Extranodal extension of lymph node metastasis influences recurrence in prostate cancer: a systematic review and meta-analysis

Abstract

The extranodal extension (ENE) of nodal metastasis involves the extension of neoplastic cells through the lymph node capsule into the perinodal adipose tissue. This morphological feature has recently been indicated as an important prognostic factor in various cancer types, but its role in prostate cancer is still unclear. We aimed to clarify it, performing the first meta-analysis on this issue, comparing prognostic parameters in surgically treated, node-positive prostate cancer patients with (ENE+) vs. without (ENE-) ENE. Data were summarized using risk ratios (RRs) for number of deaths/recurrences and hazard ratios (HRs), with 95% confidence intervals (CI), for the time-dependent risk related to ENE positivity. Six studies followed-up 1,113 patients with N1 prostate cancer (658 ENE+ vs. 455 ENE-) for a median of 83 months. The presence of ENE was associated with a significantly higher risk of biochemical recurrence (RR = 1.15; 95%CI: 1.03-1.28; I² = 0%; HR = 1.40, 95%CI: 1.12-1.74; I² = 0%) and "global" (biochemical recurrence and distant metastasis) recurrence (RR = 1.15; 95%CI: 1.04-1.28; I² = 0%; HR = 1.41, 95%CI: 1.14-1.74; I² = 0%). ENE emerged as a potential prognostic moderator, earmarking a subgroup of patients at higher risk of recurrence. It may be considered for the prognostic stratification of metastatic patients. New possible therapeutic approaches may explore more in depth this prognostic parameter.

Figure 1

A classical example of extra-nodal extension of nodal metastasis of prostate cancer is here shown. Note the rupture of nodal capsule and the invasion by the metastatic cells of the peri-nodal adipose tissue (original magnification: 4× metastatic lymph node, 10× detail of the metastasis in the box).

Figure 2

Forrest plot for relative risk of recurrence by extranodal extension status. First of all we present the data about risk of biochemical recurrence (papers of Fleischmann et al., and of Passoni et al.), then their meta-analyzed values (pooling data), then the data about risk of metastasis (Cheng et al.), its mean (only this study about the risk of metastasis, so we repeat this value), then the overall meta-analysis of these data (meta-analysis of all these papers about risk of recurrence – both biochemical and metastasis).

Figure 3

Forrest plot for hazard ratios (HRs) for recurrence (adjusted for potential confounders) by extranodal extension status. We present data in the same manner used for Fig. 2. The only difference is that there is an additional paper (Hofer et al.) for the risk biochemical recurrence.