0022-5347/03/1696-2076/0 Vol.

169, 2076 –2083, June 2003

THE JOURNAL OF UROLOGY® Printed in U.S.A.
Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION DOI: 10.1097/01.ju.0000066130.27119.1c

RENAL CELL CARCINOMA WITH RETROPERITONEAL LYMPH NODES:

ROLE OF LYMPH NODE DISSECTION

ALLAN J. PANTUCK, AMNON ZISMAN, FREDRICK DOREY, DEBBY H. CHAO, KEN-RYU HAN,
JONATHAN SAID, BARBARA J. GITLITZ, ROBERT A. FIGLIN AND ARIE S. BELLDEGRUN
From the Departments of Urology, Medicine and Pathology and Laboratory Medicine, University of California School of Medicine,
Los Angeles, California

ABSTRACT

Purpose: We better defined the benefits and morbidity of lymph node dissection in patients
with localized renal cell carcinoma using the experience of patients treated at our institution.
Materials and Methods: A retrospective cohort study was performed with outcome assessment
based on the chart review of demographic, clinical and pathological data in 1,087 patients with
renal cell carcinoma treated at our institution. Patients with renal cell carcinoma who did not
undergo nephrectomy as part of cancer treatment, those with bilateral disease and those for
whom nodal status was unknown were not included in this study. A total of 900 patients meeting
these criteria who underwent nephrectomy for unilateral renal cell carcinoma at our medical
center form the principal study population.
Results: Positive lymph nodes were associated with larger, higher grade, locally advanced
primary tumors that were more commonly associated with sarcomatoid features. Positive nodes
were 3 to 4 times more common in patients with metastatic disease and the majority of these
patients could be identified preoperatively. The survival of patients with regional lymph node
involvement only was identical to that of patients with distant metastatic disease only. Patients
with regional nodes and distant metastases had significantly inferior survival to those with
either condition alone. In node negative cases lymph node dissection can be performed with no
additional morbidity but it confers no survival advantage. In node positive cases lymph node
dissection can also be performed safely but it is associated with improved survival and a trend
toward an improved response to immunotherapy.
Conclusions: Regional lymph node dissection is unnecessary in patients with clinically nega-
tive lymph nodes since it offers extremely limited staging information and no benefit in terms of
decreasing disease recurrence or improving survival. In patients with positive lymph nodes
lymph node dissection is associated with improved survival when it is performed in carefully
selected patients undergoing cytoreductive nephrectomy and postoperative immunotherapy.
When lymph nodes are present, they should be resected when technically feasible.
KEY WORDS: carcinoma, renal cell; lymph node dissection; kidney; survival; immunotherapy

In 1969 Robson et al advocated dissection of the para-aortic
and paracaval lymph nodes from the bifurcation of the aorta
to the crus of the diaphragm as a necessary component of
radical nephrectomy, and suggested that the improved sur-
vival of patients undergoing radical nephrectomy was due in
part to this retroperitoneal lymph node dissection.1 In this
classic report written before adequate preoperative imaging
22.7% of patients undergoing radical nephrectomy had posi-
tive lymph nodes, and yet survival was equivalent to that in
patients with renal vein tumoral involvement only. The To-
ronto group continued to advocate the benefits of lymph node
dissection 2 decades later after examining long-term survival
in 162 cases of renal cell carcinoma treated with radical
nephrectomy2 despite conflicting results that have appeared
in the literature concerning the possible benefits of lymph
node dissection.1, 3–14 However, other aspects of radical ne-
phrectomy, such as the necessity of removing the whole kid-
ney15, 16 or routine adrenalectomy, have recently been shown
not to be necessary or beneficial in most adequately staged
renal cell carcinoma cases.17, 18
In the era prior to immunotherapy for advanced or meta-
static disease pathological evidence of lymph node positive
disease portended a striking decrease in life expectancy for
Accepted for publication December 13, 2002.
2076
patients with renal cell carcinoma.19, 20 However, the signif-
icance of lymphadenopathy and the relative benefit of retro-
peritoneal lymph node dissection in the context of cytoreduc-
tive nephrectomy and modern adjunctive immunotherapy
has not been adequately examined. Intuitively the inclusion
of retroperitoneal lymph node dissection during radical ne-
phrectomy should at least add information relevant to stag-
ing and the determination of prognosis but more intriguing is
the question of whether it exerts a survival advantage and
what trade-off must be made for this possible benefit in
respect to potential additional morbidity and mortality. Do
patients without evidence of adenopathy experience de-
creased recurrence rates or improved survival due to lymph
node dissection? Cytoreductive nephrectomy has been shown
in 2 phase III randomized studies to improve the survival of
patients with metastatic renal cell carcinoma21, 22 but is it
necessary to perform lymph node dissection in the context of
distant metastatic disease? Is it necessary to perform full
retroperitoneal node dissection or is more limited dissection
as beneficial? We better defined the benefits and morbidity of
lymph node dissection for patients with localized and meta-
static renal cell carcinoma using the experience of those
treated at our institution in a multidisciplinary program for
kidney cancer.
 RENAL CELL CANCER WITH RETROPERITONEAL LYMPH NODES
MATERIALS AND METHODS
Patients. With approval by the University of California-Los
Angeles institutional review board (99-233) a retrospective
cohort study was performed with outcome assessment based
on a chart review of demographic, clinical, and pathological
data on patients with renal cell carcinoma treated at our
institution. The records of 1,087 patients were reviewed.
Patients with renal cell carcinoma who did not undergo ne-
phrectomy as part of cancer treatment, patients with bilat-
eral synchronous tumors whose analysis required special
modeling, those with familial renal cell carcinoma syn-
dromes, including the von Hippel-Lindau syndrome, and pa-
tients for whom nodal status was unknown were not included
in this study. Between 1989 and 2000, 900 patients meeting
these criteria underwent nephrectomy for unilateral renal
cell carcinoma at our medical center and they form the prin-
cipal study population of this report. All patients underwent
radical or partial nephrectomy and the majority of those with
metastases were treated with recombinant interleukin-2
(IL-2) based immunotherapy regimens within the frame of 11
clinical trials. Clinical or pathological details resulting from
lymph node dissection during nephrectomy were available
for 798 of the 900 patients.
Stage was determined according to the 1997 UICC TNM
classification of malignant tumors, 5th edition.23 Clinical and
pathological findings were gathered for staging at operation.
T stage was defined by pathological examination, and the N
and M components were defined according to pathological
findings or by clinical data when applicable. Renal cell car-
cinomas were classified and graded according to current con-
sensus standards24, 25 by a small group of experienced pathol-
ogists. Grading was determined according to the 4 tiered
Fuhrman system.26 Eastern Cooperative Oncology Group
(ECOG) performance status was determined at initial pre-
sentation and at each followup.
Patients were divided into 4 pathological groups; including
those with no regional lymph nodes or metastatic disease at
diagnosis, those with regional lymph nodes only (fig. 1); those
with distant metastatic disease only and those with regional
lymph nodes as well as distant metastatic disease. These
groups were subdivided into cohorts that did and did not
undergo retroperitoneal lymph node dissection at nephrec-
tomy. Clinically lymphadenopathy was defined as enlarged
hilar or retroperitoneal lymph nodes 1 cm.3 or greater on
preoperative computerized tomography or magnetic reso-
nance imaging. The extent of lymph node dissection was
determined by a review of surgical reports. Clinical end
points for patients without nodes or metastasis at nephrec-
tomy were overall survival, disease specific survival and free-
dom from local or systemic recurrence. Clinical end points for
FIG. 1. A, 32-year-old male who presented with hematuria and nonspecific abdominal pain had small, central right renal cell carcinoma,
bulky retroperitoneal adenopathy and no evidence of distant metastatic disease. B, microscopic foci (arrows) of clear cell carcinoma within
lymph node surrounding renal pedicle. Reduced from ⫻40.
2077
patients with nodes and/or metastasis were overall survival
and disease specific survival, and local or systemic recur-
rence. The impact of lymph node dissection on operative
time, estimated operative blood loss, transfusion require-
ments, hospital stay, perioperative death and complication
rates, impact on eligibility to receive post-cytoreductive ne-
phrectomy immunotherapy and best overall response follow-
ing immunotherapy was considered. Intraoperative compli-
cations that are recorded in the kidney cancer data base and
are relevant to lymph node dissection include injuries to the
aorta and inferior vena cava, duodenal lacerations and other
enterotomies as well as hepatic and splenic tears. Acute and
delayed postoperative complications recorded include lower
extremity edema, deep vein thrombosis, postoperative bleed-
ing, renal failure, adrenal insufficiency, chylous ascites, pro-
longed ileus and ischemic colitis. In an effort to decrease the
possibility of selection bias the cohorts treated with and
without lymph node dissection were compared using the
ANOVA method to determine the relative distribution in
each group of relevant prognostic factors, including stage,
grade and ECOG performance status.
Survival analysis and statistical methods. The end point of
interest was survival time, defined as time from treatment
initiation (nephrectomy) to the date of death or last followup.
Survival distributions were estimated using the Kaplan-
Meier method. Comparisons between groups were performed
by the log rank method to assess the significance of the
Kaplan-Meier curves. To consider potential interactions
among numerous variables simultaneously clinical and
pathological parameters were evaluated using univariate
and multivariate Cox proportional hazard models27 to deter-
mine the variables that independently correlated with pro-
gressive disease and cancer death. The Pearson chi-square,
Wilcoxon rank sum (Mann-Whitney) and 2-sample Student t
tests were used when indicated. Data was analyzed using
commercially available software. For all tests a difference
was considered significant at p ⬍0.05.
RESULTS
At diagnosis 535 patients (59%) had no evidence of regional
lymph nodes or distant metastasis (N0M0), 129 (14%) had ev-
idence of regional lymph nodes (N⫹) and 236 (26%) had evi-
dence of distant metastasis only (N0M1). Of the 129 N⫹ cases
47 were pathological N1, while 82 were pathological N2. A total
of 43 patients had nodal disease only (N1M0), while 86 pre-
sented with coexisting distant metastatic disease (N⫹M1). In
M0 cases there was a 7.4% overall incidence of regional lymph
nodes compared with 26.7% of M1 cases that presented with
lymphadenopathy. Median followup for patients alive at the
2078 RENAL CELL CANCER WITH RETROPERITONEAL LYMPH NODES

last followup was 30 months. Median time to death was 16 TABLE 1. Clinical characteristics of patients with and without
months. Figure 2 shows the survival of the 4 groups. The best regional retroperitoneal lymphadenopathy
survival was seen in patients without nodal or metastatic dis- No. Node Neg. No. Node Pos.
p Value
ease. The survival of patients with nodal disease only (N⫹) was (%) (%)
equivalent to that in patients presenting with distant metasta- Total pts. 771 129
ses (p ⫽ 0.59), while the survival of patients presenting with Males 509 (66) 76 (59) 0.146
nodal and metastatic disease was significantly worse (p ⫽ 0.01). Rt. tumor 415 (54) 64 (50) 0.03
Smokers 407 (53) 73 (57) 0.456
Table 1 lists the demographics of patients presenting with Mean pack yrs. 16.5 17.5
and without regional lymph nodes at diagnosis. Patients with Metastatic disease 236 (31) 86 (66)
lymph nodes tended to present at a younger age, had larger N1 Not applicable 43 (33)
primary tumors that more commonly occurred on the right N2 Not applicable 86 (67)
Clear cell 595 (77) 84 (65)
side, were more likely to have metastatic disease at presen- Papillary 101 (13) 19 (14.7)
tation, presented with higher pathological T stage, and had Sarcomatoid 42 (5.4) 20 (15.5)
worse ECOG performance status and higher grade tumors. Stage (%): 0.008
Patients with regional nodes were 3 times more likely to have T1 (less than 7 283 (38) 7 (6)
cm.)
a tumor with predominantly sarcomatoid histology. Com- T2 (greater than 116 (16) 15 (12)
pared with 54% of N0 cases only 18% of N⫹ cases presented 7 cm.)
with organ confined disease and 67% versus 32% presented T3 310 (42) 88 (69)
with low grade (1 to 2) tumors, respectively. The median T4 33 (4) 17 (13)
Organ confined (54) (18)
survival of patients with nodal and distant metastatic dis- ECOG performance 0.006
ease was 10 months compared with twice that in patients status (%):
with nodal or distant metastases only (p ⫽ 0.002). Long-term 0 325 (45) 30 (25)
5-year survival of patients with node positive disease was 1 373 (52) 81 (66)
2 19 (3) 11 (9)
23%. Grade (%): 0.009
Table 2 shows clinical characteristics and outcomes of pa- 1/2 466 (67) 38 (32)
tients who were treated with and without regional lymph 3/4 236 (33) 83 (68)
node dissection at nephrectomy. Overall 54% of the whole
study cohort underwent some degree of lymph node dissec-
tion, including limited dissection in 64%, full template dis-
section in 20% and lymph node dissection of unspecified The overall, local, and distant recurrence-free survival of
extent in 16%. For patients without metastasis there were no 257 patients with node negative disease who underwent no
statistically significant differences between those who did lymph dissection was the same as the survival of 238 with
and did not undergo lymph node dissection in terms of sur- node negative disease who underwent lymph node dissec-
gery time, estimated blood loss, transfusion requirements, tion (p ⫽ 0.42, fig. 3). Survival was equivalent in those who
perioperative complication rates or hospitalization. Patients underwent limited, full and an unspecified degree of lymph
with metastatic disease had greater blood loss, transfusion node dissection (data not shown). However, there was a
requirements, surgery time, hospital time, and surgical com- statistically significant survival advantage in 112 patients
plication rates than patients with nonmetastatic disease. with node positive disease who underwent lymph node
However, an ANOVA test including metastatic disease and dissection compared with 17 who did not undergo lymph
lymph node dissection as variables did not demonstrate a node dissection on univariate analysis (p ⫽ 0.0002, fig. 4).
greater morbidity of lymph node dissection in M1 compared Median survival was approximately 5 months better in
with M0 cases. The differences in outcomes for patients with those undergoing lymphadenectomy. A similar proportion
M1 disease who did and who did not undergo lymph node in each group received immunotherapy following nephrec-
dissection did not achieve statistical significance. tomy. Of those who did not undergo lymph node dissection

FIG. 2. Kaplan-Meier survival curves for 4 patient cohorts. Similar survival was noted in patients with lymphadenopathy or distant
metastases, while those with positive lymph nodes and distant metastatic disease had significantly worse survival.
 RENAL CELL CANCER WITH RETROPERITONEAL LYMPH NODES 2079
TABLE 2. Clinical characteristics of patients with and without nal cell carcinoma.21, 22 The 5-year survival rate for all dis-
retroperitoneal lymph node dissection during nephrectomy ease stages in patients with renal cell carcinoma has contin-
No Node Node p ued to improve.28 However, it remains unclear what portion,
Dissection Dissection Value if any, of this improved survival can be attributed to retro-
No. pts. (%) 365 (46) 433 (54) peritoneal lymph node dissection as advocated by Robson et
No. disease (%): al in their classic study describing the surgical management
M1 108 (36) 195 (64) of renal cell carcinoma.1 Recognizing the unpredictable lym-
M0 257 (52) 238 (48)
% Dissection:
phatic drainage from renal tumors along with the incidence
Full Not applicable 20 of concomitant blood borne metastases,29 the practice of sys-
Limited Not applicable 64 tematic, extended lymphadenectomy has decreased at many
Unspecified Not applicable 16 institutions and many patients are left with unknown patho-
Mean estimated blood loss ⫾ SE (ml.): 0.057
M1 913 ⫾ 1,526 1,132 ⫾ 1,753
logical nodal status.30
M0 652 ⫾ 963 856 ⫾ 1,301 The published literature has been scant and contradictory
% Transfusion: 0.058 in its conclusions regarding the benefits of lymphadenecto-
M1 38 47 0.143 my1, 3–13 with many earlier studies promoting the value of
M0 36 34
Mean operative time ⫾ SE (mins.): 0.32
lymphadenectomy, while more recent studies failed to show
M0 178 ⫾ 63 187 ⫾ 78 any benefit. Positive lymph nodes are commonly associated
M1 201 ⫾ 93 205 ⫾ 87 with metastatic disease and yet the literature on lymph node
Mean hospital stay ⫾ SE (days): 0.65 dissection in patients with known metastatic disease is even
M0 6.7 ⫾ 5.8 7.4 ⫾ 5.03
M1 7.9 ⫾ 7.3 7.7 ⫾ 8.1
more scant.14 Johnsen and Hellsten studied 554 cases involv-
No. periop. deaths 4 4 ing renal cell carcinoma diagnosed at autopsy and found only
% Complications: 80 (14%) with positive lymph nodes, including 75 with addi-
M0 23 17 tional distant metastases, of which only 5 showed nodal
M1 24 25
% Recurrence:
disease confined to the tissues surrounding the great ves-
Local 0.01 0.06 sels.31 Thus, fewer than 1% of cases were theoretically cur-
Any 10.7 23.8 able by nephrectomy and lymph node dissection alone. The
incidence of positive lymph nodes at nephrectomy has de-
creased dramatically with the introduction of computerized
tomography1, 12 and improved preoperative staging.
71% remained eligible to receive systemic immunotherapy Lymph node dissection has been proposed to offer several
compared with 63% who underwent lymph node dissection. possible benefits, including staging and prognosis, decreas-
ANOVA analysis showed no difference in the distribution ing local or systemic recurrence, and improved survival. The
of tumor stage or ECOG performance status between these original study of Robson et al showed a 23% incidence of
2 groups. However, there was an imbalance between the 2 positive nodes in patients who underwent extensive lymph-
groups in the distribution of tumor grade with patients adenectomy, which was associated with 10-year survival that
who underwent lymph node dissection more likely to have approached 35%.1 Several contemporaneous series showed
higher grade tumors. In N⫹ cases 50% of grade 1, 72% of
5-year survival rates of only 15% but the extent of lymph
grade 2, 92% of grade 3 and 100% of grade 4 tumors were
node dissection was not specified.3–5 Phillips and Messing
associated with concomitant lymph node dissection at ne-
reported that in a series of 37 patients who underwent rad-
phrectomy. Thus, the survival of patients with N⫹ disease
ical nephrectomy and later had progression local control was
undergoing lymph node dissection was better than those
improved by lymph node dissection without extending hospi-
not undergoing lymphadenectomy despite a worse pre-
tal stay or adding to surgical morbidity.10 Herrlinger et al
dicted prognosis since patients with higher grade tumors
compared the survival of 511 patients undergoing radical
have been shown to have worse survival than those with
nephrectomy, of whom 320 underwent extended dissection
lower grade disease. Despite the positive impact on sur-
and 191 underwent only facultative or staging lymphadenec-
vival there was no difference in local or systemic recurrence
tomy.9 They found 56% 10-year survival in those who under-
rates following lymph node dissection and recurrence rates
went extended dissection compared with only 41% in those
were similar regardless of the extent of lymph node dissection
treated with facultative lymphadenectomy only (p ⬍0.01).
(p ⫽ 0.57).
More recently, Minervini et al evaluated a series of 167
A number of Cox multivariate regression models were per-
patients, including 108 who underwent nephrectomy alone
formed to analyze variables that were independently predic-
and 59 who underwent nephrectomy with regional lymph
tive of survival in N⫹ cases, including lymph node dissection,
node dissection limited to the anterior, posterior and lateral
tumor grade, ECOG performance status, immunotherapy,
sides of the ipsilateral great vessel from the level of the renal
metastatic disease and tumor stage (table 3). In each model
vessels down to the inferior mesenteric artery.13 In this se-
the absence of lymph node dissection remained a significant
ries the 5-year survival rate for the 108 patients who under-
predictor of decreased survival since patients not undergoing
went nephrectomy alone was 79%, which was the same as the
lymph node dissection were 3 times more likely to die than
78% rate for those who also underwent lymph node dissec-
those who underwent the procedure. Patients with N⫹ dis-
tion, suggesting no clinical benefit.
ease who underwent lymph node dissection had only a 44%
The only randomized phase III trial to address the benefits
incidence of progressive disease following 1 course of immu-
of lymph node dissection during radical nephrectomy for
notherapy compared with 56% of those in whom lymph nodes
patients with resectable nonmetastatic renal cell carcinoma
were left in place. In the multivariate model immunotherapy
was performed by the European Organization for the Re-
had a protective effect on the survival of those in whom the
search and Treatment of Cancer Genitourinary Group in
nodes were removed that approached statistical significance
study 30881.12 In this study dissection extended from the
(p ⫽ 0.057).
crus of the diaphragm inferior to the bifurcation of the aorta.
The incidence of unsuspected lymph nodes after proper pre-
DISCUSSION
operative staging was only 3.3% and complication rates were
Surgery remains the mainstay of treatment for locally similar between the 2 groups. Only the preliminary results of
confined renal cell carcinoma and it has recently been shown this study have been published since in 1999 only 17% of
to be a fundamental part of an integrated treatment plan patients enrolled had achieved a survival end point.
along with immunotherapy for patients with metastatic re- In the current University of California-Los Angeles data
2080 RENAL CELL CANCER WITH RETROPERITONEAL LYMPH NODES

FIG. 3. Survival of 495 patients undergoing nephrectomy for clinically localized disease was same regardless of whether they underwent
lymph node dissection (LND) at nephrectomy.

FIG. 4. Survival of patients with metastatic disease undergoing cytoreductive nephrectomy prior to planned systemic immunotherapy was
significantly better in those undergoing lymph node dissection (LND) as part of nephrectomy.

presented despite the addition of essentially no significant
additional morbidity or mortality lymph node dissection dur-
ing nephrectomy in patients with clinically negative lymph
nodes did not add a measurable benefit. We could not detect
a decrease incidence of local or systemic recurrence, or an
added benefit in terms of survival in clinically node negative
cases. Furthermore, in the current study population of 900
patients the incidence of patients presenting with regional
nodal metastases in the absence of distant disease was less
than 5% (43 of 900). It is likely that many of these patients
are identified preoperatively by computerized tomography or
intraoperatively by surgical exploration. In the remainder in
whom disease is unrecognized it is just as likely that lymph
nodes may be found in the perirenal fat and surrounding the
pedicle as along the great vessels. Fewer than 8% of node
positive cases in this study were discovered incidentally in
the sense that nodes were found in the pathological specimen
without a clinical impression of nodal involvement. Clearly
the majority of node positive cases are identified prior to
lymph node dissection. Furthermore, only 5 patients (less
than 0.5%) in the whole University of California-Los Angeles
data base presented with a tumor of less than 7 cm. and
without coexisting distant metastases, and only 10 presented
with organ confined disease without metastatic disease. This
knowledge has great implications regarding the manage-
ment of small (less than 4 cm.) incidental renal mass, for
which current trends have shifted toward minimally invasive
as well as percutaneous ablative techniques that may pre-
 RENAL CELL CANCER WITH RETROPERITONEAL LYMPH NODES
TABLE 3. Cox multivariate survival analysis of patients with
retroperitoneal lymph nodes treated with and without
retroperitoneal lymph node dissection during cytoreductive
nephrectomy
Variable HR ⫾ SE (95% CI) p Value
No dissection 3.11 ⫾ 1.1 (1.48–6.11) 0.002
Grade 1.89 ⫾ 0.41 (1.24–2.89) 0.003
ECOG performance status 1.36 ⫾ 0.29 (0.89–2.07) 0.153
Immunotherapy 0.62 ⫾ 0.16 (0.37–1.01) 0.057
Metastases 1.12 ⫾ 0.32 (0.64–1.95) 0.678
clude adequate lymphadenectomy. The current data suggest
that lymph node dissection can safely be omitted in these
patients in the absence of evidence of metastatic disease.
In the classic study of nephrectomy for metastatic renal
cell carcinoma in the pre-immunotherapy era deKernion et al
found that survival was significantly decreased in patients
with the addition of positive nodes, positive regional nodes
were strongly associated with local recurrence in the renal
fossa and patients in whom regional disease was not removed
during nephrectomy were dead within 1 year with only 20%
alive at 6 months.19 A more recent experience presented by
investigators at the National Cancer Institute described 154
patients with metastatic renal cell carcinoma who underwent
cytoreductive nephrectomy at the National Institutes of
Health as preparation for IL-2 based therapy.14 They found a
8.5-month median survival in patients with positive nodes,
which was inferior to 15-month survival in those without
nodes. Furthermore, 8.6-month median survival in those in
whom lymph nodes were completely resected was similar to
8.5-month survival in those with incomplete resection and
each result was better than 3.3-month survival in patients
deemed unresectable. These values are in general agreement
with the data on patients with metastatic renal cell carci-
noma currently presented. In the current data patients in
whom positive regional lymph nodes were left in place had
statistically inferior survival to similar patients in whom
regional disease was resected by lymphadenectomy. Further-
more, in the National Cancer Institute and University of
California-Los Angeles series no real difference could be de-
tected in survival that was related to the extent of node
dissection performed. It is possible that this fact merely
reflects the lack of prospectively defined templates dictating
surgical technique and the extent of dissection performed
was individualized to suit each particular patient with those
who had clinically evident but minimal nodal disease not
undergoing formal dissection from the diaphragm to the aor-
tic bifurcation. It is possible that a clear statement describing
exactly what surgical boundaries represent adequate node
dissection can be defined only by prospective clinical trials. It
is interesting that immunotherapy appeared to benefit pa-
tients with nodal disease who underwent surgical resection
of these lymph nodes since the University of California-Los
Angeles data suggest that patients who have regional lymph-
adenopathy do not respond in a meaningful way to systemic
immunotherapy and experience improved survival following
treatment.28
There are several limitations to the current study. Data
were collected in a retrospective manner by chart review, the
extent of lymph node dissection was not standardized and the
decision of whether to perform lymph node dissection was left
to surgeon choice rather than being assigned through a ran-
domization process. In addition, determining the extent of
node dissection retrospectively based on operative reports
depends on the completeness of surgeon dictation and is
subject to subjective interpretation. For these reasons we
hesitate to overstate the comparisons of the benefits of full
versus limited dissection, although it should be stated that
these data were collected for data base entry by reviewers
blinded to the purpose of the current study. However, more
2081
significantly, because of the nature of these limitations, we
were concerned that the group not undergoing lymph node
dissection was highly selected and the survival advantage
noted for node positive cases in which lymph node dissection
was done may have been due to unrecognized selection bias
rather than to a treatment effect. For example, were patients
who were more ill or had more extensive disease selected not
to undergo lymph node dissection?
Several strategies were used in an effort to minimize the
potential for selection bias. Surgical reports were reviewed to
determine the reason that node dissection was deferred.
From this review it became clear that few patients had the
nodes left in situ because they were believed by the primary
surgeon to be unresectable. Many patients were treated dur-
ing the earlier half of the 1990s, when a common practice was
to leave the nodes in place in patients who had N⫹M0 dis-
ease as a marker lesion that could be serially imaged to
assess the response to immunotherapy. Poorer survival of
these patients with N⫹M0 disease in whom nodes were left
in place contrasts with the overall better survival of this
group as a whole. In most patients with metastatic disease in
addition to nodal disease, the decision to leave the nodes in
place was based on the primary surgeon perception that node
dissection would not provide an added benefit in light of the
distant disease that was left in place.
ANOVA was performed to determine the relative distribu-
tion of prognostic factors in the dissection and no dissection
groups at the original presentation. In the University of
California-Los Angeles data set ECOG performance status,
tumor grade and tumor stage are the 3 variables that are
most significant for determining patient outcome and sur-
vival and they make up the University of California-Los
Angeles Integrated Staging System, which has been previ-
ously described.32 ANOVA revealed equal distributions for
stage and ECOG performance status between the groups,
while it was noted that the group that underwent lymph node
dissection was more likely to have higher grade disease,
which would normally portend worse survival. However, the
same trend for improved survival in the lymph node dissec-
tion group was noted when patients were evaluated across
each grade level separately (data not shown). Furthermore, it
is unlikely that the survival difference noted can be attrib-
uted merely to overall tumor burden since data have previ-
ously been presented showing no survival difference between
patients with microscopic and macroscopic nodal involve-
ment in the same cohort.33 We next questioned whether the
no dissection group had greater surgical complications or
became ineligible for immunotherapy due to more rapidly
progressive disease following nephrectomy. However, a sim-
ilar incidence of patients in each group remained eligible and
received immunotherapy following cytoreductive nephrec-
tomy with 71% of the no dissection group going on to immu-
notherapy compared with only 63% of the dissection group.
Since generally only patients with an ECOG performance
status of 0 or 1 are selected for high dose IL-2 therapy, this
finding indicates that the 2 groups were similar in perfor-
mance status following nephrectomy as well as diagnosis.
Furthermore, several Cox multivariate models were created
to examine the potential interactions of multiple prognostic
variables simultaneously, including lymph node dissection,
tumor stage, tumor grade, ECOG performance status, dis-
tant metastatic disease, treatment with immunotherapy and
University of California-Los Angeles Integrated Staging Sys-
tem category. In each model failure to perform lymph node
dissection remained a significant and independent predictor
of decreased survival after accounting for these other vari-
ables (RR ⬎3.0).
Recently much has been learned to explain the molecular
mechanisms behind the clinical patterns of observed meta-
static spread. For example, it is well established that angio-
genesis (the formation of new blood vessels) is necessary for
2082 RENAL CELL CANCER WITH RETROPERITONEAL LYMPH NODES
the growth and metastatic spread of solid tumors. The vas-
cular endothelial growth factor (VEGF) family of genes in-
cludes unique isoforms, of which each is capable of binding to
unique receptors. Evidence is accumulating that different
VEGF family members are important in determining the
route of metastatic spread through classic angiogenesis via
blood vessels or through lymphangiogenesis. Experimental
systems have demonstrated the importance of VEGF and
VEGF receptor-2 in tumor progression through the promo-
tion of blood vessel formation.34 VEGF-D is capable of acti-
vating VEGF receptor-2 and VEGF receptor-3, a receptor
expressed by endothelial cells of the lymphatic channels, and
it is thought to be a molecular signal for lymphangiogenesis35
and lymphatic tumor spread.36 Stacker et al noted that
VEGF-D expression in a mouse tumor model led to spread of
the tumor to lymph nodes, which could be blocked by an
antibody specific for VEGF-D, whereas the expression of the
angiogenic growth factor VEGF, which activates only
VEGFR-2 did not.37 The factors that promote the regulation
of the expression of different VEGF genes is not entirely
clear. Gunningham et al recently observed that VEGF,
VEGF-B and VEGF-D gene expression is differentially reg-
ulated by the level of tumor hypoxia and by von Hippel-
Lindau gene expression in renal cell carcinoma cell lines.38 It
is possible that different tumor genetics and different risk
factor exposures may lead to differential tumor gene expres-
sion, resulting in unique tumor biologies with unique pat-
terns of spread and response to treatment. Currently a renal
cancer tissue array study is underway at our institution to
determine expression of the VEGF genes and receptors,
which will be correlated with clinical patterns of tumor
spread, treatment response and survival.
CONCLUSIONS
The morbidity associated with retroperitoneal lymph node
dissection during nephrectomy appears to be acceptable.
However, regional lymph node dissection is unnecessary in
patients with clinically negative lymph nodes because it of-
fers extremely limited staging information and no benefit in
terms of decreasing disease recurrence or improving sur-
vival. When lymph nodes are positive, lymph node dissection
is associated with improved survival when it is performed in
carefully selected patients undergoing cytoreductive ne-
phrectomy and postoperative immunotherapy. Although de-
fining the optimal surgical boundaries would require a pro-
spective comparison of various possible templates, the
current data suggest that when lymph nodes are present,
they should be resected when technically feasible.
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