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

The extranodal extension (ENE) of nodal metastasis (i.e. the extension of tumor cells through the nodal capsule into the perinodal 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. Two independent authors searched PubMed and SCOPUS until 7 January 2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with the presence of ENE (ENE+) versus only intranodal extension (ENE-) were eligible. Data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) together with 95% confidence intervals (CIs) for time-dependent risk related to ENE+, adjusted for potential confounders. Thirteen studies including 1336 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%). Based 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.