Preoperative Lymph Node Staging by EBUS-TBNA in Clinical N0 Non Small-cell Lung Cancer

BACKGROUND AND RATIONALE The introduction of modern staging systems such as computed tomography (CT) and positron emission tomography/CT (PET/CT) with fluorodeoxyglucose (FDG) has increased the detection of small peripheral lung cancers at an early stage [1]. Stage I non-small-cell lung cancers (NSCLCs) are confined to the lung without lymph node involvement, and surgical resection is currently considered the standard therapeutic approach. Lobectomy with radical lymphadenectomy is currently considered the treatment of choice for early-stage lung cancer, irrespective of tumor size or its metabolic features on PET. However, the new TNM classification recently demonstrated that very small lung cancers may be less aggressive than others [2], suggesting a less aggressive surgical approach to reduce morbidity.

According to the new TNM classification (8th edition), the overall 5-year survival rate for pathological stage IA NSCLC was 85%, ranging from 80% to 90% for T1a and T1c tumors respectively, compared with 64% for stage IB tumors [2]. Among patients with stage I cancer, tumor size may affect outcome and drive survival, as confirmed by different studies [7-12].

Several studies demonstrated that primary invasive non- small-cell lung carcinomas > 2.0 cm were twice as likely to have nodal metastases as carcinomas ≤ 2.0 cm, emphasizing that small lung cancers had less lymph node involvement, and confirming a better survival [11-15]. Based on that, Ishida et al. and then Konaka et al. have already demonstrated the absence of lymph node involvement in sub-centimeter lung cancers and the feasibility to omit lymph node dissection in those cases [15,16]. However, Zhoua et al. recommended systematic nodal dissection in the presence of sub-centimeter disease, finding nodal metastases in 15% of NSCLC < 1 cm, but also including higher tumor stages such as stage II and III in their study without performing PET scan as part of the preoperative staging [17]. In our pilot study [18] published in 2011 in the European Journal of Thoracic Surgery, no nodal involvement was observed in any of the 62 patients with pulmonary nodule size less than 10 mm, in 20 out of 120 patients (17%) with nodule size 11-20 mm, and in 9 out of 37 tumors (24%) 21-30 mm in size (p = 0.0007). All 55 patients with nodule SUV < 2.0 and all 26 non-solid lesions were pN0 (respectively, p = 0.0001 and p = 0.03). So we adopted cut-offs of 10 mm for nodule diameter and 2.0 as peak SUV to distinguish patients with nodal involvement from those without.

These patients could be spared radical lymph node dissection if deemed not essential, thereby reducing operative risks, postoperative morbidity, and surgery time. A preoperative diagnostic determination to establish the size and correct staging of the tumor is mandatory for appropriate selection of candidates, avoiding unnecessary surgery.

Data have demonstrated that positron emission tomography (PET-FDG) is a reliable tool versus CT in evaluating both solitary pulmonary nodules and lymph node involvement [3]. Standard nodal staging is initially performed non-invasively with PET followed by minimally invasive staging with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) when PET is suggestive of mediastinal nodal involvement. In fact, EBUS-TBNA is a minimally invasive procedure with a high yield for lymph node staging of lung cancer [4]. EBUS-TBNA allows access to the paratracheal lymph node stations (levels 2R, 2L, 4R, 4L), the subcarinal lymph node (level 7), hilar, interlobar, and lobar lymph nodes (levels 10, 11, and 12). Previous studies, including systematic reviews and meta-analyses, and more recently Yasufuku et al. have demonstrated a major impact of EBUS-TBNA on management of patients with non-small cell lung cancer (NSCLC), with a diagnostic yield comparable to mediastinoscopy [5,6]. Annema et al. have recently confirmed that the sensitivity of endosonography is similar to that of mediastinoscopy (85% vs 79%, respectively), and associated with a lower complication rate (1% vs 6% for mediastinoscopy), so concluding that endosonography should be the first step for mediastinal nodal staging [19].