THE VALUE OF PROSTATIC URETHRAL TUR BIOPSIES TAKEN BEFORE RADICAL CYSTOPROSTATECTOMY AND INTRAOPERATIVE FROZEN BIOPSY SAMPLES AND URETHRAL RECURRENCE

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1 Y. ÖZCAN Adı, Y. KILIÇ, Adı YAŞAR BEDÜK, KADİR TÜRKÖLMEZ, JOURNAL SÜMER OF BALTACI, ANKARAMEDICAL C. ORHUN ECEMİŞ, SCHOOL MURAT AKAND, Vol 26, A. No HAKAN 1, 2004 HALİLOĞLU, HALİT TALAS THE VALUE OF PROSTATIC URETHRAL TUR BIOPSIES TAKEN BEFORE RADICAL CYSTOPROSTATECTOMY AND INTRAOPERATIVE FROZEN BIOPSY SAMPLES AND URETHRAL RECURRENCE Özcan Kılıç* Yaşar Bedük** Kadir Türkölmez*** Sümer Baltacı** C. Orhun Ecemiş* Murat Akand* A. Hakan Haliloğlu* Halit Talas* SUMMARY In this study, the value of preoperative TUR biopsies taken from prostatic urethra of the patients that have had radical cystoprostatectomy because of bladder cancer in determining the prostatic urethral involvement and the effect of prostatic urethral TUR biopsy with intraoperative frozen biopsy of surgical margin of prostatic urethra in selecting the type of urinary diversion and urethral recurrence are investigated. 35 male patients were included into the study. Prostatic urethral TUR biopsies before the cystoprostatectomy operation and intraoperative prostatic urethral surgical margin biopsies were taken from all of the patients. In radical cystoprostatectomy materials; superficial involvement in prostatic urethra was found in 9 (25.7%) patients and in 26 (74.3%) patients there were no prostatic urethral involvement. The sensitivity of TUR prostatic biopsies for determining the prostatic urethral involvement is 78%, the specificity is 92%, positive predictive value is 78% and the negative predictive value is 92%. 33 (94.3%) of the prostatic urethral surgical margin biopsies that are taken intraoperatively were negative and 2 (5.7%) were positive. There was prostatic urethral involvement in 2 patients who had a positive surgical margin previously. The predictive value of preoperative TUR biopsies taken from prostatic urethra for determining the involvement of prostatic urethra is high and useful for informing the patients about the type of urinary diversion. The superficial involvement of prostatic urethra is not an indication for urethrectomy and also it is not an handicap for orthotopic diversion. Biopsy specimens that are taken intraoperatively from prostatic urethral surgical margin is effective for determining urethral surgical margin involvement and decision for performing an urethrectomy and also orthotopic urinary diversion. Key Words: Bladder Cancer, Prostatic Urethral TUR Biopsy, Radical Cystoprostatectomy, Urethral Frozen Biopsy, Urethral Recurrence. ÖZET Radikal Sistoprostatektomi Öncesi Alınan Prostatik Üretral TUR Biyopsiler ve İntraoperatif Frozen Biyopsilerin Değeri ve Üretral Rekürrens Bu çalışmada, mesane kanseri nedeniyle radikal sistoprostatektomi yapılan hastalarda operasyon öncesi alınan prostatik üretra TUR biyopsilerin prostatik üretral tutulumu göstermedeki değeri ve intraoperatif prostatik üretral cerrahi sınır frozen biyopsiler ile birlikte diversiyon yönteminin seçimine etkisi ve üretral rekürrens araştırılmıştır. 35 erkek hasta çalışmaya dahil edildi. Tüm hastalardan sistoprostatektomi operasyonu öncesi prostatik üretral TUR biyopsi, ayrıca intraoperatif prostatik üretra cerrahi sınırdan frozen biyopsiler alındı. Radikal sistoprostatektomi materyallerinde; 9 hastada (%25,7) prostatik üretrada yüzeyel tutulum gözlenmiş, 26 hastada (%74,3) tutulum gözlenmemiştir. TUR prostatik biyopsilerin prostatik üretral tutulumu göstermedeki sensitivitesi %78, spesivitesi %92, pozitif prediktif değeri %78, negatif prediktif değeri % 92 dir. İntraoperatif prostatik üretra cerrahi sınır biyopsilerinden 33 ü (%94,3) negatif, 2 si (%5,7) pozitif bulunmuştur. Cerrahi sınır pozitif bulunan 2 hastada da prostatik üretral tutulum mevcuttu. Radikal sistoprostatektomi öncesi TUR prostatik üretral biyopsilerin prostatik üretral tutulumu göstermedeki değeri yüksektir ve operasyon öncesi hastaların üriner diversiyon tipi açısından bilgilendirilebilmesinde faydalıdır. Prostatik üretranın yüzeyel tutulumu üretrektomi için endikasyon olmamalı ve ortotopik diversiyon için engel teşkil etmemelidir. İntraoperatif postatik üretra cerrahi sınırdan frozen biyopsiler; prostatik üretra cerrahi sınırdaki tutulumu göstermede ve üretrektomi yapılma kararının verilmesinde, dolayısıyla ortotopik diversiyon tercihinde etkilidir. Anahtar Kelimeler: Mesane Kanseri, Prostatik Üretral TUR Biyopsi, Radikal Sistoprostatektomi, Üretral Frozen Biyopsi, Üretral Rekürrens * Ankara University Medical Faculty, Deparment of Urology, Resident ** Ankara University Medical Faculty, Deparment of Urology, Professor *** Ankara University Medical Facult, Deparment of Urology, Associate Professor Received: May 11, 2004 Accepted: May 28, 2004

2 14 THE VALUE OF PROSTATİC URETHRAL TUR BIOPSIES TAKEN BEFORE RADICAL CYSTOPROSTATECTOMY AND INTRAOPERATIVE FROZEN BIOPSY SAMPLES AND URETHRAL RECURRENCE Radical cystoprostatectomy with pelvic lymphadenectomy is the standart treatment for invasive bladder cancer. This treatment modality can be curative for early stage tumors and patients with limited extravesical and regional involvement (1). Therefore, radical cystectomy becomes the most effective treatment for invasive bladder cancer and as the orthotopic diversions with intact urethra used such common and become more popular, the position of the urethra has to be considered carefully. Most of the bladder tumors have urothelial origin, so the rest of the epithelium is under the risk of tumoral involvement or recurrence. After cystectomy, urethral recurrence risk of transitional cell carcinoma is 10 % in men (2). For urethral recurrence, most important risk factor is prostatic urethral involvement. In our study, TUR biopsies are taken before cystectomy to determine the involvement of transitional cell carcinoma to the prostatic urethra from the patients who had radical cystectomy because of invasive bladder cancer. These biopsies are compared with the pathology specimens of the cystoprostatectomy operation and the sensitivity, specificity and predictive values are determined. Also, the value of TUR biopsies from prostatic urethra and intraoperative prostatic urethral surgical margin frozen biopsies for determining the choice of diversion (orthotopic or heterotopic) and urethral recurrence is investigated. Material and Methods 35 male patients with the age of (mean 57.17) who had prostatic urethral TUR biopsies before cystoprostatectomy between January 1999 and June 2003 were included in our study. From all of the patients, intraoperative prostatic urthral surgical margin frozen biopsies were taken and evaluated. Clinical stages of all patients were determined with CT scans. After transurethral resection of bladder tumors, TUR biopsies were taken from 5 and 7 o clock positions of the prostatic urethra and the way between bladder neck and verumontanum. After histopathologic examination of cystoprostatectomy materials, patients were grouped as the patients with or without prostatic urethral involvement. The sensitivity, specificity and predictive values of TUR prostatic urethral biopsies and urethral recurrence, pathologic stage, grade and differences of follow-up periods are investigated. Within the follow-up period, patient history and complaints such as hematuria, urethral bleeding were investigated and physical examination with digital rectal examination, routine biochemical tests and abdominopelvic ultrasonography or CT were performed. Metastases and recurrences were followed-up. Intact urethra s were followed-up by digital rectal examination at each visit, and urine cytology in orthotopic diversions or urethral irrigation cytologies in heterotopic diversions. Patients were grouped according to prostatic urethral involvement. Fisher s Exact Test is used for comparing grades and stages and Mann- Whitney U Test is used for comparing follow-up periods between two groups. Results 9 (%25,7) of 35 TUR biopsies of prostatic urethra taken before radical cystectomy were positive for transitional cell carcinoma (TCC) and 26 ( % 74.3) were negative. All prostatic urethral involvement in TUR biopsy materials were superficial. In 9 (%25,7) patients there were prostatic urethral involvement at the pathological examination of cystoprostatectomy specimens (7 had positive prostatic TUR biopsies and 2 had negative). No prostatic urethral involvement was determined in 26 (% 74.3) patients (24 had negative prostatic TUR biopsies and 2 had positive). All prostatic involvements in cystectomy specimens were superficial. Prostatic urethral involvements in TUR prostatic biopsies and cystoprostatectomy specimens are shown in Table 1.

3 ÖZCAN KILIÇ, YAŞAR BEDÜK, KADİR TÜRKÖLMEZ, SÜMER BALTACI, C. ORHUN ECEMİŞ, MURAT AKAND, A. HAKAN HALİLOĞLU, HALİT TALAS 15 Table 1: Prostatic urethral involvement in TUR biopsies and cystoprostatectomy specimens. Prostatic Urethral Involvement In Cystoprostatectomy Specimen Negative Positive Total TUR Prostatic Biopsy Negative Positive Total The sensitivity of TUR prostatic biopsies for determining the prostatic urethral involvement was % 78, specificity was % 92; the positive predictive value is % 78 and the negative predictive value was % 92. False negative ratio of TUR prostatic biopsy was % 22 and false positive ratio was % 8. Frozen biopsies from the prostatic urethral surgical margin were taken in all patients during the cystoprostatectomy operation. In 33 (%94.3) patients surgical margin biopsies were negative and the remaining 2 patients (%5.7) were positive. After cystoprostatectomy operation 28 patients had orthotopic diversion, 5 patients had ileal conduit and 2 had continent rectal reservoir (Mainz Pouch II). 2 patients underwent uretrectomy simultaneous because of their positive frozen biopsy of the prostatic urethral surgical margin, and ileal conduit was selected as diversion method. Pathological examination confirmed TCC existence in both patients frozen biopsy. Diversion methods which had applied in the operation and prostatic urethral involvement are shown in table 2. Table 2: Prostatic urethral involvement and applied diversion methods. URINARY DIVERSION Orthotopic Ileal Conduit Continent Rectal Reservoir Total With psotatic involvement Without psotatic involvement Number of patient Uretrectomy 2 2

4 16 THE VALUE OF PROSTATİC URETHRAL TUR BIOPSIES TAKEN BEFORE RADICAL CYSTOPROSTATECTOMY AND INTRAOPERATIVE FROZEN BIOPSY SAMPLES AND URETHRAL RECURRENCE 7 patients of 9, whose TUR prostatic urethral biopsy was positive, had heterotopic diversion (5 ileal conduit including 2 patients who had urethrectomy, 2 continent rectal reservoir) and 2 patients had orthotopic diversion. According to pathological examination of cystoprostatectomy materials, prostatic urethral involvement was seen in 9 patients. Of these, 4 had orthotopic diversion, 4 had ileal conduit and 1 had continent rectal reservoir. TUR biopsy positiviness, prostatic urethral surgical margin involvement and patients preferences were the criterions to select diversion method. No statistically significance was found according to grade (in prostatic involvement group 4 grade II, 5 grade III; in the group without prostatic involvement 13 grade II, 13 grade III) (p 1) and stage (in prostatic involvement group 2 pt1, 4 pt2, 3 pt3; in the group without prostatic involvement 9 pt1, 11 pt2, 6 pt3) (p=0,665) in both groups with or without prostatic urethral involvement. The mean follow-up period of 26 patients who had no prostatic urethral involvement was 30.5 (5-54) months, and of 9 patients who had prostatic urethral involvement was 22.2 (6-45) months. There was no statistically significance between two groups (p= 0.19). One patient was lost to follow-up after 6 months. 2 of 9 patients with prostatic urethral involvement died (both of them due to pelvic recurrence and distant organ metastases), and 2 of 25 patients without prostatic urethral involvement died ( 1 due to pelvic recurrence, 1 due to another reason apart from his cancer) in follow-up period. All of the remaining 30 patients survived without any evidence of recurrence or metastases. No urethral recurrence was seen during the follow-up period in none of the 33 patients with intact urethra, except 2 patients who had urethrectomy. Conclusion There are two different approaches, preserving the bladder or radical cystectomy and urinary diversion, in the treatment of invasive bladder cancer. Radical cystectomy is still the standart treatment of invasive bladder cancer (3). Most of the patients prefer a normal life with a normal micturition pattern and a good voiding volume every 4-6 hours without a cutaneous stoma or external urostomy appatatus. Orthotopic substitution is the gold standart treatment method when compared with the other diversion methods (4). As radical cystectomy is an effective treatment for invasive bladder cancer and orthotopic diversion to naturel intact urethra is being done more frequently, the desting of the remaining urethra is becoming a more important issue (5). If there is a significant risk of tumor recurrence in the remaining urethra and local recurrence will affect the functional features of bladder potentially, orthotopic diversion should not be performed absolutely. Prostatic urethral involvement is the most important criterion for urethral tumor recurrence (5). Freeman et al. has reported anterior urethral tumor recurrence in 208 (10,1%) of 2062 patients who have undergone cystectomy (2). This figure provides a good estimate of the overall risk of developing an urethral recurrence after cystectomy for TCC of bladder. Hardeman and Soloway found anterior urethral recurrence in 11 (37%) of 30 patients with prostatic urethral tumors. No patient in this study with only prostatic urethral mucosa tumor developed a recurrence, whereas 25% of men with prostatic ductal involvement and 64% of men with prostatic stromal involvement in this report developed urethral recurrence. In the same series, only 2 of 56 patients (4%) whose tumors did not involve the prostatic urethra suffered urethral recurrence (6). Levinson and colleagues found 67% of urethral recurrences to be associated with prostatic urethral involvement, no patient whose tumor was confined to the prostatic urethral mucosa, 10% of patients prostatic ductal involvement and 30% of patients with prostatic stromal involvement developed a urethral recurrence(7). In our study no urethral recurrence was determined during the follow-up period in

5 ÖZCAN KILIÇ, YAŞAR BEDÜK, KADİR TÜRKÖLMEZ, SÜMER BALTACI, C. ORHUN ECEMİŞ, MURAT AKAND, A. HAKAN HALİLOĞLU, HALİT TALAS 17 patients who had superficial prostatic urtehral involvement and intact urethra. This result is concordant with the results of Hardeman and Soloway (6), Levinson et al. (7). Superficial urethral involvement should not be an indication for urethrectomy and hinder for orthotopic diversion. Patients with a tumor in any part of the prostate (prophilactic urethrectomy not performed after cutaneous diversion or has been follow-up after orthotopic diversion) have a significantly higher risk of urtehral recurrence. This risk increases significantly in patients with prostatic stromal involvement (5). It has been reported that deep TUR biopsies taken at the level of verumontanum, preferably at 5 hour and 7 hour position, may be helpful to define the prostatic urethral involvement (8,9). Lebret et al. found the sensitivity of preoperative TUR biopsy high, but the specificity low in their series of 118 cases. No urethral recurrence was found in 9 patients with positive biopsy but negative frozen biopsy in the urethral margin section. They have reported that the major risk factor is positive urethral margin, and if there is no evidence of tumor in intraoperative urethral frozen section biopsy (even if there is prostatic involvement) insidence of urethral recurrence after orthotopic diversion is low and preoperative prostate biopsy may not be necessary (10). Bulbul et al. have reported that TUR biopsy of the prostatic urethra prior to cystectomy, or biopsy of the prostatic urethral margin at the time of cystectomy in patients with cystoscopically normal, tumor free prostatic urethra has limited value in selecting candidates for orthotopic neobladder substitution (11). Presence of prostatic urethral tumor is accepted as a contraindication for constructing orthotopic bladder by most of investigators (7, 12, 13). Some investigators state that orthotopic substitution can be done if intraoperative frozen biopsy of prostatic urethral margin is negative (14). TUR prostatic biopsy before cystectomy or intraoperative frozen biopsy of prostatic urethra surgical margin are the best methods in excluding the disease and deciding the bladder substitution (15,16). Understanding that prostatic tumor involvement increases the risk of urethral tumor recurrence after radical cystectomy, we took TUR biopsy of prostatic urethra before radical cystoprostatectomy and intraoperative frozen biopsy from the surgical margin of prostatic urethra to identify these patients. It has found that the sensitivity of TUR prostatic biopsy was % 78 and the specificity was % 92. Our results show that the value of TUR biopsy of prostatic urethra before radical cystoprostatectomy in determining the prostatic urethral involvement is high. Presence of tumor in frozen biopsy from surgical margin of prostatic urethra can be accepted as a criterion for urethrectomy. Lebret et al. (10) have the same opinion. In our study, frozen biopsy from surgical margin of prostatic urethra is found in 2 of 9 patients with prostatic urethral involvement and these 2 patients underwent urethrectomy. Positiveness in surgical margin of prostatic urethra was not found in none of 26 patients with no involvement of prostatic urethra. Time to urethral cancer formation after cystectomy is generally 1-10 years (17), but most of them are seen in 5 years. In our study, of 28 patients (80%) performed orthotopic diversion (4 with prostatic urethral involvement and 24 without involvement) and of 7 patients (20%) performed heterotopic diversion (5 with prostatic urethral involvement and 2 without involvement), except 2 patients performed uretrectomy simultaneous because of prostatic urethral involvement and positive frozen biopsy, no urethral recurrence was observed in remaining 33 patient with intact urethra (7 with prostatic urethral involvement and 26 without involvement) for mean 26,36 months follow-up period. According to these results, for urethral recurrence, prostatic urethral involvement should not be an excluding criterion for orthotopic diversion; but positive surgical margin of

6 18 THE VALUE OF PROSTATİC URETHRAL TUR BIOPSIES TAKEN BEFORE RADICAL CYSTOPROSTATECTOMY AND INTRAOPERATIVE FROZEN BIOPSY SAMPLES AND URETHRAL RECURRENCE prostatic urethra should be considered as an excluding criterion for orthotopic diversion. However, the psycology of the patients have because of bladder cancer, is affected there more negatively because of organ loss when radical cystectomy is said indicated and offered. Most important anxiety of the patients is to survive close to their normal life in a disease free pattern. By this way, orthotopic diversions with normal micturation pattern reserved and without a cutaneous stoma or external urostomy apparatus should prefere primarly. The diversion method being uncertain before operation may affect patients negatively. For this reason despite it is stated by Lebret et al. (10) that positiveness of urethral margin is the major risk factor for urethral recurrence, according to our results we are in the opinion that orthotopic diversion can be performed to the patients with negative TUR biopsy if the intraoperative frozen biopsy is negative. Thus, patients can be informed about diversion method; this will help in reducing in the anxiety of patients who decided radical cystoprostatectomy. As a result, the value of TUR biopsy of prostatic urethra before cystectomy for determinig prostatic urethral involvement is high. It is observed that orthotopic diversion can be performed to all patients with negative TUR biopsy of prostatic urethra before radical cystectomy; orthotopic diversion can also be done in patients with positive TUR biopsy according to involvement of surgical margin of prostatic urethra. By this way, patients can be informed about diversion method before radical cystoprostatectomy. Intraoperative frozen biopsy from surgical margin of prostatic urethra is effective in deciding urethrectomy simultaneous, and also perefering orthotopic diversion.

7 ÖZCAN KILIÇ, YAŞAR BEDÜK, KADİR TÜRKÖLMEZ, SÜMER BALTACI, C. ORHUN ECEMİŞ, MURAT AKAND, A. HAKAN HALİLOĞLU, HALİT TALAS 19 References 1. Vieweg S, Gschwend JE, Herr HW, et al. Pelvic lymph node dissection can be curative in patients with node positive bladder cancer. J Urol 1999; 161: Freeman JA, Esrig D, Stein JP, et al. Management of the patient with bladder cancer, urethral recurrence. Urol. Clin. North. Am 1994; 21: Kuczyk M, Turkeri L, Stein JP, et al. On behavior of the European Society for Oncological Urology: Is there a role for bladder preserving strategies in the treatment of muscle-invasive bladder cancer?; European Urology 2003; 44: Hautman RE, Paiss T. Does the option of the ileal neobladder stimulate patient and physician decision toward earlier cystectomy. J Urol 1998; 159: Stein JP, Skinner DG. Orthotopic Urinary Diversion. Campbell s Urology, Eight eds. Philadelphia 2002 Vol: 4, pp Hardeman SW, Soloway MS. Urethral recurrence following radical cystectomy. J Urol 1990; 144: Levinson AK, Johnson DE, Wishnow KI. Indications for urethrectomy in an era of continent urinary diversion. J Urol 1990; 144: Wood DP Jr, Montie JE, Pontes JE, et al. Identification of transitional cell carcinoma of the prostate in bladder cancer patients: A prospective study. J Urol 1989; 142: Sakamoto N, Tsuneyoshi M, Naito S, et al. An adequate sampling of the prostate to identify prostatic involvement by urothelial carcinoma in bladder cancer patients. J Urol 1993;149: Lebret T, Herve JM, Barre P, et al. Urethral recurrence of transitional cell carcinoma of the bladder. Predictive value of preoperative lateromontanal biopsies and urethral frozen sections during prostatocystectomy. Eur Urol 1998; 33: Bulbul MA, Wazzan W, Nasr R, et al. The value of cystoscopy, prostate biopsy and frozen-section urethral biopsy prior to orthotopic neobladder substitution. The Can J Urol 2001; 8: Hardeman SW, Soloway MS. Urethral recurrence following radical cystectomy. J Urol 1990; 144: Tongaonkar HB, Dalad AV, Kulkami JN, et al. Urethral recurrences following radical cystectomy for invasive transitional cell carcinoma of the bladder. Br J Urol 1993; 72: Tarter TH, Freeman JA, Chen SC, et al. Urethral recurrence with ileal neobladders. J Urol 1995; Part 2, 153: 314A, Abstract Studer UE, Hautmann RE, Hohenfellner, et al. Indication for continent diversion following cystectomy and factors affecting long term results. Presented at fifth international consensus meeting on bladder cancer 1997, Tokoyo, Japan. 16. Skinner DJ, Studer UE, Aso OK, et al. Which patients are suitable for continent diversion or bladder substitution following cystectomy or other definitive local treatment. Int J Urol 1995; Suppl. 2: Tobisu K, Tanaka Y, Mizutani T, et al. Transitional carcinoma of the urethra in men following cystectomy for bladder cancer. Multivariate analysis for risk factors. J Urol 1991; 146:

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