The role of Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for qualitative diagnosis of mediastinal and hilar lymphadenopathy: a prospective analysis
© Ye et al; licensee BioMed Central Ltd. 2011
Received: 26 September 2010
Accepted: 21 March 2011
Published: 21 March 2011
Recently EBUS-TBNA, which has a sensitivity of 94.6%, specificity of 100% and diagnostic accuracy rate of 96.3% as previously reported, has been widely used for patients with mediastinal and hilar lymphadenopathy or suspected lung cancer to get accurate diagnosis. The purpose of the current study was to evaluate the usefulness of EBUS-TBNA in obtaining cytological and histological diagnosis of mediastinal and hilar lymph nodes compared to the results obtained with conventional mediastinoscopy as previously reported, and to assess the relationship of diagnostic accuracy and number of passes and size of lymph nodes.
101 patients with mediastinal and hilar lymphadenopathy or suspected lung cancer in our institution were included in this prospective study. EBUS-TBNA was performed in all cases. The final diagnosis was confirmed by cytology, surgical results, and/or clinical follow-up for at least 6 months. Sensitivity, specificity, accuracy, and positive and negative predictive values were calculated using standard formulas.
In 101 patients, EBUS-TBNA was successfully performed to obtain samples from 225 lymph nodes, 7 lung masses, 1 mediastinal mass and 2 esophageal masses. 63 malignant tumors and 38 benign diseases were confirmed. Epidermal growth factor receptor mutation was detected in 10 biopsy samples, and epidermal growth factor receptor mutation was detected in 4 cases. With respect to the correct diagnosis of mediastinal and hilar lymphadenopathy, EBUS-TBNA had a sensitivity of 95.08%, specificity of 100%, positive predictive value of 100%, negative predictive value of 93.02%, and overall accuracy of 97.02%. The relationship of diagnostic accuracy and number of lymph node passes or size of lymph nodes was both insignificant (p = 0.27; p = 0.23). The procedure was uneventful without complications.
EBUS-TBNA is an accurate and safe tool in diagnosis of mediastinal and hilar lymphadenopathy. It cannot completely replace mediastinoscopy, it may indeed reduce the number of mediastinoscopy procedures. In some cases, it can necessarily be the first-line procedure before mediastinoscopy.
Patients with mediastinal lymphadenopathy or suspected lung cancer required accurate diagnosis to determine optimal treatment. For these patients, mediastinal nodal sampling is often necessary and has traditionally been performed by mediastinoscopy or anterior mediastinotomy. However, mediastinoscopy, with a sensitivity of 80% to 85% and a specificity of nearly 100%, which is considered the gold standard for diagnosis with tissue confirmation of mediastinal lymphadenophy and lung cancer with mediastinal or hilar lymph nodes involved, does not allow access to all lymph node stations and is associated with a rate of morbidity that is not insignificant . This situation has led to the promotion in recent years of minimally invasive techniques for mediastinal lymph node evaluation.
Real-time endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is a new technique that combines endoscopic visualization with high frequency ultrasound imaging, which is used to obtain cytological and histological samples of lesions adjacent to the tracheobronchial tree [2–4]. This makes it easier to locate the lymph nodes to be sampled. As Yasufuku and colleagues  reported, EBUS-TBNA had a sensitivity of 94.6%, specificity of 100% and diagnostic accuracy rate of 96.3%, which seemed to be superior to those of mediastinoscopy. However, whether EBUS-TBNA can be applied as the first-line procedure for diagnosis of mediastinal lymphadenopathy is still controversial, because of its false negative rate to some extent . Moreover, there is few studies reported comparing the relationship of diagnostic accuracy and number of passes or size of lymph nodes. The main aim of our study was to evaluate the role of EBUS-TBNA in obtaining cytological and histological diagnosis of mediastinal lymph nodes compared to the results obtained with conventional mediastinoscopy as previously reported, and to assess the relationship of diagnostic accuracy with number of passes and size of lymph nodes.
Patients having mediastinal lymphadenopathy or with mediastinal or hilar lesion suspected of lung cancer detected on enhanced thoracic CT were included in this prospective study. Between March to October 2009, 101 patients in our institution met this inclusion criteria and were included in this study. The study was approved by the ethical committee of Fudan University Shanghai Cancer Center and a written informed consent was obtained in all the patients.
EBUS-TBNA was performed under venous anaesthesia. Patients were monitored for electrocardiogram, pulse oximetry, and blood pressure with the presence of an anesthesiologist. A flexible bronchoscope containing an ultrasound probe (XBF-UC206F-OL8; Olympus) was inserted via the laryngeal mask and guided through the trachea and the bronchial tree towards the appropriate area of the mediastinum. The targeted lymph nodes or masses were identified using bronchoscopic visualization and ultrasound imaging. A needle (NA-201SX-4022; Olympus) extended from the bronchoscope through the bronchial wall was used to puncture the lesion and to aspirate tissue. A lymph node or mass could be punctured three to four times to gain an adequate sample, and several lymph nodes could be punctured during the same session. The aspirates were then smeared on slides and simultaneously sent to pathology laboratory for subsequent cytology. The cytology sample was considered adequate if it contained malignant cell or a large number of lymphoid cells confirmed by the cytologist, and then the operation is terminated. The lymph nodes punctured were grouped according to the puncture site: the upper paratracheal (2R, 2L), the subcarinal station (7), the lower paratracheal and hilar station (4R, 4L, 10R, and 10L), the right paraesophageal (8R) and the interlobar station (11L,11R).
Histological cores were collected and fixed with formalin and stained with hematoxylin and eosin for further histology examination. In some cases, immunohistochemistry was performed for additional information, and EGFR mutation was also evaluated.
The EBUS-TBNA diagnosis was confirmed by cytology, surgical results, and/or clinical follow-up for at least 6 months. A positive cytological result of malignancy was accepted as evidence, and the patients were treated accordingly.
The data were entered into a database and analyzed with the SPSS statistical software package (SPSS 15.0 Chicago, Illinois, USA). A descriptive analysis was carried out in which categorical variables were expressed as absolute and relative frequencies, and continuous variables as means (SD). The χ2 was used to compare proportions in independent groups. The spearman analysis was used to compare correlation between two independent groups. A P value of less than 0.05 was considered significant. Sensitivity, specificity, accuracy, and positive and negative predictive values were calculated using standard formulas.
Patient characteristics and pre-operation diagnosis
N = 101
57.4 years (24-84)
Suspected for lung cancer
N = 55
Suspected for esophageal carcinoma
N = 2
Malignant mediastinal mass
N = 1
Mediastinal and hilar lymphadenopathy
N = 43
Operation parameters, further confirmation modalities, lymph node size and diagnostic yield
Number of lymph nodes biopsied
N = 225
Number of lung mass biopsied
N = 7
Number of esophageal masses biopsied
N = 2
Number of mediastinal masses biopsied
N = 1
Mean period of each TBNA pass (min)
Mean stay length in hospital (day)
Further confirmation modalities
N = 23
N = 2
N = 2
N = 74
Lymph node size (mm)
Diagnostic yield %
Positive predictive value (PPV)
Negative predictive value (NPV)
Location of Lymph Node Station Biopsied by EBUS-TBNA and number of TBNA passes of each Lymph Node Station
Right upper paratracheal (2R)
N = 42
Left upper paratracheal (2L)
N = 1
Right lower paratracheal (4R)
N = 110
Left lower paratracheal (4L)
N = 41
N = 80
Right paraesophageal (8R)
N = 2
Right hilar (10R)
N = 16
Left hilar (10L)
N = 7
Right interlobar (11R)
N = 4
Left intherlobar (11L)
N = 2
N = 305
The relationship of diagnostic accuracy and number of lymph node passes
Number of lymph node passes
N = 1
N > 1
Total (N = 225)
P = 0.27
The relationship of diagnostic accuracy and size of lymph nodes
Maximal diameter of lymph nodes
Total (N = 225)
P = 0.23
Final cytological and histological results
Malignancy (N = 61)
N = 24
Small cell lung cancer
N = 20
N = 5
N = 9
Renal carcinoma metastasis
N = 1
Benign diseases (N = 40)
No MT evidence
N = 13
N = 14
N = 4
N = 4
N = 2
Small B cell tumor
N = 1
Lymph node hyperplasia
N = 1
N = 1
The sensitivity of real-time EBUS-TBNA was 95.08% and specificity was 100%. Also, the positive predictive value and the negative predictive value was 100% and 93.02%, respectively. The overall accuracy was 97.02% (see Table 2). The relationships of diagnostic accuracy with number of lymph node passes and with size of lymph nodes were both insignificant (p = 0.27; p = 0.23) (see Table 4&5).
EGFR mutation measurement
Results of EGFR mutation detection on the cytological level
EGFR mutation status
Heterozygosity Deletion (E752-E759del) of Exon 19
Heterozygosity Deletion (E746-E750del) of Exon 19
Point Mutations (L858R) of Exon 21
For many years surgical biopsy - principally mediastinoscopy - has been regarded as the "standard procedure" for sampling mediastinal lymph nodes . However, mediastinoscopy can only sample nodal stations 1-4, 7, access to hilar nodal stations could be difficult and may require thoracoscopy and on occasion a thoracotomy. Moreover, it cannot be repeatedly operated on the same patient [5, 6]. Contrarily, EBUS-TBNA, when combined with EUS, can sample all the key nodal stations and also can be performed repeatedly [7, 8]. In our study, 225 lymph nodes were biopsied and 10 stations of mediastinal and hilar nodes were punctured (see Table 2 & 3). Moreover, nearly every lymph nodal group had been checked. And almost every patient was biopsied three to four lymph node stations. A total number of 305 TBNA passes of lymph nodes were conducted (see Table 3). On the other hand, mediastinoscopy is more invasive than endoscopic techniques and results in a neck scar which may be cosmetically unacceptable to some patients. Unfortunately it does have a 2% risk of morbidity and 0.08% mortality [1, 9, 10]. In this study, 101 patients received EBUS-TBNA, of which mediastinoscopy was conducted in 23 patients, 2 patients received VATS and 2 patients received TBLB procedure, no procedure-related complications ever occurred (see Table 2). The mean period of each EBUS-TBNA was 4.9 minutes and mean stay length in hospital was 2 days, which seemed to be more minimal invasive, compared with those parameters of mediastinoscopy.
Diagnostic Ability of Endobronchial Ultrasound Guided Transbronchial Needle Aspiration: Comparison With Previous Studies
Comparison of real-time EBUS-guided TBNA results with final diagnosis of all patients
Comparative diagnostic performance of EBUS-TBNA and mediastinoscopy
Another unsettled point is that whether EBUS-TBNA can replace mediastinoscopy as first-line procedure for diagnosis benign mediastinal diseases such as sarcoidosis, tuberculosis, etc. As Nakajima and colleagues reported in 2009 , EBUS-TBNA should be added to conventional diagnostic modalities for patients with suspicious stage I sarcoidosis on chest roentgenogram. In their study, they compared EBUS-TBNA with TBLB and BAL and got their conclusion, but they did not compare with mediastinoscopy. In our research, 38 benign diseases were diagnosed. And 5 cases of granulomous inflammation were diagnosed by EBUS-TBNA. Also, of 4 patients with tuberculosis, one case was diagnosis by EBUS-TBNA. Since non-caseating granuloma can be detected by EBUS-TBNA, sarcoidosis and tuberculosis can be diagnosed with the combination of clinical features and laboratory evidences.
Since there are few studies analyzing the relationship between diagnostic accuracy and number of lymph node passes or size of lymph nodes reported previously, we assessed the correlation of diagnostic accuracy and the two parameters above. Though the diagnostic accuracy of EBUS-TBNA should be higher when the lymph node size was larger or number of passes was more on the theoretical basis, we found that the relationship of diagnostic accuracy and number of passes was insignificant (see Table 4 & 5). Similarly, there was no significant correlation between diagnostic accuracy and size of lymph nodes. Our results suggest that neither number of lymph node passes nor size of lymph nodes be the key factor which determines the success of EBUS-TBNA. The certainty that the needle is punctured into the lymph node and enough samples are collected during EBUS-TBNA procedure is much more important.
Another potential advantage of EBUS-TBNA is that the cytological samples can provide molecular biological information that will possibly be useful for the treatment of advanced lung cancer. In our study, we detected EGFR mutation in ten biopsy samples. We found 4 EFGR mutation cases: one heterozygosity deletion (E752-E759del) of exon 19, one heterozygosity deletion (E746-E750del), and two point mutations (L858R) of exon 21. We detected EGFR mutation on the cytological level, which was different from what Nakajima reported on the histological level in 2007 . Though whether EGFR mutation found in metastatic lymph nodes is accordance with that of the primary tumor is still unknown, however, molecular biological information provided by EBUS-TBNA is evidently of great value and maybe it can guide targeted therapy for advanced lung cancer patients. Obviously more researches are needed for further confirmation.
EBUS-TBNA was an accurate and safe tool in diagnosis of mediastinal lymphadenopathy and lung cancer. Surely EBUS-TBNA cannot completely replace mediastinoscopy so far, it may indeed reduce the number of mediastinoscopy procedures. In patients with positive lymph nodes suspected by enhanced thoracic CT and PET/CT, it can necessarily be the first-line procedure before mediastinoscopy.
We thank Doctor Xing Wang, Doctor Shilai Wang, Professor Hua Yin and Professor Zhiming Tan for the anaesthesia and we really appreciate for the cytological diagnosis by Professor Ying Chen and histological evaluation by Professor Lei Shen.
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