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Original Research: INTERVENTIONAL PULMONOLOGY |

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration of Lymph Nodes in the Radiologically and Positron Emission Tomography-Normal Mediastinum in Patients With Lung Cancer* FREE TO VIEW

Felix J. F. Herth, MD, FCCP; Ralf Eberhardt, MD; Mark Krasnik, MD; Armin Ernst, MD, FCCP
Author and Funding Information

*From the Department of Pneumology and Critical Care Medicine (Drs. Herth and Eberhardt), Thoraxklinik am Universitätsklinikum Heidelberg, Germany; Cardiothoracic Surgery (Dr. Krasnik), Gentofte University Hospital, Copenhagen, Denmark; and Interventional Pulmonology (Dr. Ernst), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

Correspondence to: Armin Ernst, MD, FCCP, Chief, Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, One Deaconess Rd, Suite 201, Boston, MA 02115; e-mail: aernst@bidmc.harvard.edu



Chest. 2008;133(4):887-891. doi:10.1378/chest.07-2535
Text Size: A A A
Published online

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) can reliably sample enlarged mediastinal lymph nodes in patients with non-small cell lung cancer (NSCLC), and in practice is mostly used to sample nodes visible on CT or positron emission tomography (PET). Few data are available on the use of endoscopic procedures to stage the mediastinum in clinical stage 1 lung cancer. The aim of the present study was to determine the results of EBUS-TBNA in sampling mediastinal lymph nodes in patients with lung cancer and a radiographically normal mediastinum and no PET activity.

From January 2004 to May 2007, patients highly suspicious for NSCLC with CT scans showing no enlarged lymph nodes (no node > 1 cm) and a negative PET finding of the mediastinum underwent EBUS-TBNA. Identifiable lymph nodes at locations 2r, 2L, 4r, 4L, 7, 10r, 10L, 11r, and 11L were aspirated. All patients underwent subsequent surgical staging. Diagnoses based on aspiration results were compared with those based on surgical results.

One hundred patients (mean age, 52.4 years; 59 men) were included. After surgery, 97 patients (mean age, 52.9 years; 57 men) had NSCLC confirmed and were included in the analysis. In this group, 156 lymph nodes ranging 5 to 10 mm in size were detected and sampled. Malignancy was detected in nine patients but missed in one patient. Mean diameter of the punctured lymph nodes was 7.9 mm. The sensitivity of EBUS-TBNA for detecting malignancy was 89%, specificity was 100%, and the negative predictive value was 98.9%. No complications occurred.

In conclusion, EBUS-TBNA can be used to accurately sample and stage patients with clinical stage 1 lung cancer and no evidence of mediastinal involvement on CT and PET. Potentially operable patients with no signs of mediastinal involvement may benefit from presurgical staging with EBUS-TBNA.

Figures in this Article

Accurate staging of mediastinal lymph nodes is mandatory for adequate treatment of non-small cell lung cancer (NSCLC). In most centers, CT is the initial method for assessing mediastinal nodes, and lymph nodes are considered abnormal with a short-axis diameter > 10 mm. Smaller lymph nodes can harbor metastatic foci, and enlarged nodes may be benign, especially when central tumors are accompanied by inflammation. Therefore, the accuracy of CT for diagnosing mediastinal disease is low.14

Positron emission tomography (PET) has been reported to be more accurate than CT,56 especially with a high negative predictive value. PET was expected to increase the accuracy of mediastinal staging in NSCLC; indeed, a metaanalysis7has indicated its superiority. However, a more recent report8 has tempered enthusiasm for using PET as the sole tool for evaluating and staging mediastinal nodes.

In order to achieve the most accurate staging, tissue sampling is necessary and recommended. Mediastinoscopy is still the “gold standard” for the evaluation of mediastinal lymph nodes but the reach is limited; as a surgical procedure, mediastinoscopy is costly and has associated morbidity and mortality.911

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been reported as an endoscopic option to evaluate the mediastinum.1215 It compares well with mediastinoscopy but unfortunately does not allow for airway inspection during the procedure or the performance of other interventions, such a transbronchial biopsy.

Real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a highly accurate and safe method for sampling enlarged mediastinal lymph nodes.1618 In a former trial,19 the technique was also found effective to stage mediastinal nodes < 10 mm in size, but this trial did not include PET. The aim of the present study was to determine the accuracy of EBUS-TBNA for staging mediastinal lymph nodes in lung cancer patients without enlarged mediastinal lymph nodes on chest CT scans and no detectable PET activity in the mediastinum.

The protocol of this study was approved by the local institutional review board. All patients provided written informed consent. Between January 2004 and May 2007, consecutive patients with an indication for bronchoscopy and suspicion for NSCLC were screened for inclusion in the study. All patients did undergo a CT scan of the chest (plain and contrast enhanced) and a PET scan as part of their standard workup. Only patients without CT evidence of enlarged mediastinal lymph nodes as well as negative PET imaging results were included in the current study.

Bronchoscopy

Standard, conventional flexible bronchoscopy (models BF-T160 or BF-1T180; Olympus; Tokyo, Japan) was first performed to examine the tracheobronchial tree, followed by EBUS-TBNA using an ultrasound bronchoscope (model BF-UC160F-OL8; Olympus). Additional procedures were performed as clinically necessary. Bronchoscopy procedures were performed with the patient under general anesthesia. All patients underwent surgical staging within 48 h after the EBUS-TBNA not knowing the results of the endoscopic mediastinal sampling.

Imaging
CT:

Multislice CT was performed in all patients, and clinical TNM staging, including identification of distant metastases, was recorded by two thoracic CT radiologists. On-site CT examinations were performed with a helical scanner (Siemens; Erlangen, Germany), using a single breath-hold technique. Off-site CT scans were evaluated by the same radiologists and were included if their quality was similar to the on-site CT studies. If the quality of an off-site CT was inadequate, an on-site CT was performed. Lymph nodes were considered enlarged if the short-axis diameter was > 1 cm.

PET:

Whole-body F18-fluorodeoxyglucose (FDG)-PET (GE PET Advance Nxi; GE Medical Systems; Milwaukee, WI) was performed following an overnight fast. The glucose levels of patients were within normal limits prior to examination. Sixty to 90 min after injection of 300 megabecquerels of FDG, whole-body acquisition was performed. Images were reconstructed using the attenuation-weighted ordered-subset expectation maximization technique.56 Images were visually interpreted using a display of three orthogonal sections and maximum-intensity projections. One experienced nuclear medicine physician who was masked to the results of other tests read the PET images. Standardized uptake values were calculated as the ratio of the regional radioactivity concentration divided by the injected amount of radioactivity normalized to body weight.20 FDG-PET was considered positive for an N1, N2, or N3 lymph node if the PET report stated that there was hypermetabolic activity consistent with malignant disease (defined as standardized uptake value > 2.5).

EBUS-TNBA

EBUS-TBNA was performed with a dedicated flexible bronchoscope with a ultrasonic linear scanning transducer mounted at its distal tip as previously described.1718,21 The curved linear array transducer scans parallel to the insertion direction of the bronchoscope. The EBUS-TBNA endoscope is connected to a dedicated endoscopic ultrasound processor (EU-C60; Olympus Corporation) or a standard ultrasound processor (Aloka Prosound α 5; Aloka; Tokyo, Japan) with Doppler-flow imaging for the detection of blood vessels. A 22-gauge needle (NA-201SX-4022; Olympus Corporation) was used to perform transbronchial needle aspiration.

Regional lymph node stations of the mediastinum and hilar regions (stations 2, 4, 7, 10, and 11) were systematically imaged and measured (short-axis diameter) during slow withdrawal and rotation of the transducer. All visualized nodes with a size of 5 to 10 mm were punctured. According to the size of normal lymph nodes, nodes < 5 mm were not punctured.2224 Transbronchial needle aspiration was performed under real-time ultrasound control. Needle punctures were performed using the “jabbing” method.25 Integrated color power Doppler ultrasound was used to avoid intervening vessels immediately before needle puncture (Fig 1 ) if indicated. Every node was punctured twice.

The aspirates were placed onto glass slides, air-dried, stained, and classified. Papanicolaou staining and light microscopy were performed by a cytopathologist who was blinded to the details of the patients.2627 No rapid on-site cytology was performed.

Statistical Methods

The χ2 test was used, when appropriate, to compare proportional data. The type I error was set at 0.05 for all analyses. Confidence intervals were calculated to 95% using standard formulae. The sensitivity, specificity, and accuracy were calculated using the standard definitions.

In total, 1,217 patients were evaluated until 100 patients were identified meeting criteria. Mean age was 52.4 years, and 59 were men. As stipulated, CT and PET showed evidence suggesting a tumor originating from the lung suspicious for NSCLC, without enlarged mediastinal lymph nodes and without mediastinal PET activity in all patients.

After diagnostic procedures, 97 patients were confirmed to have NSCLC (59 adenocarcinoma, 29 squamous cell cancer, and 9 adenosquamous cell cancer). This group of patients was included in the analysis. Three patients were confirmed to have another diagnosis and were excluded: sarcoidosis (n = 1) and hamartochondroma (n = 2).

All 97 patients (mean age, 52.9 years; 57 men) had at least one node identified by endobronchial ultrasound, and a total of 156 lymph nodes 5 to 10 mm in size were detected and punctured by EBUS-TBNA (Table 1 ). Mean ± SD diameter of the punctured lymph nodes was 7.9 ± 0.7 mm (range, 5 to 10 mm). Additionally, 73 nodes < 5 mm were detected that were not punctured.

Despite negative CT and PET scan results, EBUS-TBNA of mediastinal lymph nodes was positive for metastatic disease in eight patients. The stage changed from N0 in one patient to stage N3 disease, in five patients to stage N2 disease, and in two patients to stage N1 disease. All punctures were adequate, and in every smear lymphocytes were visible. All patients were examined under general anesthesia.

All 100 patients underwent mediastinoscopy (11%) or thoracotomy (89%). Patients with confirmed NSCLC underwent complete lymph node resection. Additional positive nodes were detected in one patient in N1 position. Overall, six patients had stage N2 or N3 disease, of which all were identified from EBUS-TBNA, and three patients had stage N1 disease, of which two were identified by EBUS-TBNA. The patient with lymph node metastases not identified by EBUS-TBNA had nodal involvement in position 10r, and had undergone EBUS-TBNA puncture of lymph nodes in these regions. The smears showed lymphocytes but no malignancy. The sensitivity, specificity, and negative predictive value of EBUS-TBNA for detecting malignancy were 89, 100%, and 99%, respectively.

The patients with malignant nodes had adenocarcinoma (n = 8) and squamous cell cancer (n = 1). The location of the primary was in the right lower lobe (n = 4), the right upper lobe (n = 2), the left lower lobe (n = 1), and the left upper lobe (n = 2). All of the malignant nodes were detected in patients with lesions > 1.5 cm.

In a previous published trial,19 we used EBUS-TBNA in a comparable setting. Overall, 17 patients had stage N2 or N3 disease, of which 16 cases were identified from EBUS-TBNA, and 4 patients had stage N1 disease, of which 3 cases were identified by EBUS-TBNA. The sensitivity, specificity, and negative predictive value of EBUS-TBNA for detecting malignancy were 92.3%, 100%, and 96.3%, respectively. A limitation of the study was the lack of routine PET scanning. Because PET scanning is becoming routine in many cancer centers around the world, the value of presurgical endoscopic staging in the face of negative imaging results had to be reassessed. We found EBUS-TBNA to be highly accurate even in this setting, and the 9% prevalence of mediastinal lymph node metastases in the present study is similar to that of surgical studies2829 evaluating patients with negative mediastinal CT results. These studies describe metastatic lymph nodes to be present at the time of surgery in 9 to 11% of CT-negative patients with T1 tumors.

Compared with mediastinoscopy, EBUS-TBNA has the advantage that it is also able to routinely access posterior mediastinal (level 7) and hilar lymph nodes (levels 10 and 11). Additionally, it can reliably be performed as an outpatient procedure, carries an extremely low morbidity, and can easily be repeated if necessary at a later stage.

Similar approaches using EUS-FNA have been described with comparable results, albeit in smaller patient populations. A study by Wallace et al30 evaluated 69 patients without enlarged mediastinal lymph nodes. Endoscopic ultrasound detected malignant mediastinal lymph nodes in 14 of the 69 patients. The sensitivity of endoscopic ultrasound for advanced mediastinal disease was 61%, and the specificity was 98%. Additionally, Wallace et al30found advanced stage in three other patients (one patient with left adrenal metastasis, and two patients with mediastinal invasion of tumor). LeBlanc et al31 examined 76 patients with NSCLC without mediastinal lymphadenopathy on CT. EUS-FNA was performed on sites that were suspicious for metastases. Of the 62 patients who underwent surgery, 23 patients (37%) had positive lymph nodes, 6 patients had peribronchial lymph node (N1) involvement, whereas the remaining 17 patients had ipsilateral or subcarinal lymph node (N2) involvement.

Depending on the lymph node localization, EBUS- TBNA seems at least comparable to the established EUS-FNA findings in the literature. It is important to note that small lymph nodes are more difficult to identify with any imaging modality (including endobronchial ultrasound) and probably contain a small number of malignant cells, making a cytologic diagnosis difficult. Nonetheless, in 97 patients, EBUS-TBNA identified almost all (eight of nine) patients with advanced disease.

The present study supports the theory that EBUS-TBNA has excellent potential, even in the patient with a CT- and PET-normal mediastinum. It also emphasizes again that clinical staging alone based on imaging data remains insufficiently reliable. The results of this study suggest that patients with normal CT and PET findings of the mediastinum can be primarily evaluated and staged during diagnostic bronchoscopy with EBUS-TBNA of all nodes > 5 mm, especially if it is known to be an adenocarcinoma.3234

Limitations of the Study

All of the study patients were examined under general anesthesia, but as previously reported there is no known difference in yield or patient tolerance if the procedure is performed under moderate sedation or general anesthesia.18 Lymph nodes are often grouped in stations. A potential exists that the surgically sampled lymph nodes in the examined stations were not identical to the nodes punctured during endoscopy. This appears unlikely because in the present study the results of the endoscopically and surgically sampled lymph nodes were highly congruent. Lastly, PET imaging was not fused with CT imaging in this study. Fusion PET-CT is at times reported as superior to dedicated PET alone; nevertheless, dedicated PET alone is the standard in many institutions around the world.

The current findings suggest that EBUS-TBNA should be considered in the preoperative staging of all patients with and without mediastinal lymph node enlargement on CT scan and with or without PET activity in the mediastinum. EBUS TBNA could be an obvious choice for the primary procedure because it is well tolerated, carries minimal morbidity, and allows for additional pulmonary procedures in the same setting. Further studies are needed to compare the different invasive and noninvasive staging techniques (CT, PET, EBUS-TBNA, EUS-FNA, mediastinoscopy, and thoracoscopy) in patients with NSCLC.

Abbreviations: EBUS-TBNA = endobronchial ultrasound-guided transbronchial needle aspiration; EUS-FNA = endoscopic ultrasound-guided fine-needle aspiration; FDG = F18-fluorodeoxyglucose; NSCLC = non-small cell lung cancer; PET = positron emission tomography

The institutions or affiliated medical schools of the authors have received unrestricted grant support from Olympus Corporation for continuing medical education activities, and the endobronchial ultrasound imaging components are on loan in the institutions. The authors have not received any direct financial support.

Figure Jump LinkFigure 1. Image of a node puncture in station 7, with the needle clearly visible in the target.Grahic Jump Location
Table Graphic Jump Location
Table 1. All Patients With Confirmed Mediastinal Involvement by Malignancy*
* 

RUL = right upper lobe; RLL = right lower lobe; LUL = left upper lobe; LLL = left lower lobe; Adeno = adenocarcinoma.

 

Missed by EBUS-TBNA.

Silvestri, GA, Gould, MK, Margolis, ML, et al (2007) Noninvasive staging of non-small cell lung cancer: ACCP evidence-based clinical practice guidelines (second edition).Chest132(suppl),178S-201S
 
Spira, A, Ettinger, DS Multidisciplinary management of lung cancer.N Engl J Med2004;350,379-392. [PubMed] [CrossRef]
 
Toloza, EM, Harpole, L, McCrory, DC Noninvasive staging of non-small cell lung cancer: a review of the current evidence.Chest2003;123(suppl),137S-146S
 
Sihoe, AD, Yim, AP Lung cancer staging.J Surg Res2004;117,92-106. [PubMed]
 
Erasmus, JJ, Macapinlac, HA, Swisher, SG Positron emission tomography imaging in nonsmall-cell lung cancer.Cancer2007;110,2155-2163. [PubMed]
 
Pillot, G, Siegel, BA, Govindan, R Prognostic value of fluorodeoxyglucose positron emission tomography in non-small cell lung cancer: a review.J Thorac Oncol2006;1,152-159. [PubMed]
 
Al-Sarraf N, Gately K, Lucey J, et al. Lymph node staging by means of positron emission tomography is less accurate in non-small cell lung cancer patients with enlarged lymph nodes: analysis of 1145 lymph nodes. Lung Cancer 2008 (in press).
 
Detterbeck, FC, Jantz, MA, Wallace, M, et al Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (second edition).Chest2007;132(suppl),202S-220S
 
Whitson, BA, Groth, SS, Maddaus, MA Surgical assessment and intraoperative management of mediastinal lymph nodes in non-small cell lung cancer.Ann Thorac Surg2007;84,1059-1065. [PubMed]
 
De Leyn, P, Lardinois, D, Van Schil, PE, et al ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer.Eur J Cardiothorac Surg2007;32,1-8. [PubMed]
 
Yasufuku, K, Fujisawa, T Staging and diagnosis of non-small cell lung cancer: invasive modalities.Respirology2007;12,173-183. [PubMed]
 
Micames, CG, McCrory, DC, Pavey, DA, et al Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: a systematic review and metaanalysis.Chest2007;131,539-548. [PubMed]
 
Annema, JT, Rabe, KF State of the art lecture: EUS and EBUS in pulmonary medicine.Endoscopy2006;38(suppl),S118-S122
 
Vilmann, P, Herth, F, Krasnik, M State of the art lecture: mediastinal EUS.Endoscopy2006;38(suppl),S84-S87
 
Herth, FJ, Rabe, KF, Gasparini, S, et al Transbronchial and transoesophageal (ultrasound-guided) needle aspirations for the analysis of mediastinal lesions.Eur Respir J2006;28,1264-1275. [PubMed]
 
Yasufuku, K, Nakajima, T, Chiyo, M, et al Endobronchial ultrasonography: current status and future directions.J Thorac Oncol2007;2,970-979. [PubMed]
 
Yasufuku, K, Nakajima, T, Motoori, K, et al Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer.Chest2006;130,710-718. [PubMed]
 
Herth, FJ, Eberhardt, R, Vilmann, P, et al Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes.Thorax2006;61,795-798. [PubMed]
 
Herth, FJ, Ernst, A, Eberhardt, R, et al Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically normal mediastinum.Eur Respir J2006;28,910-914. [PubMed]
 
Gould, MK, Kuschner, WG, Rydzak, CE, et al Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small cell lung cancer: a meta-analysis.Ann Intern Med2003;139,879-892. [PubMed]
 
Krasnik, M, Vilmann, P, Larsen, SS, et al Preliminary experience with a new method of endoscopic transbronchial real time ultrasound guided biopsy for diagnosis of mediastinal and hilar lesions.Thorax2003;58,1083-1088. [PubMed]
 
Arita, T, Matsumoto, T, Kuramitsu, T, et al Is it possible to differentiate malignant mediastinal nodes from benign nodes by size? Reevaluation by CT, transesophageal echocardiography, and nodal specimen.Chest1996;110,1004-1008. [PubMed]
 
Gross, BH, Glazer, GM, Orringer, MB, et al Bronchogenic carcinoma metastatic to normal-sized lymph nodes: frequency and significance.Radiology1988;166,71-74. [PubMed]
 
Kerr, KM, Lamb, D, Wathen, CG, et al Pathological assessment of mediastinal lymph nodes in lung cancer: implications for non-invasive mediastinal staging.Thorax1992;47,337-341. [PubMed]
 
Mehta, AC, Kavuru, MS, Meeker, DP, et al Transbronchial needle aspiration for histology specimens.Chest1989;96,1268-1272. [PubMed]
 
Anderson, WA, Gunn, SA Cytologic detection of cancer-considerations for its future: a comparative examination of the Papanicolaou and acridine-orange techniques.Acta Cytol1962;6,468-470. [PubMed]
 
Skov, BG, Baandrup, U, Jakobsen, GK, et al Cytopathologic diagnoses of fine-needle aspirations from endoscopic ultrasound of the mediastinum: reproducibility of the diagnoses and representativeness of aspirates from lymph nodes.Cancer2007;111,234-241. [PubMed]
 
Choi, YS, Shim, YM, Kim, J, et al Mediastinoscopy in patients with clinical stage I non-small cell lung cancer.Ann Thorac Surg2003;75,364-366. [PubMed]
 
Tahara, RW, Lackner, RP, Graver, LM, et al Is there a role for routine mediastinoscopy in patients with peripheral T1 lung cancers?Am J Surg2000;180,488-491. [PubMed]
 
Wallace, MB, Ravenel, J, Block, MI, et al Endoscopic ultrasound in lung cancer patients with a normal mediastinum on computed tomography.Ann Thorac Surg2004;77,1763-1768. [PubMed]
 
LeBlanc, JK, Devereaux, BM, Imperiale, TF, et al Endoscopic ultrasound in non-small cell lung cancer and negative mediastinum on computed tomography.Am J Respir Crit Care Med2005;171,177-182. [PubMed]
 
De Leyn, P, Vansteenkiste, J, Cuypers, P, et al Role of cervical mediastinoscopy in staging of non-small cell lung cancer without enlarged mediastinal lymph nodes on CT scan.Eur J Cardiothorac Surg1997;12,706-712. [PubMed]
 
Funatsu, T, Matsubara, Y, Ikeda, S, et al Preoperative mediastinoscopic assessment of N factors and the need for mediastinal lymph node dissection in T1 lung cancer.J Thorac Cardiovasc Surg1994;108,321-328. [PubMed]
 
Tahara, RW, Lackner, RP, Graver, LM, et al Is there a role for routine mediastinoscopy in patients with peripheral T1 lung cancers?Am J Surg2000;180,488-491. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Image of a node puncture in station 7, with the needle clearly visible in the target.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. All Patients With Confirmed Mediastinal Involvement by Malignancy*
* 

RUL = right upper lobe; RLL = right lower lobe; LUL = left upper lobe; LLL = left lower lobe; Adeno = adenocarcinoma.

 

Missed by EBUS-TBNA.

References

Silvestri, GA, Gould, MK, Margolis, ML, et al (2007) Noninvasive staging of non-small cell lung cancer: ACCP evidence-based clinical practice guidelines (second edition).Chest132(suppl),178S-201S
 
Spira, A, Ettinger, DS Multidisciplinary management of lung cancer.N Engl J Med2004;350,379-392. [PubMed] [CrossRef]
 
Toloza, EM, Harpole, L, McCrory, DC Noninvasive staging of non-small cell lung cancer: a review of the current evidence.Chest2003;123(suppl),137S-146S
 
Sihoe, AD, Yim, AP Lung cancer staging.J Surg Res2004;117,92-106. [PubMed]
 
Erasmus, JJ, Macapinlac, HA, Swisher, SG Positron emission tomography imaging in nonsmall-cell lung cancer.Cancer2007;110,2155-2163. [PubMed]
 
Pillot, G, Siegel, BA, Govindan, R Prognostic value of fluorodeoxyglucose positron emission tomography in non-small cell lung cancer: a review.J Thorac Oncol2006;1,152-159. [PubMed]
 
Al-Sarraf N, Gately K, Lucey J, et al. Lymph node staging by means of positron emission tomography is less accurate in non-small cell lung cancer patients with enlarged lymph nodes: analysis of 1145 lymph nodes. Lung Cancer 2008 (in press).
 
Detterbeck, FC, Jantz, MA, Wallace, M, et al Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (second edition).Chest2007;132(suppl),202S-220S
 
Whitson, BA, Groth, SS, Maddaus, MA Surgical assessment and intraoperative management of mediastinal lymph nodes in non-small cell lung cancer.Ann Thorac Surg2007;84,1059-1065. [PubMed]
 
De Leyn, P, Lardinois, D, Van Schil, PE, et al ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer.Eur J Cardiothorac Surg2007;32,1-8. [PubMed]
 
Yasufuku, K, Fujisawa, T Staging and diagnosis of non-small cell lung cancer: invasive modalities.Respirology2007;12,173-183. [PubMed]
 
Micames, CG, McCrory, DC, Pavey, DA, et al Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: a systematic review and metaanalysis.Chest2007;131,539-548. [PubMed]
 
Annema, JT, Rabe, KF State of the art lecture: EUS and EBUS in pulmonary medicine.Endoscopy2006;38(suppl),S118-S122
 
Vilmann, P, Herth, F, Krasnik, M State of the art lecture: mediastinal EUS.Endoscopy2006;38(suppl),S84-S87
 
Herth, FJ, Rabe, KF, Gasparini, S, et al Transbronchial and transoesophageal (ultrasound-guided) needle aspirations for the analysis of mediastinal lesions.Eur Respir J2006;28,1264-1275. [PubMed]
 
Yasufuku, K, Nakajima, T, Chiyo, M, et al Endobronchial ultrasonography: current status and future directions.J Thorac Oncol2007;2,970-979. [PubMed]
 
Yasufuku, K, Nakajima, T, Motoori, K, et al Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer.Chest2006;130,710-718. [PubMed]
 
Herth, FJ, Eberhardt, R, Vilmann, P, et al Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes.Thorax2006;61,795-798. [PubMed]
 
Herth, FJ, Ernst, A, Eberhardt, R, et al Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically normal mediastinum.Eur Respir J2006;28,910-914. [PubMed]
 
Gould, MK, Kuschner, WG, Rydzak, CE, et al Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small cell lung cancer: a meta-analysis.Ann Intern Med2003;139,879-892. [PubMed]
 
Krasnik, M, Vilmann, P, Larsen, SS, et al Preliminary experience with a new method of endoscopic transbronchial real time ultrasound guided biopsy for diagnosis of mediastinal and hilar lesions.Thorax2003;58,1083-1088. [PubMed]
 
Arita, T, Matsumoto, T, Kuramitsu, T, et al Is it possible to differentiate malignant mediastinal nodes from benign nodes by size? Reevaluation by CT, transesophageal echocardiography, and nodal specimen.Chest1996;110,1004-1008. [PubMed]
 
Gross, BH, Glazer, GM, Orringer, MB, et al Bronchogenic carcinoma metastatic to normal-sized lymph nodes: frequency and significance.Radiology1988;166,71-74. [PubMed]
 
Kerr, KM, Lamb, D, Wathen, CG, et al Pathological assessment of mediastinal lymph nodes in lung cancer: implications for non-invasive mediastinal staging.Thorax1992;47,337-341. [PubMed]
 
Mehta, AC, Kavuru, MS, Meeker, DP, et al Transbronchial needle aspiration for histology specimens.Chest1989;96,1268-1272. [PubMed]
 
Anderson, WA, Gunn, SA Cytologic detection of cancer-considerations for its future: a comparative examination of the Papanicolaou and acridine-orange techniques.Acta Cytol1962;6,468-470. [PubMed]
 
Skov, BG, Baandrup, U, Jakobsen, GK, et al Cytopathologic diagnoses of fine-needle aspirations from endoscopic ultrasound of the mediastinum: reproducibility of the diagnoses and representativeness of aspirates from lymph nodes.Cancer2007;111,234-241. [PubMed]
 
Choi, YS, Shim, YM, Kim, J, et al Mediastinoscopy in patients with clinical stage I non-small cell lung cancer.Ann Thorac Surg2003;75,364-366. [PubMed]
 
Tahara, RW, Lackner, RP, Graver, LM, et al Is there a role for routine mediastinoscopy in patients with peripheral T1 lung cancers?Am J Surg2000;180,488-491. [PubMed]
 
Wallace, MB, Ravenel, J, Block, MI, et al Endoscopic ultrasound in lung cancer patients with a normal mediastinum on computed tomography.Ann Thorac Surg2004;77,1763-1768. [PubMed]
 
LeBlanc, JK, Devereaux, BM, Imperiale, TF, et al Endoscopic ultrasound in non-small cell lung cancer and negative mediastinum on computed tomography.Am J Respir Crit Care Med2005;171,177-182. [PubMed]
 
De Leyn, P, Vansteenkiste, J, Cuypers, P, et al Role of cervical mediastinoscopy in staging of non-small cell lung cancer without enlarged mediastinal lymph nodes on CT scan.Eur J Cardiothorac Surg1997;12,706-712. [PubMed]
 
Funatsu, T, Matsubara, Y, Ikeda, S, et al Preoperative mediastinoscopic assessment of N factors and the need for mediastinal lymph node dissection in T1 lung cancer.J Thorac Cardiovasc Surg1994;108,321-328. [PubMed]
 
Tahara, RW, Lackner, RP, Graver, LM, et al Is there a role for routine mediastinoscopy in patients with peripheral T1 lung cancers?Am J Surg2000;180,488-491. [PubMed]
 
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