# Retroperitoneal Lymph Nodes in Transitional Cell  Carcinoma of the Kidney and Ureter

Authors: Shilajit D. Kundu; Scott E. Eggener
Journal: Advances in Urology
 (2009)

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## Abstract

The incidence of transitional cell carcinoma of the kidney and ureter is
low and for that reason limited data exists regarding the appropriate management of
regional retroperitoneal lymph nodes.  Lymph node metastases have consistently
been associated with an adverse prognosis.  However, five-year cancer-specific survival
following nephroureterectomy and lymphadenectomy for patients with lymph node involvement ranges
from 0–39%, suggesting a therapeutic benefit.  This review covers the primary tumor characteristics
associated with lymph node involvement, imaging of the lymph nodes, as well as the rationale,
role, patient selection, suggested anatomic templates, and technical
considerations for lymphadenectomy.


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## Body

## 1. Introduction

Transitional cell carcinoma (TCC) of
the kidney and ureter, alternatively referred to as upper tract TCC (UT-TCC),
represents approximately 10% of malignancies arising from the kidney and less
than 5% of all urothelial malignancies, which primarily occur in the bladder.
In 2007, about 3000 cases of UT-TCC were diagnosed in the United States
compared to approximately 67 000 cases of bladder cancer [1, 2]. Within the upper urinary tract, TCC of the
ureter is less common than TCC of the renal pelvis by a ratio of 1:4 [3].
There are a variety of treatment options available for UT-TCC including
endoscopic excision or fulguration, segmental resection, and radical
surgery. The management strategy
selected primarily depends on the grade, stage, location, presence of
multifocality, renal functional reserve, and the patient’s comorbid
conditions. Largely due to the
infrequent disease incidence and variable lymph node templates, the role of
lymphadenectomy for UT-TCC is not well defined.
Since TCC of the bladder can be cured in approximately 25% of patients
with regional nodal spread following an extended lymph node dissection (LND)
and radical cystectomy, there is biologic plausibility to a therapeutic role
for lymphadenectomy in patients with UT-TCC [4, 5]. This review will focus on
the assessment and surgical treatment of lymph nodes in UT-TCC.


## 2. Relationship of Stage and Nodal Status with Outcome

Stage and grade of UT-TCC are independently associated with recurrence and
survival. The five-year actuarial survival rates by primary tumor stage have
been reported as 92%, 78%, 56%, and 0% for pathologic Ta-T1, T2, T3, and T4,
respectively. Patients with stage T4 disease have a dismal median survival of 6
months [6, 7]. Tumor stage has consistently been shown to be the most powerful
predictor of disease-specific survival [8–10]. However, other factors like higher grade, multifocality,
lymphovascular invasion, and previous cystectomy have also been associated with
inferior cancer-specific survival [10–12]. Transmural tumor growth (pT3 or
pT4) is less common in distal ureteral tumors (33%) compared to midureteral
(44%), proximal ureteral (75%), or renal pelvis tumors (41%). There are several plausible explanations for
this observation. First, tumors in the proximal ureter may be less likely to
cause obstructive symptoms compared to distal ureteral tumors due to greater
distensibility of the proximal ureter and therefore present at more advanced
stages than tumors in the distal ureter. Another proposed mechanism relates in
part to the differences in muscular layers between the proximal and distal
ureters. The distal ureter is encased by 3 layers of muscle in comparison to
the proximal ureter which only contains 2 relatively thin interlacing layers
[13]. This difference could explain the 2-fold higher incidence of transmural
growth of proximally located tumors as compared to more distally located tumors
[8].Recent
series show that up to 30% of patients with UT-TCC have regional nodal
involvement [7, 14]. All the tumor characteristics that are
associated with a poor prognosis are associated with an increasing likelihood
of lymph node involvement. The
likelihood of lymph node involvement is associated with increasing stage and
ranges from 4% in noninvasive TCC of the upper tract to as high as 60% in
patients with pT4 disease [10]. Hall et al. reported on 139 patients
with pTa, pT1, or pCIS followed for a median of 64 months and not a single
patient exhibited lymph node involvement at surgery or on follow-up [6]. Similarly, Kondo et al. reported on 42
patients with pTa, pT1, and pCIS, and there were no instances of lymph node
metastases [14]. The five-year cancer-specific survival among patients
with lymph node involvement varies widely and ranges from 0–39% [7, 14–17] (Table 1).Another
study showed lymph node involvement to be independently associated with a
three-fold increased risk of death at five years [7]. To our knowledge, no
study definitively demonstrates a survival benefit for patients undergoing
lymphadenectomy. Interpretations of studies including an LND are challenging
for a number of reasons: (a) indications for an LND are not standardized, (b) templates are
highly variable, (c) often only clinically suspicious lymph nodes are removed,
and (d) in many series LND is applied for staging purposes and not therapeutic
intent. Survival data from UT-TCC series is also confounded by 50% of patients
having a history of bladder cancer and a significant number having
cardiopulmonary morbidities, leading to competing risks of mortality [7]. However,
Rabbani et al. compared Surveillance Epidemiology and End Results (SEER)
outcomes for 657 patients who had UT-TCC diagnosed after bladder cancer to 7 839
patients who had de novo UT-TCC and found that patients with de novo UT-TCC had
a 1.7-fold increased risk of cancer-related death [18]. Taken together, these data suggest that stage,
grade, lymphovascular invasion, and tumor location are important factors that
impact survival and should be addressed when considering treatment of UT-TCC
and lymph node dissection.Table 1
Five-year cancer-specific survival for node-positive disease following nephroureterectomy
and lymph node dissection.
Number of node-positive patientsFive-year cancer-specific survivalJohansson and Wahlqvist [19]N/A0%Secin et al. [15]280%Miyake et al. [17]130%Novara et al. [7]2712%Kondo et al. [14]4215%Park et al. [20]1127%Roscigno et al. [16]2639%


## 3. Anatomic Distribution of Lymph Node Metastases

Anatomic lymph node mapping studies of
the upper tract are rare due to multiple factors, including relative rarity of
the disease, inconsistent dissection templates, and conflicting data on the
role of lymphadenectomy in UT-CC. Tumors of the renal pelvis and upper ureter
drain into the retroperitoneal lymph nodes, whereas tumors of the lower ureter
drain predominantly into the pelvic lymph nodes. Work from Batata et al. in 1975 showed that
node-positive tumors of the renal pelvis can involve upper retroperitoneal
nodes (retrocrural, suprahilar, paracaval, paraaortic, and interaortocaval) and
extend caudally to the external iliac lymph nodes [21]. Node-positive tumors of
the middle and lower third of the ureter can also involve both the
retroperitoneal and pelvic lymph nodes. Based on these findings, this group
advocated an extensive LND encompassing both regions. Involvement of more than
one lymph node has also been associated with an inferior 3-year cancer-specific
survival compared to only one node involved (58% versus 16%) [22]. Kondo et al.
recently reported the lymph node drainage sites of 42 patients based on
pathologic or radiographic evidence of lymph node involvement. Tumors of the
lower ureter demonstrated an approximately 10% rate of lymph node positivity,
whereas tumors in the mid to upper ureters demonstrated an increased likelihood
of positive lymph nodes (up to 42%). This was dependent on tumor stage and very
few tumors that were pathologic T1 or less had lymph node involvement. Tumors
of the right renal collecting system can metastasize to hilar, paracaval, retrocaval,
interaortocaval lymph nodes, and right common iliac lymph nodes [23]. Rarely,
in the setting of significant nodal disease, right-sided tumors will also
metastasize to preaortic or paraaortic nodes. [14]. Tumors of the left renal
collecting system may involve hilar, paraaortic, interaortocaval, and left
common iliac lymph nodes [23].Upper and
midureteral tumors may also involve the same side-specific nodal regions as
tumors of the renal pelvis, with midureteral tumors harboring the potential to
spread to lymph node regions caudal to the inferior mesenteric artery extending
along the common iliac nodal chain [14].
The nodal basins for tumors of the distal ureter include the external
iliac, obturator, and hypogastric regions.
Although constrained by limited lymph node dissections, these studies
provide updated information on the lymph node drainage of the upper tracts in
the current era.


## 4. Imaging of Lymph Nodes

Since staging of TCC plays an important
role in dictating the course of therapy, accurate pretreatment imaging is of
utmost importance. Computed tomography
(CT) and magneticresonance (MR) imaging are the primary
cross-sectional imaging modalities by which the regional lymph nodes are
assessed. The rarity of UT-TCC has
limited studies addressing imaging of these lymph nodes. However, imaging
studies relating to TCC of the bladder can provide valuable insight. CT imaging
can correctly stage lymph node involvement in over 70% of patients with muscle
invasive bladder cancer. However, almost 25% of patients are understaged with
clinically normal nodes on CT scan. CT
has shown 28% sensitivity, 93% specificity, 68% positive predictive value, and
72% negative predictive value as relates to lymph node involvement in bladder
cancer [24]. Jager et al. showed that MRI demonstrated a sensitivity,
specificity, and accuracy of 83, 98, 92%, respectively, when lymph nodes were
larger than 8–10 mm in patients
with TCC of the bladder [25]. A common theme in most studies of CT or MRI
in the staging of TCC is the relative understaging of lymph node involvement in
radiographically “normal” nodes. The role of Fluorodeoxyglucose- (FDG-) positron emission
tomography (PET) in the imaging of TCC of the urinary tract has been
limited because it is excreted into the urine and hard to distinguish from
tumor activity in the bladder or nearby lymph nodes. FDG-PET has helped to identify distant lymph
node involvement and metastases for patients with TCC of the bladder but not
well studied in UT-TCC [26]. However, with the advent and utilization of other
radiotracer agents not excreted in the urine, such as C11-choline,
the future of PET imaging for UT-TCC is promising. C11-choline PET-CT has shown encouraging
preliminary data in detecting nodal spread of TCC of the bladder with
pathologic confirmation of nodes as small as 5 mm [27]. While it seems intuitive that imaging studies
of TCC of the bladder can be extrapolated to UT-TCC, this is not proven. Given the limitations of preoperative nodal
imaging and the risk of understaging, LND remains the only way to definitively
assess lymph node involvement in UT-TCC.


## 5. Role of Lymphadenectomy

As previously mentioned, sparse data
exist to establish a well-defined role or optimal extent of LND. Virtually every study addressing LND for
UT-TCC has been retrospective and severely limited by nonuniform application of
LND, variable anatomic boundaries, and inconsistent selection for adjuvant
therapy [6, 9, 14–16, 20, 28]. Therefore, determining whether LND provides
a potential therapeutic benefit or simply offers more accurate surgical and
pathologic staging is largely unknown. Nevertheless,
the pertinent observations detailed above regarding lymph node metastases
incidence, location, and prognostic significance have been made, subsequently
reproduced, and help inform contemporary patient counseling and surgical
management.


## 6. Staging

Intuitively, retroperitoneal LND should
improve the accuracy of pathologic staging and allow for more accurate
prognostic assessment. Therefore, complete surgical staging consists of a
radical nephroureterectomy (NU) and regional LND. While no consensus has been established
regarding the appropriate and necessary extent of a regional LND, multiple
authors suggest patient-specific templates based on laterality of the primary tumor, location of
the primary tumor (renal pelvis, upper/mid/lower ureter), and presence of
radiographic or intraoperative retroperitoneal lymphadenopathy [14, 28, 29].


## 7. Therapeutic

While basic tenets of surgical oncology
make it easy to proclaim that LND improves pathologic staging, it is largely
unclear whether the time, effort, or potential morbidity of an LND is worthwhile from a therapeutic
perspective. There are currently three
lines of evidence suggesting that LND offers the potential for increasing the
probability of cancer-specific survival.
First, a proportion of patients with nodal metastases, up to 39%, exhibit
intermediate-term cancer-free survival (Table1) and highlight that regional nodal involvement
is compatible with the possibility of durable cure. Second, multiple retrospective series, albeit
with substantial limitations such as selection bias and the Will Rogers
phenomenon [30], have shown that LND is associated with improved
cancer-specific outcome [9, 16, 17, 28]. In a Japanese study by Kondo et al. of
169 patients with localized UT-TCC, a complete regional LND was associated with
a 50% decreased risk cancer-specific death [28]. Roscigno et al. analyzed 132 patients
undergoing NU for UT-TCC and five-year cancer-specific survival was 67% versus
40%, in favor of those having an LND [16]. Whether a patient underwent an LND in these series
was surgeon determined and not prespecified. Therefore, factors such as patient
age, clinical characteristics of the cancer, preoperative imaging features,
comorbid diseases, and patient performance status undoubtedly influenced the
decision of whether an
LND was performed. We are unaware of any
study that has randomized patients based on preoperative characteristics to
inclusion or extent of LND. Until such a
formal, prospective analysis is performed we will continue to debate the
merits, value, and proper extent of an LND for UT-TCC. Third,
since TCC of the UT and bladder originate from the same urothelial cells, it
can be loosely extrapolated that patients with regional nodal involvement may
respond similarly to surgical excision.
Since the incidence of bladder TCC is much higher than UT-TCC, a richer
experience with accompanying data has been established regarding the natural
history of surgically treated node-positive patients. Approximately 25% of patients with bladder
TCC and pelvic lymph node metastases will experience a durable recurrence-free
survival [31], and up to 35–40% of patients with
limited node involvement will experience low lymph node density or an
organ-confined primary tumor  [32, 33].
This attests to the curative potential of surgery for a subset of patients with
lymph-node metastases in TCC of the bladder and suggests a similar possibility
for those with node-positive UT-TCC.


## 8. Patient Selection

Without prospective studies utilizing
standardized anatomic templates, the selection of patients for LND at time of
treatment for UT-TCC remains uncertain.
While other urologic malignancies such as prostate, bladder, and
testicular cancer lack formal randomized data regarding the impact of LND, much
has been gleaned from the outcomes of a uniformly applied, extensive LND
consisting of similar anatomic boundaries for each patient [32, 34, 35]. This has not been done in a systematic manner
for patients with UT-TCC, therefore decisions regarding the application or
extent of LND must be drawn from weaker lines of evidence.Among patients undergoing NU for
UT-TCC, 16–23% will
experience a local recurrence, typically in the regional lymph nodes [20, 36]. For
patients with ureteral tumors, Park et al. reported a 37% versus 7% local
recurrence rate based on the absence or presence of an LND, respectively [20]. Whether an LND
may have prevented these recurrences, decreased progression to systemic
metastases, or improved disease-free survival is not known. However, with local recurrence rates so high
and their nearly universal association with subsequent metastases and
disease-specific mortality, the benefit of an LND appears to outweigh the
risks.The incidence of nodal metastases has
been strongly associated with primary tumor stage and multiple series have
reported that lymph node metastases in the setting of low stage UT-TCC(≤pT1) are rare at surgery or on follow-up [6, 14]. This
data initially suggests that LND may be excluded for patients with low-stage
disease however the gross limitations of preoperative clinical staging preclude
an accurate and reliable prediction of ultimate pathologic stage. Therefore, it is our belief that all patients
undergoing treatment for UT-TCC regardless of surgical approach (laparoscopic
or open) or type of surgery (segmental ureterectomy, partial nephrectomy, or
radical NU) should have a concomitantly thorough regional LND.


## 9. Technical Considerations for Lymph Node Dissection

As UT-TCC may originate from either the
renal or ureteral urothelium, the regional lymph nodes may vary and the
anatomic regions of LND should be planned accordingly.Based on the regional anatomic drainage
detailed above and presuming that
the surgeon prefers an extensive rather than a suboptimal LND, recommendations
regarding LND anatomic boundaries can be offered. The anatomic borders of dissection for a left-sided
renal pelvis, upper ureteral, or midureteral tumor should, at the minimum,
encompass the paraaortic, preaortic, and interaortocaval nodes from the level
of the renal hilum to the aortic bifurcation.For a right-sided renal pelvis, upper ureteral, or midureteral tumor the
removed node regions should include the paracaval, precaval, and interaortocaval
areas from the
renal hilum to the aortic bifurcation.
For most midureteral tumors and all distal ureteral tumors, regardless
of side of origin, a common iliac, external iliac, obturator, and hypogastric
lymphadenectomy should be performed.The method of LND, either open or
laparoscopic, is a secondary concern compared to the primary intent, which is a
thorough and safe removal of regional lymph nodes. Between 43–72% of patients
undergoing open NU have a simultaneous LND and it is our impression that
patients undergoing laparoscopic NU do so even less frequently [15, 16, 20, 28]. Busby et al. have recently compared patients
undergoing open and laparoscopic NU with LND and noted a slightly higher lymph
node yield for patients undergoing the laparoscopic approach (median: 6 versus
3) [37]. The authors do not state what
proportion of patients requiring NU had an LND. Both
groups appear to have an inadequately low yield and surgeon template preference
can easily, and likely did, account for the differences rather than surgical
approach.The surgeon's goals are to optimize
pathologic staging, minimize local recurrences, and potentially improve
disease-free survival. General technical
concerns for retroperitoneal LND include “split and roll” of the inferior vena
cava and/or aorta, meticulous hemostasis and lymphostasis, and readiness to
control and ligate lumbar vessels when necessary.For left-sided templates, the left renal vein
is positioned as the superior border unless suprahilar adenopathy is present,
in such case the
surgeon should consider a more cranial dissection. If bulky retroperitoneal metastases are
bilateral and resectable, ejaculatory function may be of concern. However, since the median age at diagnosis of
UT-TCC is typically in the late 70s [38], this situation should be
rare.Since the sympathetic trunks,
ganglia, and postsympathetic efferents are collectively responsible for
antegrade ejaculation, their preservation, either by nerve-sparing or a
modified template dissection [39], is essential to maintain normal ejaculatory function.


## 10. Future

Given the aforementioned limitations in
retroperitoneal imaging, preoperative staging, and the devastating impact of
local recurrences, we feel that an LND using a standardized template should be considered for
all patients undergoing NU. However, if
more accurate imaging with novel modalities such as lymphotrophic tracers,
molecular agents, or PET scans becomes available, the treatment paradigm for
patients with UT-TCC would be appropriately altered.Neoadjuvant chemotherapy for patients
with muscle-invasive bladder TCC results in improved disease-specific outcomes [40]
and, given the parallels between bladder and UT-TCC, may be ideally suited for
patients with high-risk UT-TCC. For
UT-TCC, neoadjuvant chemotherapy has not been adequately studied and may never,
given its relative rarity. Beside the
potential for improving cancer control, other benefits may include optimizing
renal function at the time of administration, allowing for maximum doses of the
most active agents, and eliminating the possibility of surgical complications
delaying adjuvant therapy. Since the
gemcitabine and cisplatin doublet provides similar efficacy to traditional MVAC
(methotrexate, vinblastine, doxorubicin, and cisplatin) regimens in patients
with bladder TCC, with an improved safety profile, neoadjuvant therapy for
patients with UT-TCC becomes even more attractive [41].



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