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October - December 2007: 
Volume 20, Issue 4

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Endobronchial ultrasonography: practical aspects and clinical applications
Abstract
SUMMARY. Endobronchial ultrasonography (EBUS) is a major advance in bronchoscopy. Substantial scientific evidence has confirmed its usefulness in the diagnosis and staging of lung cancer, as well as in other clinical conditions. It is of growing importance that endoscopists can perform this imaging technique and interpret its findings accurately in order to optimize the diagnosis and treatment of patients. This article provides a practical and comprehensive review of the technique and its main indications. Pneumon 2007; 20(4):342–355
Full text
Introduction

Bronchoscopy has become the mainstay of many diagnoses, especially that of bronchial cancer. Unfortunately, only a limited area of visibility can be reached within the airways using conventional bronchoscopy, and much relevant information for lung cancer diagnosis and staging thus cannot be directly assessed. A window of opportunity was opened with the introduction of endobronchial ultrasonography (EBUS) since this technique permits the acquisition of images and crucial information beyond the lumen and mucosa of the tracheobronchial tree, and assessment of extraluminal structures – intramural, paratracheal, parabronchial and mediastinal – in greater detail compared to other imaging methods, and specifically conventional computed tomography (CT) scan.

EBUS is an imaging technique that combines features of endoscopy and ultrasonography (US). It represents one of the most important advances in bronchoscopy in recent years and substantial scientific evidence has confirmed its usefulness in a variety of clinical settings.

Apart from structural information about the airway wall and surrounding structures, central and peripheral lung histological specimens can be obtained under sonographic guidance, improving diagnostis and patient management.

EBUS is a valid instrument that has been gradually integrated into the investigation of many diseases. This review attempts to offer a practical guide to the bronchoscopist who wishes to start employing this technique. The main goals are to provide a comprehensive approach to EBUS technology, to describe its role in the diagnosis and staging of lung cancer and to present an overview of its application in other relevant clinical indications.

The development of EBUS

US has been known and used for many years. It can be generated by piezoelectric crystals that vibrate when compressed and decompressed by an alternating electric current. The same crystals can act as receivers of reflected sound waves. US imaging is achieved by emitting a pulse, which is to some extent reflected from a boundary between two different tissue structures and partially transmitted. The reflection echoes depend on the difference in impedance of the two tissues.

The medical applications of US were rapidly recognized and it has become a reliable and efficient imaging method for evaluating a wide range of clinical conditions and as a guide to diagnostic and therapeutic procedures.

Endoscopic ultrasonography (EUS) was initially developed in the 1980’s to improve sonographic imaging of the pancreas, but its use was quickly extended to the upper and lower gastrointestinal tract, the hepatobiliary and portal systems and the anal sphincter, with major applications in the diagnosis and staging of oesophageal, gastric and pancreaticobiliary cancer. EUS could not be used inside the tracheobronchial tree because of its calibre.

The necessity for EBUS arose from an important health care problem and a leading cause of death from malignant diseases worldwide, namely, lung cancer. Initially, the routine procedure for the diagnosis and staging of lung cancer relied on chest CT and conventional bronchoscopy, but both of these methods have certain drawbacks: CT scan has limited ability to image the tracheobronchial wall accurately and also it is an inaccurate predictor of mediastinal involvement. With bronchoscopy the processes outside the airway lumen can be assessed only by indirect signs.

The first description of the endobronchial application of US was made by Hurter and Hanrath in 19901,2. Various technical problems dictated that the feasibility of EBUS was delayed. US waves do not propagate easily in gaseous media. Consequently the air present in the airways and lung parenchyma can act as a barrier. This problem was solved with the interposition of a balloon catheter filled with a saline-water solution. There was a need to ensure and maintain proper ventilation of the airways, which is effected with miniature probes and instruments that can be rapidly expandable and retractable. The small size of the bronchoscopic working channel posed a significant constraint that led to the development of smaller probes and a bronchoscope with an incorporated US tip.

The solution of these problems has enabled the use of EBUS for visualizing the airway layers in detail, for identifying extraluminal anatomical and pathological structures and their relationships and for guiding diagnostic and therapeutic procedures. There is increasing evidence to show that it is possible to predict by the morphology of the US picture whether a lesion is benign or malignant.

EBUS technical equipment

Two different systems are currently available: the miniprobe and the transbronchial needle aspiration-endobronchial ultrasound endoscope (EBUS-TBNA) (Fig. 1).

Figure 1. EBUS systems. A) EBUS – TBNA bronchoscope with dedicated transbronchial needle. B) Tip of EBUS – TBNA bronchoscope with sectorial 7,5MHz transducer and 22G needle with internal sheath. C) Miniature radial probe. D) Miniprobe with water-filled balloon.

Miniaturized US catheter probes, usually called miniprobes, have been commercially available since 1999 (UM-BS20-26R; Olympus, Tokyo, Japan). They can be inserted through a working channel of dimensions ≥2.6mm, allowing their use with the standard bronchoscope. The tip of the probe contains a 360Ί rotating piezoelectric crystal inside a water-filled balloon. This balloon can be inflated in order to promote maximum contact with the airway wall, creating a favourable environment for US wave propagation and permitting a resolution of less than 1mm and a depth of penetration of 4-5cm with a standard frequency of 20MHz. When used in the distal airways direct contact can be made without the need for balloon inflation. It produces a 360Ί image perpendicular to the end of the probe, providing cross-sectional images of the tracheobronchial wall and adjacent structures. This radial probe must be handled gently and with due care because excessive rotations and/or angulations can damage and diminish its normal life expectancy of 50- 100 procedures. The miniprobe must be sheathed with a disposable plastic catheter in order to prevent infectious contamination.

The EBUS-TBNA bronchoscope has been available since 2004 (XBF-UC160F Olympus, Tokyo, Japan). It has proved to be a valid tool for lung cancer staging, which remains its most common indication. It has the ability to perform real-time transbronchial needle aspiration and biopsy. The outer diameter of the bronchoscope is 6.9 mm, with a working channel of 2mm. Its tip has a built-in convex transducer 10mm in length and 6.9mm diameter, and an US frequency of 7.5MHz, which scans parallel to the insertion direction of the bronchoscope with a penetration depth of 2-5cm. A pie-shaped image of the bronchial wall and mediastinal structures can be obtained by direct contact of the probe or by attaching a balloon to its tip and inflating it with water to provide better acoustic interface. The scanning direction is parallel to the longitudinal axis of the bronchoscope with a search angle of 50Ί, which enables complete sonographic monitoring of the needle.

The US image can be processed either by a specialized US scanner (EU-C60, Olympus, Tokyo, Japan) or through connection to other compatible sonographic equipment, and is visualized along with the conventional bronchoscopic image. As with any other US equipment, the images can be frozen and the size of the lesion measured in two dimensions by the placement of cursors. A colour Doppler imaging mode can be used to show the presence of blood flow and thus discriminate between solid and vascular structures.

EBUS technique

The radial probe is a versatile instrument that can be useful in diagnostic and therapeutic procedures. Investigation of the central airways creates difficulties related to the induction of apnoea by airway occlusion and increased US artifacts due to reduced contact with the wall. Both of these problems can be managed effectively by experienced endoscopists. When the probe is manoeuvred in the central airways a collaborative patient can tolerate a partially inflated balloon for a brief time period. Under general anaesthesia, with good pre-oxygenation, the balloon can be fully inflated for up to 3 minutes. When assessing central airways with the miniaturized probe the balloon tip should always be inflated. The maximum diameter of the inflated balloon is approximately 15-20 mm and when this is achieved the main bronchus, truncus intermedius and lobar bronchi can be fully obstructed, providing a 360Ί image. If the miniprobe system is used without a balloon-tipped catheter or the balloon cannot be completely inflated or if the airway lumen is not fully blocked, the sonographic image only represents a limited sectorial view, related to the sparse points of contact of the balloon with the tracheobronchial wall. Orientation and interpretation of these findings can be very difficult.

The precise location of the target lesion, its relation to the tracheobronchial tree and the exact puncturing point need to be noted. The probe is then removed from the working channel and samples are collected. Regarding the staging of mediastinal lymph nodes, the EBUS-TBNA scope has a clear advantage over the miniprobe, since it permits puncture under visual control.

When assessing peripheral airways and lung parenchyma with the miniaturized probe there is usually no need to inflate the balloon. Based on previous radiographic findings of a peripheral lesion, the miniprobe can be advanced into the different bronchi where the lesion is suspected to be located until direct visualization of the lesion is achieved. After identification of the lesion, the probe is removed from the bronchoscope biopsy channel and either a biopsy forceps or a brush is then introduced into the subsegmental bronchus of interest and histopathology specimens are collected. In some cases there is an advantage of combining the miniature probe with fluoroscopy for the assessment of peripheral lesions. The lesion can first be documented with the radial probe and its precise location assessed by fluoroscopy. Subsequently the biopsy forceps is advanced to the exact proximal position under fluoroscopic control. By guiding the forceps within rather than adjacent to the lesion bypass of the target is avoided and yield is improved.

EBUS-TBNA can be performed in conscious patients under local anaesthesia, but it is sometimes preferable that the procedure takes place under conscious sedation or general anaesthesia, both of which allow better tolerance and control, with less cough and movement during image collection and puncture, a procedure which typically takes between 15 and 30 minutes. A balloon filled with water can be mounted around the transducer for better US contact with the bronchial wall. The bronchoscope can be inserted nasally, but the oral route is preferable (with or without the use of an endobronchial tube) since it minimizes transducer damage. Conversely to the use of conventional bronchoscopy, direct transducer contact with the wall of the trachea or bronchus is promoted.

Mediastinal and hilar lymph nodes as small as 3mm can be precisely detected by EBUS, and when their shorter sonographic diameter is greater than 5mm they can be considered enlarged. The lymph nodes contralateral to the main lesion should be sampled first, followed by subcarinal and, lastly, ipsilateral lymph nodes. After identifying the enlarged lymph nodes and the surrounding structures the bronchoscope is placed in the correct position and a special 20-22 gauge needle is introduced through the working channel in a retracted position. When the plastic tip is in the field of view (superior right corner, approximately at 20Ί) the system is firmly secured. The correct position of the plastic tip is fundamental to the procedure, because if it is inside the working channel there is a high probability of damaging the bronchoscope, and if it is too exteriorized the contact with the tracheobronchial wall may be lost during puncture.

Subsequent TBNA is performed in the conventional way. The needle is advanced through the wall into the parabronchial or paratracheal tissue with a quick and firm jab. Due to the convex shape of the needle, during the puncture process the entire needle is visualized in the sector-shaped field. Once the needle is inside the lesion the inner sheath is removed, in this way avoiding specimen contamination, and suction can be applied with a 20ml syringe at the proximal end of the system. The needle is moved back and forth within the lesion for approximately 10-20 sec and then withdrawn. At this time suction is stopped and the collected material is smeared onto glass slides. The internal diameter of this needle sometimes allows sampling a core of tissue for histological examination and the inner sheath of the needle can be gently inserted to promote sample collection and remove possible blood clots that could diminish the success of future punctures.

Sonographic findings

Successful use of EBUS is linked to the operator’s experience and sound knowledge of the anatomic relations of the airways and mediastinal structures. After the US instrument establishes contact with the tracheobronchial tree and an image is obtained it is advisable to look immediately for familiar landmarks, both endobronchial (e.g., carina) and extraluminal (e.g., oesophagus, pulmonary artery, aortic arch), as orientation within the mediastinum can be difficult (Fig. 2).

figure 2. Sonographic anatomy at the level of the right main bronchus (A) and left main bronchus (B). AZ: azygos vein; CV: cava vein; DAO: descending aorta; ES: esophagus; LN: lymph node; LPA: left pulmonary artery; LULV: left upper lobe vein; MPA: main pulmonary artery; RMB: right main bronchus; RPA: right pulmonary artery; VC: vertebral column.


The miniprobe image should be rotated and adjusted according to the anatomic orientation in order to correspond to the endoscopic view and simplify the identification of other normal structures. The presence of an air bubble inside the miniprobe water-filled balloon generates a cone-shaped artifact that before its removal can also act as a reference point (the image should be rotated until this artifact is positioned at the same angle as it displayed by the simultaneous bronchoscopic image).

When the radial probe is inside the distal trachea and the balloon is filled, the surrounding structures are the aortic arch to the left, the azygos vein to the right and the oesophagus dorsally – recognized by its peristaltic movements and air line. Once in the right main bronchus, the main pulmonary artery is situated ventrally, to the left side, the right pulmonary artery to the right side, and the superior vena cava and the azygos vein are above the right pulmonary artery. Progression to the bronchus intermedius permits visualization of the pulmonary artery ventrally, the pulmonary vein above the pulmonary artery and the mediastinal pleura dorsally. Inside the middle lobe bronchus the miniature probe can identify the lateral segment of the middle lobe and the right lower lobe, to the right and inferior positions respectively. The pulmonary artery is displayed ventrally and the pulmonary vein and the right atrium are situated to the left side.

In the left main bronchus proximal structures are the aorta, the pulmonary trunk and the left and right main pulmonary arteries ventrally, and the oesophagus and vertebral column dorsally. The left atrium and mitral valve may be observed at the distal end of the left main bronchus.

The vascular structures described are recognized as fairly hypoechoic structures. Arteries are identified from their real-time ultrasonography pulsations synchronous with arterial pulse oximetry. Usually the veins are free of pulsations unless these are transmitted from adjacent arterial or cardiac structures. Doppler examination can be made before biopsies in order to increase confidence of identification and avoid blood vessel puncture.

Lymph node stations 2L and 2R (left and right upper paratracheal), 4L and 4R (lower paratracheal), 7 (subcarinal), 10 (hilar) and 11 (interlobar) are those most commonly accessible to EBUS TBNA (Fig. 3). This technique can, in some cases, also access stations 1 (high mediastinal), 3 (pre-vascular and retrotracheal) and 12 (lobar) according to the well-known Mountain and Dressler classification of regional nodal stations for lung cancer staging. One major drawback of EBUS is its difficulty or inability to image and access stations 5, 6, 8 and 9 (subaortic, paraaortic, paraoesophageal and pulmonary ligament lymph nodes).

figure 3. Schematic representation of most common lymph node stations that can be punctured with EBUSTBNA bronchoscope (according to Mountain-Dressler TNM classification).


Even with EBUS, the endoscopist has to keep in mind that tracheobronchial anatomical landmarks are essential to avoid inaccuracy in lymph node identification and staging. The EBUS-TBNA scope is particularly helpful in accessing station 2 in the left or right proximal trachea, as there are no particular endobronchial milestones at this level. It is also useful for station 4 at the distal tracheal level, since it can prevent puncture of the azygos arch on the right, and aorta or main pulmonary artery on the left side. Subcarinal lymph nodes are easily sampled on either side of main carina in an inferior-medial direction.

To access the 10L station, the EBUS has to be in contact with the distal anterior-medial wall of the left main bronchus at the entrance to the left upper lobe bronchus. The 10R station is situated in front of the right main bronchus, close to the right upper lobe bronchus. Station 11R is in the anterior portion of the right upper lobe spur and 11L between the left upper lobe and the left lower lobe bronchus at 9 o’clock.

Under favourable conditions lymph nodes as small as 3mm can be detected by EBUS. They are characterized as well-defined echo-dense round, ovoid or elliptical shaped structures with distinct borders. Sometimes their internal features are individualized (folliculi, sinuses and small lymph vessels). EBUS has also the ability to distinguish lymph nodes from adjacent anatomical structures such as the great vessels, thyroid, oesophagus and left atrium. Direct invasion of another organ is defined by an observation of either an extensive contact or an irregular margin between the lesion and mediastinal structures.

In the peripheral lung, in contrast to the whitish image of air-containing lung tissue often described as “snow-storm like”, solid lesions appear darker and more homogenous and are usually well differentiated from normal tissue by a bright border.

The EBUS system also provides images of the layers underlying the respiratory epithelium and mucosa. The sonographic configuration of the trachea and main bronchi is described as a 3 to 7 echo layer structure1,3-8 (Table 1). The best relationship between US images and histopathological structures was obtained by Kurimoto et al3 by placing 23 and 29G needles into the different layers of resected specimens, delineating five layers in the cartilaginous portion of the trachea and extrapulmonary bronchi and three layers in the membranous portion of the trachea. Two additional outer layers were reported5,6, which might not be decipherable under suboptimal US conditions.



The cartilage layers can be easily identified, since they are much clearer than the other layers, and these can be used as a reference for evaluating the other components of the bronchial wall structure. Disruption of this normal multilayer pattern is commonly an indication of tumour infiltration, but can also be part of an inflammatory process. Malignant tissues are imaged as hypoechoic areas, and when tumour infiltration occurs, invasion of the cartilage layer can be plainly perceived (Fig. 4). A correct understanding of this laminar structure is necessary in order to perform an accurate determination of the depth of tumour invasion.

Figure 4. Fragmentation of the normal stromata of the bronchial wall by cancer in the (r) lower lobe. α) Carcinoma, β) Normal bronchial wall.


Every US finding should be systematically documented and described in the final report.

EBUS costs and training

In order for EBUS to be established as a routine procedure, apart from acquisition of the equipment (total cost around 60.000-130.000 euros), correct training of the endoscopist is vital.

As for all US procedures, there is a significant learning curve before the operator becomes skilful in EBUS. The time needed is operator-dependent and eliciting and interpreting images can be difficult. Despite its introduction some years ago, there are still only a few centres that are performing and teaching EBUS as a standard procedure. Some factors contributing to the delay in introduction can be: the cost of the equipment, the long learning curve, the length of time needed to perform the procedure, lack of such US training in pulmonology fellowship programmes. A special problem is the difficulty in obtaining excellent teaching and supervision in this rather demanding technique.

The learning curve for EBUS can be longer than for other pulmonary diagnostic procedures. This is particularly true for the radial miniaturize probe because it is a delicate instrument that generates 360Ί images. It is necessary for the operator to be familiar with the equipment and the ultrasonic view of the bronchial wall and extrabronchial anatomy, often at angles different from those in the axial CT scan. It is fundamental for interpretation that the bronchoscopist has the ability to create a three-dimensional brain imaging reconstruction of the transbronchial/mediastinal structures.

The American College of Chest Physicians9 recommends a minimum of 50 EBUS examinations to acquire basic experience and more effort has to be made to obtain expertise with complete visualization and puncture of structures from uncommon angles and views. To maintain competence a minimum of 20-25 procedures per year should be performed9,10.

EBUS indications

Increasing numbers of centres use EBUS as a routine procedure and as further scientific studies are published, there is growing evidence for its indications (Table 2).

Established clinical indications are early lung cancer detection, diagnosis and staging of advanced bronchogenic cancer, assessment of normal and pathological mediastinal structures.



Diagnosis of central lesions

Early cancer

Lung cancer diagnosis is often made in late stage disease, when definitive curative treatment can be offered to few patients. Precancerous and localized malignant lesions in the respiratory tract are usually detected accidentally in patients who perform bronchoscopy for other clinical reasons, but conventional white-light bronchoscopy is not an efficient method for identifying dysplasia and carcinoma in situ. The EBUS system can detect early cancer and has the potential to provide information concerning invasion of the bronchial wall structure through assessment of the different layers.

In 1999 Kurimoto and colleagues3 accurately determined the depth of tumour invasion, comparing US with histopathologic findings in resected lung cancer specimens. In 23 of 24 lesions the depth of invasion was estimated to be the same by the two methods, indicative of the reliability of EBUS in the assessment of small tracheobronchial lesions. The extent and depth of penetration of tumours as small as 3mm in diameter can be assessed making it clearly more sensitive than CT scanning11.

In addition, EBUS can be used with autofluorescence (AF) endoscopy to increase the effectiveness of early cancer detection. It has been shown that AF alone can enhance the diagnosis of these lesions12, but localized scar tissue formation and inflammatory or granulomatous changes can be difficult to differentiate from malignant lesions. A combination of EBUS and AF can reduce AF false-positives6,13. A prospective trial13 confirmed the usefulness of EBUS for classification of suspicious localized lesions identified by AF. The correct histology prediction with EBUS addition was far superior (91%) compared with AF alone (59%).

In other cases the miniprobe can detect not only infiltration of deeper layers but also involvement of adjacent structures, assisting in lesion restaging and planning of treatment. In a study by Herth and coworkers14 28% of patients assessed for presumed carcinoma in situ or early cancer, EBUS established advanced extent of the disease, which would have made endoscopic curative treatment not feasible. Therefore, EBUS is not only useful in evaluating the depth of tumour invasion into the bronchial wall, but also in delineating the tumour margin, and in this way improving the efficacy of endobronchial treatment or surgical resection.

Advanced cancer

Bronchogenic carcinoma is the leading cause of cancer death. Following the histological diagnosis of lung cancer, staging becomes the most important task. The staging process begins with evaluation of size and position of the primary tumour. Its relations, extent and spread to thoracic structures and to extrathoracic organs are assessed in an organized order, so as to establish treatment and prognosis. The specific site of a central tumour and its invasion of mediastinal organs, such as heart, great vessels and oesophagus most often exclude surgery. One third of presumptive curative thoracotomies for non-small cell lung carcinoma are rendered useless due to the discovery of advanced disease despite preoperative staging procedures15.

Until now processes outside the airway lumen and related structures could be assessed only by indirect signs. EBUS capabilities allow exact estimation of submucosal and intramural tumour spread, discriminating between infiltration and compression3,7,16 and assessment of the involvement of mediastinal structures such as aorta, pulmonary artery, pulmonary vein, oesophagus and even the vertebral column. A prospective study16 in 105 patients compared tumour characteristics evaluated by EBUS and CT scan with surgical pathology. EBUS examination for infiltration by central tumours yielded an accuracy of 94%, a sensitivity of 89%, and a specificity of 100% compared to chest CT, which had an accuracy of 51%, sensitivity of 75% and specificity of 28%. These results confirmed that EBUS has the ability to provide a better staging with subsequent adjustment in therapeutic options and prognosis.

A recent report by Wakamatsu17 emphasized the value of EBUS in staging other tumours. EBUS managed to determine the depth and extent of oesophageal and thyroid cancer invasion into the central airway wall, thus contributing to surgical planning.

Inflammatory diseases

As more centres are performing EBUS technique, other indications are being investigated and reported. EBUS may be used to investigate and quantify inflammatory changes in bronchial wall structures.

The usefulness of the EBUS radial probe in assessing the tracheobronchial wall has been used to document cartilage destruction of the trachea and main bronchi, facilitating the diagnosis and providing important information about the condition of the bronchial wall before stenting18,19.

Preliminary studies have been published concerning the airway wall thickness in lung transplant recipients with graft rejection or infection8 and in asthma remodelling20 where EBUS enabled discrimination and measurement of the thickness of the different bronchial layers. In the latter application, the invasiveness of the method limits its clinical utility although it can provide important clues in a research context.

Diagnosis of mediastinal lesions

Lung cancer lymph node staging

The presence of mediastinal lymph node involvement in patients with lung cancer can have a major impact not only on prognosis but also on the scheduling of an appropriate treatment plan. Accurate mediastinal lymph node staging is essential and histopathological confirmation of suspected malignant lymphadenopathy is necessary, especially before surgical resection or when administering combined or neoadjuvant treatments. Around 30% of patients undergoing mediastinal or hilar lymph node TBNA for bronchogenic carcinoma staging, are found to have no indication for surgical resection21.

Imaging methods such as thorax CT are not sufficiently reliable as a sole means of diagnosing mediastinal lymph node metastasis. Positron emission tomography (PET) has been reported to increase diagnostic yield22 but there are also false-positives, particularly with inflammatory diseases. A meta-analysis for non-invasive assessment of mediastinal involvement in non-small cell lung cancer found an overall sensitivity of 57% and specificity of 82% for CT scanning, and for PET 84% and 89% respectively23.

Conventional TBNA is a blind procedure and its sensitivity varies widely (15-89%), depending on the size and location of the lesion and the operator’s skills and experience21,24-27. Consequently many centres do not perform this procedure routinely. One of the potential applications of EBUS is the guidance of mediastinal lymph node biopsies in patients with confirmed or suspected lung cancer. It allows placement of the needle directly in the lesion, with an increased biopsy yield28-31. Lymph nodes as small as 3mm can be precisely detected by EBUS for subsequent TBNA. In patients with enlarged lymph nodes on CT scan there is a distinct statistical advantage favouring the guided procedure for to stations 2, 4, 10 and 11, although there is no difference between blind and EBUS radial probe TBNA for station 730.

EBUS has emerged as a staging method that is less invasive than mediastinoscopy or mediastinotomy. It can identify pathological lymph nodes in regions that are not accessible to mediastinoscopy29 and avoid surgical diagnostic/staging sampling in up to 76% of patients when combined with PET evaluation31.

These and other results have led to the introduction of a specialized EBUS-TBNA bronchoscope that allows real-time puncture of tissue, especially of lymph nodes (Fig. 5). The procedure has become simpler and the diagnostic yield improved. After the first report on surgically resected specimens32 the results establish its superiority for diagnosis of pathological mediastinal and hilar lymph nodes with an overall sensitivity of 94%, specificity of 100% and negative predictive value of 90%33-37.

Figure 5. Needle aspiration of lymph node cells in real time using the EBUS-TBNA bronchoscope. The arrows indicate the needle. α) Enlargement of the lymph node in position 4R. β) Normal tissue.


Two studies, using different methodologies, compared EBUS-TBNA sensitivity with other imaging methods for detecting lymph node involvement in lung cancer. In the first, non-small cell lung cancer patients with CT scans showing an absence of enlarged mediastinal lymph nodes were recruited and submitted to EBUS-TBNA and posterior surgical staging38. The prevalence of CT negative lymph node metastasis was 17%. The sensitivity of EBUS-TBNA for detecting malignancy was 92%, specificity was 100% and the negative predictive value was 96%. A limitation of this study, namely, the lack of PET staging, was addressed in a recent prospective clinical trial by Yasufuku and colleagues39. They compared EBUS-TBNA, PET and chest CT for the detection of mediastinal and hilar lymph node metastasis in patients with newly diagnosed lung cancer who were being considered for surgical resection. In 102 patients the reported sensitivities for CT, PET, and EBUS-TBNA were 77%, 80%, and 92% respectively; the specificities were 55%, 70%, and 100%, and diagnostic accuracy was 61%, 73%, and 98%, respectively. The EBUSTBNA method was far superior to CT and PET.

In conclusion, EBUS-TBNA can avoid additional invasive diagnostic and staging procedures and no complications were reported, indicating the safety of the procedure.

Other pathologies with mediastinal involvement


EBUS has the ability to diagnose other mediastinal nodes and masses of solid40,41 or vascular origin, through Doppler mode.

A recent study42 evaluated 65 patients with suspicion of sarcoidosis and sampled 77 lymph nodes. The overall sensitivity was 88% for sarcoidosis stages I and II, attesting the efficacy of EBUS-TBNA in the diagnosis of other diseases with mediastinal involvement.

It may thus constitute a novel method for differential diagnosis between inflammatory, infectious and malignant diseases.

Diagnosis of peripheral lesions

Bronchoscopy is frequently used in the evaluation of peripheral lesions of the lung. Transbronchial biopsies (TBB) are usually performed blindly or under direct fluoroscopic guidance, and they demonstrate a wide variability of diagnostic accuracy.

At an early stage of EBUS usage it was perceived that it could not be used in peripheral lung, since the presence of air in the lung parenchyma would produce total US reflection. However the echogenecity of a solid or liquid process can be discriminated straightforwardly from normal aerated lung. EBUS can locate the lesion and replace or complement fluoroscopy in guiding distal procedures. It may provide information about the nature of peripheral abnormalities, as it differentiates between atelectasis, tumour and inflammatory infiltrates.

The radial probe can create detailed images of the internal structures of peripheral pulmonary lesions (Fig. 6). Correlation between preoperative EBUS images and the histopathology of surgical specimens suggests that it has the potential to provide information about the nature of the lesion, distinguishing benign from malignant lesions43, and a three-type with six-subtype classification system was developed to categorize the sonographic images, which was non-practical. This issue was addressed by another study and an improved four-pattern system was proposed: continuous hyperechoic margin, internal echoes (homogeneous or heterogeneous), hyperechoic dots and concentric circles44. The results suggest that malignant lesions display a heterogeneous internal echo and hyperechoic dots pattern, and benign lesions a concentric circles and homogeneous internal echo pattern, but there is a lack of specificity and further studies will be necessary to confirm these descriptions or produce a better classification system.

At present EBUS appears to have a limited clinical value in studying and differentiating interstitial lung diseases based on echo findings alone. A preliminary study combining EBUS and bronchoalveolar lavage (BAL) evaluated patients with interstitial and alveolar infiltrates in order to determine different typical sonographic patterns45. The authors concluded that EBUS was helpful in monitoring optimal locations for BAL or TBNA but their findings had shortcomings as the patterns did not appear to be disease specific and could not be use to make a prospective diagnosis.

The major indication for EBUS miniaturized probe in peripheral lung lesions is to guide the correct placement of the biopsy forceps or aspiration needle inside the lesion. There is now good evidence46-52 that under EBUS control the success rate for TBB is equivalent to fluoroscopy, ranging from 58% to 80%. An additional feature is its safety, due to its low complication rates and the avoidance of radiation exposure of staff and patients. Some of these studies used a guide-sheath to direct the TBB procedure47,48 but this did not prove to be superior to the conventional miniprobe method previously described. Another possible role for EBUS is the detection and diagnosis of fluoroscopically-invisible small lesions with the potential of diminishing the need for surgical diagnostic procedures51.

In a recent randomized controlled trial, Eberhardt et al53 demonstrated a high diagnostic rate when EBUS was combined with electromagnetic navigation bronchoscopy (ENB) in peripheral lung lesions, compared to either technique alone. A total of 120 patients with peripheral lung lesions or solitary pulmonary nodes were randomized into three diagnostic groups: EBUS, ENB and EBUS plus ENB. All TBB were obtained without fluoroscopic guidance. The diagnostic yield for combined procedures was 88%, for EBUS alone 67% and for ENB alone 59%, independent of lesion size or location. The overall rate of pneumothorax was 6%.

Figure 6. Placement of the miniprobe in a peripheral lesion (adenocarcinoma) in the upper left lobe of the lung. A) X-ray image. B) The ultrasound image reveals α) tumour, β) a small blood vessel, γ) normal lung parenchyma.


Assisting therapeutic decisions

Apart from diagnosis of lung cancer there is a role for EBUS in optimizing therapeutic options for lung cancer and other patients, in view of the fact that many of the indications for interventional bronchoscopy arise from abnormalities in structures that are beyond the airway lumen.

The first recognition of the potential of EBUS to aid in therapeutic decision-making was expressed by its pioneers with reference to laser treatment and stent placement in tumour stenosis1,2. EBUS provides a new method for correctly positioning stents, since it accurately determines real-time dynamic changes of the airway during respiratory movements; in most cases the miniaturized probe can evaluate the bronchial lumen distal to the stenosis; it can estimate with precision the diameter and length of the stenotic portion and it can investigate specific details of the submucosal thickening and cartilage destruction by the tumour allowing selection of not only the most suitable stent but also its correct size and diameter18,54 ,55.

In many instances, EBUS can differentiate tumour invasion from compression and determine the extraluminal extent of bronchogenic carcinoma, so it can be coupled with endobronchial therapeutic methods in order to support therapeutic decisions, assure optimal treatment and evaluate treatment results. Miyazu and coworkers6,11 planned treatment (photodynamic therapy, chemoradiotherapy or surgery) in selected patients with centrally located early-stage lung cancer based on the evaluation of tumour depth invasion with EBUS. This method was useful in decision-making about the type of therapy, as all patients were treated successfully and were in complete remission at 32 months follow-up. EBUS was also used in the routine assessment of these patients after treatment, since its sensitivity is superior to that of other imaging techniques.

With reference to surgical resection, EBUS can be essential for the decisions about resection margins, and considerably helpful in cases of questionable tracheal involvement, for proving non-resectability, or in questionable main bronchi involvement to guide the extent, feasibility of resection and type of procedure.

A large observational study established EBUS efficacy in therapeutic interventions14. In 1,174 procedures during a three-year period, the miniaturized probe was used in mechanical tumour debridement (29%), argon plasma coagulation (23%), stent placement (20%), Nd:YAG laser resection (13%), brachytherapy (11%), foreign body removal (2%) and endoscopic abscess drainage (2%). Its findings guided or changed management of patients in 43% of cases. It was useful in: selection of patients for endoscopic rather than surgical therapy; selection of correct stent size in cases of submucosal and/or parabronchial unacknowledged tumour extension; guidance of mechanical, laser or argon-plasma tumour destruction avoiding adjacent vessels and reducing complications; assessment of local tumour depth and extension previously and after brachytherapy.

EBUS versus EUS

There is some controversy concerning EBUS-TBNA and transoesophageal EUS fine needle aspiration (FNA) in lung cancer mediastinal staging. This latter method is not performed by chest physicians on a worldwide basis, and there are anatomical considerations that have to be noted, since the oesophagus is an elastic and mobile organ without clear endoscopic landmarks for orientation, in contrast to the tracheobronchial tree were lymph nodes have a relatively fixed relationship to the airways and biopsy can be more easily performed.

Due to the anatomical position of the oesophagus, EUS-FNA allows access to the aortopulmonary window, subcarina and posterior mediastinum (stations 5, 7, 8 and 9), positions that are, besides position 7, not accessible to EBUS-TBNA. EUS-FNA has shown potential to reduce the need for mediastinoscopy and thoracoscopy or thoracotomy in up to 50% of lung cancer patients56.

In these patients the combined EBUS and EUS approach demonstrated enhancement of lymph node staging. It offers a more complete, less invasive, low cost evaluation of mediastinal and hilar metastases than mediastinoscopy, the accepted gold standard for staging of lesions in the mediastinum36,57,58.

The relevant scientific data show that rather than being in competition, EBUS and EUS are compatible and complementary methods.

Conclusions

EBUS has become a routine procedure in some institutions and is being gradually introduced into the bronchoscopy practice of many other centres.

The two systems, miniaturized probe and EBUS-TBNA bronchoscope, are complementary methods. The miniprobe is more versatile since it can analyse central and peripheral structures. However, the EBUS-TBNA bronchoscope allows real-time lymph node puncture and has proved to be a sensitive and safe technique for mediastinal staging in lung cancer patients. The combination of EBUS-TBNA and EUS can improve the diagnostic rate in identifying N2 and N3 stages. More invasive surgical staging procedures are avoided and therapeutic management of patients is enhanced.

EBUS can analyse accurately the multi-layer structure of the tracheobronchial wall in early lung cancer and differentiate tumour airway invasion from compression. It may distinguish malignant from benign lesions, guide biopsy of peripheral lung lesions or solitary pulmonary nodes. It is used to assist endoscopic therapy such as tumour debridement, stent placement, brachytherapy and photodynamic therapy, and to determine tumour margins to optimize surgical resection.

The role of EBUS is expected to grow in the near future, as an increasing number of prospective and randomized studies gather evidence of its potential in different important clinical settings.

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