Prognostic impact and implications of extra-capsular lymph node involvement in colorectal cancer:a systematic review with meta-analysis

BACKGROUND: The extra-nodal extension (ENE) of nodal metastasis, (i.e. the extension of tumor cells through the nodal capsule into the peri-nodal adipose tissue), has recently emerged as an important prognostic factor in different types of malignancies. However, the Tumor Node Metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a systematic review and meta-analysis to determine the prognostic role of ENE in patients with lymph node positive colorectal cancer.MATERIALS AND METHODS: Two independent authors searched PubMed and SCOPUS until 07/01/2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with presence of ENE (ENE+) vs. only intra-nodal extension (ENE-) were eligible. Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) together with 95% confidence intervals (CI) for time-dependent risk related to ENE+, adjusted for potential confounders.RESULTS: Thirteen studies including 1,336 patients were identified with a median follow up of 4.7 years. ENE was associated with a higher T stage and tumor grading. In addition, ENE was associated with a significantly increased risk of all-cause mortality (RR= 1.75; 95%CI: 1.42-2.16, p<0.0001, I(2)=60%; HR=1.69, 95%CI: 1.32-2.17, p<0.0001, I(2)=46%) and of recurrence of disease (RR=2.07, 95%CI: 1.65-2.61, p<0.0001, I(2)=47%; HR=2.31, 95%CI: 1.54-3.44, p<0.0001, I(2)=48%).CONCLUSIONS: On the basis of these results, in colorectal cancer, ENE should be considered from the gross sampling to the pathology report, as well as in future oncologic staging systems.