Lymph node density as a prognostic variable in node-positive bladder cancer: a meta-analysis

Up to 25 % of clinically organ-confined tumors show evidence of LN metastasis at the
time of surgery. Pathologic specimens from contemporary radical cystectomy series
reveal that the rate of LN metastasis increases from 5 % in non-muscle-invasive bladder
tumors (?pT1), to 18 % in pT2a, 27 % in pT2b, and 45 % in pT3–4 2]. Although LN-positivity is an adverse prognostic factor per se, some LN-positive
patients experience long-term survival following radical cystectomy. Therefore, LN
dissection may be curative in a selected subset of LN-positive patients 18]. However, prognostic criteria to identify this population have not been defined.

Several prognostic factors have previously been reported for LN-positive patients:
(1) pathologic stage of the primary tumor 6], 31]; (2) presence of lymphovascular invasion of the primary tumor 18]; (3) pN stage using the TNM classification; (4) number of LNs involved [2,618,20,32];
(5) number of LNs removed at cystectomy 33]–35]; (6) LN density 5], 6]; and (7) the presence of extracapsular extension 18], 28], 36]. However, factors predictive of survival in LN-positive patients are debated.

The pT stage of the TNM classification remains significant in LN-positive bladder
cancer 6], 31]. Although differentiation between pT2 and pT3 disease seems unnecessary when LN invasion
is present, Stein et al. 6] have previously shown the prognostic significance of extravesical tumor extension
compared to organ-confined tumor in LN-positive patients. However, the prognostic
significance of the pN stage is unclear 5], 28], although risk stratification of recurrence and survival following radical cystectomy
has traditionally been based on TNM staging. The accuracy of the most recent TNM staging
system has also been questioned 37], 38], as the location of positive LNs does not seem to have prognostic significance. The
number of positive LNs appears to be a significant adverse prognostic factor. Some
studies have demonstrated decreased DFS and OS associated with an increasing absolute
number of positive LNs 2], 6], 18], 20], 32], but not all studies have confirmed these findings. In addition, the cut-off number
for positive LNs that influence outcome is controversial. Furthermore, the total number
of positive LNs does not reflect the tumor burden, and its significance is influenced
by the extent of the LN dissection. Other studies have demonstrated that the total
number of LNs removed, irrespective of LN positivity, is a significant prognostic
factor 6], 33]–35]. Extracapsular extension may be an independent prognostic factor for DFS and DSS
in LN-positive bladder cancer and upper urothelial carcinoma 18], 28], 36].

It has been suggested that LN density is more useful in stratifying patients with
LN-positive bladder cancer. Herr 5] found that a LN density cut-off of 20 % was superior to the most recent TNM staging
system in predicting DSS and local recurrence, on multivariate analysis. Stephenson
et al. 23] also suggested that the aggregate LN metastasis diameter, LN density, and extranodal
extension should be considered as the novel predictors in a revised TNM-staging system.
However, despite the attempts of multiple studies to explore the association between
LN density and its potential association with disease recurrence or death, the results
have been inconsistent. For example, none of the new LN-dependent markers, such as
localization within the pelvic cavity, extracapsular extension, and LN density were
independently significant in the prospective study by Jenson et al. 25]. To our knowledge, the present meta-analysis is the first to clarify the association
between LN density and survival in LN-positive bladder cancer using meta-analysis
and systematic review. In this meta-analysis, studies reporting HRs of cumulative
survival rates were qualitatively summarized using standard meta-analysis techniques.
Fourteen studies, with a total of 3311 LN-positive patients, stratifying DFS, DSS,
and/or OS by LN density were eligible for inclusion in the meta-analysis. Higher LN
density was independently associated with poorer DFS, DSS, and OS. As our meta-analysis
includes 14 eligible studies, with a total of 3311 patients, it provides stronger
statistical power and a more precise estimation of results than previously published
reports. Moreover, our meta-analysis was mainly based on adjusted estimates, and statistical
significance was observed for all three end-points, DFS, DSS, and OS.

However, to reach a convincing conclusion regarding the value of LN density for the
prognosis of LN-positive bladder cancer, some issues should also be addressed. First,
we considered that the definition of what constitutes a “lymph node” varies among
urological pathologists in different series. This can impact the nodal yields, and
therefore, the burden of lymph node density. Second, the cut-off points for LN density
were arbitrarily determined retrospectively, and they have not been validated sufficiently
in alternative data sets 8]. Therefore, the threshold for clinically relevant LN density varies between multiple
studies and has yet to be established. Third, there is no prospectively evaluated
standardized template for pelvic LN dissection. Some data support the use of LN density
rather than the absolute number of positive LNs when extended pelvic LN dissection
is performed 27]. On the contrary, LN density may be a less sensitive determinant of outcome following
limited dissection 8]. Additionally, there were no surgical consistency and uniformity of techniques between
previous studies. Therefore, different LN dissection templates, and different surgical
procedures may contribute significant bias to a meaningful analysis. Fourth, the number
of LNs removed may affect the value of LN density. Jeong et al. 39] demonstrated that when more than 15 LNs were removed, LN density was a predictive
factor for survival. In a report by Kassouf et al., LN density proved to be a stronger
prognostic factor in patients with a LN count of ?25 (HR 4.63) than in patients with
a LN count of 25 (HR 1.62) 27]. Therefore, owing to interindividual variability in pelvic LN anatomy 40], LN density may not be a prognostic factor in patients with little lymphatic tissue.
Furthermore, although greater numbers of LNs removed would most likely correlate with
a more extended LN dissection, LN yield is intimately related to histological processing,
and to the extent of pathologic review. Fifth, it is not known whether LN density
determines survival any better than currently established pN categories of the TNM
system 8]. Future studies are needed before LN density can be widely accepted as a staging
system or used to replace pN staging. Finally, in the present study, only 2 reports
used neoadjuvant chemotherapy; and therefore, it is not enough to determine whether
LN density can be a valid marker for survival following neoadjuvant chemotherapy,
which may favorably alter the nodal burden 8]. Additionally, given the use of neoadjuvant chemotherapy had gained increasing acceptance
for treating invasive bladder cancer, the low rate of neoadjuvant therapy in this
meta-analysis may have limitation on the generalizability. Further evaluation of the
impact of neoadjuvant chemotherapy on LN density would be necessary.

Several limitations of this study should be considered. First, the HRs calculated
in our meta-analysis may be overestimated, as many of the included studies obtained
data retrospectively. Thus, adequately designed prospective studies are needed to
obtain a more precise estimate. Second, the studies retrieved for our analysis were
limited to those published in English, which may result in a language bias, although
the present analysis does not support publication bias. Third, varying numbers of
patients, median follow-up time, and quality scale might contribute to the heterogeneity
of results for DSS found in this study. Although the random-effects model considers
heterogeneity, and was used to analyze the studies with heterogeneities, the conclusions
drawn from this meta-analysis should be approached with caution. However, heterogeneity
of results for DSS was rigorously quantified and analyzed in our meta-regression and
subgroup analysis, which contributes to a more reliable conclusion.