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would benefit from consideration of preoperative systemic
therapy, adjuvant systemic therapy, or enrollment into a
clinical trial.
Interestingly, three clinicopathologic features were
prognostic of CSM and ACM: ECOG PS 1, coagulative
tumor necrosis, and sarcomatoid differentiation. This
suggests that unlike the development of distant metastases,
which appears to be largely driven by tumor biology, the
endpoints of CSM and ACM reflect not only disease biology
(as captured by adverse pathologic features) but also
patient functional status. The latter may indicate eligibility
for systemic therapy or, alternatively, cancer-related
functional decline.
Historically, LN involvement has been associated with[9_TD$DIFF] a
poor prognosis . Indeed, in the original account of
the outcomes of radical nephrectomy by Robson et al in
1969, the authors reported 3-yr survival of approximately
35% for pN1M0 disease Perhaps more notable is that
the survival figure in that study ([10_TD$DIFF]Figure 1[11_TD$DIFF] in ) appears to
capture the underlying biology of isolated LN involvement:
the survival of patients with LN involvement parallels that
of patients with distant metastases, probably because of
progression from occult systemic disease, until the LN
survival curve plateaus, reflecting the subset of durable
survivors without occult systemic disease at the time of
surgery.
Several contemporary series have examined isolated LN
disease. Investigators from the MD Anderson center
reported on a series of 40 patients with surgically resected
pN1M0 disease, and observed that disease recurred in 70%
at a median of 4.9 mo . An updated report on 68 patients
with longer follow-up noted 22.1% progression-free surviv-
al at a median of 43.5 mo after surgery . Favorable
prognostic features included ECOG PS of 0 and the absence
of sarcomatoid features. In a multi-institution series of
171 patients with median follow-up of 1.3 yr, median CSS
was 1.2 yr, and the presence of systemic symptoms was the
strongest predictor of poor survival More recently,
Trinh and colleagues conducted a population-based
study of 799 patients with median follow-up of only 17 mo,
reporting median OS of 28 mo and actuarial CSS of 38% at
5 yr. Adverse prognostic features included higher Fuhrman
grade, clear cell histology, advanced pT stage, and percent-
age of positive nodes. Randomized trials examining
adjuvant therapies have observed similar survival in the
setting of node-positive disease . Some of the
differences in oncologic outcomes reported may be related
to differences among study populations.
RCC has been associated with predominantly hematog-
enous, rather than lymphogenous, spread For
instance, in one autopsy study that included 80 patients
with pN1 RCC, only five (6.3%) were without concurrent
distant metastatic disease . Anatomic studies provide
several mechanisms to explain these findings. Lymphatic
drainage from the kidney is unpredictable, and direct
lymphatic drainage into the IVC and thoracic duct have both
been described . Alternatively, hematogenous spread
may reflect tumor biology rather than anatomic consider-
ations .
Despite these findings, there does appear to be a small
subset of patients without occult systemic disease in whom
resection of isolated LN disease is associated with durable
long-term survival. These patients are characterized by
pathologic nodal involvement (pN1) in the absence of
adverse prognostic features, as identified in this and other
studies. However, the majority of existing prediction tools
to identify patients with pN1 disease utilize the
same clinicopathologic features that have been associated
with occult systemic disease and early progression, proba-
bly reflecting the association of nodal disease with systemic
disease. Alternative prediction tools are required to identify
patients with nodal metastases independent of features
associated with systemic disease .
This retrospective study has several limitations. Most
importantly, it reflects a surgical cohort and the selection
bias inherent to surgical candidacy. In addition, LND was
performed at the surgeon’s discretion, which may intro-
duce additional selection bias. LND boundaries were not
standardized, and it is possible that more extensive LND
may be associated with different oncologic outcomes.
Moreover, variability has been reported in the assessment
of LN counts. Neither the location of positive lymph nodes
nor specific pathologic features of positive lymph nodes,
such as the presence of extranodal extension or sarco-
matoid features, was available. Furthermore, given the
rarity of isolated pN1 disease, a larger cohort may
improve the statistical power for detection of associations
between clinicopathologic features and oncologic out-
comes. Finally, assessment of pathologic features may not
be available preoperatively without renal mass biopsy.
Still, this is the largest single-institution study to examine
the topic. Accordingly, it benefits from the availability of a
comprehensive set of clinical, radiographic, and patho-
logic features, utilization of re-reviewed pathology, and
long-term follow-up.
5. Conclusions
Isolated pN1 disease portends poor prognosis, with a 5-yr
probability of metastasis-free survival of only 16%. Never-
theless, a subset of patients experience durable long-term
survival to 10 yr after surgical resection of isolated
lymphatic metastases. Adverse prognostic features includ-
ing symptoms at presentation, radiographic IVC involve-
ment, pT4 stage, coagulative tumor necrosis, and clear cell,
collecting duct, or NOS histologic subtypes were indepen-
dently associated with the development of distant metas-
tases, and may enhance patient risk stratification and
facilitate multimodal management approaches.
Author contributions: Boris Gershman had full access to all the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Gershman, Thompson, Moreira, Boorjian,
Lohse, Costello, Cheville, Leibovich.
Acquisition of data: Lohse, Thompson, Leibovich.
Analysis and interpretation of data: Gershman, Thompson, Moreira,
Boorjian, Lohse, Costello, Cheville, Leibovich.
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