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Keywords:

  • Endobronchial ultrasound;
  • lung cancer;
  • transbronchial needle aspiration

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Technical aspects of EBUS-TBNA
  5. Current guidelines in mediastinal staging of NSCLC
  6. EBUS-TBNA in mediastinal staging
  7. Other diagnostic applications of EBUS-TBNA
  8. Setting up an EBUS-TBNA service
  9. Conclusion
  10. References

The endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) bronchoscope has a built-in miniaturized ultrasound probe that facilitates real-time TBNA biopsies. The sensitivity of EBUS-TBNA in lung cancer is 88% to 90% and specificity is 100%. The test performance is excellent with an area under the summary receiver operating characteristics curve of 0.99. This diagnostic yield clearly exceeds that of conventional blind TBNA. However, the false negative rate remains high, about 20%. Therefore, negative aspirates need to be confirmed with mediastinoscopy, surgical sampling or clinical follow up. Restaging the mediastinum after neoadjuvant chemotherapy has had less success with a reported EBUS-TBNA sensitivity of only 76% and a negative predictive value of 20%. The procedure has also been used to successfully obtain biopsy specimens in primary tumors located in the paratracheal and peribronchial region with a sensitivity of 82 to 94%. The benefit of EBUS-TBNA is that it can be performed under moderate sedation in an outpatient setting without ionizing radiation. Although the current practice in most institutions remains targeted sampling of enlarged lymph nodes, complete staging of a radiologically normal mediastinum is also possible. Therefore, EBUS-TBNA can be considered one of the first-line modalities for the diagnosis and invasive staging of lung cancer if the equipment and expertise are available.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Technical aspects of EBUS-TBNA
  5. Current guidelines in mediastinal staging of NSCLC
  6. EBUS-TBNA in mediastinal staging
  7. Other diagnostic applications of EBUS-TBNA
  8. Setting up an EBUS-TBNA service
  9. Conclusion
  10. References

Flexible bronchoscopy has been previously limited by the extent of the endoscopic view. Endobronchial ultrasound (EBUS) is revolutionary because it extends the endoscopist's range beyond the airway walls and enables the biopsy of paratracheal and peribronchial structures. Mediastinal and hilar lymph nodes, as well as central thoracic tumors are therefore ideal targets for this technology. The EBUS-guided transbronchial needle aspiration (EBUS-TBNA) bronchoscope has a miniaturized linear ultrasound probe built into a dedicated flexible bronchoscope to enable real-time TBNA biopsies. This design has further enhanced diagnostic yield.

This comprehensive review aims to describe the technical aspects of EBUS-TBNA and review its efficacy as a diagnostic and staging modality in lung cancer. Sampling of mediastinal lymph nodes often produces a histological diagnosis and stages the disease concurrently without the need for biopsy of the primary tumour. Therefore, it is difficult to separate diagnostic efficacy from staging utility. The majority of the current published data has been accumulated in non-small cell lung cancer (NSCLC) cases with fewer cases in small cell lung cancer.

Technical aspects of EBUS-TBNA

  1. Top of page
  2. Abstract
  3. Introduction
  4. Technical aspects of EBUS-TBNA
  5. Current guidelines in mediastinal staging of NSCLC
  6. EBUS-TBNA in mediastinal staging
  7. Other diagnostic applications of EBUS-TBNA
  8. Setting up an EBUS-TBNA service
  9. Conclusion
  10. References

The EBUS bronchoscope has an external diameter of 6.9 mm at the insertion tip and 6.7 mm at the shaft; this is substantially larger than a standard flexible bronchoscope. Therefore, oral, rather than nasal, intubation is necessary. The endoscopic viewing optics is at 35 degrees (oblique angle) and operator compensation is required when maneuvering the bronchoscope. Particular attention is needed in intubating the trachea and often only the anterior apex of the vocal cords is visible as the scope enters the subglottic space. Usually endobronchial examination is limited because of the restricted and oblique endoscopic view. Therefore, standard bronchoscopy may also be needed to complete a full airway examination. The 7.5 MHz ultrasound transducer is convex and has a 50° sector view parallel to the long axis of the bronchoscope extending 20 to 50 mm in depth. This bronchoscope has a 2 mm working channel that can house a dedicated biopsy needle. Needle sizes come in either 21- or 22-gauge. This needle has multiple small dimples on its shaft to enhance ultrasound echogenicity.

After endobronchial intubation, the EBUS-TBNA scope is positioned at the approximate location of the target lymph node or paratracheal tumor. The scope is flexed to gain contact with the airway wall and then withdrawn gently while being rotated. Usually a balloon filled with saline is used to facilitate coupling (Fig 1). However, this is not always needed if good contact can be maintained between the airway mucosal surface and the probe. Lymph nodes and tumors appear isoechoic (grey) compared to blood vessels that appear anechoic (black; Fig 2). Color Doppler can also be used to make the distinction.

image

Figure 1. (a) Endobronchial ultrasound-guided transbronchial needle aspiration scope with balloon deflated. (b) Endobronchial ultrasound-guided transbronchial needle aspiration scope with balloon inflated with 1–2 ml of saline.

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image

Figure 2. Right paratracheal lymph node seen as a rounded isoechoic (ie grey structure; white arrow) with the superior vena cava seen as a linear anechoic (ie black structure) deep to node (yellow arrow).

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Preliminary data is also emerging on the use of Doppler to measure vascular resistive index of lymph nodes.1 Malignant nodes appear to have a higher resistive index because of neovascularisation. Other features that may suggest malignance of lymph nodes include increased size, round shape, internal heterogeneity and distortion of node structure. When lymph node structure is distorted, the lymphatic hilar stalk, which is normally seen as a hyperechoic central shadow, is no longer visualized.

Once target lymph nodes or tumour are identified, TBNA is performed. The needle sheath is pushed forward so that it is visualized on the endoscopic image before the “jabbing” technique is used to perform TBNA under real-time guidance (Fig 3). The “jabbing” technique describes the procedure when an assistant holds the bronchoscope steady at the patient's mouth while the operator pushes the needle into the tissue. Once the TBNA needle is in the target, the stylet ofthe needle is agitated to dislodge airway debris before being removed for biopsies and aspiration is performed. Aspiration is performed by moving the needle within the target lesion for about 30 seconds while suction is applied via a syringe. The depth of the needle is restricted by a catch located on the side (Fig 4). Without releasing the catch, the depth of penetration is 17 mm. However, after removing this restraint, penetration of up to 36 mm beyond the mucosal surface is possible to access deeper lesions.

image

Figure 3. Real-time endobronchial ultrasound-guided transbronchial needle aspiration with hyperechoic (ie white needle) (white arrow) in a lymph node.

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image

Figure 4. (a) Safety catch on dedicated transbronchial needle aspiration needle (white arrow). (b) Needle in full extension with catch in place. (c) Needle in full extension with catch released.

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Most mediastinal and hilar lymph nodes are accessible to the EBUS-TBNA bronchoscope; the exceptions are the aortopulmonary (station 5), subaortic (station 6), paraesophageal (station 8) and pulmonary ligament (station 9) nodes. For mediastinal sampling of NSCLC three cytology aspirations per lymph node station is recommended. If an adequate core specimen in obtained, two passes will suffice.2 The highest, contralateral lymph node station is biopsied first so that the sampling order proceeds from N3 to N2 and finally to N1 lymph nodes. This prevents upstaging the disease due to needle contamination from earlier biopsies. Alternatively, new needles can used at each lymph node station but this strategy incurs greater costs.

Current guidelines in mediastinal staging of NSCLC

  1. Top of page
  2. Abstract
  3. Introduction
  4. Technical aspects of EBUS-TBNA
  5. Current guidelines in mediastinal staging of NSCLC
  6. EBUS-TBNA in mediastinal staging
  7. Other diagnostic applications of EBUS-TBNA
  8. Setting up an EBUS-TBNA service
  9. Conclusion
  10. References

Treatment options for NSCLC are dictated by the stage of the disease. The presence of metastatic N2 or N3 mediastinal lymphadenopathy excludes surgical resection options in favor of chemoradiotherapy.3 Non-invasive staging is often the initial step in the evaluation of such patients.

Computed tomography (CT) scanning is excellent for providing anatomical detail of lung cancer. However, pooled sensitivity and specificity for identifying mediastinal lymph node metastasis is 51% and 85% respectively.4 Positron emission tomography (PET) is more accurate with sensitivity and specificity of 74% and 85%.4 The uncertain positive predictive value of such non-invasive testing means that histological evaluation of mediastinal abnormalities is prudent before definitive treatment. A possible exception would be patients with extensive mediastinal infiltration on radiographic assessment indicating clearly non-resectable disease.4 Therefore, the American College of Chest Physicians evidence-based clinical practice guidelines recommends that patients who have discrete mediastinal lymph nodes should have histological confirmation of lymph node metastases regardless of whether PET scan findings are positive or negative.5

Mediastinoscopy has been considered the reference standard for such histological staging. This procedure has a pooled diagnostic sensitivity of 80% and false negative rate of 10% .5 Although excellent for the sampling of precarinal and paratracheal lesions, there are limitations in accessing posterior tracheal and inferior mediastinal lymph node stations. It is also an invasive procedure requiring general anesthesia with a reported complication rate of 2–3%.6 Furthermore, a survey of clinical practice in 2001 showed that preoperative staging with mediastinoscopy was performed in only 27% of patients with lung cancer.7 Among the patients who underwent mediastinoscopy only 47% had any evidence of lymphatic tissue submitted to pathology, suggesting that biopsies were not representative of the nodal stations.7 These alarming data indicate that a guided and more readily available procedure to stage the mediastinum is needed. Therefore, the current guidelines recommend the use of either mediastinoscopy or needle techniques as reasonable approaches for the invasive staging of the mediastinum, depending on the available equipment and expertise.5 Needle techniques include conventional TBNA, EBUS-TBNA, endoscopic ultrasound (EUS) and transthoracic needle aspiration.

EBUS-TBNA in mediastinal staging

  1. Top of page
  2. Abstract
  3. Introduction
  4. Technical aspects of EBUS-TBNA
  5. Current guidelines in mediastinal staging of NSCLC
  6. EBUS-TBNA in mediastinal staging
  7. Other diagnostic applications of EBUS-TBNA
  8. Setting up an EBUS-TBNA service
  9. Conclusion
  10. References

The overall pooled diagnostic sensitivity of EBUS-TBNA in lung cancer is 88% to 90% and specificity is 100%. However, the false negative rate remains high at about 20%.5,8The false negative rate is explained by the high prevalence of malignancy in the studies that were included in the pooled analyses. Test performance of EBUS-TBNA is excellent with an area under the summary receiver operating characteristics curve of 0.99.8 This diagnostic yield clearly exceeds that of conventional blind TBNA.9 EBUS-TBNA has been shown to result in either nodal upstaging or downstaging in over 25% of cases as compared to non invasive modalities such as CT, PET or CT/PET.10 The current literature has over 2500 cases reported, with the majority of studies targeting pathologically enlarged lymph nodes (Table 1). Combined analysis of the available data is confused by the differing prevalence of malignancy, the size of the targeted lymph nodes, the use of preprocedure imaging, such as PET, the number of needle passes, the expertise of the endoscopist, and the availability of onsite cytology. Furthermore, nine of the 20 listed studies contributing over 1400 cases were performed by two groups of expert collaborators: Herth et al./Ernst et al.11–15 from Heidelberg/Boston and Yasafuku et al./Nakajima et al. from Japan.16–19

Table 1.  Diagnostic sensitivity and definitive histological yield of endobronchial ultrasound-guided transbronchial needle aspiration sampling of mediastinal and hilar lymph nodes in patients with suspected lung cancer
StudyNumber of patientsPrevalence of malignancy (%)Lymph node size (mm)Diagnostic sensitivity (%)Definitive histological yield (%)
Lee HS et al. 20082102315–209429
Wallace MB et al. 2008913830N/D6921
Vincent BD et al. 20081015274N/D9940
Herth F et al. 200611502988–329494
Herth F et al. 200612100214–109219
Herth F et al. 20081310095–10 PET negative898
Ernst A et al. 200814668910–218759
Ernst A et al. 200915213888–2091N/D
Yasufuku K et al. 2004167067≤ 309671
Yasufuku K et al. 200517108638–309559
Yasufuku K et al. 200618102255–229224
Nakajima T et al. 20071943583–359254
Feller-Kopman et al. 20092213535N/D8544
Bauwens O et al. 200840106585–40 PET positive9556
Rintoul RC et al. 20054618586–208565
Szlubowski A et al. 2009472266413.8 ± 98957
Hwangbo B et al. 200923117265–209023
Rintoul RC et al. 20094810977PET positive9171
Vilmann P et al. 2005493365N/D8547
Ømark Petersen H et al. 20095015743>10 or PET positive8536

The ability of EBUS-TBNA to produce a confirmed diagnosis is correlated to the prevalence of malignancy in Table 1. Negative biopsies had to be confirmed with mediastinoscopy, surgical lymph node sampling, or clinical follow up, reinforcing the limited negative predictive value of the technique. Therefore, the NSCLC invasive staging guidelines recommend that negative aspirates from needle techniques (including EBUS) need to be confirmed with mediastinoscopy.5

Real-time EBUS-TBNA has been shown to have a diagnostic yield that may be equivalent in sensitivity to cervical mediastinoscopy in a comparative study with surgical dissection as the gold standard.14 This head-to-head study is limited by the fact that all biopsied lymph nodes were enlarged (10–21 mm). It remains to be seen if similar data can be achieved with non-enlarged lymph nodes. The histological staging of a radiologically normal mediastinum with either lymphadenopathy ≤ 10 mm or negative PET has been shown to be feasible, with sensitivities approaching 90%.12,13This data would suggest that systematic staging is possible as opposed to the targeted sampling that is widely practiced. However, these two studies were performed by experts under general anesthesia and the widespread applicability of such data is still not established because EBUS-TBNA is usually performed under moderate sedation. Nevertheless, EBUS has the potential to identify lymphadenopathy that has been missed on CT.20

Even without the presence of rapid onsite cytology, diagnostic yields > 90% have been reported for real-time EBUS-TBNA.11 If onsite cytology is used, the presence of moderate numbers of lymphocytes (> 40 per high-power field) or pigmented macrophages are indicators of adequacy of lymph node sampling.21 Onsite cytological examination can also direct further testing such as flow cytometry or microbiological cultures on TBNA aspirates if lymphomas or granulomas are suspected.22

There have been no appreciable differences in the performance characteristics of EBUS-TBNA in diagnosing adenocarcinoma (sensitivity 90%) compared with squamous cell carcinoma (sensitivity 85.7%).23 The dedicated 22-gauge EBUS-TBNA needle can obtain samples that are sufficient for genetic and molecular analysis (eg epidermal growth factor receptor mutations).24,25 This information can direct treatment plans for biological agents such as gefitinib. Restaging the mediastinum after neoadjuvant chemotherapy has had considerably less success with a reported EBUS-TBNA diagnostic sensitivity of only 76% and a negative predictive value of 20%.26 Therefore, staging algorithms usually involve a needle aspiration biopsy for initial staging and mediastinoscopy for restaging.

Combined EBUS-TBNA with transesophageal EUS-guided fine needle aspiration can enable complete staging of the mediastinum with access to lymph node stations not accessible to either technique on its own. EUS has access to aortopulmonary (station 5), paraesophageal (station 8) and pulmonary ligament (station 9) nodes stations that EBUS-TBNA cannot reach. EBUS offers greater access to the paratracheal and hilar lymph node stations, while EUS can target inferior mediastinal lymph nodes and adrenal metastases. The pooled diagnostic sensitivity of EUS in mediastinal staging is 84%5 while diagnostic sensitivities of 93% to 94% have been reported for combined EBUS and EUS.9,27 However, the main drawback of such combined staging is the need for gastroenterologists and pulmonologists to coordinate procedures. A trained endoscopist in both procedures is a rarity. To overcome this problem, there has now been pioneering work done on the use of the EBUS bronchoscope to perform transesophageal needle aspirations.28 The EBUS-TBNA could then be performed first, followed by transesophageal EBUS-TBNA to complete the staging using a single scope.

EBUS-TBNA has also been used to successfully obtain biopsy specimens of primary tumors located in the paratracheal and peribronchial region with a diagnostic sensitivity of 82% to 94%.29,30 As long as there is no intervening aerated lung, these tumors can be easily identified as soft tissue structures on ultrasound. The procedure is then similar to sampling lymph nodes and is especially useful in diagnosing centrally located tumors without any airway involvement.

Other diagnostic applications of EBUS-TBNA

  1. Top of page
  2. Abstract
  3. Introduction
  4. Technical aspects of EBUS-TBNA
  5. Current guidelines in mediastinal staging of NSCLC
  6. EBUS-TBNA in mediastinal staging
  7. Other diagnostic applications of EBUS-TBNA
  8. Setting up an EBUS-TBNA service
  9. Conclusion
  10. References

In patients with clinically suspected lymphoma, a single retrospective study reported a diagnostic sensitivity of 91%.31 In the demonstration of non-caseating granulomatous inflammation, EBUS-TBNA has a diagnostic yield for sarcoidosis of 83% to 94%.32–36 This has been shown to be more effective than standard TBNA in a randomized controlled trial.35 If bigger tissue specimens are needed for histological analysis in conditions other than lung cancer, it is possible to insert 1.15 mm mini forceps through the EBUS scope and push it past the airway wall via a needle puncture. This can obtain real-time forceps biopsies of mediastinal lesions.37

Setting up an EBUS-TBNA service

  1. Top of page
  2. Abstract
  3. Introduction
  4. Technical aspects of EBUS-TBNA
  5. Current guidelines in mediastinal staging of NSCLC
  6. EBUS-TBNA in mediastinal staging
  7. Other diagnostic applications of EBUS-TBNA
  8. Setting up an EBUS-TBNA service
  9. Conclusion
  10. References

Training in EBUS needs to cover image interpretation, use of the ultrasound processor control buttons, orientation of endoscopic and ultrasound views, as well as TBNA techniques. Knowledge of thoracic anatomy and competence in basic flexible bronchoscopy are prerequisites. There are no available guidelines for the number of supervised procedures in EBUS-TBNA that should be performed; however, data suggest that after as few as 10 procedures the diagnostic accuracy rises from 50% to 96%.38 Although, this may be true for targeted sampling of enlarged mediastinal lymph nodes, complete staging and systematic sampling of non-enlarged lymph nodes is likely to take longer to master. Another study suggests that diagnostic accuracy peaks only after 50 procedures.39

Complications have been rarely attributed directly to EBUS-TBNA. Pneumothorax requiring chest drain insertion in a patient with underlying chronic obstructive pulmonary disease has been reported.40 Otherwise only minor complications such as agitation, cough and transient bleeding at the puncture site have been encountered.16,41 The risk of bleeding due to inadvertent vascular puncture is also believed to be so low that it has even been possible to perform biopsies by deliberately traversing the pulmonary artery.42

The TBNA needle may become contaminated with commensals as the bronchoscope passes through the oropharyngeal region. This can cause infections in the lung, mediastinum or the pericardium.43 There are concerns that the risk may be elevated if the TBNA needle is used at full extension (36 mm). At such depths, the tip of the needle may be poorly visualized on ultrasound.43 However, the incidence of bacteremia appears to be similar to that of routine bronchoscopy and there is no evidence to mandate the routine use of prophylactic antibiotics.44

EBUS can also add to endoscopy time initially and this has implications for what can be achieved under moderate sedation. EBUS-TBNA for targeted lymph node sampling has been reported to take a mean of 12.5 (range 8 to 21) minutes in expert hands.11 However, the procedure duration is likely to be longer if complete mediastinal staging is attempted.

Damage to the bronchoscope can be caused by perforating the insertion tube with the aspiration needle. Visualization of the needle sheath on the endoscopic view before TBNA prevents such damage. Other issues that need to be addressed will be the training of endoscopy staff to reprocess EBUS scopes and assist in procedures. The sensitive ultrasound transducer can be easily scratched by removing the balloon with sharp finger nails. Cost of the equipment and disposables should also be weighed against reimbursement before such a service is established.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Technical aspects of EBUS-TBNA
  5. Current guidelines in mediastinal staging of NSCLC
  6. EBUS-TBNA in mediastinal staging
  7. Other diagnostic applications of EBUS-TBNA
  8. Setting up an EBUS-TBNA service
  9. Conclusion
  10. References

EBUS-TBNA has been proven to have an excellent diagnostic yield in obtaining histological specimens from patients with lung cancer. As a diagnostic modality, it is the ideal choice for patients with central peribronchial tumors, as well as mediastinal adenopathy. The ability to “see through walls” without the need for ionizing radiation remains the premise on which EBUS has been developed. Current data suggest that EBUS-TBNA can be considered one of the first-line modalities for the invasive staging of NSCLC if the equipment and expertise are available. Although the current practice in most institutions remains targeted sampling of enlarged lymph nodes, complete staging of a radiologically normal mediastinum is also possible.

EBUS has the potential to become part of standard bronchoscopy because of negligible complications, improved diagnostic yield and a short learning curve. EBUS-TBNA can also save costs in several ways.45 The high diagnostic yield means that repeat or alternative procedures are seldom necessary. It can be performed under moderate sedation in an outpatient setting so that hospitalization costs are avoided. By accurately staging the mediastinum, unnecessary mediastinoscopies or surgical resections are also avoided.9,40,41 Forthcoming studies should focus on characterizing lymph nodes based on ultrasonographic features to better target pathological lymph nodes. Refinements in the equipment and increased training opportunities will make this technology more widely available and accepted in the future.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Technical aspects of EBUS-TBNA
  5. Current guidelines in mediastinal staging of NSCLC
  6. EBUS-TBNA in mediastinal staging
  7. Other diagnostic applications of EBUS-TBNA
  8. Setting up an EBUS-TBNA service
  9. Conclusion
  10. References
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  • 31
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  • 32
    Oki M, Saka H, Kitagawa C et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration is useful for diagnosing sarcoidosis. Respirology 2007; 12: 8638.
  • 33
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  • 35
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  • 37
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  • 38
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