EURURO Vol. 72 No. 2

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1. Introduction
The role of lymph node dissection (LND) in the surgical
management of renal cell carcinoma (RCC) has been
controversial . Although LND allows undisputed
pathologic assessment of nodal stage, its impact on
oncologic outcomes has been uncertain. Older retrospective
studies suggested a potential oncologic benefit , yet
data from both randomized trials and more recent
investigations have revealed no impact on survival.
Isolated lymph node (LN) involvement in the absence of
systemic disease provides an important case study in this
context, since a therapeutic benefit for nonmetastatic RCC
may be expected exclusively in this population . Histori-
cally, isolated LN involvement has been associated with poor
prognosis, dating back to the original report by Robson et al
on the outcomes of radical nephrectomy . However,
a subset of such patients may experience durable long-term
survival following surgical resection
A critical analysis of isolated LN involvement may
provide insight into the apparent lack of oncologic benefit
of LND in M0 RCC. Accordingly, the objectives of this study
were twofold. First, we examined the natural history of RCC
with isolated LN involvement following surgical resection
with long-term follow-up. Second, we evaluated clinico-
pathologic features associated with disease progression and
survival in order to guide preoperative and postoperative
risk stratification and management.
2. Patients and methods
2.1. Patient population
After obtaining institutional review board approval, we identified
3830 patients with sporadic, unilateral, M0 RCC treated with partial
or radical nephrectomy from 1980 to 2010 at the Mayo Clinic. Of these,
769 (20%) underwent LND, and 139 were found to have pN1M0 RCC. We
excluded one patient who died intraoperatively, leaving 138 patients for
the study cohort. LND was performed at the surgeon’s discretion, and a
standardized template was not utilized. Staging was based on surgical
pathology and preoperative radiographic evaluation, which included
imaging of the chest, abdomen, and pelvis, with additional imaging (eg,
bone, brain) as clinically indicated.
2.2. Clinicopathologic and radiographic features
Clinicopathologic features recorded included year of surgery, age at
surgery, sex, symptoms at presentation, smoking status, Eastern
Cooperative Oncology Group performance status (ECOG PS), Charlson
comorbidity index (non–age-adjusted and excluding RCC), body mass
index (BMI), receipt of neoadjuvant systemic therapy, surgical approach
(open or laparoscopic), stage according to the 2010 American Joint
Committee on Cancer classification, pathologic tumor size, histologic
subtype, grade according to the World Health Organization/Internation-
al Society of Urological Pathology classification, number of LNs removed,
number of positive LNs, presence of coagulative tumor necrosis, and
presence of sarcomatoid differentiation. Patients with a palpable flank or
abdominal mass, discomfort, gross hematuria, acute-onset varicocele, or
constitutional symptoms including rash, sweats, weight loss, fatigue,
early satiety, or anorexia were considered symptomatic. All pathology
slides were re-reviewed by one urologic pathologist (J.C.C.) who was
unaware of patient outcome. In addition, the following preoperative
radiographic features were recorded from medical records: lymphade-
nopathy (cN1) on computed tomography (CT), renal vein involvement on
CT or magnetic resonance imaging (MRI), and inferior vena cava (IVC)
involvement on CT or MRI.
2.3. Statistical methods
Continuous variables were summarized using the median and inter-
quartile range (IQR) and categorical variables using the frequency count
and percentage. Distant metastases–free survival (MFS), cancer-specific
survival (CSS), and overall survival (OS) were estimated using the
Kaplan-Meier method for the overall cohort and among patients who
underwent extended LND, defined as removal of 13 LNs . Associa-
tions of clinicopathologic features with the development of distant
metastases, cancer-specific mortality (CSM), and all-cause mortality
(ACM) were evaluated using Cox proportional hazards regression models
and summarized using a hazard ratio (HR) and 95% confidence interval
(CI). Multivariable models were constructed using forward stepwise
selection with p = 0.05 set as the cutoff for a feature to enter or leave the
model. Six patients died from unknown causes and were excluded from
analysis of CSS/CSM.
Statistical analyses were performed using SAS version 9.3 (SAS
Institute, Cary, NC, USA). All tests were two-sided and p < 0.05 was
considered statistically significant.
3. Results
A total of 138 patients with isolated LN metastases formed
the study cohort. Clinicopathologic features are summa-
rized in . The median number of LNs removed was
five (IQR 2–14) and the median number of positive LNs was
two (IQR 1–3), with 57 (46%) patients found to have only
one positive LN. Overall, 125 (91%) patients had symptoms
at presentation, 60 (43%) had preoperative radiographic
lymphadenopathy (cN1), 33 (24%) had a radiographic IVC
tumor thrombus, and 106 (77%) had pT3/T4 disease. There
was a high incidence of adverse pathologic features,
including grade 4 in 55 (40%) patients, coagulative tumor
necrosis in 111 (80%) patients, and sarcomatoid differenti-
ation in 30 (22%) patients. Five patients received adjuvant
systemic therapy (in the absence of recurrence or metasta-
ses) at 27, 41, 78, 105, and 111 d following surgery.
Median follow-up among survivors was 8.5 yr (IQR 5.6–
10.9), during which time 108 patients developed distant
metastases and 117 died, including 99 from RCC. Sites of
distant metastases are summarized in Supplementary
Table 1. A total of 31 patients developed recurrence in
the retroperitoneal LNs, though only two of these were in
the absence of concurrent distant metastases. MFS, CSS, and
OS are illustrated in The 5-yr and 10-yr MFS, CSS, and
OS rates were 16% and 15%, 26% and 21%, and 25% and 15%,
respectively. Notably, median time to development of
distant metastases was only 4.2 mo (IQR 2.1–11.7), and
MFS at 1 yr was only 37%. However, nearly all patients who
remained free of distant metastases at 5 yr after surgery
experienced durable MFS at longer follow-up. In patients
who underwent extended LND (defined as removal of 13
LNs), MFS, CSS, and OS were similar to rates for patients
with <13 LNs removed (Supplementary Figs. 1–3).
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