The clinical significance of intraop ureteral FSA at RC (2014.5 World J Urol)

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World J Urol (2015) 33:359–365
DOI 10.1007/s00345-014-1306-5
ORIGINAL ARTICLE
The clinical significance of intra‑operative ureteral frozen section
analysis at radical cystectomy for urothelial carcinoma of the
bladder
Hyung Suk Kim · Kyung Chul Moon ·
Chang Wook Jeong · Cheol Kwak · Hyeon Hoe Kim ·
Ja Hyeon Ku
Received: 11 February 2014 / Accepted: 17 April 2014 / Published online: 14 May 2014
© Springer-Verlag Berlin Heidelberg 2014
Intramural tumor invasion was correlated with ureteral
involvement on both FSA and PSA (p < 0.05). There was
no correlation between upper urinary tract (UUT) recur-
rence and ureteral involvement on FSA and PSA. Positive
FSA and PSA were not risk factors associated with overall
and cancer-specific survival (CSS) on multivariate analysis.
Conclusions Intra-operative FSA can reasonably detect
ureteral involvement. However, a relatively high false-posi-
tive rate (44 %) may be problematic and has the likelihood
to overestimate disease at the ureteral margin. Overall,
routine FSA of the ureters shows no correlation with UUT
recurrence as well as overall and CSS.
Keywords Bladder cancer · Urothelial carcinoma ·
Radical cystectomy · Ureteral margin · Frozen section
analysis
Introduction
Because urothelial carcinoma is associated with a panepi-
thelial field defect, tumors may occur anywhere in the uri-
nary tract after treating an initial carcinoma. Several studies
have reported an incidence of intravesical disease ranging
from 15 to 50 % after nephroureterectomy for upper uri-
nary tract (UUT) carcinoma [1], while patients undergoing
radical cystectomy develop UUT carcinoma in approxi-
mately 3 % of cases [2]. Some studies demonstrated that
the occurrence of UUT carcinoma after radical cystectomy
is associated with multiple clinical and pathologic risk fac-
tors, including association with carcinoma in situ (CIS) and
tumor disease in the distal ureter [3–7].
Accordingly, intra-operative ureteral frozen section anal-
ysis (FSA) during radical cystectomy for bladder cancer
has been performed routinely by many surgeons to prevent
Abstract
Purpose To evaluate the clinical significance of intra-
operative ureteral frozen section analysis (FSA) at the time
of radical cystectomy.
Materials and methods A total of 402 patients underwent
radical cystectomy for urothelial carcinoma of the bladder
at our institution from January 1991 to December 2011.
Except for 35 ureters who underwent nephroureterectomy,
769 ureters were finally identified. Among these, FSA was
performed at 645 ureters (83.8 %). If the first FSA result
was positive for malignancy (carcinoma in situ or carci-
noma) or demonstrated atypia or dysplasia, sequential ure-
teral resection was undertaken until normal urothelium was
identified, when possible.
Results A total of 54 ureters (8.4 %) of 46 patients
(11.2 %) had ureteral involvement (positive) on the
first FSA. On permanent section analysis (PSA), ure-
teral involvement was noted in 40 ureters (6.2 %) of 35
patients (8.7 %). The sensitivity, specificity, and accuracy
of FSA were approximately 75, 96, and 95 %, respectively.
Electronic supplementary material The online version of this
article (doi:10.1007/s00345-014-1306-5) contains supplementary
material, which is available to authorized users.
H. S. Kim · C. W. Jeong · C. Kwak · H. H. Kim · J. H. Ku
Department of Urology, Seoul National University College
of Medicine, Seoul, Korea
K. C. Moon
Department of Pathology, Seoul National University College
of Medicine, Seoul, Korea
J. H. Ku (*)
Department of Urology, Seoul National University Hospital, 101
Daehak-ro, Jongno-gu, Seoul 110-744, Korea
e-mail: randyku@hanmail.net; kuuro70@snu.ac.kr

360 World J Urol (2015) 33:359–365
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UUT recurrence and improve survival after radical cystec-
tomy. Theoretically, intra-operative FSA can identify distal
ureteral margin status and enables surgeons to ensure can-
cer-free ureterointestinal anastomosis.
However, controversy remains about whether ureteral
FSA practically achieves these goals. The aim of the cur-
rent study was to investigate the accuracy of ureteral FSA,
controlled by ureteral permanent section analysis (PSA),
in patients with bladder cancer, and to evaluate the clinical
significance of intra-operative ureteral FSA through cor-
relation analysis with the outcome endpoints such as UUT
recurrence as well as overall survival (OS) and cancer-spe-
cific survival (CSS).
Materials and methods
We reviewed 415 patients who underwent radical cystec-
tomy with pelvic lymph node dissection for bladder cancer
in our institution from January 1991 through June 2011.
Indications for radical cystectomy included recurrent blad-
der cancer that was unresponsive to repeated tumor resec-
tion and intravesical therapy, or invasive bladder tumors. A
total of 13 patients with histology other than urothelial car-
cinoma (adenocarcinoma, squamous cell carcinoma, signet
ring cell carcinoma, and lymphoepithelial carcinoma) were
excluded. Eventually, the subjects of study cohort consisted
of 402 patients with urothelial carcinoma of the bladder.
The collection of data has been described previously [8,
9]. Accessed variables included clinical parameters, such
as age, gender, previous nephroureterectomy, concurrent
nephroureterectomy, neoadjuvant chemotherapy, adjuvant
chemotherapy, and pathological parameters including path-
ologic stage, pathologic grade, associated CIS, lympho-
vascular invasion, intramural invasion, perineural invasion,
lymph node status, and urethral involvement (Table 1).
Pathologic stage was assigned according to the 2002 World
Health Organization Tumor–Node–Metastasis Classifica-
tion of 6th American Joint Committee on Cancer [10].
The decision to evaluate ureters before constructing the
ureterointestinal anastomosis was made by the surgeon on
a case-by-case basis. The distal ends of the ureters were
sent for FSA and later embedded in paraffin for subse-
quent PSA. Pathologic findings for resected distal ureteral
segment were classified as normal, atypia, dysplasia, CIS,
and urothelial carcinoma. Ureteral involvement (positive)
on FSA and PSA was defined if pathologic findings were
described as atypia, dysplasia, CIS, or urothelial carci-
noma. Only the first ureteral segments sent for FSA were
compared with the corresponding PSA. Regarding PSA
results as the reference standard, the sensitivity, specific-
ity, and overall accuracy of FSA were examined. If the first
FSA result was positive for malignancy (CIS or carcinoma)
or demonstrated atypia or dysplasia, sequential ureteral
resection was undertaken until normal urothelium was
identified, when possible. The criteria for the exact extent
of sequential ureteral resection were not established, but
Table 1 Clinicopathological parameters of the study cohort
Variables
Age, mean (interquartile range) 62.2 (57–69)
<60 years 139 (34.6 %)
≥60 years 263 (65.4 %)
Gender
Male 356 (88.6 %)
Female 46 (11.4 %)
Pathologic T stage
pT0 45 (11.2 %)
pTa/is/1 122 (30.3 %)
pT2 76 (18.9 %)
pT3/4 159 (39.6 %)
Tumor grade
Low grade 66 (16.4 %)
High grade 296 (73.6 %)
Unknown 40 (10.0 %)
Associated carcinoma in situ
Absent 309 (76.9 %)
Present 93 (23.1 %)
Lymphovascular invasion
Absent 266 (66.2 %)
Present 136 (33.8 %)
Perineural invasion
Absent 345 (85.8 %)
Present 57 (14.2 %)
Intramural invasion
Absent 270 (67.2 %)
Present 132 (32.8 %)
Lymph node status
N0 316 (76.1 %)
N1 35 (8.4 %)
N2 47 (11.3 %)
N3 4 (1.0 %)
Urethral involvement
Absent 393 (97.8 %)
Present 9 (2.2 %)
Neoadjuvant chemotherapy
Not done 355 (88.3 %)
Done 41 (10.2 %)
Unknown 6 (1.5 %)
Adjuvant chemotherapy
Not done 288 (71.6 %)
Done 113 (28.1 %)
Unknown 1 (0.3 %)

361World J Urol (2015) 33:359–365
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sequential ureteral resection was performed lest the length
of remaining ureter after repetitive resection should be too
short to connect with the intestine. The results of sequen-
tial ureteral resection were classified as initial negative (no
require further resection), conversion into uninvolved mar-
gin (negative conversion), and conversion into involved
margin (no negative conversion).
After the possible risk factors for ureteral involvement
on FSA and PSA were identified by univariate analysis,
multivariate logistic regression analysis was conducted for
the evaluation of definitive significant risk factors. Cor-
relation was considered significant when the p value was
<0.05. Outcome endpoints included UUT recurrence, OS,
and CSS. These endpoints were correlated, respectively,
with clinical and pathological parameters including FSA
and PSA results. Univariate Kaplan–Meier analysis with
log-rank test was undertaken for identification of associated
risk factors. Then, using Cox proportional hazards analy-
sis, eventual risk factors were evaluated. Likewise, p value
<0.05 was considered statistically significant.
Results
Of 402 patients, except for 20 patients who had undertaken
nephroureterectomy prior to radical cystectomy and 15
patients who underwent nephroureterectomy simultane-
ously during radical cystectomy, a total of 769 ureters were
finally identified. Of these ureters, FSA was performed at
645 ureters (83.8 %) including 326 right and 319 left ure-
ters. On the first FSA, ureteral involvement was identified
in 54 ureters (8.4 %) of 46 patients consisting of 38 uni-
lateral and 8 bilateral. Pathologic findings were 14 with
atypia, 15 with dysplasia, 11 with CIS, and 14 with urothe-
lial carcinoma (Table 2).
On PSA, 40 ureters (6.2 %) of 35 patients (8.7 %) (con-
sisting of 30 unilateral and 5 bilateral) revealed evidence
of ureteral involvement, including five with dysplasia, 18
with CIS, and 17 with urothelial carcinoma. Considering
permanent section as the reference standard, the sensitivity,
specificity, and overall accuracy of FSA evaluated were 75,
96, and 95 %, respectively, while the false-positive rate was
approximately 44 %, which was relatively high (Table 3).
When defining ureteral involvement as only the cases
presenting malignant finding (CIS or carcinoma) on FSA
and PSA, the sensitivity, specificity, and overall accuracy
rate of FSA evaluated were 69, 99, and 98 %, respectively,
similar to precedent result. However, the false-positive rate
was approximately 4 %, which was much lower than the
prior result (Table 4).
Of 54 ureters presenting positive finding on the first
FSA, further sequential ureteral resection was undertaken
in 41 ureters of 37 patients. As a result, the number of ure-
ters converted into negative margin was 32 ureters of 28
patients, and the conversion rate was just 59 %. Among
nine patients who showed no negative conversion through
sequential ureteral resection, only one patient underwent
nephroureterectomy owing to repeated CIS on the left ure-
teral margin.
Univariate analysis results for evaluating the risk factors
associated with ureteral involvement on initial FSA and
PSA were that common significant risk factors were nodal
involvement, intramural tumor invasion within bladder, and
prostate/uterus invasion (Supplemental Table 1). Multivari-
ate analysis was undertaken with the risk factors identified
by univariate analysis. The common significant risk factor
in both FSA and PSA was intramural tumor invasion within
bladder (p = 0.007 and p = 0.014, respectively) (Table 5).
Of the 402 patients, UUT recurrence after radical cys-
tectomy occurred at 11 patients (2.7 %). The location
and laterality of recurred tumors included one patient
in the right renal pelvis, three patients in the right ureter,
four patients in the left renal pelvis, one patient in the left
Table 2 Results of the first frozen section analysis
Right ureter Left ureter Total
Uninvolvement 295 296 519
Involvement
Atypia/dysplasia 17 (9/8) 12 (5/7) 29
Carcinoma in situ 7 4 11
Urothelial carcinoma 7 7 14
Table 3 Comparison of the results between frozen and permanent
section analysis
First frozen section analysis
Positive Negative Total
Permanent section analysis
Positive 30 (True positive) 10 (False negative) 40
Negative 24 (False positive) 581 (True negative) 605
Total 54 591 645
Table 4 Comparison of the malignant findings between frozen and
permanent section analysis
Malignancy on the first frozen section analysis
Positive Negative Total
Malignancy on permanent section analysis
Positive 24 (True positive) 11 (False negative) 35
Negative 1 (False positive) 609 (True negative) 610
Total 25 620 645

362 World J Urol (2015) 33:359–365
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ureter, one patient in the right renal pelvis and ureter, and
one patient on the left ureterointestinal anastomosis site.
Among these recurred patients, intra-operative ureteral
FSA was undertaken at 10 patients. Two patients of five
right-side recurred patients showed ureteral involvement on
initial FSA, which were atypia on the left and right ureteral
margin, respectively. One patient of six left-side recurred
patients showed dysplasia finding on initial FSA for the
right ureteral margin. For these three patients, further
sequential ureteral resection was performed. As a result,
two patients were converted into negative ureteral margin,
but one patient of these and the remaining one patient with
no negative conversion died of metastatic carcinoma at the
final follow-up. Of all recurred patients, nephroureterec-
tomy for nine patients and right ureteral segmental exci-
sion for one patient who had received simultaneously left
nephroureterectomy during radical cystectomy were under-
taken, respectively. Overall, of 11 patients who had UUT
recurrence, five (45.4 %) finally died, four of metastatic
carcinoma. In this study cohort, there were a total of 154
deaths with a median of 21 months (IQR 10–38), and 108
patients (70 %) of these were cancer-specific death with a
median of 28 months (IQR 13–37). Both ureteral involve-
ment on initial FSA and PSA and the results of sequential
ureteral resection were not significant predictors correlated
with UUT recurrence after radical cystectomy by univari-
ate analysis. Besides, there was no significant correlation
between UUT recurrence and other clinicopathological
parameters (Supplemental Table 2).
On univariate analysis, ureteral involvement on initial
FSA and PSA was a significant predictor associated with
OS and CSS (Fig. 1), and conversion to involved margin of
the sequential ureteral resection, results showed a signifi-
cant correlation with CSS, respectively (Fig. 2), but there
were no significant correlations by multivariate analysis.
Discussion
The aim to perform FSA at radical cystectomy for the blad-
der cancer is to achieve cancer-free anastomosis by ensur-
ing the safety margin through identification of distal ure-
teral margin status, which should prevent tumor recurrence
at UUT as well as ureterointestinal anastomosis site, and
further improve OS and CSS. Given that characteristics of
urothelial cancer such as multifocal development from dif-
fusely susceptible urothelium, although intra-operative dis-
tal ureteral margin was identified as negative, the probability
of UUT recurrence following radical cystectomy cannot be
excluded completely. Accordingly, the clinical significance
of intra-operative FSA has been controversial as previ-
ously reported [11–14]. Other issues that further make the
analyses difficult include the relative rarity (2.4–6.6 %) of
UUT recurrence after radical cystectomy for bladder cancer
[2–4], and low incidence (0.7–2.6 %) of concomitant UUT
tumor with bladder cancer [15].
In our study, ureteral involvement on the first FSA was
noted in 8.4 % of the ureters and 11.4 % of all patients.
The incidence was similar to the data previously reported
as 2–9 % [14, 16–19]. We included non-malignant find-
ing such as atypia and dysplasia as the criteria of ureteral
involvement as well as malignant finding such as CIS and
urothelial carcinoma. Likewise, the previous studies apply-
ing the criteria similar to our study reported the incidence
Table 5 Multivariate analysis
results for evaluating the risk
factors associated with ureteral
involvement on the first frozen
and permanent section analysis
FSA frozen section analysis,
PSA permanent section analysis,
OR odds ratio, CI confidence
interval
Ureteral involvement on the first FSA Ureteral involvement on the PSA
Adjusted OR (95 % CI) p value Adjusted OR (95 % CI) p value
Associated carcinoma in situ
Absent Reference
Present 11.1 (2.30–54.03) 0.003
Intramural invasion
Absent Reference Reference
Present 2.17 (1.05–4.49) 0.036 7.82 (1.97–31.04) 0.003
Lymph node status
Negative (N0) Reference Reference
Positive (N1/2/3) 1.50 (0.67–3.35) 0.317 5.01 (1.19–21.03) 0.028
Prostate/uterus involvement
Absent Reference Reference
Present 2.63 (1.14–6.07) 0.023 2.82 (0.68–11.67) 0.152
Ureteral involvement on FSA
Negative Reference
Positive 177.91 (36.27–872.67) <0.001

363World J Urol (2015) 33:359–365
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of 9.9, 9, and 8 %, respectively [11, 13, 17]. Cooper et al.
[20] reported that severe atypia was commonly found at the
urothelium of ureter, bladder, and urethra and was observed
as the precursor of carcinoma at approximately 35 % of
poorly differentiated urothelial carcinoma. In the present
study, due to the retrospective nature of our study, we could
not grasp what the degree of atypia was and whether the
degree of atypia was correlated with outcome endpoints.
The results of FSA defining ureteral involvement as only
the malignant finding (CIS or carcinoma) were 3.9 % of the
ureters and 5.2 % of all patients. Only the intramural tumor
invasion, which is defined as tumor invasion of juxtavesi-
cal or terminal ureter, at radical cystectomy specimen was
finally identified as a common significant risk factor associ-
ated with ureteral involvement on both FSA and PSA by
multivariate analysis. In our study, bladder CIS was a sig-
nificant risk factor related to ureteral involvement on PSA
by uni- and multivariate analysis. Among patients with
bladder CIS at the radical cystectomy specimen, the inci-
dence of ureteral involvement was 21.3 %, compared with
an incidence of only 6.9 % among patients without bladder
CIS. Similarly, several of the previous studies commented
Fig. 1 Overall and cancer-specific survival of bladder cancer according to ureteral involvement on initial frozen section analysis (a, c) and per-
manent section analysis (b, d). FSA frozen section analysis, PSA permanent section analysis

364 World J Urol (2015) 33:359–365
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bladder CIS as the risk factor correlated with ureteral
involvement on FSA or PSA [11, 13, 21].
Our study showed reasonable results with sensitiv-
ity of 75 %, specificity of 96 %, and overall accuracy of
96 % of intra-operative FSA in the detection of ureteral
involvement. Also, FSA results had a strong correlation
with PSA results. These findings generally corresponded to
the results of previous reports [11–13]. However, the rela-
tively high false-positive rate of 44 % in our study may be
a concern, which may have the tendency to overestimate
ureteral margin status. Naji et al. [11] also reported a false-
positive rate of 36 % similar to our study. For the purpose
of reducing false-positive rate, we re-evaluated by defining
ureteral involvement as only malignant finding such as CIS
or urothelial carcinoma on FSA and PSA and were able to
gain false-positive rate of 4 %, much lower than precedent
result.
According to previously published articles, the inci-
dence of UUT recurrence after radical cystectomy has been
reported as 2.4–6.6 % [2–4]. In particular, the incidence of
tumor recurrence at the ureterointestinal anastomosis site is
very rare, occurring in approximately 1 % as reported in
the literature [4–7]. In our study, the incidence of UUT and
ureterointestinal anastomotic recurrence after radical cys-
tectomy was 2.7 % (11 patients) and 0.2 % (only 1 patient),
respectively. The patient with tumor recurrence at the
ureterointestinal anastomosis site showed a negative find-
ing on initial FSA for both ureteral margins, but presented
dysplasia finding on further PSA for the right ureteral mar-
gin. Overall, of 11 patients who had UUT recurrence, five
(45.4 %) finally died, and four patients of these died of met-
astatic urothelial carcinoma. However, ureteral involvement
on FSA and PSA was not a significant predictor associ-
ated with UUT recurrence. Unlike our study, Raj et al. [13]
demonstrated ureteral involvement on FSA or PSA was a
significant predictor for UUT recurrence after radical cys-
tectomy. The lack of significance in our study could be due
to the small number of events (11 recurred patients), lead-
ing to lack of statistical power. However, it is noteworthy
that, among these 11 patients, three patients (approximately
27.3 %) showed ureteral involvement on the first FSA. This
hypothesis of a lack of statistical power is consistent with
the results of the univariate analysis (Supplement Table 2),
in which no potential predictive clinicopathological factors
were significantly associated with UUT recurrence.
The results of correlation analysis between ureteral FSA
and outcome endpoints including OS and CSS showed no
correlation on multivariate analysis controlling the impact
of other factors. Raj et al. [13] likewise reported neither
evidence of ureteral involvement nor ureteral margin status
on FSA or PSA was a significant predictor of OS. It was
also demonstrated in a multicenter study that the ureteric
positive surgical margin at the radical cystectomy specimen
showed no significant association with survival outcomes,
such as 5-year local recurrence-free survival, metastatic
recurrence-free survival, and CSS [22].
The conversion rate into uninvolved margin through
sequential ureteral resection was 59 %, lower than expected.
Because this study cohort consisted of the patients who
underwent radical cystectomy by various surgeons, the
lack of uniformity may be a concern in the selection and
management of ureter on FSA, which would be affected as
the limitation of our study. For instance, as to the manage-
ment of ureters at the intra-operative FSA, further ureteral
resection was not undertaken in several patients presenting
atypia or dysplasia on the first FSA, and there was no uni-
fied criteria concerning to what extent should further ure-
teral resection be performed to obtain uninvolved ureteral
margin. Even though it is successfully performed, the pos-
sibility of UUT recurrence after radical cystectomy is not
excluded completely. These conclusions are also supported
by previous studies [13, 17, 21]. Moreover, the influence
of sequential ureteral resection on survival outcome may
be insignificant, which is also supported by the results of
our study. Contrary to our study, Schumacher et al. [14]
reported in the case of undergoing further ureteral resection
en bloc by the level of common iliac artery bifurcation, the
incidence of malignancy on ureteral margin was four times
lower (1.2 %) than that without further resection.
Our study results have failed to document the definite
evidence to prove the clinical significance of intra-operative
FSA. There may be several possible causes of this result.
First, the current study was only based on a retrospective
Fig. 2 Cancer-specific survival of bladder cancer according to
sequential ureteral resection results

365World J Urol (2015) 33:359–365
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review, which could have resulted in a bias with regard to
intra-operative ureteral selection and management. Second,
this study was based on a small cohort with a small number
of cases. Therefore, we suggest further multi-institution,
large prospective studies are necessary to confirm the util-
ity and clinical significance of intra-operative FSA during
radical cystectomy.
Conclusions
Routine FSA at the time of radical cystectomy for urothe-
lial carcinoma of the bladder can accurately detect ure-
teral involvement with reliable sensitivity and specific-
ity. However, owing to relatively high false-positive rate,
there may be a tendency to overestimate distal ureteral
margin status. Definite correlation is not found between
FSA results including sequential ureteral resection results
and outcome endpoints including UUT recurrence as well
as OS and CSS. Therefore, intra-operative FSA may be
proposed selectively in some patients who show specific
findings, such as intramural tumor invasion within the
bladder, CIS within bladder, nodal involvement, and pros-
tate/uterus invasion, which are likely to increase the pos-
sibility of ureteral involvement. Further multi-institution,
large-scale prospective studies should be necessary to
confirm the utility and clinical significance of intra-oper-
ative FSA.
Conflict of interest None.
Ethical standards This study design and the use of patients’ infor-
mation stored in the hospital database were approved by the Institu-
tional Review Board (IRB) at the Seoul National University Hospital.
The approval number is H-1401-074-550. We were given exemp-
tion from getting informed consents by the IRB because the present
study is a retrospective study and personal identifiers were completely
removed and the data were analyzed anonymously. Our study was
conducted according to the ethical standards laid down in the 1964
Declaration of Helsinki and its later amendments.
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