Primary lung cancer is the most frequent cause of death

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1 Original Article Endobronchial Ultrasound versus Mediastinoscopy for Mediastinal Nodal Staging of Non Small-Cell Lung Cancer Sang-Won Um, MD, PhD,* Hong Kwan Kim, MD, PhD, Sin-Ho Jung, PhD, Joungho Han, MD, PhD, Kyung Jong Lee, MD,* Hye Yun Park, MD, PhD,* Yong Soo Choi, MD, PhD, Young Mog Shim, MD, PhD, Myung-Ju Ahn, MD, PhD, Keunchil Park, MD, PhD, Yong Chan Ahn, MD, PhD, Joon Young Choi, MD, PhD,# Kyung Soo Lee, MD, PhD,** Gee Young Suh, MD, PhD,* Man Pyo Chung, MD, PhD,* O Jung Kwon, MD, PhD,* Jhingook Kim, MD, PhD, and Hojoong Kim, MD, PhD* Introduction: Correct mediastinal staging is critical for determination of the most appropriate management strategy in patients with non small-cell lung cancer (NSCLC). The purpose of this study was to compare the diagnostic performance of endobronchial ultrasoundguided transbronchial needle aspiration (EBUS-TBNA) with that of mediastinoscopy in patients with NSCLC. Methods: A prospective trial was conducted in a tertiary referral center in Korea. Patients with histologically proven NSCLC and suspicion for N1, N2, or N3 metastasis were enrolled. Each patient underwent EBUS-TBNA followed by mediastinoscopy. Surgical resection and complete lymph node dissection were conducted in patients for whom no evidence of mediastinal metastasis was apparent after mediastinoscopy. *Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC; Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; #Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and **Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Sang-Won Um and Hong Kwan Kim contributed equally to this work. Disclosure: The authors have no conflicts of interest to disclose. This study was supported by the Samsung Medical Center Clinical Research Development Program (CRS and CRS ). Address for correspondence: Hojoong Kim, MD, PhD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul , South Korea. hjk3425@skku.edu; or Jhingook Kim, MD, PhD, Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Seoul , South Korea. jkimsmc@skku.edu DOI: /JTO ISSN: /15/ Results: In total, 138 patients underwent EBUS-TBNA and 127 completed both EBUS-TBNA and mediastinoscopy. N2/N3 disease was confirmed in 59.1% of the patients. The diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value (NPV) of EBUS-TBNA on a per-person analysis were 88.0%, 100%, 92.9%, 100%, and 85.2%, respectively. The diagnostic sensitivity, specificity, accuracy, positive predictive value, and NPV of mediastinoscopy on a per-person analysis were 81.3%, 100%, 89.0%, 100%, and 78.8%, respectively. Significant differences in the sensitivity, accuracy, and NPV were evident between EBUS-TBNA and mediastinoscopy (p < 0.005). Conclusions: EBUS-TBNA was superior to mediastinoscopy in terms of its diagnostic performance for mediastinal staging of cn1 3 NSCLC. Because EBUS-TBNA is both less invasive and affords superior diagnostic sensitivity, it should be the first-line procedure performed in patients with NSCLC. Key Words: Carcinoma, non small-cell lung, ultrasonography, mediastinoscopy, neoplasm staging, mediastinum (J Thorac Oncol. 2015;10: ) Primary lung cancer is the most frequent cause of death due to cancer worldwide. 1,2 Accurate mediastinal staging is critical for selection of the most appropriate management strategy and evaluation of the prognosis in patients with non small-cell lung cancer (NSCLC) who are potential candidates for curative resection. Many noninvasive imaging studies using chest computed tomography (CT) and positron emission tomography (PET)/ CT have been conducted. The pooled diagnostic sensitivity and specificity of chest CT and PET/CT were 55% and 81%, and 62% and 90%, respectively. 3 Noninvasive mediastinal nodal staging is not satisfactory because of its high false-positive and false-negative rates. 3 Abnormal findings on noninvasive testing must be examined by biopsy for accurate staging. 3,4 Mediastinoscopy is performed under general anesthesia and allows the subcarinal and paratracheal lymph node stations to be accessed. Although mediastinoscopy is considered to be the diagnostic standard, the pooled sensitivity and negative predictive Journal of Thoracic Oncology Volume 10, Number 2, February

2 Um et al. Journal of Thoracic Oncology Volume 10, Number 2, February 2015 values of traditional and video-assisted mediastinoscopy (VAM) for mediastinal staging were only 78% and 91%, and 89% and 92%, respectively. 3 The technique is invasive and the morbidity and mortality rates are 2% and 0.08%, respectively. 3,5 Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a less invasive intervention permitting mediastinal nodal staging under direct endobronchial ultrasonic guidance In earlier systemic reviews and meta-analyses, the diagnostic sensitivities of EBUS-TBNA ranged from 88% to 93%, comparable to those of mediastinoscopy. 3,11,12 Although such data are promising, only two prospective studies have directly compared EBUS-TBNA and mediastinoscopy. 13,14 EBUS-TBNA was superior to mediastinoscopy in terms of sensitivity in one study (87% versus 68%), 14 but the two methods were of similar diagnostic sensitivity in the other (81% versus 79%). 13 However, the cited works may not reflect the real-life clinical utility of EBUS- TBNA because the procedure was performed under general anesthesia. The objective of this study was to compare the diagnostic performance of EBUS-TBNA under conscious sedation and local anesthesia with that of mediastinoscopy used to identify N2/N3 metastasis in patients with NSCLC. PATIENTS AND METHODS Study Patients This was a single-center prospective trial involving patients with potentially resectable NSCLC. This study was conducted in accordance with the amended Declaration of Helsinki. The study was approved by the Institutional Review Board of the Samsung Medical Center (IRB No ) and was registered at (NCT ). Written informed consent was obtained from each patient. Diagnostic evaluation included a conventional workup, bronchoscopy, CT, and integrated whole-body 18 F-fluorodeoxyglucose (FDG) PET/CT scanning. A patient was included if the guidelines indicated that mediastinal nodal sampling was appropriate. 4,15 The inclusion criteria were as follows: (1) Histologically proven NSCLC; (2) a suspicion of N2 or N3 lymph node metastasis on chest CT or PET/CT scans [at least one of three criteria had to be met, and these were: (a) enlarged (short-axis diameter 1 cm or more) mediastinal node(s), (b) FDG uptake by mediastinal node(s), and/or (c) FDG uptake by N1 node(s)]; and (3) the subject was a candidate for curative surgery. The exclusion criteria were as follows: (1) distant metastasis, (2) inoperable T4 disease, (3) supraclavicular lymph node metastasis, (4) a history of prior therapy for lung cancer, (5) the presence of contraindication(s) for bronchoscopy, (6) uncorrected coagulopathy, (7) another concurrent malignancy, and/or (8) any suspicious mediastinal node metastasis inaccessible by EBUS-TBNA or mediastinoscopy (i.e., the para-aortic, aortopulmonary window, or para-esophageal lymph nodes). Study Design Each patient underwent EBUS-TBNA followed by mediastinoscopy. Thoracic surgeons and pathologists were blinded to the EBUS-TBNA data, which were used for research purposes and were disclosed only after the mediastinoscopy. However, if N3 disease was confirmed by EBUS-TBNA at any nodal station examined (the contralateral hilar, contralateral interlobar, or highest mediastinal lymph nodes) that was inaccessible by mediastinoscopy, the latter procedure was cancelled and the EBUS-TBNA results were reported because performance of mediastinoscopy was not ethically justifiable. Mediastinoscopy was performed within 3 weeks of EBUS- TBNA. The treatment decision was made according to the result of mediastinoscopy in each patient. Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration EBUS-TBNA and biopsies were conducted using a convex probe-ebus bronchoscope (BF-UC260F-OL8; Olympus, Tokyo, Japan) and a 22-gauge needle (NA-201SX-4022; Olympus). 6,16 The interventions were conducted with local anesthesia through nebulization with lidocaine and conscious sedation using midazolam. 16 Each visible station was sampled systematically. 17 If a station had multiple lymph nodes on EBUS, we chose the lymph node based on the size and 18 F-FDG uptake. Core tissue was placed on filter paper to absorb excess blood, fixed in 10% (v/v) formalin, and the tissue coagulum clot was sent for histological examination. 16,18,19 Aspirates were discharged onto slides, smeared, fixed in 95% (v/v) ethanol, and sent for cytological examination. When possible, we conducted three passes per node. When core tissue was obtained, at least two passes were conducted when possible. Rapid on-site cytopathological evaluation was not available. All interventions were conducted by two bronchoscopists (U.S.W. and L.K.J.) who had experiences with more than 300 cases of EBUS- TBNA before study initiation. All lymph nodes were classified in terms of the International Association for the Study of Lung Cancer lymph node map. 20 Mediastinoscopy Traditional cervical mediastinoscopy and VAM were performed by experienced thoracic surgeons (K.H.K., C.Y.S., S.Y.M., and K.J.) who had experiences with more than 1000 cases of mediastinoscopy before study initiation. 21,22 Mediastinoscopic examination was performed to evaluate lymph nodes in stations 2R, 2L, 4R, 4L, and 7. Each nodal station was biopsied regardless of nodal appearance or size. All specimens collected by mediastinoscopy were promptly transported to a pathologist located in the operating theater. That pathologist examined frozen sections, and surgery did not proceed until the results were received. Surgical Resection If N2/N3 disease was not noted in frozen sections of mediastinoscopy biopsies, patients immediately underwent lung resection surgery with systematic mediastinal lymph node dissection, which included resection of each node at stations 2R, 4R, 7, 8, and 9 for right-sided tumors and at stations 4L, 5, 6, 7, 8, and 9 for left-sided tumors. Diagnostic Standards The positive and negative diagnostic standards were cytopathological confirmation of the presence or absence of 332

3 Journal of Thoracic Oncology Volume 10, Number 2, February 2015 EBUS versus Mediastinoscopy in Patients with NSCLC malignancy, respectively, using all available tissue-sampling methods (EBUS-TBNA, mediastinoscopy, or mediastinal lymph node dissection). Statistical Analysis All data are presented as medians (with ranges) or numbers (with % values). The diagnostic sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of EBUS-TBNA and mediastinoscopy were calculated on a per-person basis using standard definitions. The primary end point of the study was to demonstrate that EBUS-TBNA was not inferior to mediastinoscopy in the detection of N2 or N3 metastases (sensitivity). Secondary end points were to compare the specificity, accuracy, PPV, and NPV of the two diagnostic methods. The null hypothesis was that the sensitivity of EBUS-TBNA (P E ) would be lower than that of mediastinoscopy (P M ) by a noninferiority margin of 10%, and the alternative hypothesis was that P E would be possibly higher than P M by a superiority margin of 5%. Assuming the presence of 20% discordant pairs, the noninferiority test for the null hypothesis with a one-sided alpha of 5% required 75 patients with mediastinal nodal metastasis to detect the alternative hypothesis with a 90% power. Assuming a 60% prevalence of mediastinal nodal metastasis in a prospective cohort formed using similar inclusion criteria, 23 and a 10% dropout, a sample size of 139 patients was required. Per-patient analyses of the two diagnostic methods in terms of sensitivity, specificity, and accuracy were evaluated using the asymptotic McNemar test. The comparison of PPV and NPV between two diagnostic methods was conducted using a weighted least squares test. 24 The diagnostic sensitivity of each nodal station was evaluated using the asymptotic McNemar test. Comparisons between the performance of traditional mediastinoscopy and VAM were performed using the two-sample t test. Statistical analyses were conducted using IBM SPSS Statistics version 20.0 (SPSS Inc., Chicago, IL) and R version ( RESULTS Study Algorithm Between March 2010 and May 2012, 250 consecutive patients with resectable histology-proven NSCLC were assessed for study eligibility, and 112 were excluded (Fig. 1). One hundred and thirty-eight patients underwent initial EBUS-TBNA. Of these, eight dropped out, refusing to participate further. Of 25 patients in whom the contralateral hilar or interlobar lymph nodes had been examined by EBUS-TBNA (n = 138), N3 disease was confirmed in three, who therefore did not undergo mediastinoscopy. Among these three patients, two had additional N2 metastasis and one had additional N3 metastasis. Of 127 patients who underwent mediastinoscopy, 58 yielded positive results on examination of frozen sections of mediastinoscopy tissue. Of 69 patients who yielded negative results upon examination of frozen sections after mediastinoscopy, 66 underwent lung resection surgery and systematic lymph node dissection, and N2/N3 metastasis was confirmed in nine (eight by lymph node dissection and one by both formal histopathological examination after mediastinoscopy and lymph node dissection). In three patients who did not yield positive results on examination of frozen sections of mediastinoscopy tissue, but who did not undergo lung resection surgery, malignancy was confirmed in two by formal histopathological examination of mediastinoscopy tissue and in one through EBUS-TBNA. Therefore, N2 or N3 involvement was solely confirmed by EBUS-TBNA, mediastinoscopy, and mediastinal lymph node dissection in six, four, and three patients, respectively. The trial ended when 75 patients were identified as having N2 or N3 metastasis by EBUS-TBNA, mediastinoscopy, or mediastinal lymph node dissection. Patient Demographics and Lymph Nodal Stations Examined Table 1 shows the demographic characteristics of the subjects. The median age was 62 years and 84.8% were male. The most frequent clinical T stage was T2a (34.1%), and the most common clinical N stage was N2 (68.1%), followed by N3 (17.4%) and N1 (14.5%). The most common final histopathology was squamous cell carcinoma (54.3%), followed by adenocarcinoma (39.9%). The median numbers of lymph nodal stations examined by EBUS-TBNA and mediastinoscopy were both three. Table 2 shows the nodal stations examined. A total of 524 lymph nodes were examined using at least one of the three methods. Totals of 376, 398, and 201 lymph nodes were examined by EBUS-TBNA (in 127 patients), mediastinoscopy (in 127 patients), and surgical lymph node dissection (in 64 patients), respectively. The median short- and long-axis diameters of the largest lymph node in each station examined were 9 and 14 mm, respectively. Core tissues were obtained in 97.1% of the nodes examined by EBUS-TBNA. Analysis of Diagnostic Performance The prevalence of N2/N3 metastasis in the cohort included in diagnostic performance analysis was 59.1% (75 out of 127). Table 3 shows the diagnostic performances of EBUS-TBNA and mediastinoscopy based on a per-person analysis. The sensitivity, specificity, accuracy, PPV, and NPV of EBUS-TBNA were 88.0% (95% confidence interval [CI] %), 100% (95% CI %), 92.9% (95% CI %), 100% (95% CI %), and 85.2% (95% CI %), respectively. The sensitivity, specificity, accuracy, PPV, and NPV of mediastinoscopy were 81.3% (95% CI %), 100% (95% CI %), 89.0% (95% CI %), 100% (95% CI %), and 78.8% (95% CI %), respectively. Significant differences in sensitivity (p = ), accuracy (p = ), and NPV (p = ) were evident between EBUS-TBNA and mediastinoscopy. Subgroup Analysis Table 4 shows the diagnostic sensitivities of the individual lymph nodal stations afforded by the two tests. In station 333

4 Um et al. Journal of Thoracic Oncology Volume 10, Number 2, February 2015 FIGURE 1. Enrollment of patients. Of 127 patients staged using the two techniques, 58 yielded malignant results on examination of frozen sections of mediastinoscopy. Of 69 patients who yielded benign results from frozen sections after mediastinoscopy, 66 underwent systematic lymph node dissection with resection surgery. EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; NSCLC, non small-cell lung cancer. 4L, a significant difference in diagnostic sensitivity was evident between EBUS-TBNA (81.0%; 95% CI %) and mediastinoscopy (52.4%, 95% CI %) (p = ). There was no significant difference in the diagnostic sensitivity of traditional mediastinoscopy (63.6%; 95% CI %) and VAM 83.0%; 95% CI %) (p = ). Adverse Events There were no mortalities and major events related to EBUS-TBNA or mediastinoscopy. Minor events during EBUS-TBNA included minor bleeding (n = 1) and transient hypoxemia (n = 1). Minor event during mediastinoscopy included minor bleeding (n = 1). 334

5 Journal of Thoracic Oncology Volume 10, Number 2, February 2015 EBUS versus Mediastinoscopy in Patients with NSCLC TABLE 1. Clinical Characteristics of the Patients (n = 138) Characteristic No. (%) or Median (Range) Age (years) 62 (34 76) Male gender 117 (84.8%) Smoker/nonsmoker 110 (79.7)/28 (20.3) Pack-years 35 (0 125) Tumor stage by PET/CT 138 (100) T1a 7 (5.1) T1b 19 (13.8) T2a 47 (34.1) T2b 26 (18.8) T3 38 (27.5) T4 1 (0.7) Nodal stage by PET/CT 138 (100) N1 20 (14.5) N2 94 (68.1) N3 24 (17.4) Final histopathology 138 (100) Squamous cell carcinoma 75 (54.3) Adenocarcinoma 55 (39.9) NSCLC NOS 6 (4.3) LCNEC 1 (0.7) Pleomorphic carcinoma 1 (0.7) Number of nodal stations examined EBUS-TBNA (n = 138) 3 (1 6) Mediastinoscopy (n = 127) 3 (1 6) Mediastinal lymph node dissection (n = 64) 3 (1 6) Time interval between EBUS-TBNA and 6 (0 19) mediastinoscopy, days (n = 127) Number of passes per each nodal station during 2 (1 5) EBUS-TBNA Type of mediastinoscopy 127 (100) Traditional 42 (33.1) Video-assisted 85 (66.9) Lung resection surgery 55 (100) Lobectomy 47 (85.5) Bilobectomy 8 (14.5) Pneumonectomy 9 (16.4) Wedge resection 1 (1.8) EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; LCNEC, large-cell neuroendocrine carcinoma; NSCLC NOS, non small-cell lung cancer not otherwise specified; PET/CT, positron-emission tomography/computed tomography. DISCUSSION This prospective study clearly demonstrated that the diagnostic sensitivity, accuracy, and NPV of EBUS-TBNA were higher than those of mediastinoscopy for the mediastinal nodal staging of cn1-3 NSCLC. Only two prospective studies have directly compared EBUS-TBNA and mediastinoscopy. 13,14 However, these studies may not reflect the real-life utility of EBUS-TBNA because the procedure was performed at the time of mediastinoscopy under general anesthesia in some or all study subjects. 13,14 Further, the two cited studies may not have been TABLE 2. Mediastinal Nodal Stations in 127 Patients Who Underwent Both EBUS-TBNA and Mediastinoscopy EBUS- TBNA Mediastinoscopy Lymph Node Dissection a Subtotal 1R L R A P L R L R Total Short-axis diameter of the largest lymph node in each nodal station (mm) 9 (3 30) 10 (3 30) 10 (3 28) 9 (3 30) a Mediastinal lymph node dissection was conducted in 64 patients. EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration. adequately powered to allow for a fair comparison of EBUS- TBNA with mediastinoscopy. No formal sample size calculation was conducted in either study. 13,14 The strengths of our study are that EBUS-TBNA was compared with mediastinoscopy after the formal sample size calculation and that all EBUS-TBNA procedures were conducted under conscious sedation. Although correct mediastinal staging is vital for the management of NSCLC, the optimal approach to invasive mediastinal staging remains controversial. Recent American College of Chest Physicians and European Society of Thoracic Surgeons guidelines have recommended a needle-based technique, such as endoscopic ultrasound fine needle aspiration (EUS-FNA) or EBUS-TBNA, over mediastinoscopy as the optimal first test. 3,25 This recommendation was based on systemic reviews and meta-analyses of the diagnostic performances of EBUS- TBNA and mediastinoscopy. The pooled diagnostic sensitivities of EBUS-TBNA ranged from 88% to 93%, comparable to those of traditional mediastinoscopy (78%) or VAM (89%). 3,11,12 The superiority of a combined approach of EBUS-TBNA and EUS-FNA over either procedure alone was reported previously A staging strategy combining endosonography (EUS- FNA or EBUS-TBNA) and surgery, compared with surgery alone, afforded higher sensitivity in detecting mediastinal nodal metastases, and fewer futile thoracotomies resulted. 27 Several factors contributed to the superior sensitivity of EBUS-TBNA. First, EBUS-TBNA allows for visualization and localization of a target lymph node using real-time ultrasonic guidance even when the target is deeply buried or very close to a vessel. In this study, mediastinoscopy was of lower sensitivity (52.4%) when used to diagnose metastasis in the 335

6 Um et al. Journal of Thoracic Oncology Volume 10, Number 2, February 2015 TABLE 3. Diagnostic Performance of EBUS-TBNA and Mediastinoscopy on a Per-Person Basis (n = 127) EBUS-TBNA Mediastinoscopy p Value Sensitivity 66/75 (88.0) [ ] 61/75 (81.3) [ ] Specificity 52/52 (100) [ ] 52/52 (100) [ ] NA Accuracy 118/127 (92.9) [ ] 113/127 (89.0) [ ] PPV 66/66 (100) [ ] 61/61 (100) [ ] NA NPV 52/61 (85.2) [ ] 52/66 (78.8) [ ] Data are presented as numbers/total numbers (%) [with 95% confidence intervals]. EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; NA, not applicable; NPV, negative predictive value; PPV, positive predictive value. TABLE 4. Diagnostic Sensitivities of EBUS-TBNA and Mediastinoscopy on an Individual Lymph Nodal Station Basis EBUS-TBNA Mediastinoscopy p Value 2R (n = 67) 10/18 (55.6) [ ] 11/18 (61.1) [ ] L (n = 12) 0/3 (0) [0 0] 3/3 (100) [ ] R (n = 125) 34/41 (82.9) [ ] 33/41 (80.5) [ ] L (n = 111) 17/21 (81.0) [ ] 11/21 (52.4) [ ] (n = 126) 33/40 (82.5) [ ] 30/40 (75.0) [ ] EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration. 4L lymph node than was EBUS-TBNA (81.0%). It is difficult to use mediastinoscopy to access the deeply located 4L lymph node, which is close to the ascending aorta, the pulmonary artery, and the recurrent laryngeal nerve. There was a tendency for lower diagnostic sensitivity of the subcarinal lymph node by mediastinoscopy (75.0% versus 82.5%), which could be partly due to the fact that with mediastinoscopy, it was not possible to access the posteriorly located deep subcarinal lymph node. Second, during EBUS-TBNA, we performed systematic sampling of representative nodes in all visible stations rather than selective sampling of just one or two nodal stations. The accuracy of mediastinal nodal staging depends not only on the test used but also on the thoroughness with which the procedure is performed. 17 The median number and short-axis diameter of the nodes examined by EBUS-TBNA were three and 9 mm, respectively, comparable to those of nodes examined by mediastinoscopy. Histologic cores were obtained in 97.1% of the nodes examined by EBUS-TBNA. The high success rate of EBUS-TBNA biopsy in this study suggests that it provides high diagnostic performance even without the use of rapid on-site cytopathological evaluation. Finally, EBUS-TBNA can also detect N3 disease in contralateral hilar or interlobar lymph nodes that are inaccessible using mediastinoscopy. Twenty-five of 138 patients who underwent EBUS-TBNA were evaluated in terms of contralateral hilar or interlobar lymph node metastasis; N3 disease was confirmed in three. In this study, there was a tendency of higher diagnostic sensitivity of VAM (83.0%) compared with that of traditional mediastinoscopy (63.6%), but it was not statistically significant. Potential advantages of VAM over traditional mediastinoscopy include enhanced views on the monitor and a more comfortable surgical working environment. 30 The total number of dissected nodes was higher in the VAM group than in the traditional mediastinoscopy group in the previous study. 30 A limitation of this study is that all work was conducted in a single tertiary referral center, which potentially restricts the applicability of our findings. It is also possible that less-experienced groups may be unable to use EBUS-TBNA as effectively as did we, and the sensitivity of the technique would thus be lower in other hands. Another limitation is that the median number of mediastinal nodal stations examined by lymph node dissection was relatively small (n = 3), which might be associated with high proportion of VAM (66.9%). The number of remaining lymph nodes after VAM was smaller than that after traditional mediastinoscopy because VAM enabled complete removal of more lymph nodes. 30 Finally, although recent guidelines recommended invasive nodal staging of a centrally located tumor with N0 disease, we did not include these patients. 3,25 Thus, our data regarding cn1 3 should not be extrapolated to central tumors with N0 disease. We also excluded the patients with histologically not proven NSCLC. In conclusion, EBUS-TBNA was superior to mediastinoscopy in terms of its diagnostic performance for mediastinal staging of cn1-3 NSCLC. Because EBUS-TBNA is less invasive and offers superior diagnostic sensitivity, this should be the first-line procedure performed on patients with NSCLC. ACKNOWLEDGMENTS We thank Eun Yoon Cho, MD, for data collection (Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea). REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, CA Cancer J Clin 2012;62: Devesa SS, Bray F, Vizcaino AP, Parkin DM. International lung cancer trends by histologic type: male:female differences diminishing and adenocarcinoma rates rising. Int J Cancer 2005;117:

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