Radical cystectomy with or without urethrectomy?

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1 Critical Reviews in Oncology/Hematology 47 (2003) 141/145 Radical cystectomy with or without urethrectomy? Hein Van Poppel *, Tomas Sorgeloose Division of Urology, University Hospitals of Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium Accepted 19 September 2002 Contents 1. Introduction Risk for urethral recurrence Preoperative or intraoperative assessment of the prostatic urethra Surveillance of the retained urethra Has bladder replacement increased urethral recurrence? Guidelines for management of the male urethra Technique of simultaneous urethrectomy during cystectomy Female urethra Conclusion Reviewers References Biographies Abstract After the introduction of bladder replacement procedures, the indications for prophylactic urethrectomy have become more and more restricted. While years ago, a prophylactic urethrectomy was performed in many patients with cutaneous diversions, it has become clear that only patients with invasion by transitional cell carcinoma at the level of the prostatic urethra or bladder neck have a substantial risk of developing subsequent urethral recurrence. The pre- or intra-operative assessment of the prostatic urethra in males and of the bladder neck in females is the key to appropriate management of the urethra in patients with bladder cancer. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Bladder cancer; Urethral carcinoma; Cystectomy; Urethrectomy 1. Introduction In the treatment of transitional cell carcinoma of the bladder, bladder replacement has become a well-accepted option after cystectomy in both sexes [1]. In the past the management of the urethra has been the subject * Corresponding author. Tel.: / ; fax: / address: hendrik.vanpoppel@uz.kuleuven.ac.be (H. Van Poppel). of debate. Nowadays prophylactic urethrectomy is mandatory only in a few very clear indications. There were several reasons to perform a prophylactic urethrectomy at the time of cystectomy for bladder cancer. First, the overall recurrence rate in the remnant urethra after cystectomy is estimated to be about 10% [2]. Secondly, when recurrence is diagnosed, the disease is mostly advanced because of the inaccurate follow-up of the remnant urethra. Moreover delayed urethrectomy for recurrence is technically more difficult, specifically at the level of the urethral stump because of postoperative /03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi: /s (03)

2 142 H. Van Poppel, T. Sorgeloose / Critical Reviews in Oncology/Hematology 47 (2003) 141/145 fibrotic changes [3]. Finally, when a patient gets a cutaneous urinary diversion it is considered unwise to leave a useless urethra behind even when the chance for recurrence is low. Since the introduction of bladder replacement procedures, using the native urethra, the philosophy about prophylactic urethrectomy has dramatically changed. In the past, the fear of a cutaneous stoma led many patients as well as urologists to delay and avoid radical treatment but since the availability of orthotopic neobladder the decision to undergo a cystectomy has been made more acceptable. Therefore, the risk for urethral recurrence must be weighed against the gain in quality of life and recommendations for follow-up of the remnant urethra need to be established. In general, any patient who is an appropriate candidate for cystectomy is also a potential candidate for bladder replacement connected to the urethra provided that the risk of recurrence and subsequent tumour progression is minimal. The reason why urologists might be reluctant to do a prophylactic urethrectomy is not only the added morbidity and the additional time required for resection of the urethra but more importantly the very high rate of negative pathology of the removed urethra. This makes the recognition of the risk factors for urethral recurrence even more relevant. 2. Risk for urethral recurrence The risk for a urethral recurrence following cystectomy in the retained urethra is approximately 10%. Retrospective analyses of cystectomy series have identified specific pathological characteristics of the bladder primary that can predict an increased risk for urethral recurrence. These include high tumour stage and grade, multifocal recurrent tumours, upper tract involvement, carcinoma in situ (CIS), trigonal or bladder neck invasion and involvement of the prostatic urethra, particularly invasion of the stroma of the prostate [4]. When all these situations would indicate prophylactic urethrectomy, most bladder cancer patients would be in need of a cutaneous diversion [5]. The importance of prostatic urethral involvement has first been recognized nearly half a century ago when in a cystectomy series 71% of the urethral recurrences were shown to occur in patients that had transitional cell carcinoma in the prostatic urethra [6]. This was later confirmed by other investigators who recognized different stages of prostatic urethral involvement [5]. There was a clear distinction between the presence of transitional cell carcinoma limited to the urethral mucosa (TpU), invasion in the prostatic ducts (TpD) or invasion to the prostatic stroma (TpS) with, respectively, 0, 25 and 64% of urethral recurrence after cystectomy. Analogous figures were reported by other groups, respectively, 0, 10 and 30% [7]. These studies clearly showed that the invasion of the prostatic stroma is the single best prognostic indicator for development of urethral recurrence. The origin of the growth of transitional cell carcinoma in the prostate is not clearly understood. Tumour might extend in continuity from the bladder starting at the bladder neck and the proximal prostate and growing along the urothelium and into the ducts and the prostatic stroma. In this situation urethral recurrence represents persistent tumour left behind at cystoprostatectomy. Alternatively transitional cell carcinoma of the prostate can arise from implantation of cells shed from the primary tumour in the bladder or de novo from urothelium affected by the same carcinogenic process that induced tumour growth in the bladder. The correlation between the presence of CIS in the bladder and urethral recurrence has been widely recognized since years. More recently, however, it was shown in a whole mount step section study that CIS of the bladder is not correlated with transitional cell carcinoma of the prostatic urethra. Conversely, CIS of the bladder neck and the trigone was clearly correlated to transitional cell carcinoma of the prostate but not directly correlated with urethral recurrence [8]. Therefore CIS at the bladder neck is a risk factor for transitional cell carcinoma of the prostatic urethra and the latter is a risk factor for urethral recurrence. Therefore the presence of CIS in the bladder or even at the bladder neck is not an absolute contra-indication for urethral preservation [4]. 3. Preoperative or intraoperative assessment of the prostatic urethra Since the extension of transitional cell carcinoma into the prostatic urethra is the most relevant prognosticator of urethral recurrence, a rigorous pre- or intra-operative assessment is mandatory. Since a long time, prostatic urethra cold cupbiopsies or transurethral resection biopsies were proposed [9]. In a prospective study regarding the prostatic involvement prior to cystectomy, it was shown that a transurethral resection biopsy of the prostate accurately identified 9 out of 10 patients with prostatic involvement. Fine needle aspiration and core needle biopsy were much less accurate. Therefore, a 5- and 7-h paramontanal prostatic urethral biopsy is advocated to accurately recognize involvement by transitional cell carcinoma [8,10,11]. At a time where more and more bladder substitution procedures are applied more and more authors now rely on intraoperative frozen section analysis of the urethral resection margin at the prostatic apex [4,12/15]. This intraoperative method has proven to be a reliable method for determining candidacy for orthotopic re-

3 H. Van Poppel, T. Sorgeloose / Critical Reviews in Oncology/Hematology 47 (2003) 141/ construction, without subjecting the patients to unnecessary preoperative biopsies. Patients should be counselled preoperatively regarding continent or incontinent cutaneous diversions should orthopic bladder replacement not be feasible due to intraoperative findings. 4. Surveillance of the retained urethra Although reliable pre- or intra-operative tools are available to recognize the patients at risk for urethral recurrence there is always a small risk of tumour growth in the remnant urethra. This urethral recurrence should be detected in time in order to still be curable by delayed urethrectomy or even by more conservative (endoscopic) treatment modalities. Follow-up of the retained urethra is mandatory, especially in those with cutaneous diversions given its higher propensity towards malignant change. Clinically, carcinoma of the urethra presents as a bloody urethral discharge, penile or perineal pain or a mass in the urethra or perineum. This is not the clinical picture that the urologist wants to face but this type of recurrence has been reported to occur up to 20 years after cystectomy [9]. Once overt carcinoma becomes clinically manifest, the prognosis generally is poor and nearly all patients will die within 5 years [3,9]. This emphasizes the importance of careful routine follow-up with urethral cytology and/or urethroscopy. The reason for this poor outcome relates to the fact that the lamina propria is the only barrier between the urethral mucosa and the cavernous corpora [10]. If there were no reliable tests to detect urethral recurrence earlier, one would have to advocate prophylactic urethrectomy in all cases. In a review on urethral wash cytology performed every 6 months, lifelong, all recurrences could be diagnosed in due time [10]. No patient had the chance to develop a symptomatic urethral recurrence. No patient had falsepositive results or clinically obvious tumour in the absence of positive cytology. So urethral wash cytology of the remnant urethra performed two times a year has a 100% sensitivity and specificity to detect urethral recurrence at a stage where it can be cured. A urethral wash cytology specimen can be obtained by introducing a 14-Fr catheter and a 10 ml of saline injection in the urethra while the patient actively contracts the external urethral sphincter and pelvic floor. Besides this, a halfyearly urethroscopy is indicated. 5. Has bladder replacement increased urethral recurrence? One could presume that since the introduction of orthotopic neobladder and the conservation of more urethras, an increased urethral recurrence rate would occur, unless the urine would play a protective role on the native urethra. In an excellent review from the University of South California, the recurrence rate of urethral transitional cell carcinoma was compared between patients with a cutaneous diversion and an intact defunctionalized urethra versus patients who had a neobladder and a functional native urethra [4]. The overall probability of urethral recurrence for all 436 male patients was 7.8% at 5 years. For patients with an ileal neobladder this figure was 2.9% and in those with a cutaneous diversion 11.1%. The 5-year urethral recurrence rate was significantly higher in patients with prostatic involvement but was only 5% in patients with a neobladder as compared with 24% in those with a Bricker diversion. These results indicate clearly that a functional urethra decreases the risk of developing recurrent transitional cell carcinoma. The mechanism of this event remains incompletely elucidated. It is well known that primary malignancies of the small bowel are rare and even less common in the ileum [16], and a number of intrinsic physiological, biochemical, genetic and immunological characteristics of the ileum have been suggested [4]. On the other hand, the decreased risk of transitional cell carcinoma recurrence in a urethra anastomosed to an ileal neobladder might have nothing to do with its juxtaposition to ileum and exposure to ileal secretory products. The simple continued exposure to urine may be a responsible factor or there may be an unknown systemic cancer protective effect of the orthotopic reservoir. Conversely, there may be a systemic effect of the non-orthotopic reservoir, which increases risk of urethral recurrence in the defunctionalized urethra [4]. These data have definitely changed the management of the remnant urethra and the only absolute contraindications for bladder replacement are the presence of overt transitional cell carcinoma in the anterior urethra and a positive frozen section of the urethral margin during cystectomy [4,14,15]. 6. Guidelines for management of the male urethra In a patient who is candidate for an orthotopic bladder replacement, a urethrectomy is indicated when a positive frozen section of the urethra is obtained intraoperatively. In patients who underwent a cutaneous diversion, either an ileal or colon conduit or a continent cutaneous diversion, resection of the urethra is advisable even when no poor prognostic factors are present because the risk of urethral recurrence is always present. In cutaneously diverted patients, the urethrectomy is absolutely mandatory when CIS or transitional cell carcinoma is present in the prostatic urethra. In those cases simultaneous urethrectomy during cystectomy is indicated.

4 144 H. Van Poppel, T. Sorgeloose / Critical Reviews in Oncology/Hematology 47 (2003) 141/ Technique of simultaneous urethrectomy during cystectomy The immediate urethrectomy can be performed en bloc with the cystoprostatectomy or, after an intraoperative decision-making. A delayed urethrectomy has to be performed through a perineal approach. A simultaneous urethrectomy can be done by a perineal or a prepubic approach. If the urethrectomy is performed through a perineal incision, it will add another hour to an already long and demanding operation [10]. It can also add to the morbidity and mortality. Indeed, an increased incidence of deep venous thrombosis was reported in patients undergoing a simultaneous urethrectomy [17]. This might be related to the increased discomfort and delayed mobilization of patients that underwent a perineal urethrectomy. The prepubic approach for simultaneous urethrectomy was first described in 1989 [18] and further refined [19]. The prepubic approach was shown to be a safe technique without major complications. There is no need to place the patient in a lithotomy position saving time and decreasing postoperative thromboembolic complications. The disadvantage of the classical perineal approach, hindering early postoperative mobilization, is avoided. Only few complications are mainly due to hemorrhage and can be avoided by intraoperative hemostasis and adequate postoperative management [20]. A simple modification of the technique with urethral stripping was presented more recently [21]. It is important to excise the fossa navicularis and urethral meatus since carcinoma can recur even at this distant level [9]. 8. Female urethra Female orthotopic bladder reconstruction has been much less widely applied mainly because of more frequent voiding dysfunction in the female as well as a perceived increased risk for local recurrence. In the classical cystectomy in women with cutaneous diversion, the urethrectomy is performed in a standard way. The female urethra however can also be preserved in cases of invasive bladder cancer that do not involve the trigone and it was shown that the female continence mechanism may adequately function after cystectomy [22 /25]. With these selection criteria 75% of women that have to undergo a cystectomy can be appropriate candidates for orthotopic bladder replacement [12]. It was shown that urethral tumours only occur in female patients with transitional cell carcinoma at the level of the bladder neck [22]. While some authors have recommended intraoperative frozen section at the urethral margin as the best method for determining patients suitability for orthotopic reconstruction [23], others have stated that a preoperative assessment is preferable because the quality of permanent imbedded sections is superior and because small tumour clusters and mucosal atypia can be missed by frozen section [25]. After all preservation of the female urethra is possible when the primary does not involve the bladder neck. The successful functional outcome is not comparable with that in men because of the more frequent problems of incontinence and*/even more common*/hypercontinence. It remains imperative that the radical nature of cancer surgery is not compromised. The follow-up of the remnant urethra in the female cannot be done by urethral wash cytology. One therefore has to rely on the voided urine specimen and on urethroscopy. 9. Conclusion When a male patient is candidate for a cutaneous urinary diversion, a urethrectomy is advisable and will ideally be done through a prepubic approach. The same simultaneous incontinuity urethrectomy is mandatory when there is presence of CIS or transitional cell carcinoma in the prostatic urethra, glands or stroma. A delayed urethrectomy is mandatory when the urethral cytology washing becomes positive, when a patient develops bloody discharge or when a local recurrence is clinically obvious in the perineum or penis. In females, the urethrectomy is always performed when orthotopic bladder replacement is not considered. When an orthotopic neobladder is to be constructed, frozen sections need to be done at the level of the urethral section margin in males and females. Conversion to a cutaneous diversion with immediate urethrectomy is mandatory if the frozen sections turn out to be positive. Reviewers Prof. Vito Pansadoro, Foundation Vincenzo Pansadoro, Clinic Pio XI, Via Aurelia 559, I Rome, Italy. Dr. John Peter Stein, Norris Comprehensive Cancer Center, University of South California, 1441 Eastlake Avenue, Suite 7416, Los Angeles, CA 90089, USA Prof. Dr. med. H.-J. Leisinger, Head, Urology Service, CHUV (Centre Hospitalier Universitaire Vaudois), Rue du Bugnon, CH-1011 Lausanne, Switzerland.

5 H. Van Poppel, T. Sorgeloose / Critical Reviews in Oncology/Hematology 47 (2003) 141/ References [1] Hautman RE, de Petriconi R, Gottfried H-W, Kleinschmidt K, Mattes R, Pais T. The ileal neobladder: complications and functional results in 363 patients after 11 years follow-up. J Urol 1999;161:422/8. [2] Freeman JA, Ersig D, Stein JP, Donald G, Skinner DG. Management of the patient with bladder cancer: urethral recurrence. Urol Clin North Am 1994;21:645/51. [3] Clark PB. Urethral carcinoma after cystectomy: the case for routine urethrectomy. J Urol 1984;90:173/9. [4] Freeman JA, Tarter TA, Ersig D, et al. Urethral recurrence in patients with orthotopic ileal neobladders. J Urol 1996;156:1615/ 9. [5] Hardeman SW, Soloway MS. Urethral recurrence following radical cystectomy. J Urol 1990;144:666/9. [6] Ashworth A. Papillomatosis of the urethra. Br J Urol 1956;28:3. [7] Levinson AK, Johnson DE, Wishnow KI. Indications for urethrectomy in era of continent urinary diversion. J Urol 1990;144:73/5. [8] Wood DP, Montie JE, Pontes JE, Vanderbrg Medendorp S, Levin HS. Transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer. J Urol 1989;141:346/9. [9] Schelhammer PF, Withmore FW. Transitional cell carcinoma of the urethra in man having cystectomy for bladder cancer. J Urol 1976;115:56/60. [10] Hickey DP, Soloway MS, Murphy WM. Selective urethrectomy following cystoprostatectomy for bladder cancer. J Urol 1986;136:828/30. [11] Wood DP, Montie JE, Pontes E, Levin HS. Identification of transitional cell carcinoma of the prostate in bladder cancer patients: a prospective study. J Urol 1989;141:83/5. [12] Studer UE, Zingg EJ. Ileal orthotopic bladder substitutes. What have we learned from 12 years experience with 200 patients? Urol Clin North Am 1997;24:781/93. [13] Elmajian AD. Indications for urethrectomy. Semin Urol Oncol 2001;19:37/44. [14] Iselin CE, Cary CN, Webster GD, Vieweg J, Paulson DF. Does prostate transitional cell carcinoma preclude orthotopic bladder reconstruction after radical cystoprostatectomy for bladder cancer? J Urol 1997;158:2123/6. [15] Lebret T, Hervé J-M, Barré P, Gaudez F, Lugagne P-M, Barbagelatta M, Botto H. Urethral recurrence of transitional cell carcinoma of the bladder: predictive value of preoperative latero-montanal biopsies and urethral frozen sections during prostatocystectomy. Eur Urol 1998;33:170/4. [16] Taggart DP, Imrie WC. A new pattern in histologic predominance and distribution of malignant disease of the small intestine. Surg Gynecol Obstet 1987;165:515/8. [17] Couts AG, Grigor MK, Fowler JW. Urethral dysplasia and bladder cancer in cystectomy specimens. Br J Urol 1985;57:535/ 41. [18] Van Poppel H, Strobbe E, Baert L. Prepubic urethrectomy, J. Urol. 1989;142:1536 /7. [19] Van Poppel H, Baert L. Prepubic urethrectomy. In: Hohenfellner R, Novick A, Fichtner J, editors. Innovations in Urologic Surgery. Oxford: Isis Medical Media Ltd, 1997:295/302. [20] Van Poppel H, Baert L. Innovative technique for urethrectomy: prepubic technique and results in 41 patients. Prog Clin Biol Res 1991;370:147/50. [21] Hiebl R, Langen PH, Haben B, Polsky MS, Steffens J. Prepubic urethrectomy with urethral stripping. J Urol 1999;162:127/8. [22] Coloby PJ, Kakizoe T, Tobisu K, et al. Urethral involvement in female bladder cancer patients: mapping of 47 consecutive cystourethrectomy specimens. J Urol 1994;152:1438. [23] Stein JP, Cote RJ, Freeman JA, et al. Indications for lower urinary tract reconstruction in women after cystectomy for bladder cancer: a pathological review of female cystectomy specimens. J Urol 1995;154:1329. [24] Stenzl A, Draxl H, Posch B, et al. The risk of urethral tumours in female bladder cancer: can the urethra be used for orthotopic reconstruction of the lower urinary tract? J Urol 1995;153:950. [25] Mills RD, Studer UE. Female orthotopic bladder substitution: a good operation in the right circumstances. J Urol 2000;163:1501/ 4. Biographies Hein Van Poppel is the Chairman and Head of the Department of Urology of the University Hospital Katholieke Universiteit Leuven, Belgium. He has been responsible for the development of urological oncology for more than 10 years. He is a member of the executive committee of the EORTC GU-group and a board member of the European Society of Urologic oncology (ESOU), a faculty member of the European School of Urology, a member of the executive committee of the residency review committee of the European board of Urology. He is study coordinator of several prostate and kidney trials in the EORTC. He published more than 100 papers on urologic oncological surgery; he is a reviewer for European Urology, Golden Urology, etc. and belongs to the Editorial Board of Uro-oncology and the European Journal of Pelvic surgery. He graduated in general surgery in 1980, in urology in 1983, and became fellow of the European Board of Urology in He became full professor in Urology in Tomas Sorgeloose is Senior Resident in Urology.

Koji Ichihara Hiroshi Kitamura Naoya Masumori Fumimasa Fukuta Taiji Tsukamoto

Koji Ichihara Hiroshi Kitamura Naoya Masumori Fumimasa Fukuta Taiji Tsukamoto Int J Clin Oncol (2013) 18:75 80 DOI 10.1007/s10147-011-0346-8 ORIGINAL ARTICLE Transurethral prostate biopsy before radical cystectomy remains clinically relevant for decision-making on urethrectomy in