Endobronchial and Endoesophageal Ultrasound Techniques

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Chapter 12 Endobronchial and Endoesophageal Ultrasound Techniques

Felix J.F. Herth

Lung cancer is still the leading cause of cancer deaths worldwide, with an overall 5-year survival rate of 10% to 15%. Mediastinal lymph node sampling in lung cancer is important for adequate staging to determine appropriate treatment, as well as for predicting outcome. Adequate staging of lung cancer also is important in order to improve research into lung cancer, both for accurate comparison of data and for quality control.

Mediastinal lymph node staging can be performed preoperatively by radiologic imaging, endoscopically, or surgically. CT scanning, magnetic resonance imaging (MRI), positron emission tomography (PET), and integrated PET-CT are useful noninvasive imaging techniques for staging of lung cancer; however, they are not sufficiently sensitive or specific to determine mediastinal lymph node involvement. CT scanning usually is the initial method for staging of mediastinal nodes. Only lymph nodes with a short-axis diameter greater than 1 cm (with or without positive findings on PET-CT or other PET study) usually are considered to be suspicious for malignant involvement by radiologic criteria set forth in national and international guidelines. Nevertheless, in view of the high false-positive rate for CT and PET-CT, neither of which provides a tissue diagnosis, it is important to obtain lymph node tissue to determine operability.

Mediastinoscopy with nodal biopsy has been the “gold standard” for mediastinal staging for many years and has a sensitivity of 90% to 95% for detection of metastases in this region. Only certain lymph node stations—2, 4, and anterior 7—are accessible by this approach, in which access to the posterior and inferior mediastinum is limited, typically necessitating extending the procedure to cervical mediastinoscopy or thoracoscopy. However, it is essentially a surgical approach requiring general anesthesia and occasionally hospitalization. Endoscopic techniques provide a minimally invasive alternative to surgical staging. Accordingly, the past few years have seen the development of a number of less invasive staging modalities, including endobronchial ultrasound (EBUS) and endoesophageal ultrasound (EUS) techniques.

Transbronchial Needle Aspiration

Merely a curiosity at its inception, flexible bronchoscopy has emerged as an essential diagnostic and therapeutic modality in the management of a variety of lung diseases. The addition of transbronchial needle aspiration (TBNA) not only improved bronchoscopy’s diagnostic yield but further extended the role of this modality in the evaluation of mediastinal disease, and in the diagnosis and staging of bronchogenic carcinoma. The first description of sampling mediastinal lymph nodes through the tracheal carina using a rigid bronchoscope was by Schieppati. In 1978, Wang and associates demonstrated that it was feasible to sample paratracheal nodes using TBNA. Subsequent publications highlighted the use of the technique in the diagnosis of endobronchial (Figure 12-1) and peripheral lesions and the ability of TBNA to provide a diagnosis even in the absence of endobronchial disease.

Figure 12-1 Classical transbronchial needle aspiration (TBNA) biopsy of the lymph node.

The diagnostic yield of TBNA in the assessment of hilar-mediastinal lymph node involvement in lung cancer varies greatly in published series, with reported rates ranging from 15% to 85%. Recently, a metaanalysis assessing TBNA for mediastinal staging in non–small cell lung cancer demonstrated that TBNA is highly specific for the identification of mediastinal metastases, with sensitivity depending heavily on the study population under investigation. In studies that included patient populations with a prevalence of mediastinal metastases of 34%, sensitivity was only 39%, whereas in a population with a prevalence of 81%, sensitivity for detection of metastases was 78%.

Nevertheless, even after more than 50 years since the advent of TBNA, the technique is still underused. The main reasons for the limited use of TBNA have been lack of needle monitoring, difficulties in performing the procedure, and a belief, despite good evidence to the contrary, that TBNA is not useful.

Endobronchial Ultrasound Technique

The integration of ultrasound technology and flexible fiberoptic bronchoscopy enables imaging of lymph nodes, lesions, and vessels located beyond the tracheobronchial mucosa. Developed in 2002, the EBUS bronchoscope looks similar to a normal bronchovideoscope (Figure 12-2) but is 6.9 mm wide and has a 2-mm instrument channel and a 30-degree side viewing optic. Furthermore, a curved linear array ultrasound transducer sits on the distal end and can be used either with direct contact to the mucosal surface or with an inflatable balloon that can be attached at the tip. This setup produces a conventional endoscopic picture side by side with the ultrasound view. Ultrasound scanning is performed at a frequency of 7.5 to 12 MHz, with tissue penetration of 20 to 50 mm. An ultrasound processor generates the ultrasound image.

Figure 12-2 The tip of the endobronchial ultrasound (EBUS) scope. The transbronchial needle aspiration (TBNA) needle is already inserted.

EBUS allows the bronchoscopist to visualize airway structures as well as surrounding processes. It is useful for staging advanced cancer, especially as it relates to intramural or nodal spread. EBUS can identify N1, N2, and N3 nodes without the need for surgical intervention and can hence decrease the need for expensive surgery.

Procedure

The actual TBNA is performed using direct transducer contact with the wall of the trachea or bronchus. When a lesion is outlined, a 21 or 22 gauge needle can be advanced through the working channel, and lymph nodes can be punctured under real-time ultrasound visualization. The needle is encased in an internal sheath in order to avoid contamination during biopsy. At the same time, color Doppler can be used to identify surrounding vascular structures. Once the target lymph node or mass has been clearly identified with EBUS, the needle is inserted under real-time ultrasound guidance and then placed within the lesion (Figures 12-3 and 12-4). Suction is applied with a syringe, and the needle is moved back and forth to achieve multiple punctures. The stylet of the needle is left in place on the first puncture to minimize bronchial cell contamination; once the needle tip is inside the target tissue, the stylet is removed. We stab the target 10 to 15 times without suction and apply suction only for the last two or three stabbing motions. Before retraction of the needle into the needle sheath, suction must be removed to minimize sample loss into the syringe. The specimen is then air-flushed onto a slide, and the needle is flushed with heparin-saline solution to avoid clotting; the same procedure is repeated three times at every lymph node station.

Figure 12-3 Endobronchial ultrasound–transbronchial needle aspiration (EBUS-TBNA) of a lymph node in position 4R.

Figure 12-4 A, Enlarged lymph node in the upper mediastinum in position 4r. B, The vessels are readily seen on the power Doppler image. C, Real-time ultrasound image of the aspiration biopsy procedure. D, The histopathologic pattern was consistent with a diagnosis of sarcoidosis. LN, lymph node.

Lymph node stations that can be reached using EBUS are the highest mediastinal (station 1), the upper paratracheal (2L and 2R), the lower paratracheal (4R and 4L), the subcarinal (station 7), the hilar (station 10) nodes, as well as the interlobar (station 11) and lobar (station 12) nodes. The highest-staging node (e.g., an N3 contralateral mediastinal lymph node before an N2, an ipsilateral mediastinal lymph node before an N1 hilar lymph node) should be biopsied first; otherwise, the needle needs to be changed each time.

Lymph nodes at a size of 5 mm and upwards can be successfully sampled and have to date shown excellent diagnostic yield. The number of mediastinal lymph node stations to sample depends on the purpose of the examination.

Every attempt should be made to sample nodes at these sites, even if size and ultrasonographic features are normal. At our institution, we routinely sample mediastinal lymph nodes that are 5 mm or larger in short-axis diameter.

The learning curve for EBUS-TBNA has been evaluated: performance of at least 10 procedures is necessary in order to achieve excellent sensitivity and diagnostic accuracy, although that number may be higher, depending on operator skill level.

Results

In recently published metaanalysis, EBUS-TBNA has been shown to have a high pooled sensitivity of 93% and specificity of 100%. Multiple publications have shown that even in patients with lymph nodes less than 1 cm in diameter (which had been termed N0 by CT criteria), with the use of EBUS-TBNA, a large percentage could still be shown to have N2 or N3 disease (in some cases, despite a negative result on PET-CT).

Numerous studies have looked at the use of EBUS-TBNA for biomarkers and tumor genetics in lung cancer. In a recent published trial, endothelial growth factor receptor (EGFR) gene analysis of the EBUS-TBNA sample was feasible in 26 of 36 patients (72.2%) with lymph node metastasis. Somatic mutations of the EGFR gene were detected in tissue obtained through EBUS-TBNA in 2 of 20 patients (10%) with metastatic lung adenocarcinoma. Complications such as bleeding or infection are very rare and have been reported only as case reports.

EBUS-TBNA also has been shown to have utility in diagnosis of other pulmonary diseases besides lung cancer. In patients with clinically suspected lymphoma, the reported diagnostic sensitivity is 70% to 80%. If more tissue specimens are needed for histologic analysis, it is even possible to insert a 1.15-mm mini-forceps through the EBUS scope and past the airway wall via a needle puncture, to obtain forceps biopsy specimens of mediastinal lymph nodes under real-time ultrasound guidance.

Different prospective studies have assessed the usefulness of EBUS-TBNA in evaluation of patients with suspected sarcoidosis. EBUS-TBNA has been reported to have a diagnostic yield of 85% to 93%, which increases with the number of passes performed. In one study in which a cytopathologist performed on-site evaluations, the diagnostic yield was greater than 80% at five passes and did not increase further after seven passes. In a recently published randomized controlled trial, EBUS-TBNA provided a diagnostic yield superior to that with conventional TBNA (83% versus 54%). In patients with suspected sarcoidosis, EUS-FNA has a similar diagnostic yield of 82% to 86%. The choice between the two diagnostic methods is therefore based on the location and accessibility of the enlarged lymph nodes and on the expertise of the operator.

Endoesophageal Ultrasound Technique

Gastroenterologists have been using the endoesophageal ultrasound (EUS) technique for many years in the investigation of esophageal and pancreatic malignancies. Mediastinal EUS-guided fine needle aspiration (FNA) was first used in the early 1990s and subsequently has become a popular method to diagnose a variety of intraabdominal and intrathoracic masses, including mediastinal lesions. EUS-FNA has been shown to be useful in biopsying mediastinal lesions, even in patients in whom a previous conventional technique was nondiagnostic, and may be more cost-effective as an initial staging procedure in patients with non–small cell lung cancer (NSCLC) than classical techniques.

Procedure

The linear EUS bronchoscope has the same basic architecture as that of the EBUS scope and uses a scanner frequency of between 5 and 10 MHz. The penetrating ultrasound depth can be up to 8 cm. Needles used for biopsy are 19 or 21 gauge, again equipped with a stylet. The procedure usually is performed on an outpatient basis and takes approximately 30 minutes. As with EBUS, the puncture of lymph nodes is performed under real-time ultrasound guidance (Figure 12-5). However, EUS-FNA has limited access, because only lymph node stations 2L, 4L, 7, 8, and 9 are accessible through a transesophageal approach. Lymph node station 5 is not routinely accessible by EUS, and transvascular FNA may be required to sample this tissue.

Figure 12-5 Endoesophageal ultrasound–guided fine needle aspiration (EUS-FNA) of an enlarged node in station 7.

Results

EUS is especially useful in staging of the posterior mediastinum. The left adrenal can be reached and identified in 97% of cases. It has a characteristic “seagull” shape on ultrasound images and is particularly well visualized in cases of metastatic enlargement. Furthermore, the left lobe of the liver also can be reached. The hilar and precarinal lymph nodes cannot be reached.

The procedure carries only a very small risk of mediastinitis or bleeding. Unless cysts are punctured antibiotics do not need to be administered routinely.

EUS is more accurate and has a higher predictive value than either PET scan or CT for assessment of posterior mediastinal lymph nodes.

Multiple publications and a metaanalysis of data on EUS-FNA have shown high sensitivity and specificity. Even in cases in which mediastinal lymph node enlargement is not seen on CT, EUS-FNA has been able to demonstrate metastases in 25% of patients with lung cancer.

For both techniques, however, it is important to recognize that the negative predictive value (NPV) is limited. Therefore, if samples do not contain tumor cells, follow-up evaluation with a more definitive procedure such as mediastinoscopy with biopsy or video-assisted thoracoscopic surgery (VATS) is indicated.

Combining Endobronchial and Endoesophageal Ultrasound Techniques

For tissue sampling of mediastinal lymph nodes after conventional TBNA, our own preference is for minimally invasive methods such as EBUS-TBNA and EUS-FNA over more invasive procedures such as mediastinoscopy and VATS. EUS-FNA and EBUS-TBNA have been shown to avoid the need for mediastinoscopy to a large extent (Figure 12-6). EBUS-TBNA and EUS-FNA have a complementary reach in analyzing mediastinal nodes: EBUS has access to the paratracheal, subcarinal, and hilar regions, and EUS, to the lower mediastinum and aortopulmonary window.

Figure 12-6 Region of access for endobronchial needle aspiration (blue-outlined oval) and for endoesophageal needle aspiration (red-outlined oval). Ao, aorta; PA, pulmonary artery.

Increasingly, EUS-FNA and EBUS-TBNA are thought of as complementary rather than competitive procedures. In principle, the combined access to mediastinal, hilar, and periesophageal disease affords the most complete staging possible.

As shown above, EUS and EBUS provide access to different areas of the mediastinum. In combining techniques, most lymph node stations as well as the left adrenal gland can be reached (apart from stations 5 and 6). In six recent series, the accuracy of EUS-FNA and EBUS-TBNA used in combination for the diagnosis of mediastinal cancer was 95%. With use of the EBUS scope for concurrent endobronchial and endoesophageal sampling in the same patient, the sensitivity for cancer detection combining the results with both modes of access can be as high as 96% (sensitivity of 89% for EUS and 91% for EBUS); specificity, 100%; and NPV value, 96% (NPV for EUS alone of 82% and for EBUS alone, 92%).

In a recently published trial, the hypothesis of the current guidelines recommending minimally invasive endosonography followed by surgical staging (if no nodal metastases are found by endosonography) as an alternative to immediate surgical staging was proved in a randomized design. Patients were randomly assigned to undergo either surgical staging alone (the surgical staging group, representing the current standard of care) or endosonography (combined EUS-FNA and EBUS-TBNA) followed by surgical staging if no nodal metastases were found at endosonography (the endosonography group, representing a novel alternative staging strategy). A total of 241 patients were enrolled in the trial. Nodal metastases were found in 41 patients by surgical staging and in 56 patients by endosonography, and in 62 patients by endosonography followed by surgical staging. These findings corresponded to sensitivity of 79% (versus 85%) and 94%. Thoracotomy was unnecessary in 21 patients in the mediastinoscopy group, versus 9 in the endosonography group (P = .02). The complication rates were similar in both groups, although a majority of complications in the endosonography group were due to the addition of surgery. The investigators concluded that among patients with NSCLC, a staging strategy combining endosonography and surgical staging versus surgical staging alone resulted in greater sensitivity for detection of mediastinal nodal metastases without unnecessary thoracotomies.

A reasonable approach, therefore, is to begin the staging evaluation with EBUS or EUS. If the result is positive, the staging process is complete. If it is negative, a strategy of surgical staging followed by immediate surgery is recommended.

Restaging Patients with Lung Cancer after Chemotherapy

Patients with N2 disease (stage IIIA) considered unresectable at diagnosis may nevertheless become candidates for surgical resection if chemotherapy or chemoradiation therapy can lead to successful downstaging. Documentation of downstaging (complete histopathologic response in N2 lymph nodes) is essential for such potentially curative resection. Imaging procedures (CT and PET-CT) are helpful in this regard but show unacceptably high rates of false-positive and false-negative results, and a tissue diagnosis is required to guide management. EUS-FNA or EBUS-TBNA, or both, can be performed depending on the location of the lymph nodes initially involved. Usually the mediastinal N2 lymph node that initially was proved to be positive should be rebiopsied using the same techniques. Mediastinoscopy, which is technically difficult as a consequence of fibrosis, especially after radiation therapy, usually is reserved for cases in which analysis of samples obtained by endoscopic needling techniques fails to show malignancy. Compared with initial mediastinoscopy, repeat mediastinoscopy is associated with lower sensitivity and diagnostic accuracy. With all other diagnostic techniques, restaging sensitivity and accuracy are lower than for the initial procedure as a result of the effects of chemotherapy and irradiation on tissues with ensuing fibrosis, as well as tumor shrinkage, necrosis, and cystic degeneration. In a study of 124 patients with NSCLC who had undergone induction chemotherapy, restaging by EBUS-TBNA found persistent nodal metastases in 89 patients (72%); however, 28 of the 35 patients with negative results on EBUS were found to have residual N2 disease at surgery. Therefore, the NPV of EBUS-TBNA in restaging was only 20%.

In a recent published trial, a total of 61 patients underwent restaging EBUS-TBNA. EBUS-TBNA revealed metastatic lymph node involvement in 30% of patients. In 43 patients with negative or uncertain results on EBUS-TBNA, metastatic disease remaining in nodes was diagnosed in nine patients, in seven in stations accessible for EBUS-TBNA, and in two stations not accessible for EBUS-TBNA. The false-negative results of biopsies were found only in small nodes. Moreover, all positive N2 nodes diagnosed by surgery contained only small metastatic deposits. Reported values for diagnostic sensitivity, specificity, accuracy, positive predictive value (PPV), and NPV of the restaging EBUS-TBNA were 67%, 86%, 80%, 91%, and 78%, respectively.

The value of EUS-FNA in restaging of the mediastinum also was evaluated in other trials. The numbers of patients included in these trials are limited in comparison with the EBUS trials, but all series showed an NPV above 90%.

As mentioned before, the adequate restaging technique remains a matter of debate, because comparison of the different techniques is still problematic. Endoscopic techniques are safe and minimally invasive and produce accurate results in comparison with surgical data from repeat mediastinoscopy. However, if results on needle aspiration are negative, surgical restaging is required for adequate assessment of the mediastinum.

Conclusions and Outlook

Overall, EBUS and EUS are safe and effective techniques for staging of mediastinal disease. The novel diagnostic modalities of EBUS-guided TBNA and transesophageal ultrasound–guided FNA allow ultrasound-controlled mediastinal tissue sampling. These techniques are minimally invasive, avoiding many of the risks associated with invasive staging procedures.

At present, the main limitation with TBNA is the current restriction of its use to EBUS and EUS, which are performed predominantly at major clinical centers and hence only in selected patients. Training of physicians and surgeons remains the issue, and performance of an adequate numbers of procedures per year is required in order to maintain competency. Reimbursement remains an issue in some countries, as well as actual implementation and incorporation into cancer guidelines within hospitals. Increasingly, both techniques are being used in hospitals across the world, with consequent improvement in diagnostic yield. Use of combined EBUS and EUS, as the first ultrasound techniques for detection of metastases to the mediastinum, has been termed “complete endo-echo staging.”

Beyond doubt, implementation of these techniques can be expected to drastically alter lung cancer staging algorithms in the near future. Thanks to its minimally invasive approach, safety record, accuracy, and diagnostic reach, complete ambulatory endoscopic staging of lung cancer may be the way of the future.

Suggested Readings

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