Adult Urology

Oncology: Adrenal/Renal/Upper Tract/Bladder

Radical Nephrectomy with or without Lymph Node Dissection

for High Risk Nonmetastatic Renal Cell Carcinoma:
A Multi-Institutional Analysis
Boris Gershman,* R. Houston Thompson, Stephen A. Boorjian, Alessandro Larcher,
Umberto Capitanio, Francesco Montorsi, Cristina Carenzi, Roberto Bertini, Alberto Briganti,
Christine M. Lohse, John C. Cheville and Bradley C. Leibovich
From the Division of Urology, Rhode Island Hospital and The Miriam Hospital, Providence (BG), Rhode Island, Departments of
Urology (RHT, SAB, BCL), Health Sciences Research (CML) and Pathology (JCC), Mayo Clinic, Rochester, Minnesota, and
Department of Urology, San Raffaele Scientific Institute (AL, UC, FM, CC, RB, AB), Milan, Italy

Purpose: Lymph node dissection may benefit patients at increased risk for lymph
Abbreviations
node metastases from renal cell carcinoma. Therefore, we evaluated the associ-
and Acronyms
ation of lymph node dissection with survival in patients at high risk undergoing
radical nephrectomy for renal cell carcinoma. ACM ¼ all cause mortality

Materials and Methods: We identified 2,722 patients with M0 renal cell carci- CSM ¼ cancer specific mortality
noma who underwent radical nephrectomy with or without lymph node dissection CT/MRI ¼ computerized tomog-
at 2 international centers from 1990 to 2010. The associations of lymph node raphy/magnetic resonance
dissection with the development of distant metastases, and cancer specific and all imaging
cause mortality were evaluated using propensity score techniques and traditional ECOG ¼ Eastern Cooperative
multivariable Cox regression. Subset analyses were done to examine patients at Oncology Group
increased risk of lymph node metastases. IPW ¼ inverse probability weight
Results: Overall 171 patients (6.3%) had pN1 disease. Median followup was 9.6 LN ¼ lymph node
years. Clinicopathological features were well balanced after propensity score LND ¼ lymph node dissection
adjustment. Lymph node dissection was not significantly associated with a PS ¼ propensity score
reduced risk of distant metastases, or cancer specific or all cause mortality in the RCC ¼ renal cell carcinoma
overall cohort, among patients with preoperative radiographic lymphadenopathy
RN ¼ radical nephrectomy
(cN1), or across an increasing probability of pN1 disease from 0.10 or greater to
0.50 or greater. Neither extended lymph node dissection nor the extent of lymph
Accepted for publication November 30, 2017.
node dissection was associated with improved oncologic outcomes. No direct or indirect commercial incentive
Conclusions: The current analysis of a large, international cohort indicates that associated with publishing this article.
The corresponding author certifies that, when
lymph node dissection is not associated with improved oncologic outcomes among applicable, a statement(s) has been included in
patients at high risk who undergo radical nephrectomy for M0 renal cell carci- the manuscript documenting institutional review
noma. This includes patients with radiographic lymphadenopathy (cN1) and board, ethics committee or ethical review board
study approval; principles of Helsinki Declaration
across increasing probability thresholds of pN1 disease. were followed in lieu of formal ethics committee
approval; institutional animal care and use
Key Words: lymph node excision; nephrectomy; carcinoma, renal cell; committee approval; all human subjects provided
written informed consent with guarantees of
survival; propensity score confidentiality; IRB approved protocol number;
animal approved project number.
* Correspondence: Rhode Island Hospital and
The Miriam Hospital, Warren Alpert Medical
THE role of LND in the management of benefit,1e4 more recent investigations School of Brown University, 195 Collyer St., Suite
201, Providence, Rhode Island 02904 (telephone:
RCC has been controversial with con- have not demonstrated improved 401-272-7799; FAX: 401-453-9078; e-mail: Boris.
flicting data on its oncologic benefit. survival.5e7 Still, a small subset of Gershman@lifespan.org).
While older retrospective studies pro- patients with isolated LN involve-
vided initial support for an oncologic ment has achieved long-term survival

0022-5347/18/1995-1143/0 https://doi.org/10.1016/j.juro.2017.11.114
THE JOURNAL OF UROLOGY®
Ó 2018 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Vol. 199, 1143-1148, May 2018
Printed in U.S.A.
www.jurology.com j 1143
1144 NEPHRECTOMY WITH OR WITHOUT LYMPH NODE DISSECTION FOR RENAL CELL CANCER
following resection of LN metastases.8e10 Pro-
ponents of LND have suggested that it may benefit
patients at increased risk for LN metastases.11,12
Given the rarity of LN metastases, prior studies
may have been underpowered to detect a potential
benefit in such a small subset of patients at high risk.
In a recent study of patients with nonmetastatic RCC
we found no association of LND with oncologic out-
comes regardless of the risk of nodal involvement.7
However, that study was limited by a relatively
small number of patients at high risk and single
institution experience. In the current study we used
a large multi-institutional cohort to evaluate the
association of LND with survival in patients under-
going RN for RCC with a focus on patients at
high risk.
PATIENTS AND METHODS
Patient Population
After obtaining institutional review board approval at
each study site we identified a total of 2,722 patients who
underwent RN for sporadic, unilateral, M0 RCC between
1990 and 2010 at Mayo Clinic and San Raffaele Scientific
Institute. Of these patients 1,215 (45%) underwent
concomitant LND. The decision to perform LND was
based on surgeon discretion. A standardized template was
not used.
Clinicopathological Features
Recorded clinicopathological features included study
site, surgery year, patient age at surgery, gender,
symptoms at presentation, constitutional symptoms at
presentation, ECOG performance status, Charlson co-
morbidity score, surgical approach, pathological tumor
size, RCC histological subtype, TNM stage according to
the 2010 AJCC (American Joint Committee on Cancer)
classification, tumor grade according to the WHO/ISUP
(International Society of Urological Pathology) classifi-
cation and the presence of coagulative tumor necrosis or
sarcomatoid differentiation. Radiographic features were
abstracted from the medical records, including radio-
graphic lymphadenopathy (cN1), renal vein involvement
on CT/MRI, inferior vena cava tumor thrombus on CT/
MRI and radiographic evidence of extrarenal extension,
adrenal involvement, or cystic or indeterminate cysts.
Statistical Methods
Clinicopathological and radiographic features were sum-
marized with the median and IQR or the frequency count
and percent. They were separately compared by study site
and receipt of LND using the Wilcoxon rank sum and chi-
square tests. A PS for LND was obtained using a logistic
regression model with LND as the outcome and clinico-
pathological features (supplementary table 1, http://
jurology.com/).13 Of the 2,722 patients in the combined
cohort 2,657 had nonmissing data on all covariates stud-
ied, of whom 1,183 (45%) underwent LND. We excluded
150 patients from PS analyses because they had a PS that
did not fall within the common range. The final PS
analysis cohort comprised 2,507 patients, of whom 1,063
(42%) underwent LND. Of these patients 103 with a
missing cause of death were excluded from analyses of
CSM and 104 with missing information on postoperative
distant metastases were excluded from analyses of distant
metastases.
Associations of LND with time to distant metastases,
CSM and ACM were evaluated by Cox proportional haz-
ards regression models and summarized as the HR and
95% CI. Two PS techniques were used in these models,
including adjustment for PS quintiles and reweighting by
stabilized IPWs.13,14 Stabilized IPWs were truncated by
setting weights below the first percentile to the value of
the first percentile and weights above the 99th percentile
to the value of the 99th percentile. As a sensitivity anal-
ysis we evaluated the associations of LND with oncologic
outcomes using traditional multivariable Cox models
including all covariates studied for the 2,657 patients with
nonmissing data.
To evaluate the associations of LND with oncologic
outcomes among patients at increased risk for pN1 disease
we constructed Cox models including an indicator for LND,
an indicator for risk of pN1 disease and the interaction
term between the 2 indicators. We specifically examined
patients with preoperative radiographic lymphadenopathy
(cN1) as well as patients with a predicted 0.10 to 0.50
probability of pN1 disease. The predicted probability of
pN1 disease was estimated using a multivariable logistic
regression model (supplementary methods, http://jurology.
com/). Due to the small subset size there was residual
imbalance in several characteristics among patients with a
0.50 or greater predicted probability of pN1 disease.
Therefore, we further adjusted these analyses for those
covariates with residual imbalance.
As a secondary analysis we examined the association of
extended LND, defined as the removal of 13 or more
lymph nodes,15 with oncologic outcomes using multivari-
able regression adjusted for all study covariates. We also
evaluated the association of LND extent (ie the number of
LNs removed as a continuous variable) among patients
who underwent LND with oncologic outcomes using
multivariable regression adjusted for all study covariates.
Statistical analyses were performed with SASÒ, version
9.4 and R, version 3.1.1 (https://www.r-project.org/). All
tests were 2-sided with p <0.05 considered statistically
significant.
RESULTS
Of the 2,722 patients included in the overall cohort
1,215 (45%) underwent LND, 237 (9%) had cN1
disease and 171 (6%) had pN1 disease. A median of
6 LNs (IQR 3e11) were removed. Supplementary
table 1 (http://jurology.com/) summarizes clinico-
pathological and radiographic features stratified by
study site. There were statistically significant dif-
ferences in most patient characteristics according to
study site, reflecting differences in patient cohorts
and clinical practice.
Supplementary table 2 (http://jurology.com/)
shows clinicopathological and radiographic
 NEPHRECTOMY WITH OR WITHOUT LYMPH NODE DISSECTION FOR RENAL CELL CANCER 1145

Table 1. Clinicopathological features stratified by lymph node dissection in 2,437 patients in propensity score cohort after stabilized
IPW reweighting

No LND LND p Value

No. pts 1,398 1,039
No. study site (%): 0.37
Milan 456 (33) 357 (34)
Rochester 942 (67) 682 (66)
No. surgery yr (%): 0.27
1990e1995 404 (29) 282 (27)
1996e2000 331 (24) 243 (23)
2001e2005 376 (27) 288 (28)
2006e2010 287 (21) 226 (22)
Median age at surgery (IQR) 0.81
18e54 349 (25) 267 (26)
55e64 355 (25) 257 (25)
65e72 372 (27) 278 (27)
73 or Greater 322 (23) 237 (23)
No. female (%): 460 (33) 349 (34) 0.73
No. male (%): 938 (67) 690 (66)
Median Charlson score (IQR) 1 (0e2) 1 (0e2) 0.60
No. symptom (%) 721 (52) 544 (52) 0.69
No. constitutional symptom (%) 231 (17) 177 (17) 0.75
No. ECOG performance status (%): 0.55
0 944 (68) 688 (66)
1 333 (24) 261 (25)
2 102 (7) 72 (7)
3 17 (1) 18 (2)
4 2 (less than 1) 0
No. cN1 (%) 47 (3) 47 (4) 0.15
No. involvement on CT/MRI (%):
Renal vein 146 (10) 127 (12) 0.17
Inferior vena cava 97 (7) 80 (8) 0.48
No. radiographic evidence (%):
Extrarenal extension 49 (3) 41 (4) 0.55
Adrenal involvement 5 (less than 1) 6 (1) 0.57
Cystic or indeterminate cysts 179 (13) 125 (12) 0.57
No. radical nephrectomy type (%): 0.65
Open 1,241 (89) 929 (89)
Laparoscopic 157 (11) 110 (11)
No. RCC histological subtype (%): 0.54
Clear cell 1,130 (81) 845 (81)
Papillary 162 (12) 112 (11)
Chromophobe 83 (6) 66 (6)
Collecting duct 3 (less than 1) 3 (less than 1)
Not otherwise specified 15 (1) 7 (1)
Mucinous tubular 1 (less than 1) 0
and spindle cell
Translocation-associated 1 (less than 1) 0
Clear cell papillary 3 (less than 1) 6 (1)
Tumor size 6.3 (4.3e9.0) 6.5 (4.5e9.0) 0.15
No. 2010 pT stage (%): 0.12
pT1a 299 (21) 195 (19)
pT1b 401 (29) 301 (29)
pT2a 182 (13) 136 (13)
pT2b 96 (7) 71 (7)
pT3a 321 (23) 253 (24)
pT3b 64 (5) 54 (5)
pT3c 23 (2) 18 (2)
pT4 12 (1) 11 (1)
No. grade (%): 0.09
1 104 (7) 70 (7)
2 668 (48) 471 (45)
3 531 (38) 413 (40)
4 95 (7) 85 (8)
No. Coagulative tumor necrosis (%) 473 (34) 372 (36) 0.31
No. Sarcomatoid differentiation (%) 34 (2) 34 (3) 0.26

features stratified by the performance of LND. radiographic features were well balanced after PS
Although patients who underwent LND had adjustment. There were no statistically significant
more advanced pT stage and more aggressive differences after reweighting the combined cohort
tumor characteristics, clinicopathological and by IPWs (table 1).
1146 NEPHRECTOMY WITH OR WITHOUT LYMPH NODE DISSECTION FOR RENAL CELL CANCER
Median followup among survivors was 9.6 years
(IQR 5.6e14.3). During this time distant metastases
developed in 787 patients and 1,397 died, including
622 of RCC.
We first examined the associations of LND with
oncologic outcomes in the overall cohort (table 2
and supplementary material, http://jurology.com/).
LND was not significantly associated with CSM or
ACM using PS techniques or traditional multi-
variable regression. LND was associated with a
modestly increased risk of distant metastases
using IPWs (HR 1.17, 95% CI 1.00e1.36, p ¼ 0.046)
and traditional regression (HR 1.20, 95% CI
1.01e1.42, p ¼ 0.040) which just reached statisti-
cal significance.
Next we examined the associations of LND with
oncologic outcomes among patients at increased risk
for pN1 disease (table 3). LND was not associated
with the development of distant metastases, CSM or
ACM in patients with preoperative radiographic
lymphadenopathy (cN1). No consistent association
of LND with improved oncologic outcomes was noted
across increasing probability thresholds of pN1 dis-
ease from 0.10 or greater to 0.50 or greater. Specif-
ically among patients with a threshold predicted
probability of pN1 disease ranging from 0.10 or
greater to 0.40 or greater LND was not significantly
associated with improved oncologic outcomes using
PS techniques or traditional multivariable regres-
sion. Among patients with a 0.50 or greater pre-
dicted probability of pN1 disease there was evidence
of improved oncologic outcomes with LND using PS
techniques. However, given the small size of this
subset, there was residual imbalance in several
covariates. After further adjustment for residually
imbalanced covariates there was no consistent as-
sociation of LND with oncologic outcomes. Similarly
using traditional multivariable regression LND was
not significantly associated with improved oncologic
outcomes.
Table 2. LND associations with oncologic outcomes in overall
cohort adjusted by propensity score quintiles, stabilized IPW
reweighting and multivariable adjustment for all covariates
LND vs no LND
PS Technique HR (95% CI)
Distant metastasis:
PS quintiles 1.09 (0.91e1.29)
IPWs 1.17 (1.00e1.36)
Multivariable 1.20 (1.01e1.42)
Ca specific mortality:
PS quintiles 1.01 (0.83e1.22)
IPWs 1.09 (0.92e1.30)
Multivariable 1.11 (0.92e1.34)
All cause mortality:
PS quintiles 1.01 (0.88e1.15)
IPWs 1.02 (0.91e1.14)
Multivariable 1.11 (0.97e1.26)
As a secondary analysis we assessed 241 patients
(9%) who underwent extended LND, defined as the
removal of 13 or more lymph nodes. After multi-
variable adjustment extended LND was not signif-
icantly associated with the development of distant
metastases (HR 1.08, 95% CI 0.86e1.35, p ¼ 0.50),
CSM (HR 1.07, 95% CI 0.83e1.39, p ¼ 0.60) or ACM
(HR 1.11, 95% CI 0.90e1.37, p ¼ 0.35).
In a separate secondary analysis we evaluated
the association of LND extent with oncologic out-
comes. Among patients who underwent LND the
number of LNs removed as a continuous variable
was not significantly associated with the develop-
ment of distant metastases (HR 1.07, 95% CI
0.95e1.22, p ¼ 0.26), CSM (HR 0.99, 95%
CI 0.85e1.15, p ¼ 0.90) or ACM (HR 1.04, 95% CI
0.92e1.18, p ¼ 0.54) after multivariable
adjustment.
DISCUSSION
In this study of a large international cohort we
observed no survival benefit to LND in patients
with nonmetastatic RCC. In particular even
among patients at high risk, including those with
preoperative radiographic lymphadenopathy, or
across increasing disease risk (ie the threshold
probability of pN1 disease) LND was not associ-
ated with oncologic outcomes. Similarly neither
extended LND nor the extent of LND was associ-
ated with improved survival. These results rein-
force prior retrospective studies that did not
demonstrate a survival benefit for LND5,7,16 as
well as the only randomized trial, EORTC 30881,
to examine this clinical question.6
The greatest limitation of prior studies,
including EORTC 30881,6 was a low incidence of LN
involvement. Since these are the patients who in
principle may benefit from LND, the proponents of
LND have contended that LND may benefit this small
patient subset.11,12 In support of this hypothesis
studies in patients with surgically resected pN1 M0
disease have consistently identified a subset with long-
term survival.8e10,17 Given the rarity of LN involve-
ment in nonmetastatic RCC, it would be difficult to
accrue a randomized trial to evaluate this question
p Value and single institutional series may likewise be un-
derpowered. Indeed, the impetus for the current study
0.35 arose from our recent examination of LND in non-
0.046 metastatic RCC, in which we found no benefit to LND
0.040
even in high risk patient groups.7 Like other retro-
0.94 spective investigations,5 that study was limited by a
0.33 relatively few patients at high risk. To this end the
0.29
current collaboration provides the largest interna-
0.91 tional cohort in which to evaluate the oncologic
0.80 efficacy of LND in patients with high risk, non-
0.12
metastatic RCC.
 NEPHRECTOMY WITH OR WITHOUT LYMPH NODE DISSECTION FOR RENAL CELL CANCER 1147

Table 3. Lymph node dissection associations with oncologic outcomes in patients at increased risk for pN1 disease adjusted by
propensity score quintiles, stabilized IPW reweighting and multivariable adjustment of all covariates

Distant Metastasis Ca Specific Mortality All Cause Mortality

PS Technique LND vs no LND HR (95% CI) p Value LND vs no LND HR (95% CI) p Value LND vs no LND HR (95% CI) p Value
PS quintiles
cN1 0.62 (0.32e1.19) 0.15 0.94 (0.42e2.10) 0.88 1.12 (0.59e2.14) 0.74
pN1 probability:
0.10 or Greater 1.19 (0.94e1.50) 0.15 1.05 (0.82e1.35) 0.68 1.30 (1.06e1.59) 0.01
0.20 or Greater 1.25 (0.87e1.80) 0.22 1.22 (0.84e1.79) 0.30 1.50 (1.10e2.05) 0.01
0.30 or Greater 1.34 (0.84e2.13) 0.22 1.59 (0.95e2.66) 0.08 1.67 (1.12e2.48) 0.01
0.40 or Greater 0.91 (0.50e1.65) 0.75 1.12 (0.57e2.20) 0.75 1.08 (0.61e1.89) 0.80
0.50 or Greater 0.43 (0.19e0.94) 0.03 0.72 (0.30e1.72) 0.46 0.73 (0.35e1.55) 0.42
0.50 or Greater* 0.57 (0.26e1.25) 0.16 0.95 (0.39e2.28) 0.90 0.83 (0.39e1.76) 0.62
IPWs
cN1 0.59 (0.32e1.12) 0.11 1.01 (0.47e2.20) 0.97 1.09 (0.59e1.99) 0.78
pN1 probability:
0.10 or Greater 1.21 (0.98e1.49) 0.08 1.05 (0.84e1.32) 0.65 1.12 (0.93e1.36) 0.22
0.20 or Greater 1.28 (0.91e1.80) 0.15 1.27 (0.89e1.83) 0.19 1.23 (0.91e1.67) 0.18
0.30 or Greater 1.13 (0.73e1.77) 0.58 1.41 (0.85e2.35) 0.19 1.21 (0.81e1.80) 0.36
0.40 or Greater 0.79 (0.45e1.41) 0.43 1.06 (0.56e2.00) 0.86 0.81 (0.47e1.38) 0.43
0.50 or Greater 0.43 (0.19e0.95) 0.04 0.54 (0.23e1.26) 0.15 0.32 (0.15e0.67) 0.003
0.50 or Greater* 0.62 (0.28e1.41) 0.25 0.76 (0.32e1.83) 0.55 0.37 (0.18e0.79) 0.01
Multivariable
cN1 0.97 (0.53e1.77) 0.92 1.29 (0.61e2.74) 0.50 1.37 (0.75e2.50) 0.31
pN1 probability:
0.10 or Greater 1.22 (0.97e1.54) 0.09 1.02 (0.79e1.30) 0.90 1.24 (1.01e1.51) 0.04
0.20 or Greater 1.42 (1.00e2.04) 0.05 1.25 (0.86e1.83) 0.24 1.39 (1.02e1.89) 0.04
0.30 or Greater 1.29 (0.83e2.02) 0.26 1.39 (0.84e2.31) 0.20 1.33 (0.90e1.96) 0.15
0.40 or Greater 1.33 (0.75e2.36) 0.33 1.36 (0.71e2.60) 0.36 1.15 (0.68e1.94) 0.61
0.50 or Greater 1.04 (0.51e2.09) 0.92 1.31 (0.61e2.85) 0.49 1.17 (0.60e2.26) 0.65

* Evaluated after further adjustment for covariates with evidence of residual imbalance between treatment groups with significance level of 0.10 in patient subset with 0.50
or greater predicted probability, including surgery year, ECOG performance status and histological subtype.

Several potential mechanisms may explain the
apparent lack of benefit to LND even in patients at
high risk. Perhaps most importantly RCC is rarely
associated with LN involvement in the absence of
concurrent distant metastases.1,12,18,19 Indeed,
clinical metastases develop in most patients with
clinically isolated pN1 disease within 12 months of
surgery.9 The largely hematogenous dissemina-
tion route of RCC may reflect tumor biology or
anatomical considerations since direct lymphove-
nous communications bypassing the retroperito-
neal LNs were described in several anatomical
studies.20
Despite the absence of robust data to support an
oncologic benefit to LND, it may still have an impor-
tant staging role in RCC management. Lymph node
metastases have been associated with poor prognosis
in nonmetastatic and metastatic RCC.1,9,21,22 Accord-
ingly LND may provide actionable staging informa-
tion to select patients for more intensive surveillance
protocols, consideration of adjuvant systemic ther-
apy23 or enrollment in a clinical trial.
There are several limitations to the current
study. It is retrospective, and residual selection
bias and unmeasured confounding remain a po-
tential issue despite attempts to adjust for a non-
randomized design. Evidence of reverse cause in
several subset analyses may reflect these consid-
erations. Moreover, the decision to perform LND
and the boundaries of LND were not standardized,
and they varied in and across institutions. A ran-
domized trial of LND in high risk RCC would be
ideal to overcome such limitations of observational
study design but, given the rarity of pN1 M0 dis-
ease, it may be difficult to perform.
In addition, we were unable to further categorize
cN1 status according to the size of radiographic
lymphadenopathy or the number of enlarged LNs.
Furthermore, use of a multi-institutional cohort
introduced heterogeneity in patient selection and
clinical practice. Finally, it is still possible that
there is a high risk subset which we did not examine
in this study that may derive a survival benefit
from LND.
CONCLUSIONS
The current analysis of a large, international cohort
indicates that LND is not associated with improved
oncologic outcomes among patients who undergo RN
for M0 RCC. This includes patients at increased risk
for LN metastases such as those with radiographic
lymphadenopathy (cN1) or across increasing proba-
bility thresholds for pN1 disease.
1148 NEPHRECTOMY WITH OR WITHOUT LYMPH NODE DISSECTION FOR RENAL CELL CANCER
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