Endobronchial ultrasonography – a new possibility in interventional pulmology

Diagnosis of the mediastinal formations, medi­astinal lymphadenomegaly and peripheral pul­monary lesion still represents a significant chal­lenge for pulmonologists and chest surgeons. Morphological diagnosis is related to the wide application of the fine needle aspiration biopsy, transthoracic aspiration biopsy, mediastinosco­py that is the ‘gold standard’ in the diagnosis of the mediastinal pathology, and video-assisted thoracoscopy. These methods present with their advantages and disadvantages concerning the obtained tissue material, safety and price. Bron­choscopy plays an important role in lung cancer diagnosis and staging. Endobronchial biopsy un­der visual control enables an exact diagnosis in more than 90% of the cases, however, in peripher­al tumors without any visual access things are not the same. Introduction of computer tomography (CT) considerably improved the possibilities for lung cancer diagnosis and staging; however, the experience gained concerning its reliability when determining the mediastinal involvement and the degree of bronchial wall infiltration proved to be disappointing. In approximately 100% of the patients with non-small cell lung cancer staged by means of CT, explorative thoracotomy ends without any resection because of an advanced process remaining non-detected preoperatively. Besides 25-35% of the patients with a resection appearing successful present with an early post­operative relapse (32). Introduction of positron- emission tomography (PET-CT) improved the possibilities for staging, however, without the necessary categoricalness.

It has been established that not only tumor- involved but also inflammatorily changed lymph nodes can present with an increased extent of metabolism as those of a normal size and me­tabolism can contain tumor cells (10). Konishi et al. (26) compare the role of CT and PET-CT when staging the non-small cell lung cancer and estab­lish a sensitivity of 55% and specificity of 96% in CT towards 73% and 98% in PET-CT, respectively. Falsely positive results of PET-CT are related to other pulmonary diseases such as interstitial pneumonitis, tuberculosis, silicosis, etc.

Fig. 1. “Peripheral”and “central” EBUS

a) “Peripheral” EBUS – tiny probe UM-S20-20R without balloon sleeve on top for the diagnosis of peripheral lung lesions.

b) “Central” EBUS – balloon probe UM-BS20-26R with balloon in the distal part, allowing circular contact of the ultrasound and image from 360 degrees of peritracheal and peribronchial structures.

Endoscopic ultrasound (EUS) starts its deve­lopment in the 80-ies of the 20th century as an integral part of the examination of the gastroin­testinal tract by using of a radial probe. Esopha­gus’ anatomical location behind and to the left of trachea defines EUS application when staging the lung cancer as well as for the performance of fine- needle aspiration biopsy (FNAB) of lymph nodes and adrenal gland. In 1993, Wiersema et al. (33) published the first EUS application for staging the non-small cell lung cancer by means of FNAP through the esophagus. The complete mediasti­nal visualization by EUS is restricted because of airway interference, on the one hand, and of the difficult lymph node accessibility in the positions of 2Р, 3 and 4Р, on the other. These circumstances are the precondition for the development of the idea of the ultrasonography of the airways.

The history of endobronchial ultrasonography (EBUS) begins with the communication by Hurter and Hanrath (22) about EBUS of the lung and me­diastinum in 1990. The development and expan­sion of EBUS application continues in Germany, Japan, and the USA as one makes use of endo­vascular microprobes (7, 13, 22). Becker (8) elabo­rates a flexible catheter with an ultrasonic probe for insertion into the large airways by means of a balloon on its tip with a view of ensuring a circular contact with the bronchial wall. Nowadays, two models of EBUS, i.e. radial and linear, are applied for different purposes.

Radial EBUS

Radial EBUS is provided with a rotation trans­ducer of 20 MHz with possibility of 12-30 MHz that can be inserted with or without guide sheath through the working canal of a standard fibro- bronchoscope of 2-2.8 mm. The radial probe is of different size and of an external diameter of 1.4-2.6 mm.

Fig. 2. Layers of the bronchial wall visualized by 20 MHz probe (enlarged image).

From the inside out are: mucosa (H), submucosa (L), endochongrium (H), cartilage (L), perichondrium (H), connective tissue (L), and adventitsiya. L – low-density layer, H – high-density layer.

The ‘central’ probe, Balloon Probe UM-BS20-26R is with a polyethylene sheath and latex balloon in its distal part. The contact between the bron­chial wall and transducer is accomplished though filling-up of the latex balloon with physiological serum enabling a better contact in the proximal airways with a view to inspect the bronchial wall or to perform a transbronchial biopsy (TBB) of the lymph nodes.

The ‘peripheral’ EBUS (Miniature Probe UM-S20- 20R) is without any balloon sheath and is used for identification of the peripheral pulmonary lesions with the purpose of a biopsy (Fig. 1).

It is not necessary to stimulate the contact with the bronchial wall within the distal airways be­cause they ensure a sufficient contact between the transducer and bronchial mucosa. With the radial EBUS there is an image of 360^o that is per­pendicular to the long axis of the airways. Image resolution is of 1 mm but depth of access is of 4-5 cm.

Fig. 3. Findings in СТ and EBUS:

On the left above – CT finding of central infiltrative formation.

On the right above – EBUS – intact bronchial wall. Below – enlarged EBUS image.

Fig. 4. Histological and EBUS findings:

On the left above – EBUS – tumor infiltration of tracheal wall.

On the right above – corresponding histological material – destruction of the cartilage.

Below – enlarged EBUS image – tumor infiltration of the bronchial wall (left main bronchus).

Usually, radial EBUS is carried out following a standard fibrobronchoscopy (FBS) with inspec­tion of the bronchial tree. After finding the image, both echoscopic and endoscopic images are com­pared by means of reference points such as large vessels (anechogenic), vertebral column, and  esophagus. Tumor formation looks hypoecho- genic when compared to the healthy lung tissue and there are clearly outlined borderlines be­tween the lesion and the aerated lung. After iden­tification of the target lesion, the probe moves to it and TBB is undertaken. At the same time, the biopsy guided by the radial EBUS is restricted be­cause of the absent real-time image. The diagnos­tic data described about TBB with the radial EBUS vary between 72% and 86% as this procedure demonstrates an improvement of the diagnostic level over the blind conventional TBB concern­ing the mediastinal lymph nodes at positions of 2, 3, and 4 (14). The radial EBUS enables the ex­amination of any bronchial wall layers, more than 7 ones (Fig. 2). They are the following: mucosa, endochondrium, perichondrium and adventitia, which are hyperechogenic, and submucosa, car­tilaginous tissue and connective tissue, which are hypoechogenic (1, 2). EBUS displays better than CT the extent of infiltration or compression by the tumour presenting with a sensitivity of 89% and specificity of 100% (Figs. 3 and 4). The patient can be out of range of the invasive therapeutic pro­cedure such as photodynamic therapy or brachy- therapy through identification of evidence about invasion in the cartilaginous tissue of the tumor in favor of the surgical intervention while through visualization of a nearly located blood vessel prior to debridement or thermal abrasion can avoid fa­tal bleeding.

Indications for radial EBUS application

Early central lung cancer

With small roentgenologically invisible tumors, the decision for a local endobronchial therapeutic intervention depends on their intraluminal and intramural scope of the various bronchial wall layers (2). In contrast to the x-ray examination, by means of EBUS one can analyze very small-sized tumors and differentiate them from benign neo­plasms. Herth et al. (21) demonstrate how EBUS improves the specificity that forecasts malignan­cy by 50% up to 90% in autofluorescence-positive lesions which are invisible when standard FBS with white light is applied. The combination of EBUS and autofluorescence can be an effective approach for endobronchial treatment of ma­lignant neoplasms limited within the bronchial wall (15, 16, 28). EBUS differentiates the tumour invasion from the compression of the tracheo­bronchial wall in 94% while CT does in 51% of the cases. During the preoperative staging EBUS is used for determination of the resection margin as it warrants a detailed analysis of the intraluminal, submucous and intramural tumor dissemination (17).

Advanced lung cancer

Several authors accept that the radial EBUS can be used as a means in the interventional bronchology that contributes to the restoration of the pass ability of the large airways through laser co­agulation or stenting as well as to the determina­tion of the status of the vessels in the proximity of the tumors prior to their destruction (15, 30). Within a large trial, a total of 2 446 patients have undergone a therapeutic bronchoscopy as in 1 174 of them it has been done by means of a radial EBUS. In 43% of the cases it is capable of modify­ing the therapeutic procedures by adapting the stent size, of finalizing the tumor debridement closely to the vessels and thus of more exactly performing the endoscopic treatment. In the cas­es of laser treatment, EBUS application restricts the bleeding from the nearly located vessels (6).

Diagnosis of the peripheral lesions

Malignant peripheral lesions are, usually, hy- poechogenic and of well-defined peripheral out­lines while an air bronchogram is absent (15, 27) (Fig. 5).

The histological diagnosis of the peripheral pulmonary lesions by using of FSB under fluoro­scopic control, or the biopsy under CT-control is a routine procedure. Herth et al. (15) prove that a similar procedure under EBUS-control presents with the same success and a reliability level of ap- proximately75% provided that there are consid­erably less complications. Kurimoto et al. (29) ap­ply a radial EBUS in 150 patients presenting with a solid peripheral nodule. A specific diagnosis is achieved in 116 patients (in 77% of the cases). The results are even better (in 87% of the cases) if the probe is situated in the lesion itself rather than in its proximity.

Fig. 5. Lung nodule.

(А) СТ – Lung nodule (18 mm) in the right middle lobe.

(В) EBUS – Hypoechogenic nodule with hyperechogenic areas.

Fig. 6. Map of regional lymph nodes in staging lung cancer, adapting according American Thoracic Society.

In Paone’s et al. trial (31), 206 out of a total 293 patients have been randomized either for a rou­tine FSB, or for radial EBUS. Positive results have been obtained in 76% of the patients who have undergone EBUS procedure and in 52% of the cases following FSB under fluoroscopic control. When the peripheral lesion is larger than 3 cm there are no differences while when it is smaller than 3 cm the sensitivity and accuracy of EBUS are of 75% and 83%, respectively, and of 31% and 50% after the routine examination. The diagnos­tic reliability of TBB guided during EBUS concern­ing the peripheral pulmonary lesions sized below 20-30 mm is of 61-80% (Table 1).

Lymph node staging

Non-small cell lung cancer staging is of signifi­cant importance when selecting the therapeu­tic approach. By means of EBUS, 2-3 mm-sized lymph nodes can be established and their struc­ture can be defined. The results from the trans- bronchial needle biopsy (TBNA) can be significantly improved through the endosonographic lymph node localization – up to more than 80%, especially in the cases of upper and lower para- tracheal lymph nodes that are inaccessible by using of CT. Herth et al. (18) compare the results from the TBNA under EBUS-control and from the conventional biopsy, which are of diagnostic in­formation value in 85% and in 66% of the cases. The additional analysis of lymph node positions reveals that in case of localization outside the en­doscopic range, i. e. positions of 2, 3, and 4, EBUS enhances the number of the positive results (Fig. 6). On the other hand, with enlarged subcarinal lymph nodes, both the conventional biopsy and TBNA guided during EBUS show similar results.

Table 1. Radial EBUS when performing TBB from peripheral pulmonary lesions (< 20-30 mm) with a diagnostic accuracy of 61 -80% (3).

Linear EBUS-TBNA (Convex)

It represents a bronchoscope with an integrat­ed curvilinear electron transducer on the tip that enables the real-time TBNA performance (Fig. 7). Its outer diameter is of 6.9 mm but the inner one is of 2 mm which makes it of larger volume than the common fibrobronchoscope and requires an oral manner of introduction. The angle of inspec­tion is of 80^o and the direction of the image is of 35^o. Ultrasound (US) frequency of 7.5 MHz en­sures a penetration into a depth of up to 5 cm. The transbronchial needle of 22 Gauge is inserted into the working canal of the fibrobronchoscope.

US-image is obtained either through probe placement directly to the trachea or bronchial wall, or through instillation of physiological se­rum in a balloon at the tip of the probe, which can improve image quality. US-image can be kept that enables the two-dimensional examination of the lesion. It is comfortable that both US- and bronchoscopic light images can simultaneously be observed. An additional Doppler examination is capable of differentiating the tissues from vas­cular structures and, in this way, of avoiding the puncture of a vessel. The relatively wide internal canal of the needle enables the aspiration of a material suitable for cytological and histological examination as the recommended number of the reiterated procedures is 3. The linear BUS is rec­ommended predominantly for the examination of the mediastinal lymph nodes at the positions of the upper paratracheal ones – 1, 2R and 2L, low­er paratracheal ones – 4 and 4L, subcarinal ones – 7, hillar ones – 10 as well as interlobar ones – 11, for the diagnosis of the mediastinal and pulmo­nary tumors. The paraaortic (6), aortic-pulmonary, subaortic (5), paraesophageal (8) and pulmonary ligament lymph nodes (9) are inaccessible for this technique.

A basic indication for real-time EBUS-TBNA is the examination of the enlarged mediastinal lymph nodes (1) as established after CT of the chest aiming at staging the non-small cell lung cancer (Fig. 8).

Herth et al. (19) diagnose 534 out of a total of 572 punctured lymph nodes (94% of the cases). Biopsies have been carried out from all the areas rich in lymph nodes such as 2L, 2R, 3, 4R, 4L, 7, 10R,11R, and 11L of a mean size of 1,6 cm. The es­tablished sensitivity is of 94% and specificity is of 100%. The method is useful in the cases with CT- not enlarged lymph nodes, too. By using of EBUS- TBNA, Herth et al. (20) examine 100 lung cancer patients without any enlarged mediastinal lymph nodes and juxtapose the results with its surgical proof. The sensitivity of EBUS-TBNA is of 92%, the specificity is of 100% and the negative predicting value is of 96%.

EBUS-TBNA can successfully be applied in ade­nopathies of other etiology. A diagnostic sensitiv­ity of 91% is achieved when proving the clinically suspicious lymphoma (23). The method displays a sensitivity of 85-94% concerning the primary di­agnosis of sarcoidosis. TBB being most commonly used demonstrates positive results in 46-90% as in 5% of the cases it is accompanied by bleeding or pneumothorax (3).

Fig. 7. Convex probe EBUS.

(A) The tip of the convex probe (Olympus XBF-UC180-DT8) has a curved linear transducer of 7.5 MHz.

(B) Balloon attached on the top of bronchoscope is filled with saline.

(C) Transbronchial aspiration needle is inserted through the working channel.

Fig. 8. Convex probe EBUS.

(A) Convex probe EBUS in a main bronchus.

(B) Ultrasound image – biopsy needle in a lymph node.

Conclusion

During the recent several years, EBUS has es­tablished itself as a precise and reliable diagnos­tic method. Numerous investigations and scien­tific communications confirm its high diagnostic value with a series of pulmonary and mediastinal diseases as well as with staging the non-small cell lung cancer. Its different variants possess their advantages: the linear EBUS ensures real-time bi­opsies in centrally located pulmonary and medi­astinal processes while the radial one reveals the depth of bronchial wall involvement by the tumor process and helps the diagnosis of the peripheral lesions and the interventional therapeutic endo­bronchial procedures. The method is minimally invasive and of a good tolerability on the part of the patient as well as related with minimal com­plications when compared to the other invasive diagnostic procedures.