The Clinical Respiratory Journal
ORIGINAL ARTICLE
Endobronchial ultrasound-guided transbronchial needle aspiration for diagnosing mediastinal lymphadenectasis: a cohort study from a single center Jun Zhu1, Hai-ping Zhang1, Jian Ni1, Ye Gu2, Chun-yan Wu3, Jiong Song4, Xiao-bin Ji5, Hai-wen Lu5, Ping Wei5, Cai-cun Zhou1 and Jin-fu Xu5 1 Department 2 Department 3 Department 4 Department 5 Department
of of of of of
Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China Endoscope, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
Abstract Objective: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is commonly used for clinical diagnosis of mediastinal lymphadenectasis. This study aimed to evaluate the diagnostic significance of EBUS-TBNA for mediastinal lymphadenectasis in a large single center. Methods: A total of 846 patients who were not definitively diagnosed with mediastinal lymphadenectasis underwent EBUS-TBNA were retrospectively analyzed in this study. Results: In total, 842 patients underwent EBUS-TBNA successfully. There were 589 patients with malignancy, including squamous carcinoma (118 cases; 20.6%), adenocarcinoma (187 cases; 32.7%) and small cell carcinoma (88 cases; 15.4%). A total of 253 patients were diagnosed with benign disease, including tuberculosis (111 cases; 43.9%) and sarcoidosis (93 cases; 36.7%). The diagnostic sensitivity of lung cancer, tuberculosis and sarcoidosis were 94.4%, 81.1% and 51.6%, respectively. The overall sensitivity of EBUS-TBNA was 92.0%. N2 stage in lung cancer patients who were diagnosed by EBUS-TBNA was significantly higher than other stages. The positive rate of targeted puncture is high for the lymph nodes whose short-axis diameters were larger than 1 cm. Conclusion: The operation risk of EBUS-TBNA is relatively small. In diseases complicated by mediastinal lymphadenectasis, malignant diseases are most, and benign diseases mainly are granulomatous. EBUS-TBNA is a valuable diagnostic technique in patients with mediastinal lymphadenectasis whose diagnosis have not been determined. Please cite this paper as: Zhu J, Zhang H-p, Ni J, Gu Y, Wu C-y, Song J, Ji X-b, Lu H-w, Wei P, Zhou C-c and Xu J-f. Endobronchial ultrasound-guided transbronchial needle aspiration for diagnosing mediastinal lymphadenectasis: a cohort study from a single center. Clin Respir J 2015; ••: ••–••. DOI:10.1111/ crj.12317.
Key words biopsy – diagnosis – mediastinal lymph node – pathology Correspondence Jin-fu Xu, MD, PhD, Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 200433 Shanghai, China. Tel: 0086 21 65115006 Fax: 0086 21 65111298 email: [email protected] Received: 19 November 2014 Revision requested: 24 March 2015 Accepted: 21 April 2015 DOI:10.1111/crj.12317 Authorship and contributorship Jun Zhu and Jin-fu Xu designed the study and drafted the manuscript. Hai-ping Zhang and Jian Ni participated in the design of the study and preformed the statistical analysis. Chun-yan Wu gave the pathological diagnosis of EBUS-TBNA. All authors did EBUS-TBNA and analyzed the results of this study. All authors read and approved the final manuscript. Ethics The study was approved by the Ethics Committee of Shanghai Pulmonary Hospital. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.
The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd
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Introduction Pulmonary lesions complicated by mediastinal lymphadenectasis are extremely common and are diagnosed according to the physician’s past clinical experience. However, because of the lack of pathological basis for the diagnosis of some benign diseases [such as sarcoidosis and mediastinal lymph node (MLN) tuberculosis], the misdiagnostic rate is high. In addition, pulmonary malignant tumor is always complicated by mediastinal lymphadenectasis, and lymph node (LN) staging has vital significance for tumor staging. Therefore, the pathological diagnosis for patients with MLN is especially important. In the past, diagnosis by conventional bronchoscopy was relatively difficult for patients who did not have pathological changes in bronchial lumen. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is devoted to clinical application in the early 1990s (1). During EBUSTBNA, ultrasonic probe touches the LN located at the back of the bronchial wall, and then the LN tissues are sampled by fine-needle puncture. Whether MLN staging can be obtained by EBUS-TBNA to guide the treatment of lung cancer, and which LN was the easiest way to get the right results, remains unclear. The aim of this study was to evaluate the diagnostic significance and the safety of EBUS-TBNA for mediastinal lymphadenectasis.
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general anesthesia. Patients with targeted puncture were excluded. All patients were told about the risk of operation and signed informed consent preoperatively. As a result, a total of 846 patients (aged 16–82 years) were enrolled in our study.
Instrument and methods EBUS-TBNA was performed with the special equipment called ultrasonic bronchoscope (EU-C2000, BF-UC206F-OL8, NA-201SX-4022; Olympus, Tokyo, Japan). The procedures were performed under guardianship and oxygen-enriched condition after fasting for 6 h. Patients were treated with topical anesthetic preoperatively by glottis sprays (2% lidocaine) (4). For patients who were unable to cooperate with or tolerate local anesthetic, general anesthetic was performed under the cooperation of the anesthesiologist (5). Bronchoscopy was performed nasally or orally after anesthesia. The puncture process was performed under the bronchoscope and ultrasound image monitoring. When the bronchoscopy reached the site of LNs, we used ultrasound image monitoring to locate them, avoiding the blood vessels, then punctured by needle through bronchoscopy for collecting specimens. LN specimens were smeared for liquid-based cytology examination, and the rest of LN specimens were embedded for pathological diagnosis.
Materials and methods
Detection index
Patients
LN specimens were smeared on-site for liquid-based cytology examination and then stained with hematoxylin and eosin for pathological diagnosis. The rest of the specimens were embedded and sliced for immunohistochemical detection in order to make a definitive diagnosis (6). In the following two conditions, patients were included as positive cases: (i) patients who underwent EBUS-TBNA were diagnosed with malignant disease or benign disease with definite pathology; (ii) patients with indefinite pathological diagnosis were made a definitive diagnosis by other methods (including mediastinal fine-needle puncture and surgical biopsy). The rest of the patients were included as negative cases.
This retrospective study was approved by the Ethics Committee of Shanghai Pulmonary Hospital affiliated Tongji University. A total of 1042 patients were diagnosed with mediastinal lymphadenectasis by contrastenhanced chest computerized tomography (CT) in our hospital from November 1, 2011 to November 30, 2013. Patients who underwent EBUS-TBNA due to indefinitive diagnosis by conventional bronchoscope were included in this study. The following are the inclusion criteria: (i) patients were diagnosed with mediastinum and/or hilar lymphadenectasis by contrast-enhanced chest CT (2) and the short-axis diameter of LN was ≥1 cm (3); (ii) the preoperative examinations (including electrocardiogram, pulmonary function, arterial blood gas, blood routine, hepatitis, HIV and syphilis antibodies) were accord with the standard of bronchoscopy; (iii) patients had no major organic disease and contraindications of bronchoscopy; and (iv) patients could tolerate local or
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Statistical analysis Data were analyzed by SPSS 17.0 statistical analysis software (IBM Corporation, Armonk, NY, USA). The comparison of probability was performed by
The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd
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EBUS-TBNA for diagnosing
A
B
Figure 1. Baseline characteristics of the study patients. (A) Age of the study patients. (B) Disease distribution of the whole sample. Male patients with a higher incidence of malignant diseases (P = 0.035). Female patients with no significant correlation in incidence of benign and malignant diseases (P = 0.281).
chi-squared test. A value of P < 0.05 was considered significant.
Results Puncture results A total of 846 patients were included in this study. There were 681 (80.5%) patients aged 40–70 years (Fig. 1A). There were only three patients less than 18 years old. However, Gilbert et al. (7) confirmed that it was feasible for pediatric patients who underwent EBUS-TBNA. There were 83 (9.8%) patients more than 70 years old who stayed safe with EBUS-TBNA. Recent study showed that EBUS-TBNA was safe for patients more than 70 years old (8). Eight hundred forty-two (99.5%) patients were successfully punctured, including 580 men (68.9%) and 262 women (31.1%) (Fig. 1B). EBUS-TBNA failed because of
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cardiac complications in two patients: one patient showed increased heart rhythm and decreased blood pressure; one patient had a sudden ventricular bigeminy. The two patients recovered through spot rescue and subsequent treatment. The other two patients failed to receive EBUS-TBNA because of the LNs surrounded with blood vessels. In all 842 patients (average age, 56.8 ± 1.2 years), there were 589 (68.9%) patients with malignant disease (average age, 60.1 ± 9.1 years) and 253 (31.1%) patients with benign disease (average age, 49.3 ± 1.4 years). The onset age of malignant disease significantly increased compared with benign disease (P = 0.001). The total puncture times were 2687, and the average puncture times per patient were 3.19. The puncture times was 1–8 each examination (Fig. 2A), and 83.2% patients were punctured for three or more times. For each examination, 1–4 stations of LN were sampled (Fig. 2B).
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A
B
C
D
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The MLNs were sampled at stations 2, 3, 4, 7, 10, 11 and 12 (Fig. 2C), which were based on The International Association for the Study of Lung Cancer (9). However, the remaining stations of the LNs could not be sampled because of their anatomical position. The most commonly sampled stations were 7 (52.1%) and 4R (41.3%) (Fig. 2D). According to the diagnostic results, there were 589 (70.0%) patients with malignant diseases (Table 1) and 253 (30.0%) patients with benign diseases (Table 2). The diagnostic sensitivities of EBUS-TBNA for lung cancer, tuberculosis and sarcoidosis were 94.4%, 81.1% and 51.6%, respectively (Table 3). The positive rate of targeted puncture was high for the LNs whose shortaxis diameters are larger than 1 cm. The patients in whom a specific diagnosis was not determined by EBUS-TBNA were made a definitive diagnosis according to the subsequent surgical biopsy or clinical diagnosis. EBUS-TBNA in station 7 had the highest positive rate (92.2%), followed by station 4R (89.9%), and there were no significant correlation (P = 0.445) between puncture sites of MLNs and diagnostic positive rate (Table 4). The diagnostic positive rates of lung cancer in station 10L (86.1%), 4R (82.4%) and 7 (77.3%) were higher than other stations (Table 4). At the same time, the diagnostic sensitivity of bronchoscope brush inspection or biopsy was 67.6% in our hospital, and the paired sample comparative analysis of diagnostic sensitivity was significantly elevated (P = 0.041) by EBUS-TBNA. For lung cancer patients (adenocarcinoma, squamous cell carcinoma, small cell carcinoma, non-small cell lung cancer and compound small cell carcinoma), the N2 stage confirmed by EBUS-TBNA was significantly higher than the other stages through two or more puncture times at one EBUS-TBNA (P = 0.039) (Table 5). The total diagnostic sensitivity of EBUS-TBNA was slightly lower than that of mediastinoscopy (98.2%). However, because of the small invasion, EBUS-TBNA still had obvious advantages.
Complications
Figure 2. Basic data of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). (A) Puncture times for each EBUS-TBNA. (B) Number of lymph node (LN) stations sampled for each EBUS-TBNA. (C) Station of LNs punctured by EBUS-TBNA. (D) Computed tomography scan of patients with mediastinal lymphadenectasis in stations 4R and 7.
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Two (0.24%) of the 846 patients had cardiac complications (Table 6), which were rarely reported in the previous studies. Okachi et al. (10) reported that an increased blood pressure occurred in elderly patients who underwent EBUS-TBNA. The incidence of postoperative sore throat often occurred in patients under general anesthesia. Eight (0.95%) of the 846 patients had hemorrhage more than 30 mL. The incidence of hemorrhage was similar with the report of Asano et al. (11).
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Table 1. The diagnoses of malignant diseases by endobronchial ultrasound-guided transbronchial needle aspiration
Malignant diseases Lung cancer Adenocarcinoma Squamous cell carcinoma Small cell carcinoma Non-small cell lung cancer Compound small cell carcinoma Lung cancer (non-classification) Adenosquamous cell carcinoma Large cell carcinoma Neuroendocrine carcinoma Pleomorphic carcinoma Alveolar cell carcinoma Carcinoid Lung carcinoma with heterocyst (pathological diagnosis definite) Suspected lung cancer (subsequent biopsy definite) Metastatic lung cancer Laryngeal squamous cell carcinoma Breast carcinoma Esophageal squamous cell carcinoma Gastric carcinoma Colorectal carcinoma Metastatic pulmonary adenocarcinoma (source unknown Metastatic lung cancer(indefinite) Thymic carcinoma Lymphoma Non-Hodgkin’s lymphoma Diffuse large B-cell lymphoma Suspected lymphoma (indefinite) Malignant mesothelioma Mediastinal malignant tumors
Discussion EBUS-TBNA in patients with MLN larger than 1 cm in short-axis diameter has a high diagnostic accuracy and a low risk of operation EBUS-TBNA was applied clinically by Hürter and Hanrath (12) in 1992. Compared with conventional transbronchial needle aspiration (TBNA), the safety of puncture with EBUS-TBNA was higher due to accurate positioning of Doppler probe for LNs and blood vessels (13). In this study, the short-axis diameter of LNs was ≥1 cm, which had clinical significance relatively (14). Kinsey et al. (15) showed that it was feasible for lung cancer patients with LNs larger than 5 mm in short-axis diameter to perform EBUS-TBNA. However, because the benign and malignant diseases were both included in this study, only those LNs with short-axis ≥1 cm had clinical significance. In addition, Wong et al. (16) indicated that it was safe for patients
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No.
%
589 571 187 118 88 49 36 33 16 3 2 1 1 1 4 32 7 1 1 1 1 1 1 1 3 6 1 1 4 1 1
70.0 96.9 32.7 20.6 15.4 8.6 6.3 5.8 2.8 0.5 0.4 0.2 0.2 0.2 0.7 5.6 1.2 14.3 14.3 14.3 14.3 14.3 14.3 14.3 0.5 1.0 16.7 16.7 66.6 0.2 0.2
with superior vena cava syndrome caused by lymphadenectasis to perform EBUS-TBNA. In this study, the operation was terminated because of heartrelated disease in two patients. Park et al. (17) suggested that in pulmonary artery sarcoma or pulmonary thromboembolism, an abnormality could be observed in contrast-enhanced chest CT images, so patients with these diseases were not suitable for EBUS-TBNA because of the risk of hemorrhage. The previous study reported that pneumothorax possibly occurred in patients who underwent EBUS-TBNA (18). However, pneumothorax did not occur in this study. In general, EBUS-TBNA had high safety and tolerability.
EBUS-TBNA is commonly performed in stations 4R and 7, and there is no correlation between diagnostic rate and puncture site of LNs The majority of patients with EBUS-TBNA were in stations 4R and 7, which was associated with the dis5
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Table 2. The diagnose of benign diseases by endobronchial ultrasound-guided transbronchial needle aspiration
Benign diseases Tuberculosis Tuberculosis Suspected tuberculosis (combined with clinical diagnosis) Sarcoidosis Sarcoidosis Suspected sarcoidosis (operation definite) Pulmonary inflammatory diseases Pneumoconiosis Other pulmonary benign disease Pulmonary aspergillosis Organizing pneumonia Tracheal tiny papillary fibroma Pericardial cyst Collagenic lymph node Pulmonary abscess Pleural steatosis(combined with operation) Inflammatory pseudotumor Hamartoma Benign disease of indefinite diagnosis (clinical diagnosis) Complicated diseases Sarcoidosis complicated by pneumoconiosis Non-small cell lung cancer complicated by sarcoidosis Squamous cell carcinoma complicated by parasitic disease
section site of MLN. The patients in stations 4R, 7 and 4L were 348 (41.3%), 439 (52.1%) and 112 (13.3%), respectively. The patients in stations 10 and 11 were few, followed by stations 2, 3 and 12. The ventilation
No.
%
253 111 90 21 93 48 45 23 4 17 2 1 1 2 2 1 2 1 1 4 5 1 3 1
30.0 43.9 81.1 18.9 36.7 51.6 48.4 9.1 1.6 6.7 11.8 5.9 5.9 11.8 11.8 5.9 11.8 5.9 5.9 23.3 2.0 20.0 60.0 20.0
space of main bronchus was significantly reduced when the bronchoscope examination was performed for stations 2 and 3, which would increase the risk of anoxia of the patients. Because of the deep location of
Table 3. The diagnostic sensitivity of endobronchial ultrasound-guided transbronchial needle aspiration
Lung cancer Tuberculosis Sarcoidosis Other diseases Total
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
94.4 81.1 51.6 86.6 92.0
100 100 100 100 100
100 100 100 100 100
36.0 87.1 78.0 98.9 64.5
Table 4. The station of lymph node (LN) puncture and diagnostic positive rate LN station
2L
2R
3
4L
4R
7
Puncture times Total 4 34 2 112 348 439 Positive times 3 29 1 91 313 405 Positive rate 75.0% 85.2% 50.0% 81.3% 89.9% 92.2% Number of patients with 2 21 1 59 258 313 lung cancer Positive rate of lung 66.7% 72.4% 100.0% 64.8% 82.4% 77.3% cancer in positive puncture results
6
10L
10R
11L
11R
12R
41 36 87.8% 31
65 38 58.5% 26
32 26 81.3% 19
41 4 36 2 87.8% 50.0% 27 1
86.1% 68.4% 73.1% 75.0% 50.0%
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Table 5. The lymph node stage in common lung cancer diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration
Adenocarcinoma Squamous cell carcinoma Small cell carcinoma Non-small cell lung cancer Compound small cell carcinoma
N1
N2
N3
23 (12.3%) 29 (24.6%) 14 (15.9%) 11 (22.5%) 8 (22.2%)
136 (72.7%) 82 (69.5%) 62 (70.5%) 35 (71.4%) 24 (66.7%)
28 (15.0%) 7 (5.9%) 12 (13.6%) 3 (6.1%) 4 (11.1%)
LNs and the equipment with coarser diameters and limited bending degree, the puncture of LNs was not easily performed in station 12. The diagnostic positive rate was highest in station 7 (92.2%), followed by station 4R (89.9%), and there were no significant correlations (P = 0.45) between the puncture sites of MLN and the diagnostic positive rate.
Majority of patients with mediastinal lymphadenectasis are diagnosed with malignant diseases The majority of patients were diagnosed with malignant diseases, and 96.9% of them were lung cancer. The diagnostic positive rate of lung cancer in stations 10L, 4R and 7 were relative higher. For station 3, the positive rate for diagnosis of lung cancer was 100.0%; however, it is only from one patient, and we only had punctured one time, so it did not have clinical significance. We recommend puncturing LN stations as more as possible at the same time to increase positive rate. In all lung cancer patients, adenocarcinoma represents to be the most common type, followed by small cell carcinoma and squamous cell carcinomas. These three kinds of diseases accounted for 68.7% of lung cancer. Diagnostic sensitivity of lung cancer was 94.4%. For lung adenocarcinoma, Jurado et al. (19) suggested that the LN specimens could be used to detect the expression of epidermal growth factor receptor, Kirsten rat Table 6. The complications of endobronchial ultrasoundguided transbronchial needle aspiration Complications
No.
(%)
Cardiac complications Sore throat Bloody phlegm (10–20 mL) Hemorrhage (more than 30 mL) Fever Pulmonary infection Pneumothorax Mediastinal emphysema Death
2 262 203 8 25 26 0 0 0
0.24 30.97 24.00 0.95 2.96 3.07 0.00 0.00 0.00
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sarcoma viral oncogene homologue and anaplastic lymphoma kinase in order to conduct the treatment. For patients with lung cancer, LN staging was determined by EBUS-TBNA, which provided a direct pathological basis for patients to take direct surgery or neoadjuvant chemotherapy before surgery (20). However, Bugalho et al. (21) suggested that LN specimens could be used to detect the expression of cytokeratin 19, carcinoembryonic antigen and epithelial cell adhesion molecule, which were also helpful to define the LNs and the staging of lung cancer. For patients who accepted cytotoxic chemotherapy, the role of EBUS-TBNA for LN staging was also significant (22). It was worth noting that seven patients with metastatic lung carcinoma were made a definitive diagnosis by enzyme immunohistochemistry. Only two of six patients suspected of having lymphoma were definitively diagnosed, which was similar to the research of Steinfort et al. (23). Few patients with mediastinal malignant tumor were definitively diagnosed by EBUS-TBNA, which reduced the use of mediastinoscopy. Consistently, the research of José et al. (24) for long-term follow-up of 328 patients also indicated reduced use of mediastinoscopy.
Diagnostic sensitivity of benign disease is relatively lower, and benign diseases mainly are granulomatous lesions In lung benign diseases, tuberculosis and sarcoidosis accounted for 43.9% and 36.7%, respectively. The granuloma with the background of necrosis was more likely to be diagnosed as pulmonary tuberculosis (25). The diagnostic sensitivity of EBUS-TBNA for tuberculosis was 81.1%, and 18.9% of the patients with tuberculosis were made a definitive diagnosis by combination of images, clinical experience or diagnostic anti-tuberculosis treatment. The diagnostic sensitivity of tuberculosis reported by Sun et al. (26) and Navani et al. (27) were 85% and 86%, respectively, which were similar to this study. Sarcoidosis had to be diagnosed by surgical biopsy in the past. However, by using 7
EBUS-TBNA for diagnosing
EBUS-TBNA, sarcoidosis could be definitively diagnosed after tuberculosis has been excluded through further pathological examination with LN specimens, and the diagnostic sensitivity of EBUS-TBNA for sarcoidosis was 51.6%. Gupta et al. (28) showed that compared with TBNA, diagnostic rate of EBUS-TBNA for sarcoidosis was higher. For sarcoidosis patients of stage I, the diagnostic rate of EBUS-TBNA was also significantly higher than that of transbronchial lung biopsy and bronchoalveolar lavage fluid analysis (29). Garwood et al. (30) suggested that LN size was suitable at around 16 mm in order to improve the positive rate. In the study, 23 (9.1%) patients were confirmed having pulmonary inflammatory diseases by EBUS-TBNA. The rest of the lung benign diseases were sporadic.
EBUS-TBNA is feasible for the diagnosis of lung cancer complicated by sarcoidosis There were three patients (0.35%) with lung cancer complicated by sarcoidosis in this study, which was extremely rare. They were first diagnosed with sarcoidosis, and then the cancer cells and granulomatous inflammation were both observed in LNs. Yokouchi et al. (31) reported that increased pulmonary nodule was found in one patient during the period of treatment after he had been diagnosed with sarcoidosis by mediastinoscopy pathological examination. As a result, cancer cells were found in the patient through EBUSTBNA. Previously, the diagnosis of sarcoidosis tends to be ignored in such patients.
Conclusion In conclusion, the operation risk of EBUS-TBNA is relatively low after improving the preoperative examination, and the positive rate of targeted puncture is high for the LNs whose short-axis diameter is larger than 1 cm. There is no significant correlation between the station of LNs puncture and diagnostic positive rate. In the diseases complicated by mediastinal lymphadenectasis, malignant diseases are most, and benign diseases mainly are granulomatous. EBUSTBNA is a valuable diagnostic technique for patients with mediastinal lymphadenectasis whose specific diagnosis have not been determined.
Acknowledgments This work was supported by the National Science Foundation of China (NSFC81170003 and 81370109), Programs from STCSM (12PJD004, 134119a6400 and
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12JC1402300) and the Innovation Program of Shanghai Municipal Education Commission (13SG21).
References 1. Yasufuku K, Nakajima T, Fujiwara T, et al. Role of endobronchial ultrasound-guided transbronchial needle aspiration in the management of lung cancer. Gen Thorac Cardiovasc Surg. 2008;56: 268–76. 2. Gu P, Zhao YZ, Jiang LY, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer. 2009;45: 1389–96. 3. Fielding DI, Kurimoto N. EBUS-TBNA/staging of lung cancer. Clin Chest Med. 2013;34: 385–94. 4. Xue FS, Liu HP, He N, et al. Spray-as-you-go airway topical anesthesia in patients with a difficult airway: a randomized, double-blind comparison of 2% and 4% lidocaine. Anesth Analg. 2009;108: 536–43. 5. Eapen GA, Shah AM, Lei X, et al. Complications, consequences, and practice patterns of endobronchial ultrasound-guided transbronchial needle aspiration: results of the AQuIRE registry. Chest. 2013;143: 1044–53. 6. Esterbrook G, Anathhanam S, Plant PK. Adequacy of endobronchial ultrasound transbronchial needle aspiration samples in the subtyping of non-small cell lung cancer. Lung Cancer. 2013;80: 30–4. 7. Gilbert CR, Chen A, Akulian JA, et al. The use of convex probe endobronchial ultrasound-guided transbronchial needle aspiration in a pediatric population: a multicenter study. Pediatr Pulmonol. 2014;49: 807–15. 8. Evison M, Crosbie PA, Martin J, et al. EBUS-TBNA in elderly patients with lung cancer: safety and performance outcomes. J Thorac Oncol. 2014;9: 370–6. 9. Rusch VW, Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4: 568–77. 10. Okachi S, Imai N, Imaizumi K, et al. Endobronchial ultrasound transbronchial needle aspiration in older people. Geriatr Gerontol Int. 2013;13: 986–92. 11. Asano F, Aoe M, Ohsaki Y, et al. Complications associated with endobronchial ultrasound-guided transbronchial needle aspiration: a nationwide survey by the Japan Society for Respiratory Endoscopy. Respir Res. 2013;14: 50. 12. Hürter T, Hanrath P. Endobronchial sonography: feasibility and preliminary results. Thorax. 1992;47: 565–7. 13. Yasufuku K, Chiyo M, Sekine Y, et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal and hilar lymph nodes. Chest. 2004;126: 122–8. 14. de Langen AJ, Raijmakers P, Riphagen I, et al. The size of mediastinal lymph nodes and its relation with metastatic involvement: a meta-analysis. Eur J Cardiothorac Surg. 2006;29: 26–9.
The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd
Zhu et al.
15. Kinsey CM, Arenberg DA. Endobronchial ultrasound-guided transbronchial needle aspiration for non-small cell lung cancer staging. Am J Respir Crit Care Med. 2014;189: 640–9. 16. Wong MK, Tam TC, Lam DC, et al. EBUS-TBNA in patients presented with superior vena cava syndrome. Lung Cancer. 2012;77: 277–80. 17. Park J, Chung J, Jheon S, et al. EBUS-TBNA in the differential diagnosis of pulmonary artery sarcoma and thromboembolism. Eur Respir J. 2011;38: 1480–2. 18. Koh M, Tee A, Wong P, et al. Advances in lung cancer diagnosis and staging: endobronchial ultrasound. Intern Med J. 2008;38: 85–9. 19. Jurado J, Saqi A, Maxfield R, et al. The efficacy of EBUS-guided transbronchial needle aspiration for molecular testing in lung adenocarcinoma. Ann Thorac Surg. 2013;96: 1196–202. 20. Yasufuku K, Nakajima T, Waddell T, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for differentiating N0 versus N1 lung cancer. Ann Thorac Surg. 2013;96: 1756–60. 21. Bugalho A, Martins C, Dias SS, et al. Cytokeratin 19, carcinoembryonic antigen, and epithelial cell adhesion molecule detect lung cancer lymph node metastasis in endobronchial ultrasound-guided transbronchial aspiration samples. Clin Lung Cancer. 2013;14: 704–12. 22. Almeida FA. Bronchoscopy and endobronchial ultrasound for diagnosis and staging of lung cancer. Cleve Clin J Med. 2012;79: eS11–16. 23. Steinfort DP, Conron M, Pasricha S-R, et al. Endobronchial ultrasound-guided transbronchial needle
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24.
25.
26.
27.
28.
29.
30.
31.
aspiration for the evaluation of suspected lymphoma. J Thorac Oncol. 2010;5: 804–9. José RJ, Shaw P, Taylor M, et al. Impact of EBUS-TBNA on modalities for tissue acquisition in patients with lung cancer. QJM. 2014;107: 201–6. Cancellieri A, Leslie KO, Tinelli C, et al. Sarcoidal granulomas in cytological specimens from intrathoracic adenopathy: morphologic characteristics and radiographic correlations. Respiration. 2013;85: 244–51. Sun J, Teng J, Yang H, et al. Endobronchial ultrasound-guided transbronchial needle aspiration in diagnosing intrathoracic tuberculosis. Ann Thorac Surg. 2013;96: 2021–7. Navani N, Molyneaux PL, Breen RA, et al. Utility of endobronchial ultrasound-guided transbronchial needle aspiration in patients with tuberculous intrathoracic lymphadenopathy: a multicentre study. Thorax. 2011;66: 889–93. Gupta D, Dadhwal DS, Agarwal R, et al. Endobronchial ultrasound guided TBNA vs conventional TBNA in the diagnosis of sarcoidosis. Chest. 2014;146: 547–56. Nakajima T, Yasufuku K, Kurosu K, et al. The role of EBUS-TBNA for the diagnosis of sarcoidosis–comparisons with other bronchoscopic diagnostic modalities. Respir Med. 2009;103: 1796–800. Garwood S, Judson MA, Silvestri G, et al. Endobronchial ultrasound for the diagnosis of pulmonary sarcoidosis. Chest. 2007;132: 1298–304. Yokouchi H, Miyazaki M, Miyamoto T, et al. [A case of small-sized lung cancer complicated by sarcoidosis]. Gan to Kagaku Ryoho. 2013;40: 2336–8.
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ORIGINAL ARTICLE
Endobronchial ultrasound-guided transbronchial needle aspiration for diagnosing mediastinal lymphadenectasis: a cohort study from a single center Jun Zhu1, Hai-ping Zhang1, Jian Ni1, Ye Gu2, Chun-yan Wu3, Jiong Song4, Xiao-bin Ji5, Hai-wen Lu5, Ping Wei5, Cai-cun Zhou1 and Jin-fu Xu5 1 Department 2 Department 3 Department 4 Department 5 Department
of of of of of
Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China Endoscope, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
Abstract Objective: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is commonly used for clinical diagnosis of mediastinal lymphadenectasis. This study aimed to evaluate the diagnostic significance of EBUS-TBNA for mediastinal lymphadenectasis in a large single center. Methods: A total of 846 patients who were not definitively diagnosed with mediastinal lymphadenectasis underwent EBUS-TBNA were retrospectively analyzed in this study. Results: In total, 842 patients underwent EBUS-TBNA successfully. There were 589 patients with malignancy, including squamous carcinoma (118 cases; 20.6%), adenocarcinoma (187 cases; 32.7%) and small cell carcinoma (88 cases; 15.4%). A total of 253 patients were diagnosed with benign disease, including tuberculosis (111 cases; 43.9%) and sarcoidosis (93 cases; 36.7%). The diagnostic sensitivity of lung cancer, tuberculosis and sarcoidosis were 94.4%, 81.1% and 51.6%, respectively. The overall sensitivity of EBUS-TBNA was 92.0%. N2 stage in lung cancer patients who were diagnosed by EBUS-TBNA was significantly higher than other stages. The positive rate of targeted puncture is high for the lymph nodes whose short-axis diameters were larger than 1 cm. Conclusion: The operation risk of EBUS-TBNA is relatively small. In diseases complicated by mediastinal lymphadenectasis, malignant diseases are most, and benign diseases mainly are granulomatous. EBUS-TBNA is a valuable diagnostic technique in patients with mediastinal lymphadenectasis whose diagnosis have not been determined. Please cite this paper as: Zhu J, Zhang H-p, Ni J, Gu Y, Wu C-y, Song J, Ji X-b, Lu H-w, Wei P, Zhou C-c and Xu J-f. Endobronchial ultrasound-guided transbronchial needle aspiration for diagnosing mediastinal lymphadenectasis: a cohort study from a single center. Clin Respir J 2015; ••: ••–••. DOI:10.1111/ crj.12317.
Key words biopsy – diagnosis – mediastinal lymph node – pathology Correspondence Jin-fu Xu, MD, PhD, Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 200433 Shanghai, China. Tel: 0086 21 65115006 Fax: 0086 21 65111298 email: [email protected] Received: 19 November 2014 Revision requested: 24 March 2015 Accepted: 21 April 2015 DOI:10.1111/crj.12317 Authorship and contributorship Jun Zhu and Jin-fu Xu designed the study and drafted the manuscript. Hai-ping Zhang and Jian Ni participated in the design of the study and preformed the statistical analysis. Chun-yan Wu gave the pathological diagnosis of EBUS-TBNA. All authors did EBUS-TBNA and analyzed the results of this study. All authors read and approved the final manuscript. Ethics The study was approved by the Ethics Committee of Shanghai Pulmonary Hospital. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.
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Introduction Pulmonary lesions complicated by mediastinal lymphadenectasis are extremely common and are diagnosed according to the physician’s past clinical experience. However, because of the lack of pathological basis for the diagnosis of some benign diseases [such as sarcoidosis and mediastinal lymph node (MLN) tuberculosis], the misdiagnostic rate is high. In addition, pulmonary malignant tumor is always complicated by mediastinal lymphadenectasis, and lymph node (LN) staging has vital significance for tumor staging. Therefore, the pathological diagnosis for patients with MLN is especially important. In the past, diagnosis by conventional bronchoscopy was relatively difficult for patients who did not have pathological changes in bronchial lumen. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is devoted to clinical application in the early 1990s (1). During EBUSTBNA, ultrasonic probe touches the LN located at the back of the bronchial wall, and then the LN tissues are sampled by fine-needle puncture. Whether MLN staging can be obtained by EBUS-TBNA to guide the treatment of lung cancer, and which LN was the easiest way to get the right results, remains unclear. The aim of this study was to evaluate the diagnostic significance and the safety of EBUS-TBNA for mediastinal lymphadenectasis.
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general anesthesia. Patients with targeted puncture were excluded. All patients were told about the risk of operation and signed informed consent preoperatively. As a result, a total of 846 patients (aged 16–82 years) were enrolled in our study.
Instrument and methods EBUS-TBNA was performed with the special equipment called ultrasonic bronchoscope (EU-C2000, BF-UC206F-OL8, NA-201SX-4022; Olympus, Tokyo, Japan). The procedures were performed under guardianship and oxygen-enriched condition after fasting for 6 h. Patients were treated with topical anesthetic preoperatively by glottis sprays (2% lidocaine) (4). For patients who were unable to cooperate with or tolerate local anesthetic, general anesthetic was performed under the cooperation of the anesthesiologist (5). Bronchoscopy was performed nasally or orally after anesthesia. The puncture process was performed under the bronchoscope and ultrasound image monitoring. When the bronchoscopy reached the site of LNs, we used ultrasound image monitoring to locate them, avoiding the blood vessels, then punctured by needle through bronchoscopy for collecting specimens. LN specimens were smeared for liquid-based cytology examination, and the rest of LN specimens were embedded for pathological diagnosis.
Materials and methods
Detection index
Patients
LN specimens were smeared on-site for liquid-based cytology examination and then stained with hematoxylin and eosin for pathological diagnosis. The rest of the specimens were embedded and sliced for immunohistochemical detection in order to make a definitive diagnosis (6). In the following two conditions, patients were included as positive cases: (i) patients who underwent EBUS-TBNA were diagnosed with malignant disease or benign disease with definite pathology; (ii) patients with indefinite pathological diagnosis were made a definitive diagnosis by other methods (including mediastinal fine-needle puncture and surgical biopsy). The rest of the patients were included as negative cases.
This retrospective study was approved by the Ethics Committee of Shanghai Pulmonary Hospital affiliated Tongji University. A total of 1042 patients were diagnosed with mediastinal lymphadenectasis by contrastenhanced chest computerized tomography (CT) in our hospital from November 1, 2011 to November 30, 2013. Patients who underwent EBUS-TBNA due to indefinitive diagnosis by conventional bronchoscope were included in this study. The following are the inclusion criteria: (i) patients were diagnosed with mediastinum and/or hilar lymphadenectasis by contrast-enhanced chest CT (2) and the short-axis diameter of LN was ≥1 cm (3); (ii) the preoperative examinations (including electrocardiogram, pulmonary function, arterial blood gas, blood routine, hepatitis, HIV and syphilis antibodies) were accord with the standard of bronchoscopy; (iii) patients had no major organic disease and contraindications of bronchoscopy; and (iv) patients could tolerate local or
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Statistical analysis Data were analyzed by SPSS 17.0 statistical analysis software (IBM Corporation, Armonk, NY, USA). The comparison of probability was performed by
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A
B
Figure 1. Baseline characteristics of the study patients. (A) Age of the study patients. (B) Disease distribution of the whole sample. Male patients with a higher incidence of malignant diseases (P = 0.035). Female patients with no significant correlation in incidence of benign and malignant diseases (P = 0.281).
chi-squared test. A value of P < 0.05 was considered significant.
Results Puncture results A total of 846 patients were included in this study. There were 681 (80.5%) patients aged 40–70 years (Fig. 1A). There were only three patients less than 18 years old. However, Gilbert et al. (7) confirmed that it was feasible for pediatric patients who underwent EBUS-TBNA. There were 83 (9.8%) patients more than 70 years old who stayed safe with EBUS-TBNA. Recent study showed that EBUS-TBNA was safe for patients more than 70 years old (8). Eight hundred forty-two (99.5%) patients were successfully punctured, including 580 men (68.9%) and 262 women (31.1%) (Fig. 1B). EBUS-TBNA failed because of
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cardiac complications in two patients: one patient showed increased heart rhythm and decreased blood pressure; one patient had a sudden ventricular bigeminy. The two patients recovered through spot rescue and subsequent treatment. The other two patients failed to receive EBUS-TBNA because of the LNs surrounded with blood vessels. In all 842 patients (average age, 56.8 ± 1.2 years), there were 589 (68.9%) patients with malignant disease (average age, 60.1 ± 9.1 years) and 253 (31.1%) patients with benign disease (average age, 49.3 ± 1.4 years). The onset age of malignant disease significantly increased compared with benign disease (P = 0.001). The total puncture times were 2687, and the average puncture times per patient were 3.19. The puncture times was 1–8 each examination (Fig. 2A), and 83.2% patients were punctured for three or more times. For each examination, 1–4 stations of LN were sampled (Fig. 2B).
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A
B
C
D
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The MLNs were sampled at stations 2, 3, 4, 7, 10, 11 and 12 (Fig. 2C), which were based on The International Association for the Study of Lung Cancer (9). However, the remaining stations of the LNs could not be sampled because of their anatomical position. The most commonly sampled stations were 7 (52.1%) and 4R (41.3%) (Fig. 2D). According to the diagnostic results, there were 589 (70.0%) patients with malignant diseases (Table 1) and 253 (30.0%) patients with benign diseases (Table 2). The diagnostic sensitivities of EBUS-TBNA for lung cancer, tuberculosis and sarcoidosis were 94.4%, 81.1% and 51.6%, respectively (Table 3). The positive rate of targeted puncture was high for the LNs whose shortaxis diameters are larger than 1 cm. The patients in whom a specific diagnosis was not determined by EBUS-TBNA were made a definitive diagnosis according to the subsequent surgical biopsy or clinical diagnosis. EBUS-TBNA in station 7 had the highest positive rate (92.2%), followed by station 4R (89.9%), and there were no significant correlation (P = 0.445) between puncture sites of MLNs and diagnostic positive rate (Table 4). The diagnostic positive rates of lung cancer in station 10L (86.1%), 4R (82.4%) and 7 (77.3%) were higher than other stations (Table 4). At the same time, the diagnostic sensitivity of bronchoscope brush inspection or biopsy was 67.6% in our hospital, and the paired sample comparative analysis of diagnostic sensitivity was significantly elevated (P = 0.041) by EBUS-TBNA. For lung cancer patients (adenocarcinoma, squamous cell carcinoma, small cell carcinoma, non-small cell lung cancer and compound small cell carcinoma), the N2 stage confirmed by EBUS-TBNA was significantly higher than the other stages through two or more puncture times at one EBUS-TBNA (P = 0.039) (Table 5). The total diagnostic sensitivity of EBUS-TBNA was slightly lower than that of mediastinoscopy (98.2%). However, because of the small invasion, EBUS-TBNA still had obvious advantages.
Complications
Figure 2. Basic data of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). (A) Puncture times for each EBUS-TBNA. (B) Number of lymph node (LN) stations sampled for each EBUS-TBNA. (C) Station of LNs punctured by EBUS-TBNA. (D) Computed tomography scan of patients with mediastinal lymphadenectasis in stations 4R and 7.
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Two (0.24%) of the 846 patients had cardiac complications (Table 6), which were rarely reported in the previous studies. Okachi et al. (10) reported that an increased blood pressure occurred in elderly patients who underwent EBUS-TBNA. The incidence of postoperative sore throat often occurred in patients under general anesthesia. Eight (0.95%) of the 846 patients had hemorrhage more than 30 mL. The incidence of hemorrhage was similar with the report of Asano et al. (11).
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Table 1. The diagnoses of malignant diseases by endobronchial ultrasound-guided transbronchial needle aspiration
Malignant diseases Lung cancer Adenocarcinoma Squamous cell carcinoma Small cell carcinoma Non-small cell lung cancer Compound small cell carcinoma Lung cancer (non-classification) Adenosquamous cell carcinoma Large cell carcinoma Neuroendocrine carcinoma Pleomorphic carcinoma Alveolar cell carcinoma Carcinoid Lung carcinoma with heterocyst (pathological diagnosis definite) Suspected lung cancer (subsequent biopsy definite) Metastatic lung cancer Laryngeal squamous cell carcinoma Breast carcinoma Esophageal squamous cell carcinoma Gastric carcinoma Colorectal carcinoma Metastatic pulmonary adenocarcinoma (source unknown Metastatic lung cancer(indefinite) Thymic carcinoma Lymphoma Non-Hodgkin’s lymphoma Diffuse large B-cell lymphoma Suspected lymphoma (indefinite) Malignant mesothelioma Mediastinal malignant tumors
Discussion EBUS-TBNA in patients with MLN larger than 1 cm in short-axis diameter has a high diagnostic accuracy and a low risk of operation EBUS-TBNA was applied clinically by Hürter and Hanrath (12) in 1992. Compared with conventional transbronchial needle aspiration (TBNA), the safety of puncture with EBUS-TBNA was higher due to accurate positioning of Doppler probe for LNs and blood vessels (13). In this study, the short-axis diameter of LNs was ≥1 cm, which had clinical significance relatively (14). Kinsey et al. (15) showed that it was feasible for lung cancer patients with LNs larger than 5 mm in short-axis diameter to perform EBUS-TBNA. However, because the benign and malignant diseases were both included in this study, only those LNs with short-axis ≥1 cm had clinical significance. In addition, Wong et al. (16) indicated that it was safe for patients
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No.
%
589 571 187 118 88 49 36 33 16 3 2 1 1 1 4 32 7 1 1 1 1 1 1 1 3 6 1 1 4 1 1
70.0 96.9 32.7 20.6 15.4 8.6 6.3 5.8 2.8 0.5 0.4 0.2 0.2 0.2 0.7 5.6 1.2 14.3 14.3 14.3 14.3 14.3 14.3 14.3 0.5 1.0 16.7 16.7 66.6 0.2 0.2
with superior vena cava syndrome caused by lymphadenectasis to perform EBUS-TBNA. In this study, the operation was terminated because of heartrelated disease in two patients. Park et al. (17) suggested that in pulmonary artery sarcoma or pulmonary thromboembolism, an abnormality could be observed in contrast-enhanced chest CT images, so patients with these diseases were not suitable for EBUS-TBNA because of the risk of hemorrhage. The previous study reported that pneumothorax possibly occurred in patients who underwent EBUS-TBNA (18). However, pneumothorax did not occur in this study. In general, EBUS-TBNA had high safety and tolerability.
EBUS-TBNA is commonly performed in stations 4R and 7, and there is no correlation between diagnostic rate and puncture site of LNs The majority of patients with EBUS-TBNA were in stations 4R and 7, which was associated with the dis5
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Table 2. The diagnose of benign diseases by endobronchial ultrasound-guided transbronchial needle aspiration
Benign diseases Tuberculosis Tuberculosis Suspected tuberculosis (combined with clinical diagnosis) Sarcoidosis Sarcoidosis Suspected sarcoidosis (operation definite) Pulmonary inflammatory diseases Pneumoconiosis Other pulmonary benign disease Pulmonary aspergillosis Organizing pneumonia Tracheal tiny papillary fibroma Pericardial cyst Collagenic lymph node Pulmonary abscess Pleural steatosis(combined with operation) Inflammatory pseudotumor Hamartoma Benign disease of indefinite diagnosis (clinical diagnosis) Complicated diseases Sarcoidosis complicated by pneumoconiosis Non-small cell lung cancer complicated by sarcoidosis Squamous cell carcinoma complicated by parasitic disease
section site of MLN. The patients in stations 4R, 7 and 4L were 348 (41.3%), 439 (52.1%) and 112 (13.3%), respectively. The patients in stations 10 and 11 were few, followed by stations 2, 3 and 12. The ventilation
No.
%
253 111 90 21 93 48 45 23 4 17 2 1 1 2 2 1 2 1 1 4 5 1 3 1
30.0 43.9 81.1 18.9 36.7 51.6 48.4 9.1 1.6 6.7 11.8 5.9 5.9 11.8 11.8 5.9 11.8 5.9 5.9 23.3 2.0 20.0 60.0 20.0
space of main bronchus was significantly reduced when the bronchoscope examination was performed for stations 2 and 3, which would increase the risk of anoxia of the patients. Because of the deep location of
Table 3. The diagnostic sensitivity of endobronchial ultrasound-guided transbronchial needle aspiration
Lung cancer Tuberculosis Sarcoidosis Other diseases Total
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
94.4 81.1 51.6 86.6 92.0
100 100 100 100 100
100 100 100 100 100
36.0 87.1 78.0 98.9 64.5
Table 4. The station of lymph node (LN) puncture and diagnostic positive rate LN station
2L
2R
3
4L
4R
7
Puncture times Total 4 34 2 112 348 439 Positive times 3 29 1 91 313 405 Positive rate 75.0% 85.2% 50.0% 81.3% 89.9% 92.2% Number of patients with 2 21 1 59 258 313 lung cancer Positive rate of lung 66.7% 72.4% 100.0% 64.8% 82.4% 77.3% cancer in positive puncture results
6
10L
10R
11L
11R
12R
41 36 87.8% 31
65 38 58.5% 26
32 26 81.3% 19
41 4 36 2 87.8% 50.0% 27 1
86.1% 68.4% 73.1% 75.0% 50.0%
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Table 5. The lymph node stage in common lung cancer diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration
Adenocarcinoma Squamous cell carcinoma Small cell carcinoma Non-small cell lung cancer Compound small cell carcinoma
N1
N2
N3
23 (12.3%) 29 (24.6%) 14 (15.9%) 11 (22.5%) 8 (22.2%)
136 (72.7%) 82 (69.5%) 62 (70.5%) 35 (71.4%) 24 (66.7%)
28 (15.0%) 7 (5.9%) 12 (13.6%) 3 (6.1%) 4 (11.1%)
LNs and the equipment with coarser diameters and limited bending degree, the puncture of LNs was not easily performed in station 12. The diagnostic positive rate was highest in station 7 (92.2%), followed by station 4R (89.9%), and there were no significant correlations (P = 0.45) between the puncture sites of MLN and the diagnostic positive rate.
Majority of patients with mediastinal lymphadenectasis are diagnosed with malignant diseases The majority of patients were diagnosed with malignant diseases, and 96.9% of them were lung cancer. The diagnostic positive rate of lung cancer in stations 10L, 4R and 7 were relative higher. For station 3, the positive rate for diagnosis of lung cancer was 100.0%; however, it is only from one patient, and we only had punctured one time, so it did not have clinical significance. We recommend puncturing LN stations as more as possible at the same time to increase positive rate. In all lung cancer patients, adenocarcinoma represents to be the most common type, followed by small cell carcinoma and squamous cell carcinomas. These three kinds of diseases accounted for 68.7% of lung cancer. Diagnostic sensitivity of lung cancer was 94.4%. For lung adenocarcinoma, Jurado et al. (19) suggested that the LN specimens could be used to detect the expression of epidermal growth factor receptor, Kirsten rat Table 6. The complications of endobronchial ultrasoundguided transbronchial needle aspiration Complications
No.
(%)
Cardiac complications Sore throat Bloody phlegm (10–20 mL) Hemorrhage (more than 30 mL) Fever Pulmonary infection Pneumothorax Mediastinal emphysema Death
2 262 203 8 25 26 0 0 0
0.24 30.97 24.00 0.95 2.96 3.07 0.00 0.00 0.00
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sarcoma viral oncogene homologue and anaplastic lymphoma kinase in order to conduct the treatment. For patients with lung cancer, LN staging was determined by EBUS-TBNA, which provided a direct pathological basis for patients to take direct surgery or neoadjuvant chemotherapy before surgery (20). However, Bugalho et al. (21) suggested that LN specimens could be used to detect the expression of cytokeratin 19, carcinoembryonic antigen and epithelial cell adhesion molecule, which were also helpful to define the LNs and the staging of lung cancer. For patients who accepted cytotoxic chemotherapy, the role of EBUS-TBNA for LN staging was also significant (22). It was worth noting that seven patients with metastatic lung carcinoma were made a definitive diagnosis by enzyme immunohistochemistry. Only two of six patients suspected of having lymphoma were definitively diagnosed, which was similar to the research of Steinfort et al. (23). Few patients with mediastinal malignant tumor were definitively diagnosed by EBUS-TBNA, which reduced the use of mediastinoscopy. Consistently, the research of José et al. (24) for long-term follow-up of 328 patients also indicated reduced use of mediastinoscopy.
Diagnostic sensitivity of benign disease is relatively lower, and benign diseases mainly are granulomatous lesions In lung benign diseases, tuberculosis and sarcoidosis accounted for 43.9% and 36.7%, respectively. The granuloma with the background of necrosis was more likely to be diagnosed as pulmonary tuberculosis (25). The diagnostic sensitivity of EBUS-TBNA for tuberculosis was 81.1%, and 18.9% of the patients with tuberculosis were made a definitive diagnosis by combination of images, clinical experience or diagnostic anti-tuberculosis treatment. The diagnostic sensitivity of tuberculosis reported by Sun et al. (26) and Navani et al. (27) were 85% and 86%, respectively, which were similar to this study. Sarcoidosis had to be diagnosed by surgical biopsy in the past. However, by using 7
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EBUS-TBNA, sarcoidosis could be definitively diagnosed after tuberculosis has been excluded through further pathological examination with LN specimens, and the diagnostic sensitivity of EBUS-TBNA for sarcoidosis was 51.6%. Gupta et al. (28) showed that compared with TBNA, diagnostic rate of EBUS-TBNA for sarcoidosis was higher. For sarcoidosis patients of stage I, the diagnostic rate of EBUS-TBNA was also significantly higher than that of transbronchial lung biopsy and bronchoalveolar lavage fluid analysis (29). Garwood et al. (30) suggested that LN size was suitable at around 16 mm in order to improve the positive rate. In the study, 23 (9.1%) patients were confirmed having pulmonary inflammatory diseases by EBUS-TBNA. The rest of the lung benign diseases were sporadic.
EBUS-TBNA is feasible for the diagnosis of lung cancer complicated by sarcoidosis There were three patients (0.35%) with lung cancer complicated by sarcoidosis in this study, which was extremely rare. They were first diagnosed with sarcoidosis, and then the cancer cells and granulomatous inflammation were both observed in LNs. Yokouchi et al. (31) reported that increased pulmonary nodule was found in one patient during the period of treatment after he had been diagnosed with sarcoidosis by mediastinoscopy pathological examination. As a result, cancer cells were found in the patient through EBUSTBNA. Previously, the diagnosis of sarcoidosis tends to be ignored in such patients.
Conclusion In conclusion, the operation risk of EBUS-TBNA is relatively low after improving the preoperative examination, and the positive rate of targeted puncture is high for the LNs whose short-axis diameter is larger than 1 cm. There is no significant correlation between the station of LNs puncture and diagnostic positive rate. In the diseases complicated by mediastinal lymphadenectasis, malignant diseases are most, and benign diseases mainly are granulomatous. EBUSTBNA is a valuable diagnostic technique for patients with mediastinal lymphadenectasis whose specific diagnosis have not been determined.
Acknowledgments This work was supported by the National Science Foundation of China (NSFC81170003 and 81370109), Programs from STCSM (12PJD004, 134119a6400 and
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12JC1402300) and the Innovation Program of Shanghai Municipal Education Commission (13SG21).
References 1. Yasufuku K, Nakajima T, Fujiwara T, et al. Role of endobronchial ultrasound-guided transbronchial needle aspiration in the management of lung cancer. Gen Thorac Cardiovasc Surg. 2008;56: 268–76. 2. Gu P, Zhao YZ, Jiang LY, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer. 2009;45: 1389–96. 3. Fielding DI, Kurimoto N. EBUS-TBNA/staging of lung cancer. Clin Chest Med. 2013;34: 385–94. 4. Xue FS, Liu HP, He N, et al. Spray-as-you-go airway topical anesthesia in patients with a difficult airway: a randomized, double-blind comparison of 2% and 4% lidocaine. Anesth Analg. 2009;108: 536–43. 5. Eapen GA, Shah AM, Lei X, et al. Complications, consequences, and practice patterns of endobronchial ultrasound-guided transbronchial needle aspiration: results of the AQuIRE registry. Chest. 2013;143: 1044–53. 6. Esterbrook G, Anathhanam S, Plant PK. Adequacy of endobronchial ultrasound transbronchial needle aspiration samples in the subtyping of non-small cell lung cancer. Lung Cancer. 2013;80: 30–4. 7. Gilbert CR, Chen A, Akulian JA, et al. The use of convex probe endobronchial ultrasound-guided transbronchial needle aspiration in a pediatric population: a multicenter study. Pediatr Pulmonol. 2014;49: 807–15. 8. Evison M, Crosbie PA, Martin J, et al. EBUS-TBNA in elderly patients with lung cancer: safety and performance outcomes. J Thorac Oncol. 2014;9: 370–6. 9. Rusch VW, Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4: 568–77. 10. Okachi S, Imai N, Imaizumi K, et al. Endobronchial ultrasound transbronchial needle aspiration in older people. Geriatr Gerontol Int. 2013;13: 986–92. 11. Asano F, Aoe M, Ohsaki Y, et al. Complications associated with endobronchial ultrasound-guided transbronchial needle aspiration: a nationwide survey by the Japan Society for Respiratory Endoscopy. Respir Res. 2013;14: 50. 12. Hürter T, Hanrath P. Endobronchial sonography: feasibility and preliminary results. Thorax. 1992;47: 565–7. 13. Yasufuku K, Chiyo M, Sekine Y, et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal and hilar lymph nodes. Chest. 2004;126: 122–8. 14. de Langen AJ, Raijmakers P, Riphagen I, et al. The size of mediastinal lymph nodes and its relation with metastatic involvement: a meta-analysis. Eur J Cardiothorac Surg. 2006;29: 26–9.
The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd
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15. Kinsey CM, Arenberg DA. Endobronchial ultrasound-guided transbronchial needle aspiration for non-small cell lung cancer staging. Am J Respir Crit Care Med. 2014;189: 640–9. 16. Wong MK, Tam TC, Lam DC, et al. EBUS-TBNA in patients presented with superior vena cava syndrome. Lung Cancer. 2012;77: 277–80. 17. Park J, Chung J, Jheon S, et al. EBUS-TBNA in the differential diagnosis of pulmonary artery sarcoma and thromboembolism. Eur Respir J. 2011;38: 1480–2. 18. Koh M, Tee A, Wong P, et al. Advances in lung cancer diagnosis and staging: endobronchial ultrasound. Intern Med J. 2008;38: 85–9. 19. Jurado J, Saqi A, Maxfield R, et al. The efficacy of EBUS-guided transbronchial needle aspiration for molecular testing in lung adenocarcinoma. Ann Thorac Surg. 2013;96: 1196–202. 20. Yasufuku K, Nakajima T, Waddell T, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for differentiating N0 versus N1 lung cancer. Ann Thorac Surg. 2013;96: 1756–60. 21. Bugalho A, Martins C, Dias SS, et al. Cytokeratin 19, carcinoembryonic antigen, and epithelial cell adhesion molecule detect lung cancer lymph node metastasis in endobronchial ultrasound-guided transbronchial aspiration samples. Clin Lung Cancer. 2013;14: 704–12. 22. Almeida FA. Bronchoscopy and endobronchial ultrasound for diagnosis and staging of lung cancer. Cleve Clin J Med. 2012;79: eS11–16. 23. Steinfort DP, Conron M, Pasricha S-R, et al. Endobronchial ultrasound-guided transbronchial needle
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24.
25.
26.
27.
28.
29.
30.
31.
aspiration for the evaluation of suspected lymphoma. J Thorac Oncol. 2010;5: 804–9. José RJ, Shaw P, Taylor M, et al. Impact of EBUS-TBNA on modalities for tissue acquisition in patients with lung cancer. QJM. 2014;107: 201–6. Cancellieri A, Leslie KO, Tinelli C, et al. Sarcoidal granulomas in cytological specimens from intrathoracic adenopathy: morphologic characteristics and radiographic correlations. Respiration. 2013;85: 244–51. Sun J, Teng J, Yang H, et al. Endobronchial ultrasound-guided transbronchial needle aspiration in diagnosing intrathoracic tuberculosis. Ann Thorac Surg. 2013;96: 2021–7. Navani N, Molyneaux PL, Breen RA, et al. Utility of endobronchial ultrasound-guided transbronchial needle aspiration in patients with tuberculous intrathoracic lymphadenopathy: a multicentre study. Thorax. 2011;66: 889–93. Gupta D, Dadhwal DS, Agarwal R, et al. Endobronchial ultrasound guided TBNA vs conventional TBNA in the diagnosis of sarcoidosis. Chest. 2014;146: 547–56. Nakajima T, Yasufuku K, Kurosu K, et al. The role of EBUS-TBNA for the diagnosis of sarcoidosis–comparisons with other bronchoscopic diagnostic modalities. Respir Med. 2009;103: 1796–800. Garwood S, Judson MA, Silvestri G, et al. Endobronchial ultrasound for the diagnosis of pulmonary sarcoidosis. Chest. 2007;132: 1298–304. Yokouchi H, Miyazaki M, Miyamoto T, et al. [A case of small-sized lung cancer complicated by sarcoidosis]. Gan to Kagaku Ryoho. 2013;40: 2336–8.
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