Dincer, H. Erhan MD, FCCP
TECHNOLOGY AND EQUIPMENT
The linear endobronchial ultrasound (L-EBUS) incorporates a convex transducer with a frequency of 7.5 MHz at the tip of a flexible bronchoscope, generating a 9-cm-deep ultrasound image (Fig. 1). The L-EBUS bronchoscopes have a 6.7 mm outer diameter and 6.9 mm diameter at the tip. EBUS bronchoscope system provides 2 images: an endoscopic image at an obliquely angled view of 30 degrees forward and an ultrasound image at an angled forward view of 90 degrees parallel to the EBUS bronchoscope shaft, allowing the formation of a real-time image while performing transbronchial needle aspiration (EBUS-TBNA). The oblique view should be taken under consideration while intubating the vocal cords and trachea. The transtracheal views of the structures such as the lymph nodes can be obtained either by direct contact of the probe to the tracheal wall or using the water-filled balloon. Doppler function can differentiate vascular structures from solid tissues and can also localize vascularization in the solid tissues. The size of the bronchoscope and the oblique view may make airway examination difficult; therefore, a flexible bronchoscope is used for that reason.
INDICATIONS OF EBUS
EBUS-TBNA is indicated to sample the mediastinal and/or hilar lymph nodes and masses (Table 1 and Table 2). The most important application of EBUS is to accurately stage the mediastinum in non–small cell lung cancer (NSCLC). Unexplained mediastinal lymphadenopathy because of benign conditions such as tuberculosis or sarcoidosis can also be diagnosed using this technique. EBUS-TBNA can reach and sample lymph node stations 2 (upper paratracheal), 4 (lower paratracheal), 7 (subcarinal), 10 (hilar), 11 (interlobar), 12 (lobar) through the tracheobronchial tree, and stations 8 (paraesophageal) and 9 (pulmonary ligament) through the esophagus1,2 (Fig. 2). Stations 5 and 6 are not reachable by EBUS.
LIMITATIONS OF EBUS
The limitations of L-EBUS are difficulty in general airway examination, false-negative results of biopsies, inability to reach certain stations of lymph nodes, possible costly damage to the bronchoscopes, and time and training required to obtain optimal samples.
CONTRAINDICATIONS OF EBUS
Contraindications to EBUS are similar to those of flexible bronchoscopy, such as life-threatening arrhythmias, decompensated heart failure, severe hypoxemia, and uncooperative patient.3 Additional contraindications are related to bleeding risk with antiplatelet or anticoagulation treatments, thrombocytopenia, and elevated blood urea nitrogen and creatinine levels. International normalized ratio ideally should be >1.4. EBUS should be postponed at least 6 weeks after a myocardial infarction and should not be performed in the presence of ongoing myocardial ischemia, arrhythmia, or severe hypoxemia at rest.
COMPLICATIONS OF EBUS
EBUS-TBNA is usually a safe procedure. There are rare case reports of pneumomediastinum, pneumothorax, and hemomediastinum. Chest radiography is not routinely required. Because of the real-time ultrasound imaging, major vessel puncture is theoretically less likely compared with conventional transbronchial needle aspiration (cTBNA). Major vessel puncture has been described in the aorta during cTBNA. Although unintended puncture of major vessels can lead to hematoma, it is usually clinically insignificant.4,5 Infectious complications have also been rarely reported.6
STAGING LUNG CANCER
Mediastinal staging is the key step not only to determine the nodal stage of TNM classification and prognosis but also to direct the therapeutic options of NSCLC.7 Mediastinal lymph nodes are found in 26% of newly diagnosed lung cancer patients, whereas extrathoracic metastases are found in 49% of them.8 Reliable staging of mediastinum is essential for choosing an appropriate therapy.
Selection of the staging method(s) depends on the patients’ characteristics and institutional availability of technology with skilled clinicians. The easiest and least invasive method should be chosen. Having imaging studies such as computed tomography (CT) scan and positron emission tomography (PET) scan can help to access the way to the most suspicious lesion. Diagnosis and staging should be performed simultaneously, if possible.
Mediastinal lymph node staging can be achieved with the noninvasive and invasive methods (Table 3).
Noninvasive methods include CT scan, PET scan, or PET/CT fusion images. However, a definitive tissue diagnosis is necessary.
CT scan of the chest has been used to stage the mediastinum. However, studies showed that it only staged 50% of patients correctly, with 25% of overstaged patients (false positive) and remainder understaged patients (false negative).9–11
Stand-alone PET has limited spatial resolution, allowing far less anatomic detail compared with CT. PET scan is more accurate compared with CT in detecting mediastinal involvement, and it may also be useful in detecting distant metastasis. PET has a sensitivity of 84%, with an excellent negative predictive value (NPV) of 0.93 and a specificity of 89%, and with a positive predictive value (PPV) of 0.79 in detecting NSCLC.12–16
PET/CT Fusion Study
CT provides excellent morphologic information but has significant limitations in differentiating between benign and malignant lesions either in an organ or in lymph nodes. PET using FDG provides excellent metabolic information of the tumoral lesions in a whole-body study and improves the rate of detection of mediastinal lymph node metastases and extrathoracic metastases when compared with CT. Antoch and colleagues studied 27 patients with NSCLC who underwent staging with a combined PET and CT scans. When compared with histopathologic results, the overall tumor stage was correctly classified as 0 to IV with CT scan in 19 patients (70.3%), with PET in 20 patients (74%), and with PET/CT in 26 patients (96.2%). PET/CT findings, when compared with PET findings, led to a treatment change in 4 patients (15%) and when compared with CT findings led to a treatment change in 5 patients (19%).17
Studies report better results in detecting T-factor (tumor size and location) with PET/CT in comparison with PET alone. This superiority is because of the CT component of the examination resulting in a more precise evaluation of the chest wall and mediastinal infiltration in some patients, as well as a better differentiation between tumor and accompanying inflammation and atelectasis in others on the integrated images.
Results for the N-factor (status of nodal involvement) give a similar picture, as PET/CT superior to PET alone. Accurate anatomic correlations allow an exact location of involved nodes, and thus, better distinction can be made between N1, N2, and N3 disease. One should be careful with false-negative PET findings in particular situations: minimal FDG avidity of the primary tumor and presence of a central tumor or of centrally located N1 nodes, both of which may obscure nearby existing mediastinal lymph node metastasis. False-positive findings are because of the fact that FDG uptake is not tumor specific and can be found in all active tissues with high glucose metabolism, in particular with inflammation and infection. Therefore, clinically relevant FDG avid mediastinal lymph nodes should always be examined with the most appropriate tissue sampling technique. De Wever and colleagues compared PET/CT with surgical staging in 50 patients with lung mass. Integrated PET/CT was the most accurate imaging technique in the assessment of the TNM status and predicted correctly the T, N, and M status in, respectively, 86%, 80%, 98%, and 70% versus 68%, 66%, 88%, and 46% with CT alone, 46%, 70%, 96%, and 30% with PET alone. T status and N status were overstaged, respectively, in 8% and 16% with integrated PET/CT, in 20% and 28% with CT, in 16% and 20% with PET, and in 12% and 20% with visually correlated PET/CT and under-staged in 6% and 4% with integrated PET/CT versus 12% and 6% with CT, 38% and 10% with PET.18 Because of the false-positive results, positive PET findings should be verified histologically by lymph node sampling. Therefore, old adage “tissue is the issue” still valid and confirmation is needed. Several methods are available to obtain tissue samples including: conventional bronchoscopy with TBNA, EBUS-TBNA, endoscopic ultrasound-fine-needle aspiration (EUS-FNA), and mediastinoscopy.
Although noninvasive methods can provide some information, when necessary, invasive methods may provide accurate cytologic confirmation of the abnormal imaging findings. Invasive staging techniques are divided into surgical and nonsurgical procedures. Although the surgical procedures are mediastinoscopy, anterior mediastinostomy (Chamberlain procedure), and video-assisted thoracoscopy, nonsurgical procedures include transthoracic needle aspiration, cTBNA, esophageal EUS-FNA, and EBUS-TBNA.
CT-guided Transthoracic Needle Aspiration
Conventional CT scan-guided needle biopsy is an established method for the diagnosis of pulmonary lesions. Although most lung biopsies described in earlier reports were performed using FNA, cutting needles are more commonly used today. CT fluoroscopy for interventional procedures was first introduced in 1993.19 In a large study of 1000 patients who underwent CT fluoroscopy-guided lung biopsies with 20-G coaxial cutting needle, the diagnostic accuracy and the frequency of pneumothorax were evaluated. Overall diagnostic accuracy, pneumothorax rate, and chest tube insertion rates were 77.2%, 28.4%, and 2.5%, respectively. Diagnostic accuracy was significantly affected by the length of the needle pass and lesion size (P<0.05). For diagnostic accuracy, needle pass lengths of 40 mm or less and lesion sizes >10 mm were significantly more accurate when compared with other factors (P<0.05). Pneumothorax risk was affected by the needle size, depth of the lesion, and the number of needle passes.20
Another study compared 2 different CT-guided transthoracic needle biopsy techniques: FNA (20 to 22 G) (group A) and an automated biopsy device (19.5-G coaxial biopsy device) (group B). For a diagnosis of malignancy, a statistically significant difference in sensitivity was found (82.7% vs. 97.4%) between the results obtained with the automated biopsy device and the results obtained with the FNA, respectively. The false-negative rate for diagnosing malignancy was significantly higher (P<0.005) in the FNA group (17%) than in biopsy device (2.6%). There was no statistically significant difference in diagnosing benign diseases between the 2 techniques (44% vs. 26%). There was no difference between the 2 groups concerning the pneumothorax rate, which was 20% in group A and 15% in group B, or hemoptysis rate.21 Hiraki and colleagues determined the diagnostic yield of CT fluoroscopy-guided lung biopsies performed with 20-G coaxial cutting needles for 1000 lesions in 901 patients. The biopsy results were nondiagnostic in 0.6% of the lesions (6 of 1000 lesions). The sensitivity and specificity for the diagnosis of malignancy were 94.2% (741 of 787 lesions) and 99.1% (211 of 213 lesions), respectively; diagnostic accuracy was 95.2% (952 of 1000 lesions). For lesions measuring ≤1.0 cm, the diagnostic accuracy was 92.7% (140 of 151 lesions). Diagnostic failure was encountered in the acquisition of 2 or fewer specimens, lesions in the lower lobe, malignant lesions, and lesions measuring ≤1.0 cm or ≥3.1.22 A study of 28 patients with ground-glass opacification (GGO) lesions evaluated with CT fluoroscopy-guided needle aspiration biopsy. Only 3 biopsy results (10%) were nondiagnostic, whereas others provided either a diagnosis of malignancy in 17 (61%) or benign etiology in 11 (39%). Although the diagnostic accuracy was not significantly different according to the length of the needle path, mixed GGO lesions had higher diagnostic accuracy compared with pure GGO lesions. Pneumothorax and hemoptysis were seen in 18% and 11% of the patients, respectively.23
TBNA, described in 1949, is a safe and cost-effective procedure for staging.24 cTBNA is a blind procedure and the yield varies widely ranging from 20% to 90% depending upon operators’ experience and the location of the lymph node.25–27
Although EBUS-TBNA cannot visualize the aortopulmonary window (stations 5 and 6) and posterior lymph nodes (stations 8 and 9), it has excellent sensitivity and specificity for diagnosing mediastinal lymph node involvement compared with both cTBNA and mediastinoscopy in randomized trials.28–30
Recently, bronchoscopy registries have been developed to collect data on both interventional and diagnostic bronchoscopy. The American College of Chest Physicians (ACCP) has implemented a web-based pilot project for multi-institutional databases, called as the ACCP Quality Improvement Registry, Evaluation, Education (AQuIRE) program.31 In a recent study, AQuIRE registry data were used to evaluate TBNA biopsies. In this prospective multicenter study, diagnostic yield of EBUS-TBNA varied among institutions. Overall, a specific diagnosis was made in 447 patients out of 891 (50.1%). The diagnostic yield was associated with annual hospital TBNA volume, smoking, >2 biopsy sites, lymph node size, and positive PET scan. High-volume hospitals, where general anesthesia was used more, sampled more and smaller nodes with a greater diagnostic yield rates.32
Two studies evaluated radiographically normal mediastinum in patients with known lung cancer using EBUS-TBNA. Seventeen percent of the 119 lymph nodes measuring 5 to 10 mm in size showed mediastinal metastasis.33 Another study revealed 9% prevalence of mediastinal metastasis by using EBUS-TBNA in lung cancer patients without enlarged lymph nodes on CT scan and no detectable activity by PET scan.34
EBUS-TBNA and EUS-FNA
A combination of EUS-FNA and EBUS-TBNA provides access to most of the mediastinum. EUS-FNA can detect the lymph nodes: 4 L, aortopulmonary window (station 5), lateral to the aorta (station 6), subcarinal (station 7), adjacent to the lower esophagus (station 8), and near the pulmonary ligament (station 9).35 EBUS-TBNA can sample all the lymph node stations that can be assessed by mediastinoscopy (stations 2, 3, 4, and 7) with addition of hilar lymph nodes (stations 10, 11, and 12). Therefore, a combination of EBUS-TBNA and EUS-FNA can potentially replace mediastinoscopy not only for staging and restaging purposes but also minimizing the complications that might be encountered during mediastinoscopy.36
Mediastinoscopy was first introduced in 1959 and has been considered as gold standard tool for staging the mediastinum with a high specificity and sensitivity.37 Although mediastinoscopy is still considered as gold standard for staging, its cost, requirement of general anesthesia, and possible associated morbidity and mortality limit its use.38–40
In addition, posterior subcarinal, pulmonary ligament, and aortopulmonary window (station 5) lymph nodes are not usually accessible with standard cervical mediastinoscopy. The lymph node stations 2, 3, 4, and 7 can be easily reached. One study found 57% of false-negative lymph nodes (5.5%, 56 of 1019) because of metastasis in lymph nodes not normally biopsied during cervical mediastinoscopy (stations 5, 6, 8, or 9).41 Mediastinoscopy is underutilized. A survey-based study conducted by Little et al42 found that only 27% of 11,668 patients underwent mediastinoscopy for preoperative mediastinal staging.
Anterior Thoracotomy (Chamberlain Procedure) and Video-assisted Thoracoscopic Surgery (VATS)
Left upper lobe tumors are known to metastasize predominantly to the aortopulmonary window and para-aortic lymph nodes (levels 5 and 6). These lymph node stations cannot be reached by cervical mediastinoscopy or left thoracoscopy. The anterior thoracotomy procedure is more demanding and has a higher morbidity compared with the cervical approach. When a cervical mediastinoscopy is negative, Chamberlain procedure may be performed in patients with a high suspicion of involvement in level 5 or 6 (enlarged or FDG avid lymph nodes).
VATS can be a useful add-on to cervical mediastinoscopy, as it allows one to reach subcarinal nodes or inferior mediastinal nodes on the right side and para-aortic nodes or inferior mediastinal nodes on the left side. For VATS, the false-negative rate was 15% both in enlarged and normal-sized nodes with a sensitivity varying widely from 37% to 100%.8 The advantage over a left anterior mediastinotomy is that anatomic landmarks such as the vagal and phrenic nerves are more easily recognized. There are no recent series on the use of VATS for staging of mediastinal nodes, which probably reflects the fact that less invasive staging methods such as EUS-FNA have become the preferred technique for staging of inferior mediastinal lymph nodes.
EBUS-TBNA VERSUS RADIOGRAPHIC STAGING
Recent studies have compared EBUS-TBNA with radiologic staging (CT and PET scans) in preoperative staging and studied the role of EBUS-TBNA in patients with a normal mediastinum on the basis of radiologic staging.34
EBUS-TBNA was superior to CT and PET in sensitivity (92.3% vs. 76.9% and 80%, respectively), specificity (100% vs. 55% and 70%, respectively), and accuracy (98% vs. 61% and 73%, respectively) in a prospective study of 102 patients with potentially operable lung cancer.15
Another prospective study of 117 patients with enlarged mediastinal nodes measuring 5 to 20 mm on PET/CT revealed similar superiority of EBUS-TBNA in sensitivity (90% vs. 70%, respectively), specificity (100% vs. 60%, respectively), and accuracy (97% vs. 62%, respectively).43
In terms of superiority, EBUS-TBNA in different cell types of lung cancer favors adenocarcinoma probably related to the higher rate of mediastinal and lower PET-SUV values.44,45 However, no clear superiority for either technique was found with squamous cell carcinoma. Herth and colleagues looked at 97 patients with NSCLCs with normal mediastinum by means of imaging techniques (CT and PET). Eight patients (8.2%) had mediastinal lymph node metastasis with EBUS-TBNA.34 Therefore, EBUS-TBNA may have a role in preoperative staging even in stage I disease, and it has superior diagnostic sensitivity compared with radiologic staging, as well as providing a tissue diagnosis.
EBUS-TBNA AND EUS-FNA VERSUS MEDIASTINOSCOPY
EBUS-TBNA and EUS-FNA have an equivalent sensitivity to mediastinoscopy in meta-analysis.8,46–48 In patients selected with positive CT or PET scans, sensitivity of EBUS-TBNA is found to be higher compared with unselected patients (94% vs. 76%, respectively).46 A recent prospective crossover trial of 66 patients compared EBUS-TBNA with mediastinoscopy in patients with suspected NSCLC and found that the disease prevalence was high at 89% and the diagnostic yield was favoring EBUS-TBNA (91% vs. 78%). The sensitivities and NPVs were also in favor of EBUS-TBNA (87% and 78% vs. 68% and 59%, respectively). However, there were no significant differences in determining N status (93% vs. 82%).28
Another study enrolled patients with NSCLC who subsequently underwent extensive surgical mediastinal staging if EBUS-TBNA was negative. A diagnostic sensitivity, specificity, accuracy, PPV, and NPV of EBUS-TBNA were 89.0%, 100%, 92.9%, 100%, and 83.5%, respectively. In patients with negative EBUS-TBNA, metastatic nodes were diagnosed with mediastinoscopy in 12 patients (5.3%) in stations accessible with EBUS-TBNA. The reason for false-negative results was mainly because of small metastasis.49 A prospective study of 109 patients with PET-positive nodes detected sensitivity and accuracy of EBUS-TBNA as 91% and 92%, respectively, with an NPV of 6%. Seven of 19 surgical biopsies in EBUS-TBNA–negative patients were positive for malignancy.50 The available data suggest EBUS-TBNA reduces the number of mediastinoscopy. The patients with a high pretest probability of lung cancer with negative EBUS-TBNA should undergo mediastinoscopy.
The ACCP’s guidelines advocate EBUS-TBNA instead of mediastinoscopy to stage the mediastinum with discrete N2 or N3 disease or bulky mediastinal disease. Mediastinoscopy is suggested to be used for situations where medical treatment is intended.51
EBUS-TBNA is more advantageous to mediastinoscopy being a safe and less invasive technique as mediastinoscopy has a 1.4% to 2.3% risk of complications and 0.5% risk of major complications including death.52 Because EBUS-TBNA provides only a tissue core and the volume of tissue is less than mediastinoscopy, it may result in false-negative sampling, particularly in lymphoma.
In a study of 159 patients with confirmed or suspected NSCLC, EBUS-TBNA followed by mediastinoscopy was performed in all patients. EBUS and mediastinoscopy sampled an average of 3 and 4 stations for patients, respectively. The prevalence of N2/N3 disease was 35% (53 of 153) with an excellent agreement between EBUS and mediastinoscopy (95% confidence interval, 0.7-0.9). The sensitivity, NPV, and diagnostic accuracy for mediastinal node staging for EBUS and mediastinoscopy were 81%, 91%, and 93%, and 79%, 90%, and 93%, respectively. It should be noted that the procedures were performed under general anesthesia with on-site pathologist present in all patients, increasing the diagnostic yield.53
EBUS-TBNA VERSUS cTBNA
EBUS-TBNA is superior to cTBNA. In a recent systematic review, the pooled sensitivity for cTBNA was 76%.37 In contrast, EBUS-TBNA obtained a sensitivity of 95% in a prospective cohort of 108 patients with suspected NSCLC, with a 9% NPV and 96% accuracy in diagnosis. In a comparative trial, EBUS-TBNA was superior to cTBNA in stations other than station 7 (84% vs. 58% positive) compared with station 7 (86% vs. 74% positive).30 EBUS-TBNA has a superior yield to cTBNA at stations other than station 7.2,3,4,10,11
EBUS Characteristics of Lymph Nodes
The most widely accepted criterion to define abnormal lymph node suspicious for malignancy is a short axis diameter >1 cm and increased PET activity.18
However, no size can reliably predict malignancy. Nodes <1 cm on CT scan of the chest can have positive histology on mediastinoscopy. Moreover, PET scanning has a false-negative rate of 35.6%.54 The need to sample lymph nodes is also well documented despite radiographic negativity. Herth et al33 demonstrated that in 19 of 100 patients evaluated with CT scan, normal (<1 cm) lymph nodes were positive for malignancy by EBUS. The same author also studied PET scan and CT scan of normal lymph nodes in 100 patients and 8 of them were upstaged by EBUS.34
EBUS and EUS had gained acceptance as dependable procedures to stage lung cancer with comparable accuracy to surgical methods. Direct visualization of the lymph nodes with ultrasound may offer information regarding nodal characteristics of malignancy. Ultrasound characteristics of metastatic lymph node using EUS have been described earlier.55,56 Similarly, a recent prospective study tried to describe the characteristics of malignant lymph nodes using EBUS in 100 patients. In this study, an increased chance of being malignant was found if the lymph nodes were larger and round or oval shaped.57 These findings were found to be similar to another retrospective study in which in patients with known lung cancer, lymph node >1 cm in size, round shape, heterogenous echogenicity, and coagulation necrosis sign (hypoechoic area within the lymph node that has no blood flow) suggested malignancy.58
In a recent Spanish study of 161 patients, it was reported that a short axis diameter >2 cm had a 90% probability of malignancy, and a spherical shape with a short to long axis ratio of 1 had a 55% probability of malignancy.59
EBUS-Miniforceps Biopsy (EBUS-MFB)
EBUS-MFB is a technique combining the guidance of EBUS with forceps biopsy. Earlier this technique has been used for subcarinal lymph nodes through a small incision in the airway mucosa60 and with fluoroscopic guidance.61
Herth et al62 have previously published the use of EBUS guidance of MFB for subcarinal lymph nodes, demonstrating a higher yield compared with EBUS-TBNA for sarcoidosis and lymphoma for lesions >25 mm in size.
In a recent prospective study, patients with mediastinal or hilar lymphadenomegaly and a low likelihood of non–small cell lung carcinoma enrolled and underwent EBUS-TBNA and EBUS-MFB (1-mm miniforceps) of mediastinal and hilar abnormalities. A total of 50 patients and 74 lymph node stations tested. The overall diagnostic yield of EBUS-TBNA and EBUS-MFB were 81% (60 of 74) and 91% (67 of 74), respectively (P=0.09). When both techniques are combined, the overall diagnostic yield was higher at 97% (72 of 74) (P<0.01), attributed to the collection of more specimens. There were no complications due to additional biopsies with miniforceps. For nonmalignant disease, the diagnostic yield of EBUS-TBNA and EBUS-MFB was the same at 88% (29 of 33 cases) but resulted in a diagnosis in 48 of 49 cases (P=0.025) when both techniques were combined. However, for malignant disease, EBUS-TBNA was diagnostic in 68% of patients (17 of 25) and EBUS-MFB was diagnostic in 96% of patients (24 of 25). For small cell lung carcinoma, TBNA was diagnostic in 75% (6 of 8) and MFB in 100% (8 of 8). For NSCLC, TBNA was diagnostic in 80% (4 of 5) and MFB in 100% (5 of 5). For lymphoma, MFB was diagnostic in 100% (4 of 4) and none could be diagnosed by TBNA. This technique would be a good addition especially in those lymphomas in which sarcoiodis is suspected.63
In a recent pilot study, an ultrasound guided-transbronchial needle forceps (EBUS-TBNF) that has characteristics of a needle (beveled tip for penetrating through the bronchial wall) with forceps (2 separated jaws) was used through the working channel of the EBUS scope for patients with enlarged and PET avid lymph nodes. Tissue for histologic diagnosis was obtained from 45 of 50 patients and specific diagnosis was established in 43 patients (86%), either malignant or benign. There were no clinically significant complications reported. TBNF is not FDA approved yet.64
Needle Size and Number of Passes
The number of passes required at each lymph node station to optimize diagnostic sensitivity has been studied. Lee and colleagues found sample adequacy 90.1% for the first pass and 100% for the third pass, without having the benefit of rapid on-site evaluation (ROSE). The sensitivity did not increase with subsequent passes. They concluded that 3 passes was optimal.65 A recent study by Trisolini et al66 found that having ROSE available can decrease the number of biopsies needed without affecting the accuracy.
A 22-G needle is typically used for EBUS-TBNA. Efficacy of a larger needle (21 G) was compared on the same lesion. Forty lymph nodes (33 mediastinal and 7 hilar) at different levels (levels 2, 4, 7, and 11), 2 lung tumors, and 3 mediastinal tumors from 33 patients were obtained by using 22-G needle first, followed by a 21-G needle, each passing 10 to 15 times in the node. Diagnostic yield was the same but quantity of cancer cells had a better-preserved histologic structure with 21-G needle.67
EBUS With Rose
Immediate cytologic examination, known as ROSE, offers a theoretical advantage because the bronchoscopist can plan the procedure on the basis of the results. ROSE is a cost-effective technique and may potentially improve the diagnostic yield of transbronchial aspirates while decreasing unnecessary diagnostic attempts and potential complications of transbronchial biopsies.68,69
ROSE by a cytopathologist is an important component for EBUS-TBNA. ROSE warrants the accuracy of TBNA but does not necessarily improve its diagnostic yield. In a recent retrospective study of 294 EBUS-TBNA specimens, the final cytology for malignant or benign diagnoses did not significantly differ with or without ROSE.70 Another study compared diagnostic value of ROSE in EBUS-TBNA and cTBNA specimens. Although there was no statistical benefit in diagnosis of EBUS-TBNA specimens, using ROSE in cTBNA significantly improved diagnostic yield.71 The main expectation is to confirm the specimens being representation of the targeted lesion and adequacy of material to make a final diagnosis. Because the endoscopic procedure can be interrupted as soon as the cytopathologist confirms that the sampling is adequate, ROSE minimizes the duration and further biopsies and its associated risks. It also provides information whether more tissue is required for testing, such as flow cytometry in case of lymphoma and immunohistochemical and/or molecular analysis for adenocarcinoma.
Lymph Node Sample Handling
Processing the tissue sample obtained through EBUS-TBNA is not only important to make a definitive diagnosis but also important to provide further cellular and molecular information for targeted treatment options. As an example, molecular testing to determine gene alterations or mutations allows specific treatments in adenocarcinoma such as EGFR tyrosine kinase inhibitors.72,73
Therefore, TBNA samples should be handled by an on-site cytopathologist to avoid further need of other interventions. In a recent study, multidirectional analysis of EBUS-TBNA samples has been described. In this single-center experience, cytologic smears are prepared for both air-dry smear and 95% ethanol-fixed smear (for Giemsa, Diff-Quick and Papanicolaou), aspiration kept in saline (for microbiology, cell block, flow cytometry, and DNA/RNA analyses), and aspiration kept in 10% formalin (for histology, immunohistochemistry, fluorescence in situ hybridization, and DNA/RNA).74
EBUS in Benign Diseases and Lymphoma
EBUS-TBNA can be useful to diagnose benign diseases such as sarcoidosis and tuberculosis. Recent case series demonstrated diagnostic yield of EBUS-TBNA as 78% in sarcoidosis.75 Other studies reported higher sensitivity (85% to 93%) when patients had a lymph node >1 cm in size and had a CT scan before EBUS-TBNA.76–78
A recent study of 75 patients with subcarinal lesions showed that 1.15-mm MFB (TBNA-MFB) were superior to both 22- and 19-G TBNA needle biopsies (sensitivities 88% vs. 36% and 49%, respectively).62
Although this is not the standard practice, EBUS-TBNA can provide diagnosis of lymphoma. It should be noted that sampling requires higher volume of tissue and specific handling. Therefore, clinical suspicion before performing the EBUS-TBNA is important. Having ROSE available will also prompt bronchoscopists to obtain more tissue if initially collected specimens are suggestive of lymphoma. Diagnostic yield has been reported as 60% to 90% by EBUS in patients with lymphoma.62,79,80
EBUS TBNA With or Without Aspiration
Application of aspiration (suction) during lymph node passes in EBUS-TBNA procedure is the current practice. Only 1 study addressed whether suctioning has greater diagnostic value or not. In this single-blinded prospective randomized trial, EBUS-TBNA (with suction) and EBUS-guided transbronchial capillary sampling (without suction) were compared in a total of 115 patients and 192 lymph nodes. There was no significant difference in adequacy of specimens (88% vs. 88%, respectively), overall diagnosis (36% vs. 34%, respectively), and diagnosis of malignancy (28% vs. 26%) regardless to the size of the lymph node. Therefore, authors suggested no evidence of benefit in the practice of applying suction to EBUS-guided biopsies.81
1. Herth FJF, Krasnik M, Khan N, et al. Combined endoscopic-endobronchial ultrasound guided fine needle aspiration of mediastinal lymph nodes through a single bronchoscope in 150 patients with suspected lung cancer. Chest. 2012;138:790–794
2. Hwangbo B, Lee GK, Lee HS, et al. Transbronchial and transesophageal fine-needle aspiration using an ultrasound bronchoscope in mediastinal staging of potentially operable lung cancer. Chest. 2012;138:795–802
3. . British Thoracic Society guidelines on diagnostic flexible bronchoscopy. Thorax. 2001;56(suppl 1):11–21
4. Agli LL, Trisolini R, Burzi M, et al. Mediastinal hematoma following transbronchial needle aspiration. Chest. 2002;122:1106–1107
5. Kucera RF, Wolfe GK, Perry ME. Hemomediastinum after transbronchial needle aspiration. Chest. 1986;90:466
6. Haas AR. Infectious complications from full extension endobronchial ultrasound transbronchial needle aspiration. Eur Respir J. 2009;33:935–938
7. Dillemans B, Deneffe G, Verschakelen J, et al. Value of computed tomography and mediastinoscopy in preoperative evaluation of mediastinal nodes in non-small cell lung cancer. A study of 569 patients. Eur J Cardiothorac Surg. 1994;8:37–42
8. Detterbeck FC, Jantz MA, Wallace M, et al. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd ed). Chest. 2007;132(suppl 3):202S–220S
9. Wahl RL, Quint LE, Greenough RL, et al. Staging of mediastinal non-small cell lung cancer with FDG PET, CT, and fusion images: preliminary prospective evaluation. Radiology. 1994;191:371–377
10. Bonomo L, Ciccotosto C, Guidotti A, et al. Lung cancer staging: the role of computed tomography and magnetic resonance imaging. Eur J Radiol. 1996;23:35–45
11. Prenzel KL, Mönig SP, Sinning JM, et al. Lymph node size and metastatic infiltration in non-small cell lung cancer. Chest. 2003;123:463–467
12. Berlangieri SU, Scott AM. Metabolic staging of lung cancer. N Engl J Med. 2000;343:290–292
13. Silvestri GA, Tanoue LT, Margolis ML, et al. The noninvasive staging of non-small cell lung cancer: the guidelines. Chest. 2003;123:147s–156s
14. Toloza EM, Harpole L, McCrory DC. Noninvasive staging of nonsmall cell lung cancer: a review of the current evidence. Chest. 2003;123:137s–146s
15. 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;130:710–718
16. Silvestri GA, Gould MK, Margolis ML, et al. Non invasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd ed). Chest. 2007;132:178S–201S
17. Antoch G, Stattaus J, Nemat AT, et al. Non-small lung cancer: dual modality PET/CT in preoperative staging. Radiology. 2003;229:526–533
18. De Wever W, Ceyssens S, Mortelmans L, et al. Additional value of PET-CT in the staging of lung cancer: comparison with CT alone, PET alone and visual correlation of PET and CT. Eur Radiol. 2007;17:23–32
19. Katada K, Kato R, Anno H, et al. Guidance with real-time CT fluoroscopy: early clinical experience. Radiology. 1996;200:851–856
20. Ohno Y, Hatabu H, Takenaka D, et al. CT-guided transthoracic needle aspiration biopsy of small (<20 mm) solitary pulmonary nodules. Am J Radiol. 2003;180:1665–1669
21. Laurent F, Latrabe V, Vergier B, et al. Percutaneous CT-guided biopsy of the lung: comparison between aspiration and automated cutting needles using a coaxial technique. Cardiovasc Intervent Radiol. 2000;23:266–272
22. Hiraki T, Mimura H, Gobara H, et al. CT fluoroscopy guided biopsy of 1000 pulmonary lesions performed with 20-gauge coaxial cutting needles; diagnostic yield and risk factors for diagnostic failure. Chest. 2009;136:1612–1617
23. Hur J, Lee HJ, Nam JE, et al. Diagnostic accuracy of CT-fluoroscopy guided needle aspiration biopsy of ground-glass opacity pulmonary lesions. Am J Radiol. 2009;192:629–634
24. Schieppati E. Mediastinal puncturing through the trachea. Rev As Med Argent. 1949;663:497–499
25. Mehta AC, Kavuru MS, Meeker DP, et al. Transbronchial needle aspiration for histology specimens. Chest. 1989;96:1228–1232
26. Gasparini S. Evolving role of interventional pulmonology in the interdisciplinary approach to the staging and management of lung cancer: bronchoscopic mediastinal staging of lung cancer. Clin Lung Cancer. 2006;8:110–115
27. Harrow EM, Abi-Saleh W, Blum J, et al. The utility of transbronchial needle aspiration in the staging of bronchogenic carcinoma. Am J Respir Crit Care Med. 2000;161:601–607
28. Ernst A, Anantham D, Eberhardt R, et al. Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy. J Thorac Oncol. 2008;3:577–582
29. Eberhardt R, Anantham D, Ernst A, et al. Multimodality bronchoscopic diagnosis of peripheral lung lesions: a randomized controlled trial. Am J Respir Crit Care Med. 2007;176:36–41
30. Herth F, Becker HD, Ernst A. Conventional vs endobronchial ultrasound-guided transbronchial needle aspiration: a randomized trial. Chest. 2004;125:322–325
32. Ost D, Ernst A, Lei X, et al. Diagnostic yield of endobronchial ultrasound guided transbronchial needle aspiration: results of the AQuIRE registry. Chest. 2011;140:1557–1566
33. 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;28:910–914
34. Herth FJ, Eberhardt R, Krasnik M, et al. Endobronchial ultrasound guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer. Chest. 2008;133:887–891
35. 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;28:1264–1275
36. Ernst A, Feller-Kopman D, Herth FJ. Endobronchial ultrasound in the diagnosis and staging of lung cancer and other thoracic tumors. Semin Thorac Cardiovasc Surg. 2007;19:201–205
37. Toloza EM, Harpole L, Detterbeck F, et al. Invasive staging of non-small cell lung cancer: a review of the current evidence. Chest. 2003;123:157S–166S
38. 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;32:1–8
39. 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;84:1059–1065
40. Yasufuku K, Fujisawa T. Staging and diagnosis of non-small cell lung cancer: invasive modalities. Respirology. 2007;12:173–183
41. Lemaire A, Nikolic I, Petersen T, et al. Nine-year single center experience with cervical mediastinoscopy: complications and false negative rate. Ann Thorac Surg. 2006;82:1185–1189
42. Little AG, Rusch VW, Bonner JA, et al. Patterns of surgical care of lung cancer patients. Ann Thorac Surg. 2005;80:2051–2056
43. Hwangbo B, Kim SK, Lee HS, et al. Application of endobronchial ultrasound-guided transbronchial needle aspiration following integrated PET/CT in mediastinal staging of potentially operable non-small cell lung cancer. Chest. 2009;135:1280–1287
44. Fibla JJ, Molins L, Simon C, et al. The yield of mediastinoscopy with respect to lymph node size, cell type, and the location of the primary tumor. J Thorac Oncol. 2006;1:430–433
45. Vesselle H, Salskov A, Turcotte E, et al. Relationship between non-small cell lung cancer FDG uptake at PET, tumor histology, and Ki-67 proliferation index. J Thorac Oncol. 2008;3:971–978
46. 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;45:1389–1396
47. Adams K, Shah P, Edmonds L, et al. Endobronchial ultrasound and transbronchial needle aspiration biopsy for mediastinal staging in patients with lung cancer: systematic review and meta-analysis. Thorax. 2009;64:757–762
48. Varela-Lema L, Fernandez-Villar A, Ruano-Ravina A. Effectiveness and safety of endobronchial ultrasound-transbronchial needle aspiration: a systematic review. Eur Respir J. 2009;33:1156–1164
49. Szlubowski A, Kuzdzal J, Kolodziej M, et al. Endobronchial ultrasound-guided needle aspiration in the non-small cell lung cancer staging. Eur J Cardiothorac Surg. 2009;35:332–335
50. Rintoul RC, Tournoy KG, El Daly H, et al. EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes-an international multi-centre experience. J Thorac Oncol. 2009;4:44–48
51. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol. 2007;2:706–714
52. Cybulsky IJ, Bennett WF. Mediastinoscopy as a routine outpatient procedure. Ann Thorac Surg. 1994;58:176–178
53. Yasufuku K, Pierre A, Darling G, et al. A prospective controlled trial of ultrasound guided trans-bronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg. 2011;142:1393–1400
54. Gonzalez-Stawinski GV, Lemaire A, Merchant F, et al. A comparative analysis of positron emission tomography and mediastinoscopy in staging non-small cell lung cancer. J Thorac Cardiovasc Surg. 2003;126:1900–1905
55. Bhutani MS, Hawes RH, Hoffman BJ. A comparison of the accuracy of echo features during endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration for diagnosis of malignant lymph node invasion. Gastrointest Endosc. 1997;45:474–479
56. Catalano MF, Sivak MV Jr, Rice T, et al. Endosonographic features predictive of lymph node metastasis. Gastrointest Endosc. 1994;40:442–446
57. Wang Memoli JS, El-Bayoumi E, Pastis NJ, et al. Using endobronchial ultrasounds features to predict lymph node metastasis in patients with lung cancer. Chest. 2011;140:1550–1556
58. Fujiwara T, Yasufuku K, Nakajima T, et al. The utility of sonographic features during endobronchial ultrasound-guided transbronchial needle aspiration for lymph node staging in patients with lung cancer: a standard endobronchial ultrasound image classification system. Chest. 2010;138:641–647
59. Garcia-Olive I, Monso E, Andreo F, et al. Sensitivity of linear endobronchial ultrasonography and guided transbronchial needle aspiration for the identification of nodal metastasis in lung cancer staging. Ultrasound Med Biol. 2009;35:1271–1277
60. Prakash UB. A better bronchoscopic technique to obtain diagnostic tissue from the mediastinal lymph nodes. J Bronchol. 2005;12:1–2
61. Oki M, Saka H, Sako C. Bronchoscopic miniforceps biopsy for mediastinal nodes. J Bronchol. 2004;11:150–153
62. Herth FJ, Morgan RK, Eberhardt R, et al. Endobronchial ultrasound-guided miniforceps biopsy in the biopsy of subcarinal masses in patients with a low likelihood of non-small cell lung cancer. Ann Thorac Surg. 2008;85:1874–1878
63. Chrissian A, Misselhorn D, Chen A, et al. guided miniforceps biopsy of mediastinal and hilar lesions. Ann Thorac Surg. 2011;92:284–289
64. Herth FJF, Schuler H, Gompelmann D, et al. Endobronchial ultrasound-guided lymph node biopsy with transbronchial needle forceps: a pilot study. Eur Respir J. 2012;39:373–377
65. Lee HS, Lee GK, Lee HS, et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal staging of non-small cell lung cancer: how many aspirations per target lymph node station? Chest. 2008;134:368–374
66. Trisolini R, Cancellieri A, Tinelli C, et al. Rapid on-site evaluation of transbronchial aspirates in the diagnosis of hilar and mediastinal adenopathy: a randomized trial. Chest. 2011;139:395–401
67. Nakajima T, Yasufuku K, Takahashi R, et al. Comparison of 21-gauge and 22-gauge aspiration needle during endobronchial ultrasound-guided transbronchial needle aspiration. Respirology. 2011;16:90–94
68. Layfield LJ, Bentz JS, Gopez EV. Immediate on-site interpretation of fine-needle aspiration smears: accost and compensation analysis. Cancer Cytopathol. 2001;93:319–322
69. Boyan LCW. On-site cytopathological analysis of bronchoscopic needle aspiration. J Bronchol. 2003;10:152–154
70. Griffin AC, Schwartz LE, Baloch ZW. Utility of on-site evaluation of endobronchial ultrasound guided transbronchial needle aspiration specimens. Cytojournal. 2011;8:20 [Abstract]
71. Labib MM, Qureiyeh F, Zias N, et al. Comparison of conventional transbronchial needle aspiration vs endobronchial ultrasound guided transbronchial needle aspiration with and without rapid onsite evaluation in a single center. Abstract. Chest. 2009;136:112S
72. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring muta-tions of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–128
73. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–957
74. Nakajima T, Yasufuku K. How I do it—optimal methodology for multidirectional analysis of endobronchial ultrasound-guided transbronchial needle aspiration samples. J Thorac Oncol. 2011;6:203–206
75. Medford AR, Agrawal S, Bennett JA. Sarcoidosis: technique to enable diagnosis. BMJ. 2009;339:766–767
76. Garwood S, Judson MA, Silvestri G, et al. Endobronchial ultrasound for the diagnosis of pulmonary sarcoidosis. Chest. 2007;132:1298–1304
77. Wong M, Yasufuku K, Nakajima T, et al. Endobronchial ultrasound: new insight for the diagnosis of sarcoidosis. Eur Respir J. 2007;29:1182–1186
78. Oki M, Sako H, Kitagawa C, et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration is useful for diagnosing sarcoidosis. Respirology. 2007;12:863–868
79. Kennedy MP, Jimenez CA, Bruzzi JF, et al. Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of lymphoma. Thorax. 2008;63:360–365
80. Steinfort DP, Conron M, Tsui A, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for the evaluation of suspected lymphoma. J Thorac Oncol. 2010;5:804–809
81. Casal RF, Staerkel GA, Ost D, et al. Randomized clinical trial of endobronchial ultrasound new biopsy with and without aspiration. Chest. 2012;142:568–573
© 2013 Lippincott Williams & Wilkins, Inc.