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

Radical cystectomy with lymph node (LN) dissection remains the standard treatment for patients with muscle-invasive urothelial carcinoma of the bladder, and also for non-muscle-invasive disease, refractory to intravesical therapy. Pelvic LN involvement occurs in approximately 25 % of patients undergoing radical cystectomy for urothelial cancer [1]; when LN positivity is observed, the 10-year mortality rate can reach 80 %, despite adjuvant chemotherapy [2, 3]. Although LN involvement portends a relatively poor prognosis, some patients exhibit long-term survival following surgery, with, or without systemic chemotherapy [4]. Efforts have been made to stratify LN-positive patients according to different prognostic factors to obtain more individualized risk estimations. Although several prognostic factors have previously been reported for LN-positive patients, predictive factors for survival in LN-positive patients have not been clearly defined.

The concept of LN density, i.e. the number of LNs containing metastatic deposits divided by the total number of LNs removed, was first described for bladder cancer in 2003 [5, 6]. Recent studies have suggested that LN density is superior to the tumor-node-metastasis (TNM) classification system [5], and to the absolute number of positive LNs [5, 7] in predicting disease-free survival (DFS) and disease-specific survival (DSS). Although radical surgery alone cures 5–34 % of patients with LN-positive disease, most survivors have only 1–2 microscopically involved LNs, rather than grossly positive, or multiple LN involvement [8]. Therefore, LN metastasis (LN status), and the number of involved LNs (LN burden) determine the outcome of patients with bladder cancer treated with cystectomy [8]. Compelling arguments have been made for the incorporation of LN density into the current American Joint Committee on Cancer (AJCC) staging system [9]. The present study aimed to elucidate the relationship between LN density and clinical outcome in LN-positive patients with bladder cancer following radical cystectomy.

This analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Additional file 1) [10].

The search strategy retrieved 253 publications, of which 81 were reviewed for eligibility, with 14 studies finally included [5, 18‐30]. The detailed screening process used is shown in Fig. 1.

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.