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Is There an Indication for Frozen Section Examination of the Ureteral Margins During Cystectomy for Transitional Cell Carcinoma of the Bladder?
Is There an Indication for Frozen Section Examination of the Ureteral Margins During Cystectomy for Transitional Cell Carcinoma of the Bladder? Martin C. Schumacher, Michael Scholz, Erik S. Weise, Achim Fleischmann, George N. Thalmann and Urs E. Studer* From the Department of Urology, Institute of Pathology (AF), University Hospital Bern, Bern, Switzerland
Purpose: We evaluated the incidence of pathological findings of the ureter at cystectomy for transitional cell carcinoma of the bladder and assessed the usefulness of intraoperative frozen section examination of the ureter. Materials and Methods: Histopathological findings of ureteral frozen section examination were compared to the corresponding permanent sections and the diagnostic accuracy of frozen section examination was evaluated. These segments were then compared to the more proximal ureteral segments resected at the level where they cross over the common iliac arteries. The histopathological findings of the ureteral segments were then correlated for upper urinary tract recurrence and overall survival. Results: Transitional cell carcinoma or carcinoma in situ was found on frozen section examination of the distal ureter in 39 of 805 patients (4.8%) and on permanent sections in 29 (3.6%). In 755 patients the false-negative rate of frozen section examination of the ureters was 0.8%. Of the patients with carcinoma in situ diagnosed on the first frozen section examination 80% also had carcinoma in situ in the bladder. Transitional cell carcinoma or carcinoma in situ in the most proximally resected ureteral segments was found in 1.2% of patients. After radical cystectomy there was tumor recurrence in the upper urinary tract in 3% of patients with negative ureteral frozen section examination and in 17% with carcinoma in situ on frozen section examination. Conclusions: Routine frozen section examination of the ureters at radical cystectomy is only recommended for patients with carcinoma in situ of the bladder, provided the ureters are resected where they cross the common iliac arteries. Key Words: carcinoma, transitional cell; bladder; cystectomy; ureter; frozen sections
n incidence of 8% to 18% of CIS or solid urothelial cancer in the distal ureters of patients undergoing radical cystectomy for TCC with coexisting CIS in the bladder has been reported in series from the late 1960s and early 1970s.1–3 Based on these findings FSE of the ureters was recommended at radical cystectomy.1,4 – 6 It has been suggested that this procedure reduces the risk of missing pathological findings in the remaining ureters, and in case malignancy is found a more proximal ureteral segment can be excised to assure a tumor-free ureterointestinal anastomosis. The incidence of urothelial malignancies is highest in the distal ureter.7 Therefore, we hypothesized that resection of the ureters at the level where they cross over the common iliac arteries should increase the probability of a tumor-free ureterointestinal anastomosis. In this study we analyzed the incidence of positive ureteral margins in a consecutive series of patients undergoing radical cystectomy for TCC of the bladder.
A
PATIENTS AND METHODS We prospectively performed FSE of the ureters in 805 consecutive patients between January 1984 and January 2005
Submitted for publication December 28, 2005. * Correspondence: Department of Urology, University of Bern, 3010 Bern, Switzerland (telephone: 0041 31 632 42 36; FAX: 0041 31 632 21 81; e-mail: [email protected]).
0022-5347/06/1766-2409/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
with TCC of the bladder who underwent standardized pelvic lymph node dissection and cystectomy. Patients who underwent preoperative radiation therapy were excluded from analysis. The surgical technique for radical cystectomy has previously been described in detail.8,9 The ureters are mobilized together with the surrounding tissue and transected approximately 1 cm proximal to the entry into the perivesical fat (see figure). A 0.5 cm ureteral segment of both ureters is sent for FSE. If the first FSE of the distal ureteral segment is negative for TCC or CIS, a further resection of a more proximal ureteral segment of approximately 4 cm, ie at the level where they cross the common iliac arteries, is performed in all patients (see figure). If the first FSE is positive for TCC or CIS a more proximal segment of the ureter is resected and FSE is repeated. This procedure is repeated until FSE is negative. In these cases resection of the more proximal ureteral segments may be above the level where the ureter crosses the common iliac artery (see figure). The ureteral segments sent intraoperatively for FSE are later embedded in paraffin (permanent sections) and step sectioned for confirmation of the frozen section findings. The most proximally resected ureteral segments are also embedded in paraffin and step sectioned. The histopathological findings of the ureteral segments taken for FSE are compared to the corresponding permanent sections. The histopathological findings of the ureteral segments sent first for
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Vol. 176, 2409-2413, December 2006 Printed in U.S.A. DOI:10.1016/j.juro.2006.07.162
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FROZEN SECTION EXAMINATION OF URETERAL MARGINS DURING CYSTECTOMY Diagnosis of CIS in the First Ureteral Segments Sent for FSE In 30 of 805 patients (3.7%) CIS was diagnosed on FSE. In 22 (73%) of these patients CIS was confirmed in the corresponding permanent sections. CIS of the most proximal ureteral segment resected was diagnosed in only 1 of these 22 patients (table 1). All of these 22 patients underwent second frozen section examination of a more proximal ureteral segment which revealed CIS in 9. These patients underwent further resection of the ureter with FSE, which then was normal, before completing the ureteroileal anastomosis. In these cases proximal resection of an additional 1 to 2 cm ureteral segment was performed above the common iliac arteries and sent for permanent sections. In 8 of the 30 patients with CIS on FSE no second frozen section was performed, but the more proximal ureteral segments resected were normal on permanent section. These 8 patients had organ confined bladder cancer and none had recurrence in the remaining upper urinary tract after radical cystectomy. Of the 30 patients 24 (80%) with CIS in the first FSE of the ureters were found to have multifocal CIS in the cystectomy specimen or in the previous transurethrally resected bladder tumor material.
Site where intraoperative frozen sections of both ureters were performed and sent for FSE, and where more proximally resected ureteral segments at their crossing with common iliac artery were taken.
FSE are further compared to the more proximal resected ureteral segments. Pathological findings in the urothelium of the ureters are classified as normal, severe atypia, CIS or solid urothelial cancer (TCC). The histopathological results in patients with CIS of the ureter were correlated to the possible presence of concomitant CIS of the bladder. Final pathology was reported according to the TNM classification of 1997.
RESULTS Diagnosis of TCC in the First Ureteral Segments Sent for FSE In 9 of 805 patients (1.1%) TCC was found on frozen section and was confirmed in the corresponding permanent sections in 7 patients (table 1). There was no pathology report on permanent sections for the remaining 2 patients. From preoperative staging examinations (excretory urography and/or computerized tomography) a distal ureteral tumor was diagnosed before radical cystectomy in 4 of these 9 patients. Of these 9 patients 7 had a second FSE performed, which showed TCC in 5. The next, more proximal ureteral segment resected was normal in 3 patients and showed TCC in 4 (table 1). All 7 patients had nonorgan confined bladder cancer on final pathology and in 4 patients multifocal CIS was found in the cystectomy specimen.
Diagnosis of Severe Atypia in the First Ureteral Segments Sent for FSE In 11 of 805 patients (1.4%) severe atypia was diagnosed on FSE (table 1). Of these patients 1 had severe atypia and 2 had CIS in the corresponding permanent sections. The 2 patients with CIS were found to have CIS in the more proximally resected ureteral segments as well. Both had multifocal pT1 G3 and CIS bladder cancer. The 1 patient with severe atypia on permanent sections had no urothelial malignancy in the more proximally resected segments. Diagnosis of Normal Findings in the First Ureteral Segments Sent for FSE In 755 of 805 (94%) patients FSE was diagnosed as normal (table 1). The corresponding permanent sections revealed TCC in 1 (0.1%) and CIS in 5 (0.7%) patients, resulting in a false-negative rate of 0.8% for FSE. The patient with TCC
TABLE 1. Histopathological diagnosis in patients treated with radical cystectomy for TCC of the bladder No./Total No. First Ureteral FSE (%)
No./Total No. Corresponding Permanent Sections (%)
TCC 9/805 (1.1)
TCC 7/9 (78)
CIS 30/805 (3.7)
No information 2/9 (22) CIS 22/30 (73)
Severe atypia 11/805 (1.4) Normal 755/805 (93.8)
Normal 8/30 (27) Severe atypia 1/11 (9) CIS 2/11 (18) Normal 8/11 (73) Normal 710/755 (94) Severe atypia 3/755 (0.4) CIS 5/755 (0.7) TCC 1/755 (0.1) No information 36/755 (4.8)
More Proximal Ureteral Segments (No. pts) TCC (4) Normal (3) Normal (2) CIS (1) Normal (21) Normal (8) Normal (1) CIS (2) Normal (8) Normal (683) Normal (2) CIS (1) Normal (4) CIS (1) Carcinomatous angiosis (1) No information (63)
FROZEN SECTION EXAMINATION OF URETERAL MARGINS DURING CYSTECTOMY
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TABLE 2. Upper urinary tract recurrence and overall survival according to histopathological diagnosis of intraoperative ureteral FSE in patients treated with radical cystectomy for TCC of the bladder Histopathological Classification of First Ureteral FSE
No. Pts According to Histopathological Results of First Ureteral FSE
No. Upper Urinary Tract Recurrence (%)
Median Mos Overall Survival (range)
TCC CIS Severe atypia Normal
9 30 11 755
2 (22) 5 (17)* 2 (18) 22 (3)*
15 (3–180) 32 (2–137) 15 (3–191) 32 (0.4–242)
* Single patient had local recurrence at site of ureteroileal anastomosis.
had carcinomatous angiosis in the most proximally resected ureteral segment. Of the 5 patients with CIS 1 was also found to have CIS in the more proximally resected ureteral segment, whereas this was normal in the other 4 patients. In 3 of 755 patients (0.4%) severe atypia was diagnosed in the paraffin embedded segments. Of these 3 patients 1 had CIS in the more proximally resected ureteral segment. In 36 patients with normal ureteral FSE a pathology report of the permanent sections was not available. None of them had recurrence in the remaining upper urinary tract after radical cystectomy (table 1). Incidence of Ureteral Involvement and Upper Urinary Tract Recurrence Upper urinary tract recurrence was diagnosed in 31 of 805 patients (3.9%) after a median of 30 months (range 2 to 96) (table 2). Median cancer specific survival was 42 months (range 1 to 142). Of these 31 patients 20 (65%) have died of metastatic disease. Of 755 patients with negative first FSE of the most distal ureteral margin 22 (2.9%) had upper urinary tract recurrence after a median of 31 months (range 2 to 86). Upper urinary tract recurrence after radical cystectomy occurred in 5 of 30 patients (16.7%) with CIS diagnosed on the first ureteral FSE. Of these patients 1 had recurrence at the site of ureteroileal anastomosis. Of the 9 patients 2 (22%) with TCC on first ureteral FSE had upper urinary tract recurrence. Median cancer specific survival in the 10 patients with TCC or CIS in the most proximally resected ureteral segments was 13 months (range 2 to 84). Of these 10 patients 7 (70%) have died of systemic metastatic disease.
DISCUSSION Recommendations to perform FSE of the ureteral margins at cystectomy are based on the concept of improved cancer control through FSE by achieving a tumor-free ureterointestinal anastomosis. However, the validity of this approach for reducing upper urinary tract recurrence is controversial. FSE of the ureteral margins has been further questioned because of the false-negative intraoperative results due to the possibility of a pagetoid tumor spread within the ureter, which is only detectable with sequential sectioning and because of the relative rarity (2.4% to 6.6%) of upper urinary tract recurrence after radical cystectomy for TCC of the bladder.5,10 –15 Therefore, the questions remain which patients require FSE of the ureteral margins and to what extent should ureteral resection be performed to obtain a tumor-free ureterointestinal anastomosis. In this study FSE showed TCC, CIS or severe atypia of the first resected ureteral margins close to the bladder in 6.2% of our patients (table 1). These findings are comparable to the results reported by others (table 3). Culp et al reported CIS on FSE of the distal ureters in 13 of 231 patients (6%) undergoing partial or total cystectomy.2 Similar results were reported by Schoenberg et al in a series of 97 patients with 8% urothelial abnormalities ranging from mild atypia to CIS on FSE of the distal ureters.11 Silver et al found a 7.7% (31 of 401) incidence of ureteral abnormalities in the distal ureters sent for FSE in patients treated with radical cystectomy for invasive bladder cancer.12 In patients with positive ureteral FSE for TCC or CIS, the corresponding permanent section was only positive in
TABLE 3. Overview of intraoperative FSE results %
References 2
Culp et al Sharma et al1 Linker and Whitmore13 Herr and Whitmore7 Johnson et al6 Batista et al5 Malkowicz and Skinner4 Schoenberg et al11 Silver et al12 Present study
No. Pts
Multifocal Bladder Ca
Concomitant CIS in Cystectomy Specimen or Previous TUR-BT Material in Pts With Ureteral CIS on FSE
231 205 107 105 403 242 210 97 401 805
Present Not available Not available Present Not available Not available Not available Not available Not available Present
Present Not available Not available Present Not available 85.7 Not available Not available Not available 80
* Overall incidence of urothelial abnormalities.
Urothelial Abnormalities on Ureteral FSE
Histopathological Diagnosis of Corresponding Permanent Sections
Histopathological Diagnosis of Most Proximally Resected Ureteral Segments
17,* 6 (CIS) 8.5 (CIS) 15.7,* 8.7 (CIS) 35 (CIS) 7.2,* 2 (CIS) 5.7 (CIS) Not available 8* 7.7,* 6.2 (CIS) 6.2,* 4.8 (TCC, CIS)
Not available Not available Not available Not available Not available Not available Not available Not available Not available, 3.7 (CIS) 3.6 (TCC, CIS)
Not available Not available Not available 14 (CIS) 6 (CIS, dysplasia) Not available 1.4 (TCC) 4 (CIS) Not available 1.2 (TCC, CIS)
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FROZEN SECTION EXAMINATION OF URETERAL MARGINS DURING CYSTECTOMY
75%. This result may be due to a shedding of CIS cells during ureteral manipulations, nonexistence of CIS in the remaining ureter not sent for FSE or a false-positive diagnosis. However, when FSE is normal the false-negative rate is low, less than 1% in our series. In a series of 401 patients Silver et al questioned the value of intraoperative ureteral FSE as it did not detect CIS in 17% compared to the corresponding permanent sections.12 In the most proximally resected ureteral segment TCC or CIS was found in only 1.2% of our patients. Thus, if resection of the ureters at the level where they cross over the common iliac arteries is performed, there is a high probability of a tumor-free ureterointestinal anastomosis. Furthermore, shortening of the ureters minimizes the risk of strictures of the remaining ureter and the ureterointestinal anastomosis due to ischemia.16 We reported an ureteroileal stricture rate of less than 3% in a consecutive series of 482 patients undergoing radical cystectomy and orthotopic bladder substitution combined with an afferent tubular ileal segment for TCC of the bladder.17 Furthermore, after radiotherapy to the pelvis for malignancies other than bladder cancer before cystectomy, resection of the ureters at the level where they cross with the common iliac arteries has a higher probability of being outside the field of radiation, resulting in a lower risk of ischemic ureteral stenosis.18,19 The incidence of an invasive tumor recurrence at the ureterointestinal anastomosis after radical cystectomy for TCC of the bladder is uncommon, occurring in approximately 1% as reported in the literature.1,5–7,14 In our series of 805 patients only 2 (0.3%) had recurrence at the ureteroileal anastomosis. In 1 patient ureteral FSE was normal whereas in the other patient CIS was diagnosed. He was also found to have concomitant CIS in the bladder. We attribute the low incidence of less than 1% recurrence at the ureteroileal anastomosis to the FSE of the ureteral margins at radical cystectomy, which in instances of a positive result led to further FSE. Another reason is the routine second ureteral resection at the level where it crosses the common iliac artery. In a series of 17 patients with CIS on ureteral FSE Sharma et al reported only 1 ureteroileal recurrence.1 They stated that the prevalence of ureteral CIS was highest (19.6%) in patients with multifocal bladder cancer and concomitant CIS. Similarly Johnson et al reported that FSE of the ureters is only indicated in patients with multifocal CIS of the bladder or prostatic tumor involvement, which is in accordance with our findings.6 Opponents of FSE of the ureteral margins argued that given the low incidence of upper urinary tract recurrence of 2.4% to 6.6% and the even rarer incidence of an anastomotic recurrence, it is unlikely that FSE of the ureteral margins will have an impact on upper urinary tract recurrence and long-term survival.4,10,14,15,20,21 However, our results show that patients with negative histology in the distal ureteral segments are at a 3% risk of upper urinary tract recurrence, whereas patients with CIS on FSE are at a 17% risk. Nevertheless, it must be kept in mind that the majority of these patients ultimately die of systemic disease.
(80%). If ureteral CIS is diagnosed then there is a 5-fold risk of upper urinary tract recurrence after radical cystectomy for TCC of the bladder. Except for patients with CIS in the bladder, FSE of the ureters is not necessary if the ureters are resected at the level where they cross the common iliac vessels.
Abbreviations and Acronyms CIS ⫽ carcinoma in situ FSE ⫽ frozen section examination TCC ⫽ transitional cell carcinoma
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8. 9.
10.
11.
12.
13. 14.
CONCLUSIONS TCC and CIS are found in the most distal ureter in 4.8% and at the iliac cross in 1.2% of our patients, respectively. Most patients with CIS in the ureter have CIS in the bladder
15.
Sharma, T. C., Melamed, M. R. and Whitmore, W. F., Jr.: Carcinoma in-situ of the ureter in patients with bladder carcinoma treated by cystectomy. Cancer, 26: 583, 1970 Culp, O. S., Utz, D. C. and Harrison, E. G., Jr.: Experiences with ureteral carcinoma in situ detected during operations for vesical neoplasm. J Urol, 97: 679, 1967 Cooper, P. H., Waisman, J., Johnston, W. H. and Skinner, D. G.: Severe atypia of transitional epithelium and carcinoma of the urinary bladder. Cancer, 31: 1055, 1973 Malkowicz, S. B. and Skinner, D. G.: Development of upper tract carcinoma after cystectomy for bladder carcinoma. Urology, 36: 20, 1990 Batista, J. E., Palou, J., Iglesias, J., Sanchotene, E., da Luz, P., Algaba, F. et al: Significance of ureteral carcinoma in situ in specimens of cystectomy. Eur Urol, 25: 313, 1994 Johnson, D. E., Wishnow, K. I. and Tenney, D.: Are frozensection examinations of ureteral margins required for all patients undergoing radical cystectomy for bladder cancer? Urology, 33: 451, 1989 Herr, H. W. and Whitmore, W. F., Jr.: Ureteral carcinoma in situ after successful intravesical therapy for superficial bladder tumors: incidence, possible pathogenesis and management. J Urol, 138: 292, 1987 Turner, W. H. and Studer, U. E.: Cystectomy and urinary diversion. Semin Surg Oncol, 13: 350, 1997 Kessler, T. M., Burkhard, F. C., Perimenis, P., Danuser, H., Thalmann, G. N., Hochreiter, W. W. et al: Attempted nerve sparing surgery and age have a significant effect on urinary continence and erectile function after radical cystoprostatectomy and ileal orthotopic bladder substitution. J Urol, 172: 1323, 2004 Balaji, K. C., McGuire, M., Grotas, J., Grimaldi, G. and Russo, P.: Upper tract recurrences following radical cystectomy: an analysis of prognostic factors, recurrence pattern and stage at presentation. J Urol, 162: 1603, 1999 Schoenberg, M. P., Carter, H. B. and Epstein, J. I.: Ureteral frozen section analysis during cystectomy: a reassessment. J Urol, 155: 1218, 1996 Silver, D. A., Stroumbakis, N., Russo, P., Fair, W. R. and Herr, H. W.: Ureteral carcinoma in situ at radical cystectomy: does the margin matter? J Urol, 158: 768, 1997 Linker, D. G. and Whitmore, W. F.: Ureteral carcinoma in situ. J Urol, 113: 777, 1975 Hautmann, R. E., Volkmer, B. G., Schumacher, M. C., Gschwend, J. E. and Studer, U. E.: Long-term results of standard procedures in urology: the ileal neobladder. World J Urol, 24: 305, 2006 Sved, P. D., Gomez, P., Nieder, A. M., Manoharan, M., Kim, S. S. and Soloway, M. S.: Upper tract tumour after radical
FROZEN SECTION EXAMINATION OF URETERAL MARGINS DURING CYSTECTOMY
16. 17.
18.
19.
20.
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cystectomy for transitional cell carcinoma of the bladder: incidence and risk factors. BJU Int, 94: 785, 2004 Stenzl, A., Bartsch, G. and Rogatsch, H.: The remnant urothelium after reconstructive bladder surgery. Eur Urol, 41: 124, 2002 Studer, U. E., Burkhard, F. C., Schumacher, M. C., Kessler, T. M., Thoeny, H., Fleischmann, A. et al: Twenty years experience with an ileal orthotopic low pressure bladder substitute–lessons to be learned. J Urol, 176: 161, 2006 Kim, H. L. and Steinberg, G. D.: Complications of cystectomy in patients with a history of pelvic radiation. Urology, 58: 557, 2001 Maier, U., Ehrenbock, P. M. and Hofbauer, J.: Late urological complications and malignancies after curative radiotherapy for gynecological carcinomas: a retrospective analysis of 10,709 patients. J Urol, 158: 814, 1997 Zincke, H., Garbeff, P. J. and Beahrs, J. R.: Upper urinary tract transitional cell cancer after radical cystectomy for bladder cancer. J Urol, 131: 50, 1984 Kenworthy, P., Tanguay, S. and Dinney, C. P.: The risk of upper tract recurrence following cystectomy in patients with transitional cell carcinoma involving the distal ureter. J Urol, 155: 501, 1996
EDITORIAL COMMENT Risk factors for upper tract recurrence following radical cystectomy are documented in this study as a history of diffuse CIS, multifocal tumor, intramural tunnel or juxtavesical ureteral involvement with CIS, or a prior ureteral tumor (references 6, 11 and 12 in article). The initial impetus for frozen section analysis was to ensure a cancer-free anastomosis, which theoretically would translate into reduced upper tract recurrence rates and longer cancer-free
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survival. However, controversy remains concerning the usefulness of ureteral margin frozen section analysis in achieving these goals due to the rarity of upper tract recurrence (3.9% in this study) and, in particular, anastomotic recurrence (2 of 805 or 0.3% in this study and 2 of 31 or 6% of the total upper tract recurrence), the typical pagetoid spread of CIS (negative margin does not guarantee CIS is not higher up), the inaccuracy of frozen section analysis, and the disparity in pathological interpretation of atypia, dysplasia and CIS (references 6, 11 and 12 in article). This study confirms the rate of upper tract recurrence is higher in those with risk factors (17% vs 3%) and routine division of the ureters at the mid common iliac artery would decrease the risk of a positive ureteral margin in patients with risk factors for upper tract recurrence. However, negative ureteral margins did not result in a decrease in upper tract recurrence rate or improve survival. In addition, the study does not show how frozen section analysis at the level of the mid common iliac ureter would add anything to the simple division of the ureter at this level in all patients given the low incidence of anastomotic recurrence. The data confirm the risk factors for upper tract recurrence and lower ureteral involvement up to the level of the common iliac artery, and should be considered when selecting patients for minimally invasive extracorporeal diversions in which a greater ureteral length is needed. S. Machele Donat Department of Urology Memorial Sloan-Kettering Cancer Center New York, New York
Purpose: We evaluated the incidence of pathological findings of the ureter at cystectomy for transitional cell carcinoma of the bladder and assessed the usefulness of intraoperative frozen section examination of the ureter. Materials and Methods: Histopathological findings of ureteral frozen section examination were compared to the corresponding permanent sections and the diagnostic accuracy of frozen section examination was evaluated. These segments were then compared to the more proximal ureteral segments resected at the level where they cross over the common iliac arteries. The histopathological findings of the ureteral segments were then correlated for upper urinary tract recurrence and overall survival. Results: Transitional cell carcinoma or carcinoma in situ was found on frozen section examination of the distal ureter in 39 of 805 patients (4.8%) and on permanent sections in 29 (3.6%). In 755 patients the false-negative rate of frozen section examination of the ureters was 0.8%. Of the patients with carcinoma in situ diagnosed on the first frozen section examination 80% also had carcinoma in situ in the bladder. Transitional cell carcinoma or carcinoma in situ in the most proximally resected ureteral segments was found in 1.2% of patients. After radical cystectomy there was tumor recurrence in the upper urinary tract in 3% of patients with negative ureteral frozen section examination and in 17% with carcinoma in situ on frozen section examination. Conclusions: Routine frozen section examination of the ureters at radical cystectomy is only recommended for patients with carcinoma in situ of the bladder, provided the ureters are resected where they cross the common iliac arteries. Key Words: carcinoma, transitional cell; bladder; cystectomy; ureter; frozen sections
n incidence of 8% to 18% of CIS or solid urothelial cancer in the distal ureters of patients undergoing radical cystectomy for TCC with coexisting CIS in the bladder has been reported in series from the late 1960s and early 1970s.1–3 Based on these findings FSE of the ureters was recommended at radical cystectomy.1,4 – 6 It has been suggested that this procedure reduces the risk of missing pathological findings in the remaining ureters, and in case malignancy is found a more proximal ureteral segment can be excised to assure a tumor-free ureterointestinal anastomosis. The incidence of urothelial malignancies is highest in the distal ureter.7 Therefore, we hypothesized that resection of the ureters at the level where they cross over the common iliac arteries should increase the probability of a tumor-free ureterointestinal anastomosis. In this study we analyzed the incidence of positive ureteral margins in a consecutive series of patients undergoing radical cystectomy for TCC of the bladder.
A
PATIENTS AND METHODS We prospectively performed FSE of the ureters in 805 consecutive patients between January 1984 and January 2005
Submitted for publication December 28, 2005. * Correspondence: Department of Urology, University of Bern, 3010 Bern, Switzerland (telephone: 0041 31 632 42 36; FAX: 0041 31 632 21 81; e-mail: [email protected]).
0022-5347/06/1766-2409/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
with TCC of the bladder who underwent standardized pelvic lymph node dissection and cystectomy. Patients who underwent preoperative radiation therapy were excluded from analysis. The surgical technique for radical cystectomy has previously been described in detail.8,9 The ureters are mobilized together with the surrounding tissue and transected approximately 1 cm proximal to the entry into the perivesical fat (see figure). A 0.5 cm ureteral segment of both ureters is sent for FSE. If the first FSE of the distal ureteral segment is negative for TCC or CIS, a further resection of a more proximal ureteral segment of approximately 4 cm, ie at the level where they cross the common iliac arteries, is performed in all patients (see figure). If the first FSE is positive for TCC or CIS a more proximal segment of the ureter is resected and FSE is repeated. This procedure is repeated until FSE is negative. In these cases resection of the more proximal ureteral segments may be above the level where the ureter crosses the common iliac artery (see figure). The ureteral segments sent intraoperatively for FSE are later embedded in paraffin (permanent sections) and step sectioned for confirmation of the frozen section findings. The most proximally resected ureteral segments are also embedded in paraffin and step sectioned. The histopathological findings of the ureteral segments taken for FSE are compared to the corresponding permanent sections. The histopathological findings of the ureteral segments sent first for
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Vol. 176, 2409-2413, December 2006 Printed in U.S.A. DOI:10.1016/j.juro.2006.07.162
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FROZEN SECTION EXAMINATION OF URETERAL MARGINS DURING CYSTECTOMY Diagnosis of CIS in the First Ureteral Segments Sent for FSE In 30 of 805 patients (3.7%) CIS was diagnosed on FSE. In 22 (73%) of these patients CIS was confirmed in the corresponding permanent sections. CIS of the most proximal ureteral segment resected was diagnosed in only 1 of these 22 patients (table 1). All of these 22 patients underwent second frozen section examination of a more proximal ureteral segment which revealed CIS in 9. These patients underwent further resection of the ureter with FSE, which then was normal, before completing the ureteroileal anastomosis. In these cases proximal resection of an additional 1 to 2 cm ureteral segment was performed above the common iliac arteries and sent for permanent sections. In 8 of the 30 patients with CIS on FSE no second frozen section was performed, but the more proximal ureteral segments resected were normal on permanent section. These 8 patients had organ confined bladder cancer and none had recurrence in the remaining upper urinary tract after radical cystectomy. Of the 30 patients 24 (80%) with CIS in the first FSE of the ureters were found to have multifocal CIS in the cystectomy specimen or in the previous transurethrally resected bladder tumor material.
Site where intraoperative frozen sections of both ureters were performed and sent for FSE, and where more proximally resected ureteral segments at their crossing with common iliac artery were taken.
FSE are further compared to the more proximal resected ureteral segments. Pathological findings in the urothelium of the ureters are classified as normal, severe atypia, CIS or solid urothelial cancer (TCC). The histopathological results in patients with CIS of the ureter were correlated to the possible presence of concomitant CIS of the bladder. Final pathology was reported according to the TNM classification of 1997.
RESULTS Diagnosis of TCC in the First Ureteral Segments Sent for FSE In 9 of 805 patients (1.1%) TCC was found on frozen section and was confirmed in the corresponding permanent sections in 7 patients (table 1). There was no pathology report on permanent sections for the remaining 2 patients. From preoperative staging examinations (excretory urography and/or computerized tomography) a distal ureteral tumor was diagnosed before radical cystectomy in 4 of these 9 patients. Of these 9 patients 7 had a second FSE performed, which showed TCC in 5. The next, more proximal ureteral segment resected was normal in 3 patients and showed TCC in 4 (table 1). All 7 patients had nonorgan confined bladder cancer on final pathology and in 4 patients multifocal CIS was found in the cystectomy specimen.
Diagnosis of Severe Atypia in the First Ureteral Segments Sent for FSE In 11 of 805 patients (1.4%) severe atypia was diagnosed on FSE (table 1). Of these patients 1 had severe atypia and 2 had CIS in the corresponding permanent sections. The 2 patients with CIS were found to have CIS in the more proximally resected ureteral segments as well. Both had multifocal pT1 G3 and CIS bladder cancer. The 1 patient with severe atypia on permanent sections had no urothelial malignancy in the more proximally resected segments. Diagnosis of Normal Findings in the First Ureteral Segments Sent for FSE In 755 of 805 (94%) patients FSE was diagnosed as normal (table 1). The corresponding permanent sections revealed TCC in 1 (0.1%) and CIS in 5 (0.7%) patients, resulting in a false-negative rate of 0.8% for FSE. The patient with TCC
TABLE 1. Histopathological diagnosis in patients treated with radical cystectomy for TCC of the bladder No./Total No. First Ureteral FSE (%)
No./Total No. Corresponding Permanent Sections (%)
TCC 9/805 (1.1)
TCC 7/9 (78)
CIS 30/805 (3.7)
No information 2/9 (22) CIS 22/30 (73)
Severe atypia 11/805 (1.4) Normal 755/805 (93.8)
Normal 8/30 (27) Severe atypia 1/11 (9) CIS 2/11 (18) Normal 8/11 (73) Normal 710/755 (94) Severe atypia 3/755 (0.4) CIS 5/755 (0.7) TCC 1/755 (0.1) No information 36/755 (4.8)
More Proximal Ureteral Segments (No. pts) TCC (4) Normal (3) Normal (2) CIS (1) Normal (21) Normal (8) Normal (1) CIS (2) Normal (8) Normal (683) Normal (2) CIS (1) Normal (4) CIS (1) Carcinomatous angiosis (1) No information (63)
FROZEN SECTION EXAMINATION OF URETERAL MARGINS DURING CYSTECTOMY
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TABLE 2. Upper urinary tract recurrence and overall survival according to histopathological diagnosis of intraoperative ureteral FSE in patients treated with radical cystectomy for TCC of the bladder Histopathological Classification of First Ureteral FSE
No. Pts According to Histopathological Results of First Ureteral FSE
No. Upper Urinary Tract Recurrence (%)
Median Mos Overall Survival (range)
TCC CIS Severe atypia Normal
9 30 11 755
2 (22) 5 (17)* 2 (18) 22 (3)*
15 (3–180) 32 (2–137) 15 (3–191) 32 (0.4–242)
* Single patient had local recurrence at site of ureteroileal anastomosis.
had carcinomatous angiosis in the most proximally resected ureteral segment. Of the 5 patients with CIS 1 was also found to have CIS in the more proximally resected ureteral segment, whereas this was normal in the other 4 patients. In 3 of 755 patients (0.4%) severe atypia was diagnosed in the paraffin embedded segments. Of these 3 patients 1 had CIS in the more proximally resected ureteral segment. In 36 patients with normal ureteral FSE a pathology report of the permanent sections was not available. None of them had recurrence in the remaining upper urinary tract after radical cystectomy (table 1). Incidence of Ureteral Involvement and Upper Urinary Tract Recurrence Upper urinary tract recurrence was diagnosed in 31 of 805 patients (3.9%) after a median of 30 months (range 2 to 96) (table 2). Median cancer specific survival was 42 months (range 1 to 142). Of these 31 patients 20 (65%) have died of metastatic disease. Of 755 patients with negative first FSE of the most distal ureteral margin 22 (2.9%) had upper urinary tract recurrence after a median of 31 months (range 2 to 86). Upper urinary tract recurrence after radical cystectomy occurred in 5 of 30 patients (16.7%) with CIS diagnosed on the first ureteral FSE. Of these patients 1 had recurrence at the site of ureteroileal anastomosis. Of the 9 patients 2 (22%) with TCC on first ureteral FSE had upper urinary tract recurrence. Median cancer specific survival in the 10 patients with TCC or CIS in the most proximally resected ureteral segments was 13 months (range 2 to 84). Of these 10 patients 7 (70%) have died of systemic metastatic disease.
DISCUSSION Recommendations to perform FSE of the ureteral margins at cystectomy are based on the concept of improved cancer control through FSE by achieving a tumor-free ureterointestinal anastomosis. However, the validity of this approach for reducing upper urinary tract recurrence is controversial. FSE of the ureteral margins has been further questioned because of the false-negative intraoperative results due to the possibility of a pagetoid tumor spread within the ureter, which is only detectable with sequential sectioning and because of the relative rarity (2.4% to 6.6%) of upper urinary tract recurrence after radical cystectomy for TCC of the bladder.5,10 –15 Therefore, the questions remain which patients require FSE of the ureteral margins and to what extent should ureteral resection be performed to obtain a tumor-free ureterointestinal anastomosis. In this study FSE showed TCC, CIS or severe atypia of the first resected ureteral margins close to the bladder in 6.2% of our patients (table 1). These findings are comparable to the results reported by others (table 3). Culp et al reported CIS on FSE of the distal ureters in 13 of 231 patients (6%) undergoing partial or total cystectomy.2 Similar results were reported by Schoenberg et al in a series of 97 patients with 8% urothelial abnormalities ranging from mild atypia to CIS on FSE of the distal ureters.11 Silver et al found a 7.7% (31 of 401) incidence of ureteral abnormalities in the distal ureters sent for FSE in patients treated with radical cystectomy for invasive bladder cancer.12 In patients with positive ureteral FSE for TCC or CIS, the corresponding permanent section was only positive in
TABLE 3. Overview of intraoperative FSE results %
References 2
Culp et al Sharma et al1 Linker and Whitmore13 Herr and Whitmore7 Johnson et al6 Batista et al5 Malkowicz and Skinner4 Schoenberg et al11 Silver et al12 Present study
No. Pts
Multifocal Bladder Ca
Concomitant CIS in Cystectomy Specimen or Previous TUR-BT Material in Pts With Ureteral CIS on FSE
231 205 107 105 403 242 210 97 401 805
Present Not available Not available Present Not available Not available Not available Not available Not available Present
Present Not available Not available Present Not available 85.7 Not available Not available Not available 80
* Overall incidence of urothelial abnormalities.
Urothelial Abnormalities on Ureteral FSE
Histopathological Diagnosis of Corresponding Permanent Sections
Histopathological Diagnosis of Most Proximally Resected Ureteral Segments
17,* 6 (CIS) 8.5 (CIS) 15.7,* 8.7 (CIS) 35 (CIS) 7.2,* 2 (CIS) 5.7 (CIS) Not available 8* 7.7,* 6.2 (CIS) 6.2,* 4.8 (TCC, CIS)
Not available Not available Not available Not available Not available Not available Not available Not available Not available, 3.7 (CIS) 3.6 (TCC, CIS)
Not available Not available Not available 14 (CIS) 6 (CIS, dysplasia) Not available 1.4 (TCC) 4 (CIS) Not available 1.2 (TCC, CIS)
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FROZEN SECTION EXAMINATION OF URETERAL MARGINS DURING CYSTECTOMY
75%. This result may be due to a shedding of CIS cells during ureteral manipulations, nonexistence of CIS in the remaining ureter not sent for FSE or a false-positive diagnosis. However, when FSE is normal the false-negative rate is low, less than 1% in our series. In a series of 401 patients Silver et al questioned the value of intraoperative ureteral FSE as it did not detect CIS in 17% compared to the corresponding permanent sections.12 In the most proximally resected ureteral segment TCC or CIS was found in only 1.2% of our patients. Thus, if resection of the ureters at the level where they cross over the common iliac arteries is performed, there is a high probability of a tumor-free ureterointestinal anastomosis. Furthermore, shortening of the ureters minimizes the risk of strictures of the remaining ureter and the ureterointestinal anastomosis due to ischemia.16 We reported an ureteroileal stricture rate of less than 3% in a consecutive series of 482 patients undergoing radical cystectomy and orthotopic bladder substitution combined with an afferent tubular ileal segment for TCC of the bladder.17 Furthermore, after radiotherapy to the pelvis for malignancies other than bladder cancer before cystectomy, resection of the ureters at the level where they cross with the common iliac arteries has a higher probability of being outside the field of radiation, resulting in a lower risk of ischemic ureteral stenosis.18,19 The incidence of an invasive tumor recurrence at the ureterointestinal anastomosis after radical cystectomy for TCC of the bladder is uncommon, occurring in approximately 1% as reported in the literature.1,5–7,14 In our series of 805 patients only 2 (0.3%) had recurrence at the ureteroileal anastomosis. In 1 patient ureteral FSE was normal whereas in the other patient CIS was diagnosed. He was also found to have concomitant CIS in the bladder. We attribute the low incidence of less than 1% recurrence at the ureteroileal anastomosis to the FSE of the ureteral margins at radical cystectomy, which in instances of a positive result led to further FSE. Another reason is the routine second ureteral resection at the level where it crosses the common iliac artery. In a series of 17 patients with CIS on ureteral FSE Sharma et al reported only 1 ureteroileal recurrence.1 They stated that the prevalence of ureteral CIS was highest (19.6%) in patients with multifocal bladder cancer and concomitant CIS. Similarly Johnson et al reported that FSE of the ureters is only indicated in patients with multifocal CIS of the bladder or prostatic tumor involvement, which is in accordance with our findings.6 Opponents of FSE of the ureteral margins argued that given the low incidence of upper urinary tract recurrence of 2.4% to 6.6% and the even rarer incidence of an anastomotic recurrence, it is unlikely that FSE of the ureteral margins will have an impact on upper urinary tract recurrence and long-term survival.4,10,14,15,20,21 However, our results show that patients with negative histology in the distal ureteral segments are at a 3% risk of upper urinary tract recurrence, whereas patients with CIS on FSE are at a 17% risk. Nevertheless, it must be kept in mind that the majority of these patients ultimately die of systemic disease.
(80%). If ureteral CIS is diagnosed then there is a 5-fold risk of upper urinary tract recurrence after radical cystectomy for TCC of the bladder. Except for patients with CIS in the bladder, FSE of the ureters is not necessary if the ureters are resected at the level where they cross the common iliac vessels.
Abbreviations and Acronyms CIS ⫽ carcinoma in situ FSE ⫽ frozen section examination TCC ⫽ transitional cell carcinoma
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8. 9.
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11.
12.
13. 14.
CONCLUSIONS TCC and CIS are found in the most distal ureter in 4.8% and at the iliac cross in 1.2% of our patients, respectively. Most patients with CIS in the ureter have CIS in the bladder
15.
Sharma, T. C., Melamed, M. R. and Whitmore, W. F., Jr.: Carcinoma in-situ of the ureter in patients with bladder carcinoma treated by cystectomy. Cancer, 26: 583, 1970 Culp, O. S., Utz, D. C. and Harrison, E. G., Jr.: Experiences with ureteral carcinoma in situ detected during operations for vesical neoplasm. J Urol, 97: 679, 1967 Cooper, P. H., Waisman, J., Johnston, W. H. and Skinner, D. G.: Severe atypia of transitional epithelium and carcinoma of the urinary bladder. Cancer, 31: 1055, 1973 Malkowicz, S. B. and Skinner, D. G.: Development of upper tract carcinoma after cystectomy for bladder carcinoma. Urology, 36: 20, 1990 Batista, J. E., Palou, J., Iglesias, J., Sanchotene, E., da Luz, P., Algaba, F. et al: Significance of ureteral carcinoma in situ in specimens of cystectomy. Eur Urol, 25: 313, 1994 Johnson, D. E., Wishnow, K. I. and Tenney, D.: Are frozensection examinations of ureteral margins required for all patients undergoing radical cystectomy for bladder cancer? Urology, 33: 451, 1989 Herr, H. W. and Whitmore, W. F., Jr.: Ureteral carcinoma in situ after successful intravesical therapy for superficial bladder tumors: incidence, possible pathogenesis and management. J Urol, 138: 292, 1987 Turner, W. H. and Studer, U. E.: Cystectomy and urinary diversion. Semin Surg Oncol, 13: 350, 1997 Kessler, T. M., Burkhard, F. C., Perimenis, P., Danuser, H., Thalmann, G. N., Hochreiter, W. W. et al: Attempted nerve sparing surgery and age have a significant effect on urinary continence and erectile function after radical cystoprostatectomy and ileal orthotopic bladder substitution. J Urol, 172: 1323, 2004 Balaji, K. C., McGuire, M., Grotas, J., Grimaldi, G. and Russo, P.: Upper tract recurrences following radical cystectomy: an analysis of prognostic factors, recurrence pattern and stage at presentation. J Urol, 162: 1603, 1999 Schoenberg, M. P., Carter, H. B. and Epstein, J. I.: Ureteral frozen section analysis during cystectomy: a reassessment. J Urol, 155: 1218, 1996 Silver, D. A., Stroumbakis, N., Russo, P., Fair, W. R. and Herr, H. W.: Ureteral carcinoma in situ at radical cystectomy: does the margin matter? J Urol, 158: 768, 1997 Linker, D. G. and Whitmore, W. F.: Ureteral carcinoma in situ. J Urol, 113: 777, 1975 Hautmann, R. E., Volkmer, B. G., Schumacher, M. C., Gschwend, J. E. and Studer, U. E.: Long-term results of standard procedures in urology: the ileal neobladder. World J Urol, 24: 305, 2006 Sved, P. D., Gomez, P., Nieder, A. M., Manoharan, M., Kim, S. S. and Soloway, M. S.: Upper tract tumour after radical
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cystectomy for transitional cell carcinoma of the bladder: incidence and risk factors. BJU Int, 94: 785, 2004 Stenzl, A., Bartsch, G. and Rogatsch, H.: The remnant urothelium after reconstructive bladder surgery. Eur Urol, 41: 124, 2002 Studer, U. E., Burkhard, F. C., Schumacher, M. C., Kessler, T. M., Thoeny, H., Fleischmann, A. et al: Twenty years experience with an ileal orthotopic low pressure bladder substitute–lessons to be learned. J Urol, 176: 161, 2006 Kim, H. L. and Steinberg, G. D.: Complications of cystectomy in patients with a history of pelvic radiation. Urology, 58: 557, 2001 Maier, U., Ehrenbock, P. M. and Hofbauer, J.: Late urological complications and malignancies after curative radiotherapy for gynecological carcinomas: a retrospective analysis of 10,709 patients. J Urol, 158: 814, 1997 Zincke, H., Garbeff, P. J. and Beahrs, J. R.: Upper urinary tract transitional cell cancer after radical cystectomy for bladder cancer. J Urol, 131: 50, 1984 Kenworthy, P., Tanguay, S. and Dinney, C. P.: The risk of upper tract recurrence following cystectomy in patients with transitional cell carcinoma involving the distal ureter. J Urol, 155: 501, 1996
EDITORIAL COMMENT Risk factors for upper tract recurrence following radical cystectomy are documented in this study as a history of diffuse CIS, multifocal tumor, intramural tunnel or juxtavesical ureteral involvement with CIS, or a prior ureteral tumor (references 6, 11 and 12 in article). The initial impetus for frozen section analysis was to ensure a cancer-free anastomosis, which theoretically would translate into reduced upper tract recurrence rates and longer cancer-free
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survival. However, controversy remains concerning the usefulness of ureteral margin frozen section analysis in achieving these goals due to the rarity of upper tract recurrence (3.9% in this study) and, in particular, anastomotic recurrence (2 of 805 or 0.3% in this study and 2 of 31 or 6% of the total upper tract recurrence), the typical pagetoid spread of CIS (negative margin does not guarantee CIS is not higher up), the inaccuracy of frozen section analysis, and the disparity in pathological interpretation of atypia, dysplasia and CIS (references 6, 11 and 12 in article). This study confirms the rate of upper tract recurrence is higher in those with risk factors (17% vs 3%) and routine division of the ureters at the mid common iliac artery would decrease the risk of a positive ureteral margin in patients with risk factors for upper tract recurrence. However, negative ureteral margins did not result in a decrease in upper tract recurrence rate or improve survival. In addition, the study does not show how frozen section analysis at the level of the mid common iliac ureter would add anything to the simple division of the ureter at this level in all patients given the low incidence of anastomotic recurrence. The data confirm the risk factors for upper tract recurrence and lower ureteral involvement up to the level of the common iliac artery, and should be considered when selecting patients for minimally invasive extracorporeal diversions in which a greater ureteral length is needed. S. Machele Donat Department of Urology Memorial Sloan-Kettering Cancer Center New York, New York