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Survival of Non-Small Cell Lung Cancer Patients with Unexpected N2 after Complete Resection: Role of Aggressive Invasive Mediastinal Staging should be Considered

Objective: Mediastinal lymph node (N2) metastasis is one of the poor prognostic factors in non-small cell lung cancer patients (NSCLC). However, the accuracy of mediastinal lymph node staging in real practice is uncertain and inadequate. Consequently, the aim of this study was to determine the survival of NSCLC patients with clinically non-suspicious mediastinal lymph node metastases who underwent complete resection but were pathologically confirmed as having N2 metastases (unexpected N2).Materials and Methods: A retrospective review was performed of all pathology-proven N2 metastases NSCLC patients who underwent curative surgical resection from January 2007 to December 2016. A total of 158 patients were initially included in the study. After the exclusions (known N2, small cell carcinomas, neuroendocrine tumor), 125 unexpected N2 patients who underwent complete resection were analyzed. Survival analysis was determined using the Kaplan–Meier method and multivariate analysis was determined using the Cox regression method.Results: The overall 2-year, 3-year, and 5-year survival rates were 40%, 24%, and 20% respectively. Complete resection was achieved in all patients. Invasive mediastinal staging (IMS) was performed in 47 patients (37.6%), by endobronchial ultrasonography (EBUS) in 46 (36.8%) patients (82.6% negative and 17.4% inadequate tissue) while only 1 patient underwent mediastinoscopy. The factors affecting the survival rate upon comparison were the histology type (p=0.019), differentiate characteristics (p=0.004), adjuvant therapy (p=0.011), and presence of distant metastasis by postoperative re-staging (p=0.003). The independent predictive factors for survival werechemo-radiation therapy (odds ratio 0.367, 95% confidence interval 0.176–0.766) and distant metastasis (odds ratio 2.280, 95% confidence interval 1.334–3.897). However, a small size, periphery lesion, T staging, and number of N2 lesions were not significant factors.Conclusion: The survival rate of unexpected N2 patients was low despite complete resection being achieved in these patients. Adjuvant therapy seemed to improve survival for those with unexpected N2 metastasis as it is a systemic disease. However, not all patients received IMS, which was mostly done by EBUS and which had a high false negative, leading to underestimating the staging. Other modalities, such as cervical mediastinoscopy, videoassisted mediastinoscopic lymphadenectomy (VAMLA) or open biopsy should be considered for the adequate evaluation of N2 metastasis, nonetheless further study is still needed.