JU Insight

www.auajournals.org/journal/juro

Role of Lymphadenectomy during Radical Cystectomy for

Nonmuscle-Invasive Bladder Cancer: Results from a
Multi-Institutional Experience
Abhinav Khanna, Tanner Miest, Vidit Sharma et al.
Correspondence: Stephen A. Boorjian (email: Boorjian.stephen@mayo.edu).
Full-length article available at www.auajournals.org/10.1097/JU.0000000000002266.

Study Need and Importance: The role of lymph

node dissection (LND) during radical cystectomy
(RC) for muscle-invasive bladder cancer has been
investigated extensively, and indeed performing
LND at RC for muscle-invasive bladder cancer is
supported by current national/organizational
guidelines. In contrast, the role of LND at the
time of RC for nonmuscle-invasive bladder cancer
(NMIBC) is less well defined, as few studies have
reported pathological and oncologic outcomes of
LND specifically in the clinical NMIBC setting.
Herein, therefore, we examined the relationship
between extent of LND during RC for NMIBC and
local pelvic recurrence-free survival, cancer-specific
survival and overall survival. Figure. Cancer-specific survival among patients undergoing RC
for nonmuscle-invasive bladder cancer with lymph node yield
What We Found: We reviewed a multi-institutional >20 versus
20.
cohort of 1,647 patients who underwent RC for
clinical NMIBC at 3 high-volume academic referral
centers in the United States. We examined onco- Limitations: This study was limited by its retro-
logic outcomes across the full spectrum of lymph spective study design and lack of data on anatomical
node yields and found that patients who had un- templates of dissection for LND.
dergone a more extensive LND (greater lymph Interpretation for Patient Care: We found that
node yield at surgery) experienced more favorable greater extent of LND in NMIBC was associated
local recurrence-free survival, cancer-specific sur- with improved long-term oncologic outcomes. Based
vival and overall survival (see figure). These re- on these results, we propose that LND should be
sults were also observed specifically for the included as part of RC for patients with NMIBC,
subgroups of patients with clinical Tis and T1 dis- particularly for patients with cTis or T1 disease.
ease, suggesting that LND may be of particular Future studies should investigate the optimal
relevance in these populations. anatomical template of LND at RC for NMIBC.

0022-5347/22/2073-0551/0 https://doi.org/10.1097/JU.0000000000002266
THE JOURNAL OF UROLOGY® Vol. 207, 551-558, March 2022
Ó 2021 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Printed in U.S.A.

www.auajournals.org/jurology j 551

Copyright © 2022 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 www.auajournals.org/journal/juro

Role of Lymphadenectomy during Radical Cystectomy for

Nonmuscle-Invasive Bladder Cancer: Results from a
Multi-Institutional Experience
Abhinav Khanna,1,* Tanner Miest,2,* Vidit Sharma,1 Rebecca Campbell,3 Patrick Hensley,2
Prabin Thapa,1 Andrew Zganjar,1 Matthew K. Tollefson,1 R. Houston Thompson,1 Igor Frank,1
R. J. Karnes,1 Prithvi B. Murthy,3 Georges P. Haber,3 Neema Navai,2 Ashish M. Kamat,2
Colin Dinney,2 Byron Lee3 and Stephen A. Boorjian1,†
1
Department of Urology, Mayo Clinic, Rochester, Minnesota
2
Department of Urology, MD Anderson Cancer Center, Houston, Texas
3
Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio

Abbreviations
and Acronyms
BCG [ bacillus Calmette-Gu
erin
CSS [ cancer-specific survival
LND [ lymph node dissection
LNY [ lymph node yield
LPR [ local pelvic recurrence
LPRS [ local pelvic recurrence-
free survival
MIBC [ muscle-invasive bladder
cancer
NMIBC [ nonmuscle-invasive
bladder cancer
OS [ overall survival
RC [ radical cystectomy
Accepted for publication September 17, 2021.
* Equal study contribution.
† Correspondence: Department of Urology,
Mayo Clinic, 200 1st St. SW, Rochester, Minne-
sota (telephone: 507-284-4015; email: Boorjian.
stephen@mayo.edu).
Editor’s Note: This article is the
second of 5 published in this issue
for which category 1 CME credits
can be earned. Instructions for
obtaining credits are given with
the questions on pages 744 and
745.
Purpose: While lymph node dissection (LND) at radical cystectomy (RC) for
muscle-invasive bladder cancer has been studied extensively, the role of LND for
nonmuscle-invasive bladder cancer (NMIBC) remains incompletely defined.
Herein, we aim to assess the association between extent of LND during RC for
NMIBC and local pelvic recurrence-free survival (LPRS), cancer-specific survival
(CSS) and overall survival (OS).
Materials and Methods: A multi-institutional retrospective review was per-
formed of patients with NMIBC undergoing RC at 3 large tertiary referral cen-
ters. To identify a threshold for lymph node yield (LNY) to optimize LPRS, CSS
and OS, separate Cox regression models were developed for each possible LNY
threshold. Model performance including Q-statistics and hazard ratios (HRs)
were used to identify optimal LNY thresholds.
Results: A total of 1,647 patients underwent RC for NMIBC, with a median LNY of
15 (quartiles 9,23). Model performance curves suggested LNY of 10 and 20 to
optimize LPRS and CSS/OS, respectively. On multivariable regression, LNY >10
was associated with lower risk of LPR compared to LNY
10 (HR 0.63, 95% CI
0.42e0.93, p[0.02). Similarly, LNY >20 was associated with improved CSS (HR
0.67, 95% CI 0.52e0.87, p[0.002) and OS (HR 0.75, 95% CI 0.64e0.88, p <0.001)
compared to LNY
20. Similar results were observed in the cT1 and cTis subgroups.
Conclusions: Greater extent of LND during RC for NMIBC is associated with
improved LPRS, CSS and OS, supporting the inclusion of LND during RC for
NMIBC, particularly among patients with cTis or cT1 disease. Future prospective
studies are warranted to assess the ideal anatomical template of LND in NMIBC.
Key Words: lymph node excision, cystectomy, urinary bladder neoplasms
THE American Urological Association, recommendation is supported by
National Comprehensive Cancer Net- robust retrospective evidence demon-
workÒ and European Association of strating an oncologic benefit from
Urology guidelines recommend at LND during RC for MIBC.4e13 In
minimum a standard template lymph addition, 2 randomized trials aim to
node dissection (LND) during radical further discern the optimal anatom-
cystectomy (RC) for muscle-invasive ical template for LND at RC for
bladder cancer (MIBC). 1e3 This MIBC.14,15

0022-5347/22/2073-0552/0 https://doi.org/10.1097/JU.0000000000002266
THE JOURNAL OF UROLOGY® Vol. 207, 551-558, March 2022
Ó 2021 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Printed in U.S.A.

552 j www.auajournals.org/jurology
Copyright © 2022 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 LYMPH NODE DISSECTION IN NONMUSCLE-INVASIVE BLADDER CANCER
In contrast, limited data exist regarding the role
of LND for nonmuscle-invasive bladder cancer
(NMIBC). Prior studies of patients with clinical
NMIBC undergoing RC have demonstrated pND
rates of 7.9e16.2%,16,17 suggesting the relevance of
LND for these patients. However, few studies have
examined the association between LND and onco-
logic outcomes specifically in NMIBC, and these
demonstrate conflicting results.18,19 Accordingly,
guideline panels do not offer specific guidance on
LND in the NMIBC setting. Indeed, data from the
National Cancer Database suggest that approxi-
mately 1 in 6 patients treated with RC for NMIBC
do not undergo any LND at all.19 This practice
pattern likely reflects the dearth of evidence sur-
rounding LND in NMIBC.
Herein, we aim to assess the association between
extent of LND during RC for NMIBC and local
pelvic recurrence (LPR)-free survival (LPRS),
cancer-specific survival (CSS) and overall survival
(OS) using a multi-institutional cohort of patients
treated with RC for NMIBC.
METHODS
A multi-institutional retrospective review was performed
of patients with clinical stage T <2N0M0 urothelial car-
cinoma of the bladder (NMIBC) undergoing RC at 3 large
tertiary referral centers in the United States. Patients
who underwent RC for pure nonurothelial histology,
received neoadjuvant chemotherapy prior to RC or un-
derwent RC for palliative indications were excluded.
Lymph node yield (LNY) was assessed via retrospective
review of pathology reports. Anatomical template of LND
was at the treating surgeon’s discretion and was not
available. LPR was defined as recurrence of urothelial
carcinoma in the pelvis (excluding remnant urothelium).
CSS and OS were measured from RC to event.
In order to identify a LNY threshold to optimize
LPRS, CSS and OS, individual Cox proportional hazards
models were separately developed for each possible LNY
cutoff across the full range of LNYs for each outcome
(totaling 611 individual models). Based on model per-
formance characteristics, data-driven LNY thresholds
were selected for each outcome (see supplementary table 1,
https://www.jurology.com for details of LNY threshold
development).20,21
Parsimonious Cox multivariable regression models
were built using a stepwise approach to assess the rela-
tionship between LNY thresholds and LPRS, CSS and OS.
An additional set of Cox multivariable regression models
that included all covariables of clinical relevance was also
performed. Analyses were repeated in clinical stage
Ta (cTa), clinical stage carcinoma in situ (cTis) and clinical
stage T1 (cT1) NMIBC subgroups. Statistical significance
was defined as p <0.05. Schoenfeld Residuals plots were
developed to test the proportionality assumption for Cox
proportional hazards models (data not shown) and did not
demonstrate significant departure from the proportional-
ity assumption. This study was approved by the Mayo
Copyright © 2022 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
553
Clinic, Cleveland Clinic, and MD Anderson Cancer Center
Institutional Review Boards (IRB No. 20-008027).
RESULTS
We analyzed a total of 1,647 patients who under-
went RC for NMIBC between 1980e2018. Table 1
provides baseline demographic and clinical charac-
teristics of the overall cohort (1,647), as well the cTa
(307), cTis (366) and cT1 (974) subgroups. Median
LNY was 15 (quartiles 9, 23). Of note, 64 (3.9%)
patients received no LND at all during RC,
including 24 (7.8%), 11 (3%) and 29 (3%) in the cTa,
cTis and cT1 subgroups, respectively.
Median followup after RC was 4.1 years (quar-
tiles 2.3, 7.8), during which time 313 patients expe-
rienced recurrence of urothelial carcinoma, including
102 with LPR, and 864 died, including 341 who died of
urothelial carcinoma. As shown in the supplementary
figure (https://www.jurology.com), LND demonstrated
a benefit for LPRS above a threshold of LNY[8,
which persisted until an apparent plateau above
LNY[14. Meanwhile, for both CSS and OS, LND
began to demonstrate a benefit at a LNY[7, which
continued to increase until an apparent plateau
above LNY[24. Based on these findings, an
analytical threshold of LNY >10 was selected for
the subsequent evaluation of LPRS, and LNY >20
for CSS and OS. Overall, 98 patients (6.0%) had
pathological ND disease at RC (pND) and 314 pa-
tients (19.0%) were up staged to pT2 or greater at
RC. Patients with greater extent of LND had higher
rates of pND (19 [3.7%] in LNY
10 versus 79
[7.0%] in LNY >10), p[0.01; 57 [5.1%] in LNY
20
versus 41 [7.7%] in LNY >20, p[0.04).
These LNY thresholds were then utilized to
explore the associations of LND with LPRS, CSS
and OS. As shown in figure 1, patients with an LNY
>10 had a significantly higher 5-year LPRS
compared to patients with an LNY
10 (93.7% vs
91%; p[0.003). Similarly, patients with an LNY
>20 had a significantly higher 5-year CSS (86.7% vs
78.4%; p[0.002) and 5-year OS (75.4% vs 65.3%;
p <0.001) than patients with an LNY
20.
Further, on multivariable Cox regression ana-
lyses, LNY >10 remained associated with a signifi-
cantly lower risk of LPR (HR 0.63, 95% CI
0.42e0.93; p[0.02; table 2). Similarly, LNY >20
was independently associated with a decreased risk
of death from bladder cancer (HR 0.67, 0.52e0.87;
p[0.002) as well as all-cause mortality (HR 0.75,
0.64e0.88; p <0.001). Similar relationships between
LNY and CSS/OS were observed when Cox multi-
variable regression models included all covariables
of clinical relevance (supplementary table 2, https://
www.jurology.com), cohort was restricted to pa-
tients who received RC in the years 2000e2018
554 LYMPH NODE DISSECTION IN NONMUSCLE-INVASIVE BLADDER CANCER

Table 1. Baseline demographic and clinical characteristics of overall cohort of patients undergoing RC for NMIBC, as well as the cTa,
cTis and cT1 subgroups
Overall Cohort cT1 cTis cTa p Value
No. pts 1,647 974 366 307
Median yrs age at surgery (IQR) 68 (62, 74) 68 (61, 74) 70 (65, 75.4) 68 (61, 74) <0.0001
No. female (%) 281 (17.1) 167 (17.1) 54 (14.8) 60 (19.5) 0.26
Median body mass index (IQR) 28 (25.1, 31.1) 28 (24.9, 30.8) 28 (25.7, 31.9) 28.2 (25.7, 32) 0.003
Median Charlson Comorbidity Index (IQR) 3 (2,6) 3 (2,6) 3 (2,6) 3 (2,5) 0.57
No. smoking history (%) 1,251 (76.0) 744 (76.5) 285 (77.9) 222 (72.3) 0.21
No. BCG prior to cystectomy (%) 789 (47.9) 351 (36.0) 266 (72.7) 172 (56.0) <0.0001
No. clinical high grade (%)* 901 (70.4) 742 (76.3) Not reported 159 (52) <0.0001
No. decade of cystectomy (%): 0.02
1980s 267 (16.2) 179 (18.4) 52 (14.2) 36 (11.7)
1990s 225 (13.7) 142 (14.6) 48 (13.1) 35 (11.4)
2000s 339 (20.6) 193 (19.8) 85 (23.2) 61 (19.9)
2010s 816 (49.5) 460 (47.2) 181 (49.5) 175 (57.0)
Median LNY (IQR) 15 (9,23) 15 (9,24) 15 (9,24) 14 (6,21) 0.003
No. pathological T-stage at cystectomy (%): <0.0001
pT0 317 (19.2) 175 (18.0) 60 (16.4) 82 (26.7)
pTa/pTis/pT1 1,016 (61.7) 544 (55.9) 283 (77.3) 189 (61.6)
pT2 160 (9.7) 129 (13.2) 14 (3.8) 17 (5.5)
pT3/4 154 (9.4) 126 (12.9) 9 (2.5) 19 (6.2)
No. pathological Nþ at cystectomy (%) 98 (6.0) 83 (8.5) 2 (0.5) 13 (4.2) <0.0001
No. pos surgical margin (%) 16 (1.0) 12 (1.2) 1 (0.3) 3 (1.0) 0.28
No. adjuvant chemotherapy (%) 57 (3.5) 48 (5.0) 2 (0.6) 7 (2.4) <0.001

* Clinical grade is not reported for cTis subgroup. Denominator for “overall cohort” includes only cT1 and cTa subgroups for this variable.

(supplementary table 3, https://www.jurology.com),
cohort was restricted to patients with pathological
stage less than pT4 (supplementary table 4, https://
www.jurology.com) and on Cox models in which
LNY was included as a continuous variable (sup-
plementary table 5, https://www.jurology.com).
Analyses were then repeated separately for the
cTa, cTis and cT1 subgroups. Optimal LNY thresh-
olds in the cTis and cT1 subgroups were similar to
those from the overall cohort (10 for LPRS and 20
for CSS and OS; individual Q-statistic curves not
shown). Indeed, on survival analyses, patients with
cTis and cT1 who underwent LND with an LNY
above the aforementioned thresholds had signifi-
cantly better LPRS, CSS and OS (fig. 2; p <0.05)
than patients with LNY below these thresholds. In
contrast, in the cTa subgroup there were no statis-
tically significant differences in LPRS, CSS nor OS
between patients with LNY above versus below the
aforementioned thresholds (fig. 2, p >0.05). Based
on Q-statistic performance curves of individual Cox
models within the cTa subgroup (data not shown),
alternative LNY thresholds of LNY[5, 13 and 13
for LPR, CSS and OS, respectively, were also tested
for patients with cTa disease. However, compari-
sons using these LNY thresholds were not statisti-
cally significant for any of the oncologic end points
studied (p >0.05 for all).
DISCUSSION
In this large multi-institutional study of patients
undergoing RC for NMIBC, greater extent of LND
was associated with improved LPRS, CSS and OS.
In particular, the benefit of increased LNY was most
pronounced in patients with cT1 and cTis disease.
To our knowledge, this represents the first analysis
to demonstrate an association between the extent of
LND and each of these oncologic outcomes specif-
ically in clinical NMIBC patients.
The few studies to date which have evaluated the
importance of the role of LND at RC for NMIBC have
reported inconsistent results and have been limited
by relatively small sample sizes of NMIBC patients
and/or the inability to evaluate all oncologically
relevant end points.14,16,18,19 For example, in an
institutional analysis of 196 patients with NMIBC
undergoing RC, Lin et al demonstrated no difference
in recurrence-free survival between those who
received more versus less extensive LND, despite
exploring multiple LNY thresholds.18 Gschwend et al
conducted a randomized trial of extended versus
limited LND, which included cT1 NMIBC pa-
tients.14 The trial did not demonstrate superiority
of extended LND, although only 55/401 patients
(13.7%) had pT1 disease. Interestingly, the authors
partly attribute the negative trial result to the in-
clusion of cT1 NMIBC patients in their cohort, thus
underscoring the uncertainty surrounding the role
of LND in NMIBC. Similarly, while Bruins et al16
detailed the anatomical location of lymph node
metastases among patients with NMIBC, compar-
ative analysis of survival outcomes based on LNY
were not reported.
Lenis et al examined 3,226 patients from the
National Cancer Database with NMIBC who un-
derwent RC and reported that an adequate (10
nodes removed) LND was associated with improved

Copyright © 2022 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 LYMPH NODE DISSECTION IN NONMUSCLE-INVASIVE BLADDER CANCER 555

Figure 1. Comparative LPRS (A), CSS (B) and OS (C) among patients with LNY above vs below optimal threshold.

OS. However, LPR/CSS end points were notably at RC.4e7,9e13 We postulate that PLND may trans-
absent from the study.19 Examination of OS without late into improved oncologic outcomes via removal
a concomitant assessment of upstream oncologic of not only grossly positive lymph node metastases,
end points introduces the risk for potential con- but perhaps also via removal of micrometastatic
founding, as healthier patients with longer preop- disease harbored in the pelvic lymph nodes. Addi-
erative life expectancy may be more likely to receive tionally, our data support the hypothesis that the
a more extensive LND, as previously proposed by OS benefits associated with more extensive LND are
Froehner et al.22 Thus, assessments of LPR and associated with upstream oncologic factors, and
CSS in addition to OS are requisite in establishing perhaps not attributable entirely to competing risk
the role of LND during RC for NMIBC. as has been suggested previously.22
In an analysis of the SEER (Surveillance,
Epidemiology, and End Results) database, Abdollah
Table 2. Cox multivariable proportional hazards regression
et al demonstrated that LND at RC was associated
models evaluating factors associated with LPR, death from
with higher CSS as compared to no LND, including bladder cancer and all-cause mortality in overall cohort
among patients with pTa/Tis and pT1 NMIBC.23
Variable Hazard Ratio 95% CI p Value
However, this analysis was stratified by patholog-
ical tumor stage and not clinical tumor stage. Thus, Local pelvic recurrence
it is quite possible that many of the patients in this Male 0.50 0.32e0.76 0.001
T-stage at RC:
cohort had clinical MIBC but were down staged at pT0 Referent
the time of RC, particularly those who received pTa/TIS/T1 1.91 0.97e3.74 0.06
neoadjuvant chemotherapy (chemotherapy status pT2 3.05 1.31e7.07 0.01
pT3/4 7.46 3.49e15.92 <0.0001
was not available in SEER). Importantly, a sur- LNY >10 0.63 0.42e0.93 0.02
geon’s decision to perform LND during RC is based Pos margin at RC 2.02 0.81e5.03 0.13
upon clinical, not pathological, risk stratification. Death from bladder cancer
Age 1.02 1.01e1.03 <0.001
Thus, to help guide surgeons on the relevance of Male 0.76 0.58e0.98 0.04
LND in clinical NMIBC, an analysis of patients with Charlson Comorbidity Index >5 1.59 1.27e2.0 <0.0001
clinical NMIBC is needed. History of BCG 1.24 1.0e1.55 0.05
T-stage at RC:
The strengths of our study include utilization of a pT0 Referent
large multi-institutional cohort with long-term fol- pTa/TIS/T1 1.73 1.19e2.51 0.004
lowup and the granular assessment of several rele- pT2 3.36 2.12e5.32 <0.0001
pT3/4 6.95 4.52e10.69 <0.0001
vant oncologic outcomes. In addition, we did not Pathological Nþ at RC 3.41 2.43e4.78 <0.0001
apply a pre-specified LNY cutoff for analyses. LNY >20 0.67 0.52e0.87 0.002
Instead, we employed a data-driven approach in Pos margin at RC 2.95 1.89e4.61 <0.0001
All-cause mortality
which the benefit of LND was examined across the Age 1.06 1.05e1.07 <0.0001
full spectrum of LNY to determine if any oncologic Charlson Comorbidity Index >5 1.48 1.28e1.71 <0.0001
benefit of LND was present for each individual Smoking history 1.37 1.15e1.62 0.0004
T-stage at RC:
outcome. This allowed for analyses that were pT0 Referent
informed by trends in the observed data rather than pTa/TIS/T1 1.27 1.05e1.53 0.02
utilizing a pre-specified cutoff, as has been done pT2 2.03 1.55e2.66 <0.0001
pT3/4 3.04 2.35e3.94 <0.0001
previously.18,19 Our data demonstrating an associ- Pathological Nþ at RC 2.86 2.18e3.75 <0.0001
ation between increased LNY and favorable onco- LNY >20 0.75 0.64e0.88 0.0004
logic outcomes in NMIBC extend the literature from Pos margin at RC 2.14 1.48e3.11 <0.0001
MIBC, which has likewise documented an associa- For LPR, LNY >10 was compared to LNY
10, while for mortality outcomes LNY
tion between the extent of LND and cancer control >20 was compared to LNY
20.

Copyright © 2022 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
556 LYMPH NODE DISSECTION IN NONMUSCLE-INVASIVE BLADDER CANCER

Figure 2. Comparative LPRS, CSS and OS among patients with LNY above vs below optimal threshold in cTa (aec), cTis (def ) and cT1
subgroups (gei), respectively.

In addition to LNY, male sex was also associated
with improved oncologic outcomes on multivariable
analyses. This is consistent with prior literature
suggesting that women undergoing RC have worse
OS than men.24,25 Meanwhile, although the asso-
ciation between the presence of a positive surgical
margin and LPR was not found to be statistically
significant, this finding may reflect a relatively
low number of events, given the hazard ratio and
wide confidence interval, as well as the significant
associations between LPR and cancer-specific and
all-cause mortality. Further, as positive surgi-
cal margins are associated with significantly in-
creased risk for subsequent metastatic disease
and death from bladder cancer, patients with this
adverse pathological feature may have progressed
and thereby been diagnosed with distant metas-
tases or experienced death from bladder cancer
rapidly.
Recognizing the heterogeneity in disease risk
among patients with NMIBC, we further performed
separate subgroup analyses stratified by clinical T-
stage to investigate whether the benefits of LND
were restricted to certain subgroups. We deter-
mined that the optimal LNY thresholds for LPRS,
CSS and OS identified within the overall cohort
remained applicable to the cTis and cT1 subgroups,
suggesting particular benefit to the performance of
LND in these patients. In contrast, no statistically
significant LNY threshold was identified in the cTa
subgroup, and as such the oncologic benefit of LND
during RC among patients with cTa disease remains
uncertain. Notably, approximately half of the cTa
subgroup had clinically low-grade disease. Although
we do not have the granularity in our data set to
discern individual indications for RC, we postulate
that the decision to proceed to RC among these
patients may have included the presence of

Copyright © 2022 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 LYMPH NODE DISSECTION IN NONMUSCLE-INVASIVE BLADDER CANCER
endoscopically unresectable disease, refractory he-
maturia and patient preferences. It is thereby
possible that the inclusion of low-grade cTa patients
with limited oncologic risk for progression may have
diluted a potential benefit of LND in the cTa sub-
group. Conversely, it is also possible that some pa-
tients with clinical suspicion for MIBC underwent
minimal transurethral resection of bladder tumor to
establish a diagnosis of urothelial carcinoma prior
to RC, thus leading to potential under staging in
this subset of patients. Further, we do not have the
granularity in our data set to determine bacillus
Calmette-Gu
erin (BCG) eligibility, and thus cannot
comment on the rates of BCG utilization prior to RC
in the study subgroups.
We recognize that our study is limited by its
retrospective design. For example, the anatomical
extent of LND was not standardized. Further, pa-
tients receiving more extensive LND could have
theoretically had better performance status, more
favorable surgical anatomy, or higher volume or
more skilled surgeons, all of which could serve as
potential unmeasurable confounders. We also
acknowledge that although some studies have
demonstrated an association between LNY and
anatomical extent of LND,26 LNY as an outcome
metric has often been reported to be less relevant
prognostically than the anatomical extent (tem-
plate) of LND.27,28 This distinction may be particu-
larly relevant for MIBC, wherein the inclusion of
LND during RC is widely accepted and supported by
guidelines,1e3 and the current debate has pro-
gressed to a more focused consideration of the
optimal anatomical extent of LND in MIBC.14,15
However, in contrast, the discourse on LND in
NMIBC remains relatively incipient. A recent
REFERENCES
1. Chang SS, Bochner BH, Chou R et al: Treatment
of non-metastatic muscle-invasive bladder can-
cer: AUA/ASCO/ASTRO/SUO guideline. J Urol
2017; 198: 552.
2. Flaig TW, Spiess PE, Agarwal N et al: Bladder
cancer, version 3.2020, NCCN clinical practice
guidelines in oncology. J Natl Compr Canc Netw
2020; 18: 329.
3. Witjes JA, Lebret T, Comp
erat EM et al: Updated
2016 EAU guidelines on muscle-invasive and
metastatic bladder cancer. Eur Urol 2017; 71:
462.
4. Leissner J, Hohenfellner R, Th€uroff JW et al:
Lymphadenectomy in patients with transitional
cell carcinoma of the urinary bladder; signifi-
cance for staging and prognosis. BJU Int 2000;
85: 817.
Copyright © 2022 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
557
analysis of national practice patterns noted that
approximately 45% of patients undergoing RC for
NMIBC in the United States had <10 lymph nodes
removed, of which over a third received no LND at
all,19 suggesting significant surgical heterogeneity
regarding LND in the NMIBC setting. Further, as
the current literature supporting an oncologic
benefit to LND during RC for NMIBC have been
limited, we believe correlating LNY with LPRS,
CSS and OS represents a necessary first step in
establishing a role for LND at RC for NMIBC. The
optimal template for LND in the NMIBC setting
warrants future study. We also acknowledge that
data on morbidity from LND were not available. In
addition, as our study cohort was comprised from 3
centers, variations in followup may have impacted
the results as well. Further, the lack of centralized
pathology review precludes a subset analysis of the
role of LND during RC for patients with variant
histology. Finally, the proportion of patients who
underwent no LND during RC was limited (3.9% of
the overall cohort, supplementary table 6, https://
www.jurology.com), precluding a direct comparison
of patients who received LND vs no LND. Due to the
lack of data on clinical N-stage, we cannot comment
on the rationale for LND omission in these patients.
CONCLUSIONS
Greater LNY during RC for NMIBC is associated
with LPRS, CSS and OS. The oncologic benefit of
increased LNY is most pronounced among patients
with cTis or cT1 disease. These results support the
inclusion of LND during RC for NMIBC. Future
prospective studies are warranted to ascertain the
optimal anatomical template for LND in NMIBC.
5. Herr HW, Bochner BH, Dalbagni G et al: Impact survival among patients with lymph node me-
of the number of lymph nodes retrieved on tastases undergoing radical cystectomy. Cancer
outcome in patients with muscle invasive 2008; 112: 2401.
bladder cancer. J Urol 2002; 167: 1295.
10. Morgan TM, Barocas DA, Penson DF et al: Lymph
6. Herr HW: Extent of surgery and pathology node yield at radical cystectomy predicts mor-
evaluation has an impact on bladder cancer tality in node-negative and not node-positive
outcomes after radical cystectomy. Urology patients. Urology 2012; 80: 632.
2003; 61: 105.
11. Dhar NB, Klein EA, Reuther AM et al: Outcome
7. Herr HW, Faulkner JR, Grossman HB et al: Sur- after radical cystectomy with limited or extended
gical factors influence bladder cancer outcomes: pelvic lymph node dissection. J Urol 2008; 179:
a cooperative group report. J Clin Oncol 2004;
873 .
22: 2781.
12. May M, Herrmann E, Bolenz C et al: Association
8. Capitanio U, Suardi N, Shariat SF et al:
Assessing the minimum number of lymph nodes between the number of dissected lymph nodes
during pelvic lymphadenectomy and cancer-
needed at radical cystectomy in patients with
bladder cancer. BJU Int 2009; 103: 1359. specific survival in patients with lymph node-
negative urothelial carcinoma of the bladder
9. Wright JL, Lin DW and Porter MP: The associ- undergoing radical cystectomy. Ann Surg Oncol
ation between extent of lymphadenectomy and 2011; 18: 2018.
558 LYMPH NODE DISSECTION IN NONMUSCLE-INVASIVE BLADDER CANCER

13. Simone G, Papalia R, Ferriero M et al: Stage-
specific impact of extended versus standard
pelvic lymph node dissection in radical cys-
tectomy. Int J Urol 2013; 20: 390.
14. Gschwend JE, Heck MM, Lehmann J et al:
Extended versus limited lymph node dissection in
bladder cancer patients undergoing radical cys-
tectomy: survival results from a prospective,
randomized trial. Eur Urol 2019; 75: 604.
15. Lerner SP, and Svatek RS: What is the standard
of care for pelvic lymphadenectomy performed at
the time of radical cystectomy? Eur Urol 2019;
75: 612.
16. Bruins HM, Skinner EC, Dorin RP et al: Incidence
and location of lymph node metastases in pa-
tients undergoing radical cystectomy for clinical
non-muscle invasive bladder cancer: results from
a prospective lymph node mapping study. Urol
Oncol 2014; 32: 24
17. Fritsche HM, Burger M, Svatek RS et al: Char-
acteristics and outcomes of patients with clinical
T1 grade 3 urothelial carcinoma treated with
radical cystectomy: results from an international
cohort. Eur Urol 2010; 57: 300.
18. Lin J, Deibert CM, Holder D et al: The role of
pelvic lymphadenectomy in non-muscle invasive
bladder cancer. Can J Urol 2014; 21: 7108.
19. Lenis AT, Lec PM, Michel J et al: Predictors of
adequate lymph node dissection in patients with
non-muscle invasive bladder cancer undergoing
radical cystectomy and effect on survival. Urol
Oncol 2020; 38: 796.e7.
20. Contal C and O'Quigley J: An application of
changepoint methods in studying the effect of
age on survival in breast cancer. Comput Stat
Data Anal 1999; 30: 253.
21. Mandrekar J, Mandrekar SJ and Cha SS: Cut-
point determination methods in survival analysis
using SAS. Proc 28th SAS Users Group Inter-
national (SUGI) March 28eApril 2, 2003, Seattle,
Washington. Available at https://support.sas.
com/resources/papers/proceedings/
proceedings/sugi28/261-28.pdf.
22. Froehner M, Novotny V, Heberling U et al:
Relationship of the number of removed lymph
nodes to bladder cancer and competing mortality
after radical cystectomy. Eur Urol 2014; 66: 987.
23. Abdollah F, Sun M, Schmitges J et al: Stage-
specific impact of pelvic lymph node dissection on
survival in patients with non-metastatic bladder
cancer treated with radical cystectomy. BJU Int
2012; 109: 1147.
24. Madeb R and Messing EM: Gender, racial and
age differences in bladder cancer incidence and
mortality. Urol Oncol 2004; 22: 86.
25. Mungan NA, Aben KK, Schoenberg MP et al:
Gender differences in stage-adjusted bladder
cancer survival. Urology 2000; 55: 876.
26. Bochner BH, Cho D, Herr HW et al: Prospectively
packaged lymph node dissections with radical
cystectomy: evaluation of node count variability
and node mapping. J Urol 2004; 172: 1286.
27. Dorin RP, Daneshmand S, Eisenberg MS et al:
Lymph node dissection technique is more
important than lymph node count in identifying
nodal metastases in radical cystectomy patients:
a comparative mapping study. Eur Urol 2011; 60:
946.
28. Zehnder P, Moltzahn F, Mitra AP et al: Radical
cystectomy with super-extended lymphadenec-
tomy: impact of separate vs en bloc lymph node
submission on analysis and outcomes. BJU Int
2016; 117: 253.

EDITORIAL COMMENT
The therapeutic utility of lymph node dissection
(LND) in muscle-invasive bladder cancer has been
established and incorporated into national guide-
lines. In this analysis, the authors sought to inves-
tigate and provide evidence for the role of LND in
nonmuscle-invasive bladder cancer (NMIBC). On
this multi-institutional review, increasing lymph
node yield correlates with improved oncologic and
survival outcomes, in particular for patients with
pT1 and pTis disease. This data driven conclusion
encourages increased application and thoroughness
of LND in the NMIBC setting.
Most urologists who perform radical cystectomy
will include LND as a standard part of the opera-
tion, even with NMIBC, and a recent analysis of the
National Cancer Database quoted the utilization of
LND for NMIBC to be approximately 80% (reference
19 in article). Khanna et al should be commended
for setting out to ascertain the value of LND in
NMIBC. They demonstrate that even with only 6%
of patients found to have pND disease, LND with
an increasing nodal yield is a harbinger for
improved oncologic and survival outcomes. Other
multi-institutional analyses of NMIBC patients
receiving LND have shown rates of pND as high as
16% when including only those with high grade
disease (reference 17 in article). Certainly, the
oncologic and survival value of LND is compelling
even with suspected NMIBC, and urologists should
consider LND the “gold standard” for radical cys-
tectomy with NMIBC.
Zachary Hamilton1 and Facundo Davaro1
1
Division of Urology
Saint Louis University
St. Louis, Missouri

Copyright © 2022 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.