Accurate preoperative prediction of

BJUI BJU INTERNATIONAL

non-organ-confined bladder urothelial
carcinoma at cystectomy
David A. Green1, Michael Rink1,2, Jens Hansen2,3, Eugene K. Cha1,
Brian Robinson4, Zhe Tian3, Felix K. Chun2, Scott Tagawa1,5,6,
Pierre I. Karakiewicz3, Margit Fisch2, Douglas S. Scherr1,6 and
Shahrokh F. Shariat1,5
1
Department of Urology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA;
2
Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3Cancer Prognostics
and Health Outcomes Unit, University of Montreal Health Center, Montréal, Québec, Canada; 4Department of
Pathology, 5Division of Hematology and Medical Oncology, and 6Weill Cornell Cancer Center, Weill Cornell Medical
College, New York Presbyterian Hospital, New York, NY, USA
Accepted for publication 19 April 2012
D.A.G. and M.R. contributed equally.

Study Type – Prognosis (case series)
Level of Evidence 4
OBJECTIVE
• To create an accurate pre-cystectomy
decision-making tool that allows for the
accurate identification of patients with
clinically organ-confined urothelial
carcinoma of the bladder (UCB) who have
non-organ-confined UCB (NOC-UCB) at
cystectomy, as identification of patients
with UCB most likely to benefit from
neoadjuvant chemotherapy (NACTx) is
hampered by inaccurate clinical staging.
PATIENTS AND METHODS
• A prospectively maintained single-
institution database containing 201
patients who underwent cystectomy and
pelvic lymph node (LN) dissection without
NACTx for UCB was analysed.
• Predictive variables for NOC-UCB
included, among others, age, gender,
transurethral resection of bladder tumour
(TURBT) findings (stage, grade, histology,
size, presence of carcinoma in situ,
lymphovascular invasion [LVI],
multifocality), history of intravesical
therapy, time from TURBT to cystectomy,
and cross-sectional imaging findings.
What’s known on the subject? and What does the study add?
Upstaging to non-organ-confined (NOC) disease is frequent at the time of radical
cystectomy for urothelial carcinoma of the bladder (UCB). Pre-surgical models that can
accurately predict which patients are likely to have more extensive disease are sparse.
The present study developed an accurate nomogram for the prediction of NOC-UCB
based on a cohort of patients with clinically organ-confined disease. Adoption of such
a tool into daily clinical decision-making may lead to more appropriate integration of
perioperative chemotherapy, thereby potentially improving survival in patients with
UCB.
RESULTS highly accurate (area under the curve
0.828) and well calibrated, deviating <8%
• Clinical stage distribution was 19 from ideal prediction. Decision curve
patients with Ta, 15 with Tis, 67 with T1, analysis showed net benefit across all
and 100 with T2. threshold probabilities.
• At the time of cystectomy, NOC-UCB and
LN-positive disease were found in 71 (35%) CONCLUSIONS
and 38 (19%) of patients, respectively;
81 (40%) of patients had NOC-UCB (≥pT3/ • NOC-UCB can be predicted with high
Nany or pTany/N+). accuracy by integrating standard
• Tumour stage (P [trend] <0.001), clinicopathological factors with imaging
presence of LVI (odds ratio [OR] 5.2; information.
P = 0.02), and radiographic evidence • This model may help to identify patients
of NOC-UCB or hydronephrosis (OR 3.2; with NOC-UCB who may benefit from
P = 0.01) were independently associated NACTx.
with ≥pT3 Nany UCB.
• Tumour stage (P [trend] < 0.001) and KEYWORDS
presence of LVI (OR 6.64; P = 0.01) were
independently associated with (≥ pT3/Nany bladder cancer, urothelial carcinoma of
or pTany/N+) UCB. bladder, radical cystectomy, non-organ-
• A nomogram to predict (≥ pT3/Nany or confined (extravesical), lymph node,
pTany/N+) based on all three variables was predictive model

© 2 0 1 2 B J U I N T E R N A T I O N A L | doi:10.1111/j.1464-410X.2012.11370.x 1
GREEN ET AL.
INTRODUCTION
Radical cystectomy with bilateral pelvic
lymph-node dissection (PLND) is the
mainstay therapy for non-metastatic
high-risk non-muscle-invasive and
muscle-invasive urothelial carcinoma of
the bladder (UCB), resulting in durable
oncological control and long-term survival
for most patients with organ-confined UCB.
However, 42–44% of patients without lymph
node (LN) metastases but with disease
extending to the perivesical fat and 65–67%
of those with regional LN metastases have
disease recurrence ≤5 years after cystectomy
[1,2]. Disease recurrence often manifests as
distant metastases [2], suggesting a high
prevalence of early systemic dissemination.
Level I evidence supports the use of
neoadjuvant chemotherapy (NACTx) for
clinical (c) T2–T4aN0M0 UCB [3]. However,
to date, NACTx has been seldom used in the
general community and may indeed be less
commonly used than adjuvant
chemotherapy. A recent multi-institutional
study reported that only 12% of patients
with cT2–T4aN0M0 received NACTx, whereas
22% received adjuvant systemic
chemotherapy [4]. The exact reasons for
these practice patterns remain unclear, but
under-usage of NACTx may be due to the
belief that cystectomy alone will cure a
significant proportion of patients who
would incur unnecessary and avoidable
side-effects of overtreatment with NACTx.
The mainstay of clinical staging for UCB, an
integration of pathological examination of
the transurethral resection (TUR) specimen,
bimanual physical examination, and
cross-sectional imaging studies, is highly
inaccurate [5]. It is not infrequent to find
that the clinical stage is discordant with the
pathological stage at cystectomy, with
pathological upstaging to ≥ pT3 and/or N+
disease occurring in up to 60% of patients
[6–10]. Current predictive tools, e.g.
nomograms, which are commonly used for
outcome prediction in prostate cancer, do
not substantially improve prediction of
non-organ-confined (NOC)-UCB in patients
with clinically organ-confined disease
[11,12]. This is in part due to the fact that
they rely only on clinical stage and grade.
More accurate clinical staging would allow
for the selection of patients most likely to
benefit from NACTx, thereby possibly
2 ©
resulting in wider adoption of this therapy
by the urology community, potentially
improving survival. Therefore, our primary
objective was to develop a preoperative
multivariable model, integrating clinical,
pathological, and imaging variables to
accurately identify patients with clinically
organ-confined UCB who are at increased
risk for pathologically NOC-UCB. We
hypothesised that NOC-UCB could be
predicted with reasonable accuracy.
PATIENTS AND METHODS
After Institutional Review Board approval,
we retrospectively reviewed all prospectively
collected data for 296 consecutive patients
with bladder cancer who were treated with
radical cystectomy or partial cystectomy and
bilateral PLND. We excluded patients who
had inadequate TUR of bladder tumour
(TURBT) data (11 patients), patients with
non-urothelial pathology (16), those who
underwent NACTx (58), patients with clinical
T3–T4 stage disease (seven) based on TURBT
and bimanual examination, and those with
a concomitant diagnosis of high-grade
upper tract urothelial cancer (three). The
remaining 201 patients were the subject of
the present analysis; all had clinically
localised disease.
All surgical specimens were processed
according to standard pathological
procedures at our institution and were
histologically confirmed to be UCB by a
dedicated genitourinary pathologist. If the
TURBT procedure was performed at another
institution, representative slides were
obtained and reviewed before proceeding to
cystectomy. Tumours were staged according
to the 2002 American Joint Committee on
Cancer/Union Internationale Contre le
Cancer TNM classification [13]. Tumour
grading was assessed according to the 1998
WHO/International Society of Urological
Pathology consensus classification [14].
lymphovascular invasion (LVI) was defined
as the unequivocal presence of tumour cells
within an endothelium-lined space, with no
underlying muscular walls [15].
To identify predictors of pathological stage
at the time of cystectomy, we created
multivariable logistic regression models to
predict (≥ pT3/Nany) and (≥ pT3/Nany or
pTany/N+). Discrimination was measured by
area under the curve (AUC). Regression
coefficients were used to develop a
nomogram.
Decision curve analysis [16] was used to
explore the clinical value of the model
predicting (≥ pT3/Nany or pTany/N+)
NOC-UCB. Because the value of a true
positive (i.e. detection of NOC-UCB and
subsequent treatment with NACTx) may
differ from the disadvantages resulting from
a false positive (i.e. potential over-treatment
with systemic chemotherapy), the net
benefit differentially weights true and false
positives by using the threshold probability
at which one would opt for NACTx. For
example, if a provider (or patient) would opt
for NACTx with a 30% risk of NOC-UCB but
would forgo NACTx with only a 29% risk,
then the threshold probability is 30%.
Clinically valuable models show a net benefit
to alternative treatment strategies
throughout the clinically applicable range of
threshold probabilities. Alternative strategies
include treating all patients with NACTx or
treating no one with NACTx. For the
purposes of this analysis, we assume that
the preoperative identification of NOC-UCB
would lead to treatment with NACTx. All
statistical tests were two-sided with
significance set at P < 0.05. Statistical tests
were performed with SPSS® 18 (SPSS Inc.,
IBM Corp., Somers, NY, USA) and R-statistics
(the R foundation for Statistical Computing,
version 2.1.13).
RESULTS
The descriptive variables of the 201
evaluable patients are shown in Table 1.
The median (range) age at the time of
cystectomy was 72.9 (41–92) years and 165
(82.1%) patients were male. Overall, 71
(35.4%) patients had (≥pT3/Nany) NOC-UCB
and 38 (18.9%) had LN metastases (N+). In
all, 81 (40.3%) patients had (≥pT3/Nany or
pTany/N+) NOC-UCB.
Tables 2 and 3 show the univariable and
multivariable regression models, respectively,
for the prediction of NOC-UCB. In
univariable analyses, TURBT tumour size,
TURBT stage, TURBT LVI, intravesical therapy
history, and an abnormal preoperative
imaging study were associated with
NOC-UCB in both models. In multivariable
analyses TURBT stage, TURBT LVI, and
abnormal preoperative imaging were
independently associated with (≥pT3/Nany)
2012 BJU INTERNATIONAL
 ACCURATE PREOPERATIVE PREDICTION OF NON-ORGAN-CONFINED UCB AT CYSTECTOMY

NOC-UCB, and stage and LVI were

Variable Value TABLE 1
independently associated with (pTany/N+ or
Median (range) age, years 72.9 (41–92) Pre- and postoperative
≥pT3/Nany) NOC-UCB. The AUC of these two
N (%): clinical and pathological
Gender :
models was 0.836 and 0.828, respectively.
features of 201 patients
Male 165 (82.1) For both models, preoperative imaging
who underwent cystectomy
Female 36 (17.9) improved the accuracy of LVI and TURBT
with PLND for UCB
TURBT stage: stage combined (AUC 0.807 and 0.809,
Ta 19 (9.5) respectively) by a statistically significant
Tis 15 (7.5) margin (P < 0.001).
T1 67 (33.3)
T2 100 (49.8) Figure 1 shows the nomogram and
TURBT grade calibration plot for predicting (≥pT3/Nany or
Low 3 (1.5) pTany/N+) NOC-UCB. The nomogram was
High 198 (98.5) well-calibrated deviating maximally 7.7%
TURBT histology: from ideal predictions. In the decision curve
Urothelial carcinoma 169 (84.1) analysis (Fig. 2), the model predicting
Urothelial carcinoma variant 32 (15.9)
(≥pT3/Nany or pTany/N+) NOC-UCB provided
TURBT concomitant carcinoma in situ*:
net benefit throughout the entire range of
Absent 147 (76.2)
threshold probabilities as compared with the
Present 46 (22.9)
TURBT LVI*:
strategy of treating all patients with NACTx,
Absent 172 (85.6) or alternatively, treating no one. Table 4
Present 21 (10.4) shows the clinical effects of using the
TURBT tumour size, cm†: prediction model to guide the decision to
≤2 20 (13.6) use NACTx as compared with treating all
>2 and <5 42 (28.6) patients, or no patients with NACTx. For
≥5 85 (57.8) example, only administering NACTx to
TURBT tumour multifocality‡: patients with a nomogram-predicted
No 115 (63.5) probability of NOC-UCB of ≥50% would
Yes 66 (36.5) result in 81 patients in our cohort receiving
Median (range) TURBT procedures, n 2 (1–13) this treatment. In all, 27 (33%) of the 81
N (%): patients would be treated with NACTx in the
History of intravesical therapy: absence of NOC-UCB, representing the
No 130 (64.7) ‘over-treated’ group. The remaining 54
Yes 71 (35.3)
patients of the 81 predicted to have
Abnormal imaging§:
NOC-UCB, and thus treated with NACTx, had
No 112 (72.3)
pathologically confirmed NOC-UCB.
Yes 43 (27.7)
Weeks from TURBT to cystectomy
Therefore, 54 of the 65 (83%) patients with
≤12 176 (87.6) pathologically confirmed NOC-UCB would
>12 25 (12.4) have been ‘appropriately’ treated with
Pathological stage: NACTx and 11 of 65 (17%), would have been
pT0 20 (10) ‘undertreated’.
pTa 13 (6.5)
pTis 37 (18.4)
pT1 24 (11.9) DISCUSSION
pT2 36 (17.9)
pT3 52 (25.9) We developed a highly accurate nomogram
pT4 19 (9.5) (AUC 0.828) to predict pathologically
Pathological LVI: NOC-UCB in patients diagnosed with
Absent 153 (76.1) clinically organ-confined UCB; these patients
Present 48 (23.9)
often do not receive NACTx due to the
Pathological LN status:
*Evaluable, n = 193; concern of possible over-treatment [17]. In
Negative 163 (81.1)
Positive 38 (18.9) †evaluable, n = 147; agreement with the literature [7], we found
≥pT3/Nany: ‡evaluable, n = 181; a significant rate of upstaging to NOC-UCB
No 130 (64.7) §evaluable, n = 155; at the time of cystectomy, with 14% of
Yes 71 (35.3) abnormal imaging defined clinical stage ≤ T1 and 67% of clinical stage
≥pT3/Nany or pTanyN+: by presence of T2 patients upstaged to (≥pT3/Nany or
No 120 (59.7) hydronephrosis and/or pTany/N+). The model in the present study,
Yes 81 (40.3) suggestion of NOC-UCB. which includes T-stage, LVI found at TURBT,
and abnormal preoperative imaging, shows

© 2012 BJU INTERNATIONAL 3

GREEN ET AL.

TABLE 2 Univariable preoperative logistic regression analyses predicting NOC-UCB in patients treated with cystectomy and PLND

≥pT3/Nany ≥pT3/Nany or pTany/N+

Variable OR (95% CI) P OR (95% CI) P
Age at cystectomy (continuous) 1.03 (0.99–1.06) 0.06 1.03 (0.99–1.06) 0.08
Male gender 1.39 (0.67–2.91) 0.38 1.23 (0.59–2.55) 0.58
Tumour size, cm 0.03* 0.03*
>2 and <5 vs ≤2 2.01 (0.49–8.21) 0.33 3.15 (0.79–12.52) 0.10
≥5 vs ≤2 4.37 (1.19–16.03) 0.03 5.28 (1.44–19.36) 0.01
Received IVT vs never received 0.49 (0.26–0.94) 0.03 0.54 (0.29–0.99) 0.048
Weeks from TURBT to cystectomy
>12 vs ≤12 1.03 (0.43–2.48) 0.94 0.81 (0.34–1.94) 0.64
TURBT stage <0.001* <0.001*
T1 vs Ta–Tis 6.48 (0.80–52.5) 0.08 9.52 (1.2–75.49) 0.03
T2 vs Ta–Tis 47.49 (6.24–361.2) <0.001 61.29 (8.04–467.3) <0.001
TURBT histology
UCB variant vs UCB 1.12 (0.51–2.45) 0.78 1.18 (0.55–2.54) 0.66
TURBT multifocality 0.54 (0.28–1.05) 0.07 0.53 (0.28–1.0) 0.05
TURBT concomitant CIS 0.95 (0.47–1.89) 0.88 0.83 (0.42–1.64) 0.58
TURBT LVI 4.26 (1.63–11.14) 0.003 5.68 (1.98–16.25) 0.001
Abnormal imaging† 2.93 (1.42–6.05) 0.004 2.41 (1.17–4.93) 0.02

*P value for trend. †Abnormal imaging defined by presence of hydronephrosis and/or suggestion of NOC-UCB. IVT, intravesical therapy; CIS, carcinoma in situ.

improved accuracy compared with a

previous study where separate nomograms
were developed to predict NOC-UCB
(Accuracy 75.7%) and LN metastases
(Accuracy 63.1%), respectively [11]. The first
model included age at cystectomy, grade,
stage, and concomitant carcinoma in situ
and the second model included only stage
and grade.
We found that abnormal imaging was a
strong independent predictor of NOC-UCB.
These findings support those of previous
investigators such as Stimson et al. [18],
who reported that preoperative
hydronephrosis was independently
associated with NOC-UCB and LN
metastases at the time of cystectomy.
Additionally, in a recently analysed
upper-tract urothelial cohort, local invasion
on preoperative imaging (odds ratio [OR]
4.34; P < 0.001) as well as ureteroscopic
biopsy grade (OR 3.86; P = 0.003)
independently predicted non-organ-confined
(≥pT3 or pN+) disease at the time of radical
nephroureterectomy [19].
We also found that LVI found at TURBT
independently predicted NOC-UCB at
cystectomy. Previously, we and others have
shown the strong association between LVI
and the rate of metastases to regional LNs,
TABLE 3 Multivariable preoperative logistic regression analyses predicting NOC-UCB in patients
treated with cystectomy and PLND
≥pT3/Nany ≥pT3/Nany or pTany/N+
Variable OR (95% CI) P OR (95% CI) P
TURBT stage <0.001* <0.001*
T1 vs Ta–Tis 6.47 (0.75–55.92) 0.09 6.83 (0.80–58.2) 0.08
T2 vs Ta–Tis 41.32 (5.16–331.05) <0.001 49.76 (6.26–395.49) <0.001
TURBT LVI 5.19 (1.37–19.67) 0.02 6.64 (1.55–28.46) 0.01
Abnormal imaging† 3.19 (1.30–7.87) 0.01 2.44 (0.98–6.08) 0.06
*P value for trend; †Abnormal imaging defined by presence of hydronephrosis and/or suggestion of
NOC-UCB.
supporting the hypothesis that lymphatic LVI in the cystectomy specimen was
vessel invasion precedes or occurs independently associated with disease
concurrently with LN metastasis [15,20–24]. recurrence and decreased cause-specific
Resnick et al. [25] reported decreased survival. The impact of LVI was most
recurrence-free survival and decreased pronounced in the subset of patients who
overall survival in patients whose TURBT did not have LN metastases and for those
specimens contained evidence of LVI. Lotan patients, when LVI was added to a base
et al. [22] showed that LVI at the time of model, the predictive accuracy for
cystectomy was associated with UCB recurrence-free-survival and disease-specific
recurrence (OR 2.02, P < 0.001), and survival was improved by a prognostically
decreased overall (HR 1.84, P < 0.001) and significant margin. Indeed, infiltration of
cause-specific survival (OR 2.07, P = 0.001) these microscopic lymphovascular spaces by
in pN0 patients only. In an external tumour cells is probably the initial entry of
multi-institution validation cohort, Shariat neoplastic cells into the circulation, prior to
et al. [15] confirmed that the presence of the development of fulminant LN metastasis.

4 © 2012 BJU INTERNATIONAL

 ACCURATE PREOPERATIVE PREDICTION OF NON-ORGAN-CONFINED UCB AT CYSTECTOMY

FIG. 1. Pre-cystectomy nomogram predicting NOC-UCB stage (≥pT3/Nany or pTany/N+) at cystectomy and FIG. 2. Decision curve analysis of the effect of the
its calibration plot. Abnormal imaging defined by presence of hydronephrosis and/or suggestion of preoperative prediction model for detection of
NOC-UCB. (≥pT3/Nany or pTany/N+) in 151 patients who
underwent cystectomy. Assumption is made that
Prediction of (≥pT3 / Nany) or (pTany / N+) the identification of NOC-UCB would lead to
0 10 20 30 40 50 60 70 80 90100 treatment with NACTx. Net benefit is plotted
Points 1.0 AUC = 0.828 against threshold probabilities compared with
‘NACTx for all’ strategy and ‘NACTx for none’.
TURBT T1
0.8

Observed Probability
Stage Ta-Tis 1.0
T2 NACTx None
TURBT Yes NACTx All
0.6
LVI 0.8 NACTx per
No Nomogram
Abnormal Yes 0.4

Net benefit
Imaging 0.6
No ldeal
0.2 Longistic calibration
Total Points 0.4
Nonparametric
0
20
40
60
80

120
140
160
180
200
220
0
10

0.0
Probability of 0.0 0.2 0.4 0.6 0.8 1.0 0.2
≥pT3 / Nany or
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.86
0.9
0.93
0.95
0.97

pTany / N+ Nomogram Predicted Probability

0.0
0 20 40 60 80 100
Threshold probability, %

TABLE 4 Number of patients with and without pathologically confirmed NOC-UCB (pT3–4/pNany or pTany/pN+) who would receive NACTx at various
threshold probabilities based on nomogram prediction; all patients with clinically organ-confined UCB

Patients with pathologically

confirmed NOC- UCB (n = 65)
Would receive NACTx based
Would receive NACTx based on nomogram prediction of on nomogram prediction of
Probability of NOC-UCB required in order to NOC-UCB NOC-UCB
treat with NACTx (threshold probability), % Yes, n (%) No, n (%) Over-treated, n (%)* Yes, n (%) No†, n (%)
Treat all 151 (100) 0 86 (57) 65 (100) 0
Treat none 0 151 0 0 65 (100)
30 90 (60) 61 (40) 34 (38) 56 (86) 9 (14)
50 81 (54) 70 (46) 27 (33) 54 (83) 11 (17)
75 33 (22) 118 (78) 4 (12) 29 (45) 36 (55)
90 12 (8) 139 (92) 0 12 (18) 53 (82)

*Number over-treated = (number of patients predicted to have NOC-UCB) − (number of patients with pathologically confirmed NOC-UCB). % over-treated =
number over-treated/ number of patients predicted to have NOC-UCB. For a risk threshold of 30%, the number over-treated is 90 − 56 = 34, and %
over-treated is 34/90 × 100 = 38%. Assumption is that prediction of NOC-UCB drives the decision to use NACTx. †Column describes the ‘undertreated’ group;
those patients with pathologically NOC-UCB who were not treated with NACTx. The percentage is based upon a total of 65 patients with pathologically
confirmed NOC-UCB.

To examine the potential clinical impact that
the present predictive model provides, we
performed a decision curve analysis, a
technique that evaluates the clinical
consequences of using predictive models
[16,26]. The use of the present model to
predict (≥ pT3/Nany or pTany/N+) NOC-UCB
for the purpose of guiding the use of
NACTx, provided a net benefit relative to the
two strategies of treating all patients with
NACTx, or alternatively, treating no one
(Fig. 2). This was true across almost the
entire range of threshold probabilities.
A recent study reported that only 12% of
patients with cT2–T4aN0M0 received NACTx
[4] showing that the threshold probability
for urologists to use NACTx may be very
high. In other words, many urologists
probably require a very high degree of
suspicion that NOC-UCB is present before
treating a patient with NACTx, showing a
very low risk-tolerance for what they may
perceive as overtreatment of organ-confined
UCB. Using the present predictive model
(Fig. 1) in our cohort, a highly risk-intolerant
clinician (threshold probability 90%) would
administer NACTx to 12 patients, all of
whom would in fact have pathologically
confirmed NOC-UCB (Table 4).

© 2012 BJU INTERNATIONAL 5

GREEN ET AL.
Lastly, the present nomogram predicts that
for patients with clinically ≤ T1 UCB and the
presence of TURBT LVI and/or abnormal
imaging, a significant number of patients
will have NOC-UCB at cystectomy. Current
European Association of Urology guidelines
recommend NACTx for all patients with
cT2–T4N0M0 UCB [5]. However, there is no
such recommendation for patients with
clinically non-muscle-invasive UCB. While
treating all cT2–T4N0M0 patients with
NACTx may over-treat a significant number
of patients, excluding all patients with < cT2
UCB from NACTx without consideration
given to features such as LVI on TURBT or
abnormal preoperative imaging, may deny
some of these patients optimal therapy.
The present study is not without its
limitations including, but not limited to the
retrospective analysis and the small cohort.
For example, there is inherent difficulty in
determining the presence of LVI at the
morphological level with significant
differences between local pathologists and
central pathology review [15]. Additionally,
repeat TUR was not done for every patient,
but rather was performed at the discretion
of the surgeon, which could have
contributed to under-staging. For example,
13 of 67 patients with T1 UCB at TURBT had
high-grade recurrent and/or BCG refractory
UCB without muscularis propria in the
specimen and were directed to cystectomy.
Moreover, some data points that have been
analysed by other authors were not included
such as the frequency of variant UCB
histology [27]. Lastly, imaging protocols
were not standardised, nor was the use of
i.v. contrast for CT or MRI.
In conclusion, the current conventional
clinical staging for patients with UCB before
cystectomy results in a high rate of staging
inaccuracy; therefore more accurate tools
are needed, particularly for the purpose of
efficaciously directing patients towards
NACTx. The present study provides such a
tool and reiterates that LVI found at TURBT
and abnormal preoperative imaging findings
can predict NOC-UCB at the time of
cystectomy in patients with presumed
clinically localised UCB. Decision curve
analysis of the nomogram shows clinical
benefit both for clinicians hesitant to use
NACTx and for those who liberally
recommend for its use. Adoption of such a
tool into daily clinical decision-making may
lead to more appropriate integration of
6 ©
perioperative chemotherapy, thereby
potentially improving survival in patients
with UCB. The clinical value of this model
needs to be further assessed in external
multi-institutional validation cohorts.
SOURCE OF FUNDING
Supported by Frederick J. and Theresa Dow
Wallace fund of the New York Community
Trust.
CONFLICT OF INTEREST
None declared.
REFERENCES
1 Stein JP, Lieskovsky G, Cote R et al.
Radical cystectomy in the treatment of
invasive bladder cancer: long-term
results in 1,054 patients. J Clin Oncol
2001; 19: 666–75
2 Madersbacher S, Hochreiter W,
Burkhard F et al. Radical cystectomy
for bladder cancer today – a
homogeneous series without
neoadjuvant therapy. J Clin Oncol 2003;
21: 690–6
3 Grossman HB, Natale RB, Tangen CM
et al. Neoadjuvant chemotherapy plus
cystectomy compared with cystectomy
alone for locally advanced bladder
cancer. N Engl J Med 2003; 349: 859–66
4 Feifer A, Taylor J, Shouery M et al.
B.C.A.N. Muscle-Invasive Bladder Cancer
Quality of Care Consortium. Multi-
institutional quality-of-care initiative for
non-metastatic, muscle-invasive,
transitional cell carcinoma of the
bladder. J Clin Oncol 2011; 29 (Suppl. 7):
240 [abstract]
5 Stenzl A, Cowan NC, De Santis M
et al. Treatment of muscle-invasive and
metastatic bladder cancer: update of the
EAU guidelines. Eur Urol 2011; 59:
1009–18
6 Shariat SF, Palapattu GS, Karakiewicz
PI et al. Discrepancy between clinical
and pathologic stage: impact on
prognosis after radical cystectomy. Eur
Urol 2007; 51: 137–51
7 Svatek RS, Shariat SF, Novara G et al.
Discrepancy between clinical and
pathological stage: external validation of
the impact on prognosis in an
international radical cystectomy cohort.
BJU Int 2011; 107: 898–904
8 Bianco FJ, Justa D, Grignon DJ, Sakr
WA, Pontes JE, Wood DP. Management
of clinical T1 bladder transitional cell
carcinoma by radical cystectomy. Urol
Oncol 2004; 22: 290–4
9 Dutta SC, Smith JA, Shappell SB,
Coffey CS, Chang SS, Cookson MS.
Clinical under staging of high risk
nonmuscle invasive urothelial carcinoma
treated with radical cystectomy. J Urol
2001; 166: 490–3
10 Cheng L, Neumann RM, Weaver AL
et al. Grading and staging of bladder
carcinoma in transurethral resection
specimens. Correlation with 105
matched cystectomy specimens. Am J
Clin Pathol 2000; 113: 275–9
11 Karakiewicz PI, Shariat SF, Palapattu
GS et al. Precystectomy nomogram for
prediction of advanced bladder cancer
stage. Eur Urol 2006; 50: 1254–62
12 Shariat SF, Margulis V, Lotan Y,
Montorsi F, Karakiewicz PI.
Nomograms for bladder cancer. Eur Urol
2008; 54: 41–53
13 Edge SB, Byrd DR, Compton CC, Fritz
AG, Greene FL, Trotti A eds. American
Joint Committee on Cancer (AJCC)
Staging Manual, Seventh Edn. New York:
Springer, 2010
14 Eble JN, Sauter G, Epstein JI,
Sesterhenn IA. World Health
Organization Classification of Tumours.
Pathology and Genetics of Tumours of
the Urinary System and Male Genital
Organs. Lyon: IARCC Press, 2004
15 Shariat SF, Svatek RS, Tilki D et al.
International validation of the
prognostic value of lymphovascular
invasion in patients treated with radical
cystectomy. BJU Int 2010; 105: 1402–12
16 Vickers AJ, Elkin EB. Decision curve
analysis: a novel method for evaluating
prediction models. Med Decis Making
2006; 26: 565–74
17 Sonpavde G, Shariat SF. Preoperative
chemotherapy for bladder cancer: a
standard waits to be optimally deployed.
Cancer 2012; 118: 8–11
18 Stimson CJ, Cookson MS, Barocas DA
et al. Preoperative hydronephrosis
predicts extravesical and node positive
disease in patients undergoing
cystectomy for bladder cancer. J Urol
2010; 183: 1732–7
19 Favaretto RL, Shariat SF, Savage C
et al. Combining imaging and
2012 BJU INTERNATIONAL
 ACCURATE PREOPERATIVE PREDICTION OF NON-ORGAN-CONFINED UCB AT CYSTECTOMY
ureteroscopy variables in a preoperative
multivariable model for prediction of
muscle-invasive and non-organ confined
disease in patients with upper tract
urothelial carcinoma. BJU Int 2012; 109:
77–82
20 Quek ML, Stein JP, Nichols PW et al.
Prognostic significance of
lymphovascular invasion of bladder
cancer treated with radical cystectomy.
J Urol 2005; 174: 103–6
21 Canter D, Guzzo T, Resnick M et al.
The presence of lymphovascular invasion
in radical cystectomy specimens from
patients with urothelial carcinoma
portends a poor clinical prognosis. BJU
Int 2008; 102: 952–7
22 Lotan Y, Gupta A, Shariat SF et al.
Lymphovascular invasion is
independently associated with overall
survival, cause-specific survival, and
local and distant recurrence in patients
with negative lymph nodes at radical
© 2012 BJU INTERNATIONAL
cystectomy. J Clin Oncol 2005; 23:
6533–9
23 Hong SK, Kwak C, Jeon HG, Lee E, Lee
SE. Do vascular, lymphatic, and
perineural invasion have prognostic
implications for bladder cancer after
radical cystectomy? Urology 2005; 65:
697–702
24 Leissner J, Koeppen C, Wolf HK.
Prognostic significance of vascular and
perineural invasion in urothelial bladder
cancer treated with radical cystectomy.
J Urol 2003; 169: 955–60
25 Resnick MJ, Bergey M, Magerfleisch L,
Tomaszewski JE, Malkowicz SB, Guzzo
TJ. Longitudinal evaluation of the
concordance and prognostic value
of lymphovascular invasion in
transurethral resection and radical
cystectomy specimens. BJU Int 2011;
107: 46–52
26 Vickers AJ. Prediction models:
revolutionary in principle, but do they
do more good than harm? J Clin Oncol
2011; 29: 2951–2
27 Black PC, Brown GA, Dinney CP. The
impact of variant histology on the
outcome of bladder cancer treated with
curative intent. Urol Oncol 2009; 27:
3–7
Correspondence: Shahrokh F. Shariat, Brady
Urologic Health Center, Weill Cornell Medical
College, New York Presbyterian Hospital, 525
East 68th Street, Box 94, Starr 900, New
York, NY 10065, USA.
e-mail: sfshariat@gmail.com
Abbreviations: AUC, area under the curve;
LN, lymph node; LVI, lymphovascular
invasion; NACTx, neoadjuvant
chemotherapy; NOC, non-organ-confined;
PLND, pelvic lymph-node dissection;
TUR(BT), transurethral resection (of bladder
tumour); UCB, urothelial carcinoma of the
bladder.
7