Using the Endoscope for Endobronchial Ultrasound in the Esophagus

Endoscopic ultrasound is a key procedure in the diagnosis and staging of lung cancer and allows safe sampling from mediastinal or hilar lymph nodes^1,2. Endoscopic ultrasound comprises endobronchial (EBUS) and transesophageal ultrasound (EUS), are considered complementary procedures².

Interventional pulmonologists are trained with the EBUS endoscope but are rarely familiar with the larger EUS endoscope (Figure 1), which requires special training to handle correctly³. EBUS and EUS are often performed by different departments and on separate sessions/days⁴. However, trained pulmonologists experienced with EBUS techniques can insert the smaller EBUS endoscope into the esophagus and perform safe examination and biopsy sampling from mediastinal lymph nodes and other lesions adjacent to the esophagus and stomach - a technique termed as EUS-B⁵. This leads to extension of pulmonologists' ability to safely and conclusively sample lesions in many different anatomical sites such as lung⁶, pleura⁷, pericardial effusion⁸, mediastinal lymph nodes^1,5, left liver lobe and retroperitoneal lymph nodes⁹, pancreas¹⁰ and the left adrenal gland^11,12 (Figure 2).

The EUS-B procedure is a pulmonologist friendly version of the gastroenterologists´ EUS using an endoscope that the pulmonologist already masters. The EUS procedure is performed with a gastroendoscope which is both larger and heavier than the EBUS endoscope, has a different handle (with wheels, see Figure 1) and is unlike EBUS performed with the patient in left lateral decubitus. Learning EUS as a pulmonologist is challenging and requires a lot of training and supervision².

EUS-B and EUS are so far very similar regarding diagnostic yield when performed in the field of pulmonology^5,13,14,15. EUS-B is patient friendly since the endoscope is significantly thinner than that of EUS, and therefore less unpleasant for the pharynx and esophagus. Unlike EBUS, EUS-B does not cause direct airway irritation and is therefore safe to use in patients with suspected cancer resulting in severe respiratory impairment due to mediastinal tumor masses¹⁶.

The combination of EBUS and EUS-B is preferred over either test alone in any patient suspected of lung cancer, but EUS-B should especially be considered in patients with suspicious lesions out of reach by EBUS, but within range by transesophageal ultrasound (Figure 2). Adding EUS-B to EBUS in lung cancer work-up expands the interventional pulmonologists´ ability to perform diagnostic work-up during a single session using the same endoscope by one proceduralist, which is more convenient for the patient, saving both time and costs.

The complication risk of EUS-B is extremely low and is to our knowledge only limited to infectious complications^17,18. EUS-B training should be easy and a natural continuation of EBUS, and the following protocol will describe how to perform EUS-B in mild sedation in an out-patient clinical setting.

The following protocol developed at our institution (Zealand University Hospital) follows the Danish national guidelines on human research ethics.Written and informed consent was obtained from the human subjects.

1. Preparation for EUS-B

NOTE: This procedure requires experience in performing bronchoscopy / EBUS, thus the following instruction will not include details on basic steps such as sedation, monitoring etc. which are common for bronchoscopy, EBUS and EUS-B.

1. Evaluate available computed tomography (CT) or positron emission tomography (PET)-CT scans in order to locate target lesions reachable by EUS-B (see Figure 2). Make sure that antithrombotic therapy is paused according to guidelines. Obtain patient's informed consent.
2. Exclude patients with increased risk of perforation (e.g., recent bowel surgery, bowel obstruction, esophageal stenosis), coagulopathy or impaired platelet function.
3. Position the patient in a supine position and apply monitoring similar to bronchoscopy or EBUS according to institutional standards. Many sites continuously monitor 3-lead telemetry, oxygen saturation, pulse and intermittent blood pressure.
4. Initiate conscious sedation similar to bronchoscopy or EBUS according to institutional standards, such as IV midazolam 2.5 mg (for sedation) and IV Fentanyl 25 µg (for cough and pain).

2. Performing EUS-B

1. Perform EUS-B using the EBUS echoendoscope, which is typically 60 cm long (EUS is 125 cm) and the average diameter of the regular scope is between 6 and 7 mm (EUS is 12 - 14 mm).
2. Stand behind the patient´s head who is in a supine position. Hold the handle of the endoscope with the left hand with the thumb on the lever and hold the distal end of the endoscope with the right hand.
3. Apply local anesthetic gel (nasal route) or spray (oral route) on the mucosa 1-2 min before endoscopy.
4. Introduce the endoscope into the oropharynx, either orally or through the nostril, after applying local anesthetic gel on the tip of the endoscope.
5. Advance into the laryngopharynx while the epiglottis is in front of the scope and visualize the vocal cords using the bronchoscopic view.
   1. Turn the scope left or right to direct the scope lateral to the arytenoids. Ask the patient to swallow and slowly bend the endoscope posteriorly and introduce it into the esophagus. Never use force but follow the downward direction of the patient's voluntary swallowing movement, where the esophageal lumen is widened. Patient-operator coordination is vital.
   2. Spray 2 mL of topical lidocaine in the oropharynx if the endoscope is not successfully introduced into the esophagus.
6. Shift to the ultrasonic image and introduce the endoscope into the stomach, and start identifying the six EUS landmarks in a stepwise and chronological order as described in¹⁹ and below (Figure 3).
   1. The left liver lobe - turn the endoscope slightly counterclockwise (Landmark 1).
   2. The abdominal aorta with the celiac trunk and superior mesenteric artery - turn the scope clockwise (Landmark 2).
   3. The left adrenal gland - turn the scope further clockwise (Landmark 3).
   4. Mediastinal lymph node station 7 -retract the endoscope to the mediastinum. This is situated close to the left atrium and right pulmonary artery (Landmark 4).
   5. Mediastinal lymph node station 4L - retract the endoscope a few centimeters and notice the reflections from the trachea. Then, turn the endoscope counterclockwise and find 4L between the aortic arch and the left pulmonary artery (the mickey mouse sign; Landmark 5).
   6. Mediastinal lymph node station 4R - turn the endoscope clockwise, pass the trachea and find the azygos vein (confirm by retracting the scope and the vein should disappear into the superior vena cava). 4R is near the azygos vein (Landmark 6).

3. Tissue sample collection

1. Take tissue samples from suspected lesions under real-time ultrasonographic guidance using the FNA needle. The needles on the market are slightly different, but the principles for their use are the same.
   1. Insert the sheath in the endosope and adjust the length so that the tip is 1 mm outside the endoscope and lock it.
   2. Move the needle with the stylet forward and retract the stylet a few millimeters (if the tip is rounded) to make the needle sharp. This step is not needed if the stylet is sharp.
   3. Hit the target, retract the stylet, and apply suction to the needle.
   4. Move the needle back and forth. Then remove suction, lock the needle in the upper position and remove the equipment from the endoscope.
2. Make sure that the biopsy order is M1b-M1a-N3-N2-N1-T (M = metastasis, N = lymph node, T = tumor) to avoid iatrogenic upstaging.

The described technique allows the EBUS-skilled pulmonologist to safely and efficiently sample lesions adjacent to the esophagus and stomach - above or below the diaphragm - using the EBUS echoendoscope (Figure 1 and Figure 2). Table 1 shows that diagnostic hit rates vary according to location, with slightly higher diagnostic success rates of intrathoracic lesions.

The systematic six landmarks approach (Figure 3) is considered a basic step in learning EUS-B, and is a reliable technique in helping the operator to correctly navigate in the esophagus and stomach, and thus locating and sampling suspicious lesions¹⁹. EUS-B allows the pulmonologist to reach lesions otherwise not reached by bronchoscopy or EBUS (Figure 2), and EUS-B can be performed directly following EBUS, using the same endoscope and needle if the M1b-M1a-N3-N2-N1-T order can be respected⁵.

Concerning lesions that can be reached by both EBUS and EUS-B, guidelines recommend biopsy e.g., mediastinal lymph nodes both from the tracheal and the esophageal route, since the combination significantly improves diagnostic yield with 0.13 (95%CI 0.08-0.20) compared to EBUS alone, and 0.21 (95%CI 0.13-0.30) compared to EUS-B alone². Thus, addition of EUS-B to EBUS most likely reduces the need for repeat diagnostic procedures (fewer inconclusive tissue samples).

Figure 1: Equipment images showing the structural differences. Photos of the (A) handle and (B) tip of the EUS echoendoscope. Photos of the (C) handle and (D) the tip of the EBUS echoendoscope. Please click here to view a larger version of this figure.

Figure 2: Diagnostic reach of EBUS and transesophageal ultrasound (EUS and EUS-B). Yellow: only EBUS, Blue: only transesophageal ultrasound, Green: EBUS and/or transesophageal ultrasound. Please click here to view a larger version of this figure.

Figure 3: The six anatomical landmarks of transesophageal ultrasound (EUS and EUS-B). Landmark 1: The left liver lobe. Landmark 2: Abdominal aorta. Landmark 3: Left adrenal gland. Landmark 4: Station 7. Landmark 5: Station 4L. Landmark 6: Station 4R. Please click here to view a larger version of this figure.

Table 1: Diagnostic hit rates of EUS-B tissue sampling stratified by anatomical structure. The presented results are obtained from previously published studies. Please click here to download this Table.

EUS-B has significantly changed the field of interventional pulmonology^2,5,6,13. EUS-B allows the pulmonologist to access lesions not reachable with EBUS, simply by using the EBUS endoscope in a new way. A patient with a central lung tumor, enlarged mediastinal lymph nodes and abnormal left adrenal gland can have all lesions sampled with one endoscope in a single interventional session, saving time and resources for patients, relatives, and professionals^13,20.

The evidence of the safety and utility of EUS-B is steadily growing, yet the main focus of systematic reviews and guidelines has been on the role of mediastinal sampling in lung cancer^2,14,20. These recommend to biopsy the same lymph nodes with both EBUS and EUS-B as this increases diagnostic yield significantly, both when compared to EBUS alone and EUS-B alone². Shen et al. found in 16 studies with 1778 patients no significant difference in sensitivity when comparing EBUS and EUS to EBUS and EUS-B (0.87, 95%CI 0.83 to 0.90 vs. 0.84, 95%CI 0.80 to 0.88)¹⁴. Dhooria et al. found in 10 studies with 1080 patients that adding EUS-B to EBUS of mediastinal lymph nodes increases diagnostic gain by 7.6%²⁰. No meta-analyses or systematic reviews have been conducted concerning the diagnostic performance of EUS-B from other sites. Most studies have been conducted on left adrenal gland sampling. Crombag et al. found comparable diagnostic yield with EUS and EUS-B (83% [95%CI 62%-95%] vs 87% [95%CI 65%-97%], p>0.05)¹³. A retrospective study also suggests a high diagnostic yield and few adverse events of EUS-B-FNA from liver metastases or retroperitoneal lymph nodes⁹. Lung tumors can be biopsied from the esophagus, even when CT shows intervening lung tissue between tumor and esophagus. We have shown that the ability to reach and obtain a successful biopsy of lung lesion increases with lesion size. Larger tumors allow for more compression of lung tissue between the esophagus and the tumor. Thus the larger the lesion, the longer tumor-esophagus distance can be traversed⁶.

EUS-B training is crucial for patient safety and quality assurance²¹. EUS-B is logically a procedure learned by operators, who already master EBUS, since EUS-B orientation completely depends on the ultrasonic image due to the absence of directly visible esophageal landmarks²². With EBUS, when in doubt of localization the operator can use bronchoscopic direct visualization of airway landmarks for guidance, such as the58688 main carina or subcarinae^19,23. EUS-B orientation is facilitated by systematic approach, such as the six landmarks presented here (Figure 3). The EBUS-skilled operator will recognize the landmark principle from EBUS training, including simulator-based EBUS training^19,23,24.

Simulator-based training in EBUS is superior to traditional apprenticeship training when performed according to an evidence-based curriculum and checklists^24,25. Concerning EUS-B, a curriculum has been developed²⁶ but upscaling of EUS-B training awaits development and validation of EUS-B simulators. Until then, alternatives that may improve the standard of training includes watching videos, practice under supervision and submitting images/videos to accredited experts for feedback.

Modifications
The mentioned protocol can easily be adapted to a setting with general sedation. Our experience is that general anesthesia is only performed when the patient is very anxious and/or restless. Tissue sampling in this protocol is performed using the standard FNA needle, but a new generation of fine needle biopsy (FNB) needles have been developed for obtaining core tissue samples and recent studies show that FNB do not compromise safety and may even increase the diagnostic yield^27,28,29,30. However, this remains to be proven in EUS-B, preferably in a prospective study.

Troubleshooting
We have listed errors that the user may encounter and suggestions for solutions/prevention below.

Difficulty entering the esophagus:
Patient cooperation is key. The operator must encourage the patient to swallow efficiently and time the endoscope advancement with the swallowing motion.
Try spraying more lidocaine into the oropharynx to facilitate lubrication.

Difficulty in visualizing target lesion(s):
Visualize the landmarks systematically and take them as starting points.
Make sure that imaging (CT, PET-CT, etc.) are up to date prior to endoscopy.

Difficulty in sampling sufficient amount of tissue:
Try repeating tissue sampling from a different angle if possible.
Change needle size (e.g., from 22G to 19G) or switch to a 3^rd generation FNB needle with same diameter.

Limitations
EUS-B is a procedure that can only reach structures adjacent to the esophagus. Therefore, hilar structures e.g., lymph node stations 10L and 10R are not reachable. Moreover, lung lesions have to be centrally located to be reached by EUS-B. Lymph node station 4R, even though mediastinal, is not always visible, especially if normal in size, due to positioning behind the trachea. Dynamic structures e.g., gastric mucosa movement may challenge the smaller EBUS endoscope, whereas EUS is larger and more solid and can repress the gastric wall. This will probably provide better ultrasound picture quality but has not yet been proved clinically significant in larger studies.

Conclusion
EUS-B is an efficient new tool in lung cancer work-up that is both safe and well tolerated, and adding EUS-B to EBUS increases the diagnostic yield of endosonographical tissue sampling in the hands of pulmonologists. EUS-B allows the pulmonologist to reach and biopsy lesions not otherwise reachable by bronchoscopy and EBUS, thus reducing the need for additional procedures in other sessions. Simulator training in EBUS is evidence-based while simulator training for EUS-B is still undergoing development and validation. Skills in EBUS lead to competency in EUS-B with systematic training.