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The Remnant Urothelium after Reconstructive Bladder Surgery
European Urology
European Urology 41 (2002) 124±131
Review
The Remnant Urothelium after Reconstructive Bladder Surgery Arnulf Stenzl*, Georg Bartsch, Hermann Rogatsch Department of Urology and Institute of Pathology, University of Innsbruck Medical School, A-6020 Innsbruck, Austria Accepted 24 September 2001
Abstract The pathology of the remnant urinary tract in an increasing population of cystectomy patients with orthotopic and heterotopic bladder substitution due to primary bladder carcinoma, and its management is discussed. The incidence of urethral tumours in primary or recurrent bladder cancer in long-term studies is approximately 6% for male and 2% for female patients. Risk factors for urethral tumour occurrence are tumours at the bladder neck and recurrent multifocal tumours. CIS of the bladder not involving the bladder neck, and muscle invasive tumours with or without lymph node involvement are not signi®cantly correlated with urethral cancer. Those patients at risk for urethral tumours need additional work-up (multiple urethral biopsies and/or urethral brushings, frozen section of the membranous urethra) before an orthotopic lower urinary tract reconstruction to the urethra should be considered. In a large series of male patients, the majority of patients with urethral tumours had a single conservative treatment session, and did not recur thereafter demonstrating the feasibility of a conservative approach for super®cial urethral tumour recurrences in patients with an orthotopic neo-bladder to the urethra. The incidence of upper tract tumours following cystectomy and lower urinary tract reconstruction lies between 2.4± 17%. In a group of 258 patients with an orthotopic bladder substitution, we have seen an incidence of 3.5%. Tumour multifocality, carcinoma in situ in the bladder and/or distal ureter, locally advanced bladder tumour stage, and invasion of the intramural ureter were seen as risk factors in some series. A tendency for a higher incidence can be seen in those series with longer follow-up. The median time between cystectomy and diagnosis of upper tract tumours lies between 8 and 69 months in most series. A longer observation period in larger numbers of patients with an orthotopic neo-bladder and longer survival rates in general after cystectomy may reveal an increase in the incidence of upper tract tumours over the next decade. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Urinary diversion; Transitional cell carcinoma; Bladder cancer; Recurrence; Urethra; Upper urinary tract
1. Introduction Transitional cell cancer (TCC) of the bladder is regarded an organ speci®c disease. Due to its size and storage function allowing urinary carcinogens to alter the urothelium it is by far the most common site of TCC. Radical cystectomy still shows the best treatment results regarding progression and survival of muscle-invasive disease. A major part of the urothelium in the upper urinary tract and at times a small *
Corresponding author. Tel. 43-512-504-4813; Fax: 43-512-504-8411. E-mail address: [email protected] (A. Stenzl).
fraction in the urethra, however, remain after attempted surgical cure, i.e. radical cystectomy and lower urinary tract reconstruction. Several recent reports dealing with the long-term follow-up of TCC patients with an orthotopic neo-bladder after radical cystectomy have demonstrated that urethral recurrence was considerably lower than initially reported, but that a longer follow-up may increase the number of upper urinary tract recurrences. An orthotopic neo-bladder is currently the most natural way to reconstruct the urinary bladder. An increasing number of reports dealing with median term experiences with ureterointestinal urethrostomy has given us more details on how to select patients, how
0302-2838/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 2 - 2 8 3 8 ( 0 1 ) 0 0 0 3 1 - 8
A. Stenzl et al. / European Urology 41 (2002) 124±131
to reduce pre- and post-operative morbidity [1], and the follow-up. Access of the upper urinary tract in case of a pathological ®nding in patients with an intestinal lower urinary tract reconstruction may become more important, when more and more patients who are cured of their bladder disease will be seen with upper urinary tract pathology. 2. Remnant urethra in the male Several authors either suggested [2] or strongly recommended [3,4] urethrectomy in conjunction with radical cystectomy for bladder cancer. However, in recent years orthotopic reconstruction of the lower urinary tract has gained popularity both by patients and doctors [5], which precludes a simultaneous prophylactic urethrectomy at the time of cystectomy. The reported incidence of secondary urethral tumours in patients with bladder cancer is diverging. Gowing [6] autopsied patients dying with bladder cancer and found in 6 of 33 autopsies (18%) carcinoma in situ. Looking at urethral tumour recurrences after radical cystoprostatectomy several reports found urethral recurrences in around 10% of the patients and usually suggested a generous decision to perform primary prophylactic urethrectomy [7]. In unselected series of male bladder cancer patients [8,9], there was an incidence of concomitant urethral tumours of 5.4 and 6.1% in 914 and 910 patients, respectively. The majority of the patients in both groups were treated conservatively, i.e. without major surgery or radiation allowing to assess the incidence of urethral tumours of patients with primary and recurrent bladder tumours of all stages. Overall the average incidence of secondary urethral tumours in bladder cancer patients in the literature is
125
Table 2 Frequency of urethral tumours among primary versus recurrent and solitary versus multifocal bladder tumoursa,b Characteristic of tumour
Number of urethral tumours
%
Primary unilocular
10
2.6
Recurrent unilocular
22
4.1
Primary multifocal
27
5.8
Recurrent multifocal
67
10.1
a
910 men with bladder cancer observed at a single institution over a period of 25 years. Adapted from [9]. b An arrow pointing downwards and increasing in size should emphasise the increasing percentages in the 3rd column.
6.2% and seems to be similar when broken up for studies with an intact bladder (5.8%) and those with tumours in the remnant urethra after cystectomy (6.2%) (Table 1) [8,10±14]. A signi®cant difference was evident between those patients where a solitary TCC occurred in the bladder for the ®rst time (2.6%) and those with recurrent multifocal cancer (10.1%, Table 2). This may be a factor in the decision making process, whether an orthotopic neo-bladder is prudent or whether a synchronous urethrectomy should be performed. In this report, it has also been shown that only 17 of 87 patients with bladder cancer and concomitant urethral cancer treated endoscopically had recurrences in the urethra [9]. Transurethral resection and/or fulguration may be seen therefore as a possible way of treatment for super®cial papillary TCC in the urethra. A recent report also demonstrated the possible use of
Table 1 Metaanalysis with documented cases References
Number of patients
Number of urethral tumor events
Urethral tumour involvement in male patient with bladder cancer [2,6,8±14,18,33,59±61]
5657
349 (6.2%)
841
30 (3.6%)
Urethral tumour involvement or carcinoma in situ in female patients with bladder cancer [3,8,19,26,28±31] References
Number of patients
Number of recurrences
Urethral tumour recurrence after cystoprostatectomy for bladder cancer [7,21,62±65]
3165
256 (8.1%)
Upper tract recurrences after cystectomy for bladder cancer [1,43,44,47±52,64]
3090
104 (3.3%)
126
A. Stenzl et al. / European Urology 41 (2002) 124±131
¯uorescence-guided diagnosis and therapy of carcinoma in situ and super®cial papillary tumours [15]. Those patients which according to their clinical staging would nowadays be good candidates for radical surgery with the option of an orthotopic neo-bladder were sorted out in this study. Patients with a clinically staged T2-3 N-0, M-0 TCC had a lower rate (4.2%) of urethral tumour occurrence than the average 6.1% of the whole study group. If all node positive patients (N0-2) were included in this group, the urethral tumour rate was still 4.3%. A tendency towards solitary primary tumours, a more aggressive initial therapy, and a decreased life expectancy resulting in shorter follow-up times may account for the lower urethral tumour rate in this group. Due to a changing treatment pattern of bladder cancer in an increasing number of patients resulting in radical surgery at an earlier stage [16,17], these data may nevertheless be helpful when consenting a patient to a subsequent orthotopic neobladder. Another aspect is the occurrence of CIS or papillary tumours in the remaining urethra after an orthotopic neo-bladder. Contrary to other authors [18±20], Erckert et al. did not see an increased risk of urethral tumours in patients with CIS of the bladder. This may in part be due to the fact that dysplasia or CIS of the urethra may have beenmissedinconservativelytreatedpatients.Onemight argue, however, that clinically important dysplasia or CIS left untreated or treated conservatively and followed for a long-term should eventually have resulted in overt and clinically important urethral cancer. 2.1. Urethral recurrence in heterotopic versus orthotopic lower urinary tract reconstructions In most of the older studies, urethral recurrence is de®ned as tumour in the remnant, blind-ending urethra [21]. Apart from a longer follow-up, there might have been other contributing factors responsible for a considerably higher incidence of secondary urethral tumours than observed with the functioning remnant urethra connected to a neo-bladder (Table 1). It may be speculated that scarring, chronic in¯ammation with certain E. coli strains, absence of cancer-preventing properties of the urine, and a lack of careful follow-up may play a role. The only larger study comparing urethral recurrence in orthotopic and heterotopic diversions did reveal a signi®cant advantage for orthotopic neo-bladders independent from the length of follow-up in each group [7]. The outcome of patients with TCC in the prostatic urethra and/or parenchyma was assessed in two large studies. Freeman et al. [7] looked at 436 patients undergoing cystectomy and either a heteroropic or orthotopic
lower urinary tract reconstruction. Their calculated recurrence rates demonstrated the highest probability of urethral recurrence in patients with invasive prostatic TCC followed by super®cial TCC. Despite prostatic TCC, however, urethral recurrence was 5% in orthotopic neo-bladder patients versus 24% in the blindending urethra after heterotopic urinary diversion. Iselin et al. looked at urethral recurrence in 70 men with prostatic TCC undergoing radical cystectomy for bladder cancer with a mean follow-up of 35 months [22]. The overall urethral recurrence rate was 3%. None of the patients with prostatic TCC in the cystectomy specimen died secondary to a urethral recurrence. The results presented are in line with other data in the literature [23,24] suggesting that orthotopic neo-bladder reconstruction may not be contraindicated in bladder cancer patients with prostatic involvement provided the margins of resection are negative. However, one recent report in a relative small series of 40 male patients with an orthotopic neo-bladder with a minimum follow-up of 5 years showed urethral recurrences in 5 patients (12%) [25]. No details regarding stage of the urethral tumours nor their treatment were given. 3. Remnant urethra in the female Few data exist about urethral involvement in women with bladder cancer. In the older literature concentrating on urethral tumour involvement of male patients with bladder cancer, female cases are only rarely discussed. Numbers in many studies dealing with concommittant urethral tumours or urethral recurrence in patients with bladder cancer have been small and any conclusions or at least a trend for female patients was not possible [3,6,11,18,19,26,27]. There has recently been focused interest, however, in data concerning the risk of secondary urethral tumours in female bladder cancer patients undergoing surgery [28±30]. If an adequate segment of the caudal urethra could be spared at cystectomy with a minimal risk of tumour recurrence, it might be used for continent orthotopic reconstruction of the lower urinary tract like in males. Risk factors for urethral involvement in female bladder cancer patients were not known until then. Ashworth [8] in a large cystoscopy study found urethral tumour involvement in 1.4% of female patients compared to 4.1% of male patients presenting with bladder cancer. In a more recent report retrospectively working up 22 female cystectomy specimens obtained over a period of 15 years, a 36%-incidence (8 of 22 patients) of super®cial or invasive urethral tumours was found. A strong argument for routine urethrectomy in
A. Stenzl et al. / European Urology 41 (2002) 124±131
all female patients with bladder cancer was therefore made [31]. However, no details about the total number of women treated with bladder cancer during this period, the tumour sites in bladder and urethra in patients subject to study, nor number and type(s) of treatment prior to cystectomy were given in this study. A contemporary study [30] showed urethral tumour involvement as being 2% in female patients with biopsy proven bladder cancer of all grades and stages. The mean follow-up was 5.5 years. One of the reasons for the apparent lower incidence of secondary urethral tumours in females in comparison to males [2,9] in several studies may be the fact that transitional cell mucosa covers a much smaller urethral segment in females, whereas, the rest is normal or metaplastic squamous cell mucosa. The area at risk in the female urethra is therefore small, and probably even diminishes with increasing age, because the demarcation line between squamous and transitional cell mucosa moves craniad during the menopause [32]. In the sixth and seventh decade where most of the bladder tumours occur, metaplastic squamous cell mucosa may cover the whole urethra, bladder neck and at times even a portion of the trigone. The fact that tumour involvement of the bladder neck and prostatic urethra is a possible predictor for synchronous or recurrent urethral tumours in male patients has been shown by several authors [2,18,33]. Most recent reports describe also a close coincidence between tumour involvement of the bladder neck and urethra in females [28±30]. In these studies, there was no urethral bladder cancer involvement without tumour involvement at the bladder neck at the same time, a fact that was statistically highly signi®cant. There was also a signi®cant correlation between the primary tumour location trigone and concomitant ure-
127
thral tumours, but only if the bladder neck was involved as well. In an unselected study of 356 female patients with different stages of bladder tumour followed for up to 33 years the incidence of urethral tumour involvement was 2% for the whole study group, 3.1% for a subgroup of invasive (T2-4) TCC, and 1% for localised (T2-3b, N-0, M-0) invasive cancer amenable to radical cystectomy. None of the patients with recurrent bladder tumours, whether progressing or not, had overt urethral tumour at any of the recurrences over the years. There was no correlation between urethral cancer and any other prognostic factor. Neither stage, multicentricity, number of tumours, presence of CIS, or duration of the disease seemed to play a predominant role. From these data one may conclude that female patients without tumour either at the bladder neck or at frozen section of the proximal urethra at the time of cystectomy can probably be spared a portion of the urethra to enable lower urinary reconstruction to the urethra without running a greater risk of developing recurrent urethral tumours than their selected male counterparts. Reviewing the literature, we found 30 cases of documented urethral tumour involvement (including CIS) in female patients with bladder cancer (Table 3). The overall incidence according to this table would be 3.6% (30 out of 841 patients). Most of the authors, however, used a highly selected group of patients, namely those undergoing cystectomy. The actual number of women seen and treated for all stages of bladder cancer at any of these institutions should have been higher than just an average of two cases per year. In order to obtain an overall urethral involvement rate for female bladder cancer patients it is therefore misleading to use percentages only out of the total number of cystectomized patients at a time several decades ago
Table 3 Review of the literature with documented cases of urethral tumour involvement or carcinoma in situ in female patients with bladder cancer Authors (references)
Study period
Number of patients
Number of BN tumours
Riches and Cullen [26] Ashworth [8] Richie and Skinner [19] Coutts et al. [3] De Paepe et al. [31] Stein et al. [29] Stenzl et al. [30] Coloby et al. [28]
n.g.a n.g. 1969±1971 1974±1983 1974±1988 1982±1992 1973±1992 1970±1990
19b 293 21b 18b 22b 65b 356 47 (341)
3 n.g. n.g. n.g. n.g. 16 49 9
Total a b
841
n:g: no data were given, BN bladder neck. Adapted from [30]. Heterogeneously selected bladder cancer study populations.
Urethral tumours 3 4 ± 2 5 7 6 3 30 (3.6%)
CIS
Tumours CIS
± ± 1 1 3 ± ±
3 4 1 3 8 7 6 22
5
54 (6.4%)
128
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when only few patients had exenteration for highly advanced bladder tumours. Several biopsies of the bladder neck should be performed in those patients where a subtotal urethrectomy is considered [34]. Any woman with a ®nding of atypia or overt tumour at the bladder neck is at risk for developing recurrent urethral tumour after cystectomy and should therefore undergo simultaneous total urethrectomy. But those patients where curative radical cystectomy is indicated and who are good candidates for an orthotopic reconstruction of the lower urinary tract may be spared a segment of the urethra for that purpose provided that pre-operative biopsies of the bladder neck and frozen section of the urethra at the time of surgery are free of atypia or tumour. Paraf®n embedded slides of super®cial biopsies taken pre-operatively allow a better staging regarding super®cial (mucosal) bladder neck involvement. Frozen sections of the urethral margin at the time of cystectomy on the other hand lead to better evaluation of both the entire urethral wall and circumference, however, with a higher possibility of error due to suboptimal embedding of frozen sections. Based on these pathological studies and anatomical data of the continence mechanism of the female urethra clinical protocols offering an ureteroileal urethrostomy to carefully selected female patients undergoing radical cystectomy for localised bladder cancer was initiated at several centres [35±39]. Their preliminary data and subsequent reports have been promising and have led to an increase in the number of both patients and centres where orthotopic neo-bladders are performed [40]. However, the urethraÐor a portion of itÐshould not be left in unless it is used for reconstructive purposes, because it can easily be removed en bloc with the bladder specimen and it requires additional efforts to follow oncologically when left in as a blind-ending sac. Now that orthotopic bladder substitution to the urethra has been popularised in female patients, one eventually expects urethral recurrences after bladder substitution in women as well. Seven years after the ®rst report of a larger series of women undergoing a neo-bladder procedure, a recent report has for the ®rst time illustrated a local failure at the anastomosis of pouch and urethra [41]. This failure among many successfully operated women by now shows shortcomings of this procedure. However, in this speci®c case several adverse signs for performing an urethrasparing cystectomy, namely tumour location and preservation of the entirely vaginal wall, and advanced pelvic lymph node involvement, were disregarded at the time of cystectomy [34]. It is therefore important in
future cases to put diagnostic and therapeutic errors into consideration before setting up new guide lines based on individual cases. 4. Upper urinary tract after intestinal bladder substitution Undoubtedly an enormous progress has been achieved since Simon's ®rst report in the middle of the 1900s about ureteral diversion into the rectum by creating a ®stula with the help of a silk thread. Subsequently, several techniques have been developed to restore continuity between the upper urinary tract and the reconstructed lower urinary tract which have helped to reduce the long-term morbidity and complication rate of intestinal urinary diversion [42]. The incidence of upper urinary tract tumours secondary to primary bladder cancer lies around 2±4% [43±45]. There is a higher risk in patients with multiple recurrences of super®cial Ta or T1 tumours [46]. The incidence of upper tract tumours following cystectomy and lower urinary tract reconstruction has been reported as 1.5±17.4% [1,43,47±55] (Table 4). In our own series looking at 258 patients undergoing cystectomy and orthotopic bladder substitution for transitional cell carcinoma between 1992 and 2000, we have seen an incidence of 3.5% (9 of 258 patients). In some series, there are indications that prolonged survival and follow-up in neo-bladder patients may lead to an increase in the incidence of upper tract recurrences in future years. Multifocality, carcinoma in situ and other super®cial tumours in the bladder was seen as a risk factor in some series, whereas, a report from Memorial Sloan-Kettering Cancer Center [52] put those patients with locally advanced tumour stage at a higher risk. Most likely tumour invasion of the intramural ureter, CIS in the distal ureter and/or the frozen section of the dissected ureter are additional risk factors. The median time between cystectomy and diagnosis of the upper tract tumours lies between 8 and 69 months in most series, but upper tract cancer recurrences more than 10 years after cystectomy have been observed. Most of the upper tract tumours in patients with bladder substitution are diagnosed following symptoms such as ¯ank pain, macrohematuria or a positive cytology. Routine radiological assessment of the upper urinary tract may not be worthwhile due to its poor detection rate according to this series. The development of smaller and ¯exible ureteroscopes has led to an increase use of mostly retrograde endoscopy both for treatment as well as surveillance of upper urinary tract tumours [56,57].
A. Stenzl et al. / European Urology 41 (2002) 124±131
129
Table 4 Review of the recent literature and our own results regarding upper tract recurrences after cystectomy for bladder cancer Authors (references)
Number of patients
Number of upper tract recurrences (%)
Interval to recurrence (months)
Balaji et al. [52] Slaton et al. [64] Solsona et al. [50]
529 382 179a 46b 200 61 430 638 180 220 425 258
16 9 7 8 3 4 11 20 10 5 14 9
Median 37.2 Median 25 Mean 28.3 Mean 18.3 ± Mean 69 Median 40 Mean 8 Mean 44 22±54 Mean 40 Mean 9
Studer and Zingg [1] Tsuji et al. [51] Kenworthy et al. [48] Schwartz et al. [44] Hastie et al. [47] Malkowicz and Skinner [49] Zincke et al. [43] Innbruck (2000)c
(3) (2.4) (3.9) (17.4) (1.5) (6.5) (2.6) (3.1) (5.5) (2.4) (3.3) (3.5)
a
Following cystectomy due to invasive bladder cancer. Following cystectomy due to bladder Tis. c Exclusively patients with TCC and an orthotopic neo-bladder. b
In general, open surgical removal of a tumorous portion of the upper urinary tract has been the preferred method of treatment so far, but successful management of tumours by endourological and conservative treatment has been reported. Suspicion of an upper tract recurrence in neo-bladder patients not clearly visible on radiographic examinations or small super®cial tumours amenable to endourologic treatment usually are a dilemma for the treating physician. Access to the upper urinary tract for diagnostic and therapeutic purposes is usually not easy in neo-bladder patients due to either an antire¯ux valve mechanism, a long afferent ileal segment, dif®culties in localizing the ureteral neo-ori®ce(s) implanted end-toside according to Nesbit, and/or ureteral kinking at the reimplanation site.
A variation of the technique of the original T-pouch has been suggested to overcome these problems [58]. The T-pouch already has a wide well-visible ori®ce of the tapered afferent segment in the pouch which makes its localization and catheterization much easier compared to other forms of neo-ori®ces in neo-bladders. Instead of an end-to-side ureteroileal anastomosis, the end-to-end Wallace type anastomosis with the same preparation and coverage of periureteral adventitial tissue as described above was applied. This considerably facilitated retrograde catheterization and insertion of ureteroscopes whenever a diagnostic workup and/or treatment of upper tract tumours, strictures, etc. became necessary. It may also enable the management of complicated upper tract urolithiasis without percutaneous nephrostomy.
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voiding from the urethra: A case report. Jpn J Clin Oncol 1992;22:359±63. Stein J, Stenzl A, Esrig D, Freeman J, Boyd S, Lieskovsky G, Cote R, Bennett C, Colleselli K, Draxl H et al. Lower urinary tract reconstruction following cystectomy in women using the Kock ileal reservoir with bilateral ureteroileal urethrostomy: Initial clinical experience. J Urol 1994;152:1404±8. Stenzl A, Jarolim L, Coloby P, Golia S, Bartsch G, Babjuk M, Robertson C. Urethra-sparing cystectomy and orthotopic urinary diversion in women with malignant pelvic tumors. Cancer 2001;92:1864±71. Jones J, Melchior SW, Gillitzer R, Fichtner J, El-Mekresh M, Thuroff JW. Urethral recurrence of transitional cell carcinoma in a female patient after cystectomy and orthotopic ileal neo-bladder. J Urol 2000;164:1646. Lotheissen G. Ueber Uretertransplantationen. Wiener Klin. Wochenschrift 1899;12:883±9. Zincke H, Garbeff PJ, Beahrs JR. Upper urinary tract transitional cell cancer after radical cystectomy for bladder cancer. J Urol 1984;131:50±2. Schwartz CB, Bekirov H, Melman A. Urothelial tumors of upper tract following treatment of primary bladder transitional cell carcinoma. Urology 1992;40:509±11. Shinka T, Uekado Y, Aoshi H, Hirano A, Ohkawa T. Occurrence of uroepithelial tumors of the upper urinary tract after the initial diagnosis of bladder cancer. J Urol 1988;140:745±8. Ferriere JM, Pariente JL, Mettetal PJ, Allard P, Chabannes E, Maire J, Mevel O, Le Guillou M. Tumors of the upper urinary tract in patients following bladder tumors: multicentric locations or seeding? Apropos of 14 cases. Prog Urol 1994;4:563±8. Hastie KJ, Hamdy FC, Collins MC, Williams JL. Upper tract tumours following cystectomy for bladder cancer. Is routine intravenous urography worthwhile? Br J Urol 1991;67:29±31. Kenworthy P, Tanguay S, Dinney CP. The risk of upper tract recurrence following cystectomy in patients with transitional cell carcinoma involving the distal ureter [see comments]. J Urol 1996;155:501±3. Malkowicz SB, Skinner DG. Development of upper tract carcinoma after cystectomy for bladder carcinoma. Urology 1990;36:20±2. Solsona E, Iborra I, Ricos JV, Dumont R, Casanova JL, Calabuig C. Upper urinary tract involvement in patients with bladder carcinoma in situ (Tis): Its impact on management. Urology 1997;49:347±52. Tsuji Y, Nakamura H, Ariyoshi A. Upper urinary tract involvement after cystectomy and ileal conduit diversion for primary bladder carcinoma. Eur Urol 1996;29:216±20. Balaji KC, McGuire M, Grotas J, Grimaldi G, Russo P. Upper tract recurrences following radical cystectomy: An analysis of prognostic factors, recurrence pattern and stage at presentation. J Urol 1999;162: 1603±6. Batista JE, Palou J, Iglesias J, Sanchotene E, da Luz P, Algaba F, Villavicencio H. Significance of ureteral carcinoma in situ in specimens of cystectomy. Eur Urol 1994;25:313±5. Lindell O. Ileal conduit urinary diversion: A review of 148 patients. Ann Chir Gynaecol 1986;75:229±35. Silver DA, Stroumbakis N, Russo P, Fair WR, Herr HW. Ureteral carcinoma in situ at radical cystectomy: Does the margin matter? J Urol 1997;158:768±71. Chen G, El-Gabry E, Bagley D. Surveillance of upper urinary tract transitional cell carcinoma: The role of ureteroscopy, retrograde pyelography, cytology and urinalysis. J Urol 2000;164:1901±4. Mills I, Laniado M, Patel A. The role of endoscopy in the management of patients with upper urinary tract transitional cell carcinoma. BJU Int 2001;87:150±62. Stenzl A, Hobisch A, Strasser H, Bartsch G. Ureteroileal anastomosis in orthotopic urinary diversion: how much is necessary? Tech Urol 2001;7:188±95.
A. Stenzl et al. / European Urology 41 (2002) 124±131 [59] Schellhammer P, Whitmore W. Transitional cell carcinoma of the urethra in men having cystectomy for bladder cancer. J Urol 1976;115:56±60. [60] Tongaonkar H, Dalal A, Kulkarni J, Kamat M. Urethral recurrences following radical cystectomy for invasive transitional cell carcinoma of the bladder. Br J Urol 1993;72:910±4. [61] Hickey D, Soloway M, Murphy W. Selective urethrectomy following cystoprostatectomy for bladder cancer. J Urol 1986;136:828±30. [62] Lebret T, Herve JM, Barre P, Gaudez F, Lugagne PM, Barbagelatta M, Botto H. Urethral recurrence of transitional cell carcinoma of the bladder. Predictive value of preoperative latero-montanal biopsies
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and urethral frozen sections during prostatocystectomy. Eur Urol 1998;33:170±4. [63] Robert M, Burgel JS, Serre I, Guiter J, Grasset D. Urethral recurrence after cysto-prostatectomy for bladder tumor. Prog Urol 1996;6:558±63. [64] Slaton JW, Swanson DA, Grossman HB, Dinney CP. A stage specific approach to tumor surveillance after radical cystectomy for transitional cell carcinoma of the bladder. J Urol 1999;162:710±4. [65] Steven K, Poulsen AL. The orthotopic Kock ileal neo-bladder: Functional results, urodynamic features, complications and survival in 166 men. J Urol 2000;164:288±95.
European Urology 41 (2002) 124±131
Review
The Remnant Urothelium after Reconstructive Bladder Surgery Arnulf Stenzl*, Georg Bartsch, Hermann Rogatsch Department of Urology and Institute of Pathology, University of Innsbruck Medical School, A-6020 Innsbruck, Austria Accepted 24 September 2001
Abstract The pathology of the remnant urinary tract in an increasing population of cystectomy patients with orthotopic and heterotopic bladder substitution due to primary bladder carcinoma, and its management is discussed. The incidence of urethral tumours in primary or recurrent bladder cancer in long-term studies is approximately 6% for male and 2% for female patients. Risk factors for urethral tumour occurrence are tumours at the bladder neck and recurrent multifocal tumours. CIS of the bladder not involving the bladder neck, and muscle invasive tumours with or without lymph node involvement are not signi®cantly correlated with urethral cancer. Those patients at risk for urethral tumours need additional work-up (multiple urethral biopsies and/or urethral brushings, frozen section of the membranous urethra) before an orthotopic lower urinary tract reconstruction to the urethra should be considered. In a large series of male patients, the majority of patients with urethral tumours had a single conservative treatment session, and did not recur thereafter demonstrating the feasibility of a conservative approach for super®cial urethral tumour recurrences in patients with an orthotopic neo-bladder to the urethra. The incidence of upper tract tumours following cystectomy and lower urinary tract reconstruction lies between 2.4± 17%. In a group of 258 patients with an orthotopic bladder substitution, we have seen an incidence of 3.5%. Tumour multifocality, carcinoma in situ in the bladder and/or distal ureter, locally advanced bladder tumour stage, and invasion of the intramural ureter were seen as risk factors in some series. A tendency for a higher incidence can be seen in those series with longer follow-up. The median time between cystectomy and diagnosis of upper tract tumours lies between 8 and 69 months in most series. A longer observation period in larger numbers of patients with an orthotopic neo-bladder and longer survival rates in general after cystectomy may reveal an increase in the incidence of upper tract tumours over the next decade. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Urinary diversion; Transitional cell carcinoma; Bladder cancer; Recurrence; Urethra; Upper urinary tract
1. Introduction Transitional cell cancer (TCC) of the bladder is regarded an organ speci®c disease. Due to its size and storage function allowing urinary carcinogens to alter the urothelium it is by far the most common site of TCC. Radical cystectomy still shows the best treatment results regarding progression and survival of muscle-invasive disease. A major part of the urothelium in the upper urinary tract and at times a small *
Corresponding author. Tel. 43-512-504-4813; Fax: 43-512-504-8411. E-mail address: [email protected] (A. Stenzl).
fraction in the urethra, however, remain after attempted surgical cure, i.e. radical cystectomy and lower urinary tract reconstruction. Several recent reports dealing with the long-term follow-up of TCC patients with an orthotopic neo-bladder after radical cystectomy have demonstrated that urethral recurrence was considerably lower than initially reported, but that a longer follow-up may increase the number of upper urinary tract recurrences. An orthotopic neo-bladder is currently the most natural way to reconstruct the urinary bladder. An increasing number of reports dealing with median term experiences with ureterointestinal urethrostomy has given us more details on how to select patients, how
0302-2838/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 2 - 2 8 3 8 ( 0 1 ) 0 0 0 3 1 - 8
A. Stenzl et al. / European Urology 41 (2002) 124±131
to reduce pre- and post-operative morbidity [1], and the follow-up. Access of the upper urinary tract in case of a pathological ®nding in patients with an intestinal lower urinary tract reconstruction may become more important, when more and more patients who are cured of their bladder disease will be seen with upper urinary tract pathology. 2. Remnant urethra in the male Several authors either suggested [2] or strongly recommended [3,4] urethrectomy in conjunction with radical cystectomy for bladder cancer. However, in recent years orthotopic reconstruction of the lower urinary tract has gained popularity both by patients and doctors [5], which precludes a simultaneous prophylactic urethrectomy at the time of cystectomy. The reported incidence of secondary urethral tumours in patients with bladder cancer is diverging. Gowing [6] autopsied patients dying with bladder cancer and found in 6 of 33 autopsies (18%) carcinoma in situ. Looking at urethral tumour recurrences after radical cystoprostatectomy several reports found urethral recurrences in around 10% of the patients and usually suggested a generous decision to perform primary prophylactic urethrectomy [7]. In unselected series of male bladder cancer patients [8,9], there was an incidence of concomitant urethral tumours of 5.4 and 6.1% in 914 and 910 patients, respectively. The majority of the patients in both groups were treated conservatively, i.e. without major surgery or radiation allowing to assess the incidence of urethral tumours of patients with primary and recurrent bladder tumours of all stages. Overall the average incidence of secondary urethral tumours in bladder cancer patients in the literature is
125
Table 2 Frequency of urethral tumours among primary versus recurrent and solitary versus multifocal bladder tumoursa,b Characteristic of tumour
Number of urethral tumours
%
Primary unilocular
10
2.6
Recurrent unilocular
22
4.1
Primary multifocal
27
5.8
Recurrent multifocal
67
10.1
a
910 men with bladder cancer observed at a single institution over a period of 25 years. Adapted from [9]. b An arrow pointing downwards and increasing in size should emphasise the increasing percentages in the 3rd column.
6.2% and seems to be similar when broken up for studies with an intact bladder (5.8%) and those with tumours in the remnant urethra after cystectomy (6.2%) (Table 1) [8,10±14]. A signi®cant difference was evident between those patients where a solitary TCC occurred in the bladder for the ®rst time (2.6%) and those with recurrent multifocal cancer (10.1%, Table 2). This may be a factor in the decision making process, whether an orthotopic neo-bladder is prudent or whether a synchronous urethrectomy should be performed. In this report, it has also been shown that only 17 of 87 patients with bladder cancer and concomitant urethral cancer treated endoscopically had recurrences in the urethra [9]. Transurethral resection and/or fulguration may be seen therefore as a possible way of treatment for super®cial papillary TCC in the urethra. A recent report also demonstrated the possible use of
Table 1 Metaanalysis with documented cases References
Number of patients
Number of urethral tumor events
Urethral tumour involvement in male patient with bladder cancer [2,6,8±14,18,33,59±61]
5657
349 (6.2%)
841
30 (3.6%)
Urethral tumour involvement or carcinoma in situ in female patients with bladder cancer [3,8,19,26,28±31] References
Number of patients
Number of recurrences
Urethral tumour recurrence after cystoprostatectomy for bladder cancer [7,21,62±65]
3165
256 (8.1%)
Upper tract recurrences after cystectomy for bladder cancer [1,43,44,47±52,64]
3090
104 (3.3%)
126
A. Stenzl et al. / European Urology 41 (2002) 124±131
¯uorescence-guided diagnosis and therapy of carcinoma in situ and super®cial papillary tumours [15]. Those patients which according to their clinical staging would nowadays be good candidates for radical surgery with the option of an orthotopic neo-bladder were sorted out in this study. Patients with a clinically staged T2-3 N-0, M-0 TCC had a lower rate (4.2%) of urethral tumour occurrence than the average 6.1% of the whole study group. If all node positive patients (N0-2) were included in this group, the urethral tumour rate was still 4.3%. A tendency towards solitary primary tumours, a more aggressive initial therapy, and a decreased life expectancy resulting in shorter follow-up times may account for the lower urethral tumour rate in this group. Due to a changing treatment pattern of bladder cancer in an increasing number of patients resulting in radical surgery at an earlier stage [16,17], these data may nevertheless be helpful when consenting a patient to a subsequent orthotopic neobladder. Another aspect is the occurrence of CIS or papillary tumours in the remaining urethra after an orthotopic neo-bladder. Contrary to other authors [18±20], Erckert et al. did not see an increased risk of urethral tumours in patients with CIS of the bladder. This may in part be due to the fact that dysplasia or CIS of the urethra may have beenmissedinconservativelytreatedpatients.Onemight argue, however, that clinically important dysplasia or CIS left untreated or treated conservatively and followed for a long-term should eventually have resulted in overt and clinically important urethral cancer. 2.1. Urethral recurrence in heterotopic versus orthotopic lower urinary tract reconstructions In most of the older studies, urethral recurrence is de®ned as tumour in the remnant, blind-ending urethra [21]. Apart from a longer follow-up, there might have been other contributing factors responsible for a considerably higher incidence of secondary urethral tumours than observed with the functioning remnant urethra connected to a neo-bladder (Table 1). It may be speculated that scarring, chronic in¯ammation with certain E. coli strains, absence of cancer-preventing properties of the urine, and a lack of careful follow-up may play a role. The only larger study comparing urethral recurrence in orthotopic and heterotopic diversions did reveal a signi®cant advantage for orthotopic neo-bladders independent from the length of follow-up in each group [7]. The outcome of patients with TCC in the prostatic urethra and/or parenchyma was assessed in two large studies. Freeman et al. [7] looked at 436 patients undergoing cystectomy and either a heteroropic or orthotopic
lower urinary tract reconstruction. Their calculated recurrence rates demonstrated the highest probability of urethral recurrence in patients with invasive prostatic TCC followed by super®cial TCC. Despite prostatic TCC, however, urethral recurrence was 5% in orthotopic neo-bladder patients versus 24% in the blindending urethra after heterotopic urinary diversion. Iselin et al. looked at urethral recurrence in 70 men with prostatic TCC undergoing radical cystectomy for bladder cancer with a mean follow-up of 35 months [22]. The overall urethral recurrence rate was 3%. None of the patients with prostatic TCC in the cystectomy specimen died secondary to a urethral recurrence. The results presented are in line with other data in the literature [23,24] suggesting that orthotopic neo-bladder reconstruction may not be contraindicated in bladder cancer patients with prostatic involvement provided the margins of resection are negative. However, one recent report in a relative small series of 40 male patients with an orthotopic neo-bladder with a minimum follow-up of 5 years showed urethral recurrences in 5 patients (12%) [25]. No details regarding stage of the urethral tumours nor their treatment were given. 3. Remnant urethra in the female Few data exist about urethral involvement in women with bladder cancer. In the older literature concentrating on urethral tumour involvement of male patients with bladder cancer, female cases are only rarely discussed. Numbers in many studies dealing with concommittant urethral tumours or urethral recurrence in patients with bladder cancer have been small and any conclusions or at least a trend for female patients was not possible [3,6,11,18,19,26,27]. There has recently been focused interest, however, in data concerning the risk of secondary urethral tumours in female bladder cancer patients undergoing surgery [28±30]. If an adequate segment of the caudal urethra could be spared at cystectomy with a minimal risk of tumour recurrence, it might be used for continent orthotopic reconstruction of the lower urinary tract like in males. Risk factors for urethral involvement in female bladder cancer patients were not known until then. Ashworth [8] in a large cystoscopy study found urethral tumour involvement in 1.4% of female patients compared to 4.1% of male patients presenting with bladder cancer. In a more recent report retrospectively working up 22 female cystectomy specimens obtained over a period of 15 years, a 36%-incidence (8 of 22 patients) of super®cial or invasive urethral tumours was found. A strong argument for routine urethrectomy in
A. Stenzl et al. / European Urology 41 (2002) 124±131
all female patients with bladder cancer was therefore made [31]. However, no details about the total number of women treated with bladder cancer during this period, the tumour sites in bladder and urethra in patients subject to study, nor number and type(s) of treatment prior to cystectomy were given in this study. A contemporary study [30] showed urethral tumour involvement as being 2% in female patients with biopsy proven bladder cancer of all grades and stages. The mean follow-up was 5.5 years. One of the reasons for the apparent lower incidence of secondary urethral tumours in females in comparison to males [2,9] in several studies may be the fact that transitional cell mucosa covers a much smaller urethral segment in females, whereas, the rest is normal or metaplastic squamous cell mucosa. The area at risk in the female urethra is therefore small, and probably even diminishes with increasing age, because the demarcation line between squamous and transitional cell mucosa moves craniad during the menopause [32]. In the sixth and seventh decade where most of the bladder tumours occur, metaplastic squamous cell mucosa may cover the whole urethra, bladder neck and at times even a portion of the trigone. The fact that tumour involvement of the bladder neck and prostatic urethra is a possible predictor for synchronous or recurrent urethral tumours in male patients has been shown by several authors [2,18,33]. Most recent reports describe also a close coincidence between tumour involvement of the bladder neck and urethra in females [28±30]. In these studies, there was no urethral bladder cancer involvement without tumour involvement at the bladder neck at the same time, a fact that was statistically highly signi®cant. There was also a signi®cant correlation between the primary tumour location trigone and concomitant ure-
127
thral tumours, but only if the bladder neck was involved as well. In an unselected study of 356 female patients with different stages of bladder tumour followed for up to 33 years the incidence of urethral tumour involvement was 2% for the whole study group, 3.1% for a subgroup of invasive (T2-4) TCC, and 1% for localised (T2-3b, N-0, M-0) invasive cancer amenable to radical cystectomy. None of the patients with recurrent bladder tumours, whether progressing or not, had overt urethral tumour at any of the recurrences over the years. There was no correlation between urethral cancer and any other prognostic factor. Neither stage, multicentricity, number of tumours, presence of CIS, or duration of the disease seemed to play a predominant role. From these data one may conclude that female patients without tumour either at the bladder neck or at frozen section of the proximal urethra at the time of cystectomy can probably be spared a portion of the urethra to enable lower urinary reconstruction to the urethra without running a greater risk of developing recurrent urethral tumours than their selected male counterparts. Reviewing the literature, we found 30 cases of documented urethral tumour involvement (including CIS) in female patients with bladder cancer (Table 3). The overall incidence according to this table would be 3.6% (30 out of 841 patients). Most of the authors, however, used a highly selected group of patients, namely those undergoing cystectomy. The actual number of women seen and treated for all stages of bladder cancer at any of these institutions should have been higher than just an average of two cases per year. In order to obtain an overall urethral involvement rate for female bladder cancer patients it is therefore misleading to use percentages only out of the total number of cystectomized patients at a time several decades ago
Table 3 Review of the literature with documented cases of urethral tumour involvement or carcinoma in situ in female patients with bladder cancer Authors (references)
Study period
Number of patients
Number of BN tumours
Riches and Cullen [26] Ashworth [8] Richie and Skinner [19] Coutts et al. [3] De Paepe et al. [31] Stein et al. [29] Stenzl et al. [30] Coloby et al. [28]
n.g.a n.g. 1969±1971 1974±1983 1974±1988 1982±1992 1973±1992 1970±1990
19b 293 21b 18b 22b 65b 356 47 (341)
3 n.g. n.g. n.g. n.g. 16 49 9
Total a b
841
n:g: no data were given, BN bladder neck. Adapted from [30]. Heterogeneously selected bladder cancer study populations.
Urethral tumours 3 4 ± 2 5 7 6 3 30 (3.6%)
CIS
Tumours CIS
± ± 1 1 3 ± ±
3 4 1 3 8 7 6 22
5
54 (6.4%)
128
A. Stenzl et al. / European Urology 41 (2002) 124±131
when only few patients had exenteration for highly advanced bladder tumours. Several biopsies of the bladder neck should be performed in those patients where a subtotal urethrectomy is considered [34]. Any woman with a ®nding of atypia or overt tumour at the bladder neck is at risk for developing recurrent urethral tumour after cystectomy and should therefore undergo simultaneous total urethrectomy. But those patients where curative radical cystectomy is indicated and who are good candidates for an orthotopic reconstruction of the lower urinary tract may be spared a segment of the urethra for that purpose provided that pre-operative biopsies of the bladder neck and frozen section of the urethra at the time of surgery are free of atypia or tumour. Paraf®n embedded slides of super®cial biopsies taken pre-operatively allow a better staging regarding super®cial (mucosal) bladder neck involvement. Frozen sections of the urethral margin at the time of cystectomy on the other hand lead to better evaluation of both the entire urethral wall and circumference, however, with a higher possibility of error due to suboptimal embedding of frozen sections. Based on these pathological studies and anatomical data of the continence mechanism of the female urethra clinical protocols offering an ureteroileal urethrostomy to carefully selected female patients undergoing radical cystectomy for localised bladder cancer was initiated at several centres [35±39]. Their preliminary data and subsequent reports have been promising and have led to an increase in the number of both patients and centres where orthotopic neo-bladders are performed [40]. However, the urethraÐor a portion of itÐshould not be left in unless it is used for reconstructive purposes, because it can easily be removed en bloc with the bladder specimen and it requires additional efforts to follow oncologically when left in as a blind-ending sac. Now that orthotopic bladder substitution to the urethra has been popularised in female patients, one eventually expects urethral recurrences after bladder substitution in women as well. Seven years after the ®rst report of a larger series of women undergoing a neo-bladder procedure, a recent report has for the ®rst time illustrated a local failure at the anastomosis of pouch and urethra [41]. This failure among many successfully operated women by now shows shortcomings of this procedure. However, in this speci®c case several adverse signs for performing an urethrasparing cystectomy, namely tumour location and preservation of the entirely vaginal wall, and advanced pelvic lymph node involvement, were disregarded at the time of cystectomy [34]. It is therefore important in
future cases to put diagnostic and therapeutic errors into consideration before setting up new guide lines based on individual cases. 4. Upper urinary tract after intestinal bladder substitution Undoubtedly an enormous progress has been achieved since Simon's ®rst report in the middle of the 1900s about ureteral diversion into the rectum by creating a ®stula with the help of a silk thread. Subsequently, several techniques have been developed to restore continuity between the upper urinary tract and the reconstructed lower urinary tract which have helped to reduce the long-term morbidity and complication rate of intestinal urinary diversion [42]. The incidence of upper urinary tract tumours secondary to primary bladder cancer lies around 2±4% [43±45]. There is a higher risk in patients with multiple recurrences of super®cial Ta or T1 tumours [46]. The incidence of upper tract tumours following cystectomy and lower urinary tract reconstruction has been reported as 1.5±17.4% [1,43,47±55] (Table 4). In our own series looking at 258 patients undergoing cystectomy and orthotopic bladder substitution for transitional cell carcinoma between 1992 and 2000, we have seen an incidence of 3.5% (9 of 258 patients). In some series, there are indications that prolonged survival and follow-up in neo-bladder patients may lead to an increase in the incidence of upper tract recurrences in future years. Multifocality, carcinoma in situ and other super®cial tumours in the bladder was seen as a risk factor in some series, whereas, a report from Memorial Sloan-Kettering Cancer Center [52] put those patients with locally advanced tumour stage at a higher risk. Most likely tumour invasion of the intramural ureter, CIS in the distal ureter and/or the frozen section of the dissected ureter are additional risk factors. The median time between cystectomy and diagnosis of the upper tract tumours lies between 8 and 69 months in most series, but upper tract cancer recurrences more than 10 years after cystectomy have been observed. Most of the upper tract tumours in patients with bladder substitution are diagnosed following symptoms such as ¯ank pain, macrohematuria or a positive cytology. Routine radiological assessment of the upper urinary tract may not be worthwhile due to its poor detection rate according to this series. The development of smaller and ¯exible ureteroscopes has led to an increase use of mostly retrograde endoscopy both for treatment as well as surveillance of upper urinary tract tumours [56,57].
A. Stenzl et al. / European Urology 41 (2002) 124±131
129
Table 4 Review of the recent literature and our own results regarding upper tract recurrences after cystectomy for bladder cancer Authors (references)
Number of patients
Number of upper tract recurrences (%)
Interval to recurrence (months)
Balaji et al. [52] Slaton et al. [64] Solsona et al. [50]
529 382 179a 46b 200 61 430 638 180 220 425 258
16 9 7 8 3 4 11 20 10 5 14 9
Median 37.2 Median 25 Mean 28.3 Mean 18.3 ± Mean 69 Median 40 Mean 8 Mean 44 22±54 Mean 40 Mean 9
Studer and Zingg [1] Tsuji et al. [51] Kenworthy et al. [48] Schwartz et al. [44] Hastie et al. [47] Malkowicz and Skinner [49] Zincke et al. [43] Innbruck (2000)c
(3) (2.4) (3.9) (17.4) (1.5) (6.5) (2.6) (3.1) (5.5) (2.4) (3.3) (3.5)
a
Following cystectomy due to invasive bladder cancer. Following cystectomy due to bladder Tis. c Exclusively patients with TCC and an orthotopic neo-bladder. b
In general, open surgical removal of a tumorous portion of the upper urinary tract has been the preferred method of treatment so far, but successful management of tumours by endourological and conservative treatment has been reported. Suspicion of an upper tract recurrence in neo-bladder patients not clearly visible on radiographic examinations or small super®cial tumours amenable to endourologic treatment usually are a dilemma for the treating physician. Access to the upper urinary tract for diagnostic and therapeutic purposes is usually not easy in neo-bladder patients due to either an antire¯ux valve mechanism, a long afferent ileal segment, dif®culties in localizing the ureteral neo-ori®ce(s) implanted end-toside according to Nesbit, and/or ureteral kinking at the reimplanation site.
A variation of the technique of the original T-pouch has been suggested to overcome these problems [58]. The T-pouch already has a wide well-visible ori®ce of the tapered afferent segment in the pouch which makes its localization and catheterization much easier compared to other forms of neo-ori®ces in neo-bladders. Instead of an end-to-side ureteroileal anastomosis, the end-to-end Wallace type anastomosis with the same preparation and coverage of periureteral adventitial tissue as described above was applied. This considerably facilitated retrograde catheterization and insertion of ureteroscopes whenever a diagnostic workup and/or treatment of upper tract tumours, strictures, etc. became necessary. It may also enable the management of complicated upper tract urolithiasis without percutaneous nephrostomy.
References [1] Studer UE, Zingg EJ. Ileal orthotopic bladder substitutes. What we have learned from 12 years' experience with 200 patients. Urol Clin North Am 1997;24:781±93. [2] StoÈckle M, GoÈkcebay E, Riedmiller H, Hohenfellner R. Urethral tumour recurrences after radical cystoprostatectomy: The case for primary cystoprostatourethrectomy? J Urol 1990;143:41±3. [3] Coutts A, Grigor K, Fowler J. Urethral dysplasia and bladder cancer in cystectomy specimens. Br J Urol 1985;57:535±41. [4] Schellhammer P, Whitmore W. Urethral meatal carcinoma following cystourethrectomy for bladder carcinoma. J Urol 1976;115:61±4. [5] Skinner DG, Boyd SD, Lieskovsky G, Bennett C, Hopwood B. Lower urinary tract reconstruction following cystectomy: Experience and results in 126 patients using the Kock ileal reservoir with bilateral ureteroileal urethrostomy. J Urol 1991;146:756±60. [6] Gowing N. Urethral carcinoma associated with cancer of the bladder. Br J Urol 1960;32:428±38. [7] Freeman JA, Tarter TA, Esrig D, Stein JP, Elmajian DA, Chen SC, Groshen S, Lieskovsky G, Skinner DG. Urethral recurrence in patients with orthotopic ileal neo-bladders. J Urol 1996;156:1615±9.
[8] Ashworth A. Papillomatosis of the urethra. Br J Urol 1956;28:3±11. [9] Erckert M, Stenzl A, Falk M, Bartsch G. Incidence of urethral tumor involvement in 910 men with bladder cancer. World J Urol 1996;14:3±8. [10] Beahrs J, Fleming T, Zincke H. Risk of local urethral recurrence after radical cystectomy for bladder carcinoma. J Urol 1984;131:264±6. [11] Cordonnier J, Spjut H. Urethral ocurrence of bladder carcinoma following cystectomy. J Urol 1962;87:398±403. [12] Faysal M. Urethrectomy in men with transitional cell carcinoma of the bladder. Urology 1980;16:23±6. [13] Raz S, McLorie G, Johnson S, Skinner D. Management of the urethra in patients undergoing radical cystectomy for bladder carcinoma. J Urol 1978;120:298±300. [14] Zabbo A, Montie J. Management of the urethra in men undergoing radical cystectomy for bladder cancer. J Urol 1984;131:267±8. [15] Holtl L, Eder IE, Klocker H, Hobisch A, Bartsch G, Stenzl A. Photodynamic diagnosis with 5-aminolevulinic acid in the treatment of secondary urethral tumours: First in vitro and in vivo results. Eur Urol 2001;39:178±82.
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