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

Transcription

1 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* Felix J. F. Herth, MD, FCCP; Ralf Eberhardt, MD; Mark Krasnik, MD; and Armin Ernst, MD, FCCP 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. (CHEST 2008; 133: ) Key words: endobronchial ultrasound; lung cancer; mediastinal lymphadenopathy; positron emission tomography; transbronchial needle aspiration 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 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 shortaxis 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. 1 4 Positron emission tomography (PET) has been reported to be more accurate than CT, 5,6 especially CHEST / 133 / 4/ APRIL,

2 with a high negative predictive value. PET was expected to increase the accuracy of mediastinal staging in NSCLC; indeed, a metaanalysis 7 has indicated its superiority. However, a more recent report 8 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 Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been reported as an endoscopic option to evaluate the mediastinum 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 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. Materials and Methods 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 *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. 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. Manuscript received October 14, 2007; revision accepted December 5, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). 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; aernst@bidmc.harvard.edu DOI: /chest 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, wholebody acquisition was performed. Images were reconstructed using the attenuation-weighted ordered-subset expectation maximization technique. 5,6 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. 17,18,21 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 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 Transbronchial needle aspiration was performed under real-time ultrasound control. Needle punctures were performed using the jabbing 888 Original Research

3 Table 1 All Patients With Confirmed Mediastinal Involvement by Malignancy* Patient No. Lymph Node Station Node Stage Histology Local Primary Size Primary, cm Figure 1. Image of a node puncture in station 7, with the needle clearly visible in the target. 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. 26,27 No rapid on-site cytology was performed. Statistical Methods The 2 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. Results 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 mm (range, 5 to 10 mm). Additionally, 73 nodes 5 mm were detected that were not punctured. 1 10r N1 Squamous RLL N2 Adeno LUL r N2 Adeno RUL N2 Adeno RLL r N1 Adeno RLL r N2 Adeno LUL r N3 Adeno LLL N2 Adeno RUL r N1 Adeno RLL 2.5 *RUL right upper lobe; RLL right lower lobe; LUL left upper lobe; LLL left lower lobe; Adeno adenocarcinoma. Missed by EBUS-TBNA. 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. Discussion 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 CHEST / 133 / 4/ APRIL,

4 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 studies 28,29 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 al 30 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 al 30 found advanced stage in three other patients (one patient with left adrenal metastasis, and two patients with mediastinal invasion of tumor). LeBlanc et al 31 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 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. Conclusions 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. References 1 Silvestri GA, Gould MK, Margolis ML, et al. Noninvasive staging of non-small cell lung cancer: ACCP evidence-based clinical practice guidelines (second edition). Chest 2007; 132(suppl):178S 201S 2 Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004; 350: Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest 2003; 123(suppl): 137S 146S 4 Sihoe AD, Yim AP. Lung cancer staging. J Surg Res 2004; 117: Erasmus JJ, Macapinlac HA, Swisher SG. Positron emission 890 Original Research

5 tomography imaging in nonsmall-cell lung cancer. Cancer 2007; 110: Pillot G, Siegel BA, Govindan R. Prognostic value of fluorodeoxyglucose positron emission tomography in non-small cell lung cancer: a review. J Thorac Oncol 2006; 1: 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) 8 Detterbeck FC, Jantz MA, Wallace M, et al. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (second edition). Chest 2007; 132(suppl): 202S 220S 9 Whitson BA, Groth SS, Maddaus MA. Surgical assessment and intraoperative management of mediastinal lymph nodes in non-small cell lung cancer. Ann Thorac Surg 2007; 84: 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 Surg 2007; 32: Yasufuku K, Fujisawa T. Staging and diagnosis of non-small cell lung cancer: invasive modalities. Respirology 2007; 12: 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. Chest 2007; 131: Annema JT, Rabe KF. State of the art lecture: EUS and EBUS in pulmonary medicine. Endoscopy 2006; 38(suppl): S118 S Vilmann P, Herth F, Krasnik M. State of the art lecture: mediastinal EUS. Endoscopy 2006; 38(suppl):S84 S87 15 Herth FJ, Rabe KF, Gasparini S, et al. Transbronchial and transoesophageal (ultrasound-guided) needle aspirations for the analysis of mediastinal lesions. Eur Respir J 2006; 28: Yasufuku K, Nakajima T, Chiyo M, et al. Endobronchial ultrasonography: current status and future directions. J Thorac Oncol 2007; 2: Yasufuku K, Nakajima T, Motoori K, et al. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest 2006; 130: Herth FJ, Eberhardt R, Vilmann P, et al. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax 2006; 61: Herth FJ, Ernst A, Eberhardt R, et al. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically normal mediastinum. Eur Respir J 2006; 28: 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 Med 2003; 139: 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. Thorax 2003; 58: 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. Chest 1996; 110: Gross BH, Glazer GM, Orringer MB, et al. Bronchogenic carcinoma metastatic to normal-sized lymph nodes: frequency and significance. Radiology 1988; 166: Kerr KM, Lamb D, Wathen CG, et al. Pathological assessment of mediastinal lymph nodes in lung cancer: implications for non-invasive mediastinal staging. Thorax 1992; 47: Mehta AC, Kavuru MS, Meeker DP, et al. Transbronchial needle aspiration for histology specimens. Chest 1989; 96: Anderson WA, Gunn SA. Cytologic detection of cancerconsiderations for its future: a comparative examination of the Papanicolaou and acridine-orange techniques. Acta Cytol 1962; 6: 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. Cancer 2007; 111: Choi YS, Shim YM, Kim J, et al. Mediastinoscopy in patients with clinical stage I non-small cell lung cancer. Ann Thorac Surg 2003; 75: Tahara RW, Lackner RP, Graver LM, et al. Is there a role for routine mediastinoscopy in patients with peripheral T1 lung cancers? Am J Surg 2000; 180: Wallace MB, Ravenel J, Block MI, et al. Endoscopic ultrasound in lung cancer patients with a normal mediastinum on computed tomography. Ann Thorac Surg 2004; 77: 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 Med 2005; 171: 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 Surg 1997; 12: 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 Surg 1994; 108: Tahara RW, Lackner RP, Graver LM, et al. Is there a role for routine mediastinoscopy in patients with peripheral T1 lung cancers? Am J Surg 2000; 180: CHEST / 133 / 4/ APRIL,