Extranodal extension (ENE) of nodal metastasis is defined as the extension of metastatic cells through the nodal capsule into the perinodal tissue. This morphological parameter, recently proposed as an important prognostic factor in different types of malignancy, has not been included in the TNM staging system for non-small cell lung cancer (NSCLC). In this systematic review with meta-analysis, we weighted the prognostic role of ENE in patients with lymph node-positive NSCLC. Two independent authors searched SCOPUS and PubMed through 28 February 2017. Prospective and retrospective studies on NSCLC, comparing patients with presence of ENE (ENE+) ENE+) vs. only intranodal extension (ENE-) and including data regarding prognosis, were considered as eligible. Data were summarized using risk ratios (RR) for the number of deaths/recurrences, and hazard ratios (HR) with 95% confidence intervals (CI) for time-dependent risk related to ENE+, adjusted for potential confounders. We identified 13 studies, including 1709 patients (573 ENE+ and 1136 ENE-) with a median follow-up of 60 months. ENE was associated with a significantly increased risk of mortality of all causes (RR = 1.39, 95% CI: 1.18-1.65, P < 0.0001, I2 = 70%; HR = 1.30, 95% CI: 1.01-1.67, P = 0.04, I2 = 0%) and of disease recurrence (RR = 1.32, 95% CI: 1.04-1.68, P = 0.02, I2 = 42%; HR = 1.93, 95% CI: 1.53-2.44, P < 0.0001, I2 = 0%). We conclude that in NSCLC, requirements for assessment of ENE should be included in gross sampling and ENE status should be included in the pathology report. Inclusion of ENE status in oncology staging systems will allow further assessment of its role as prognostic parameter.
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