit urothelium to a malignant phenotype. We also sought to determine the feasibility of multiple endoscopic maulpulations of the rabbit bladder, similar to that required in humans. MATERIAL & METHODS: Eight adult male NZW rabbits were anaesthetized and the bladder was distended for 30 minutes following which nitrosomethylurea 2.5-5 mg in 25 ml of normal saline was instilled into the bladder, once/week for up to 8 weeks. A paediatric cystoscope was used prior to each instillation to inspect the urothelium and obtain biopsies from abnormal appearing areas. The control group included two rabbits without distention or instillation. The animals were sacrificed at the end of the study and full thickness bladder walls were sectioned and formalin-fixed for pathologic evaluation. The specimens were reviewed by a pathologist and a urologist, who were blinded to the origin of tissue samples. RESULTS: We found that the rabbits did not experience any significant untoward effects from multiple cystoscopies or biopsies. At 4 weeks, the urotheliurn appeared to develop lesions that cystoscopically appeared similar to human papillary TCC. In most of the animals, the biopsies revealed presence ofpre-malignant and early malignant lesions such as papillary hyperplasia, intestinal metaplasia, squamous metaplasia and low-grade dysplasia. The full thickness bladder wall specimens revealed presence of mild to marked papillary hyperplasia, focal to diffuse atypia, and low-grade dysplasia in all animals. CONCLUSIONS: The findings of this preliminary study suggest that exposing the urothelium to a carcinogen at a time when it is undergoing specific cellular and molecular changes, can result in a malignant phenotype. This model allows us to perform serial cystoseopic examinations to assess disease progression or response to therapy, without sacrificing the animals. In order to develop a more reliable and reproducible range of mmours, further experiments with modifications in the overdistention/instillation schedules, or carcinogen doses are currently ongoing.